breast surgery

OBSTETRICS AND GYNECOLOGY ADVANCES
BREAST SURGERY
INDICATIONS AND TECHNIQUES
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OBSTETRICS AND GYNECOLOGY ADVANCES
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OBSTETRICS AND GYNECOLOGY ADVANCES
BREAST SURGERY
INDICATIONS AND TECHNIQUES
CIRO COMPARETTO
AND
FRANCO BORRUTO
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Contents
Preface
vii
Introduction
xiii
Chapter I
Historical Overview
1
Chapter II
Breast Biopsy
17
Chapter III
Benign Breast Diseases
31
Chapter IV
Breast Cancer
55
Chapter V
Imaging-Guided Breast Surgery
85
Chapter VI
Breast Lymphadenectomy
97
Chapter VII
Endoscopic Breast Surgery
117
Chapter VIII Prophylactic Breast Surgery
123
Chapter IX
Breast Reconstruction
137
Chapter X
Aesthetic Breast Surgery
157
Chapter XI
Breast Surgery Complications
181
Chapter XII
Anesthesiological Issues
201
Chapter XIII Conclusion
207
References
209
About the Authors
275
Index
277
Preface
Breast surgery is the surgical treatment of breast diseases. Its fields of application are
particularly breast cancer therapy and the plastic-reconstructive time after it. Oncological
surgery is one of the most important stages of breast cancer therapy. The history of
breast interventions, known since ancient times, has been marked by several moments,
coincident with the evolution of medical knowledges and with some important
discoveries in this field. This allowed, after thousands of years, to arrive, by the end of
the last century, to a type of intervention that, in the utmost respect for physical integrity,
offers women a concrete chance of healing. From the oncological point of view, breast
lymphatic structure is of particular importance, following that of the venous system,
since it is well known that metastatic cancer spread mainly follows this pathway. In the
early 1900s, breast cancer was believed to be a largely district-related disease that only
in the advanced stages becomes systemic for the peripheral diffusion of metastases. In
this period of time, William Stewart Halsted in 1894 published the results of a radical
mastectomy intervention consisting of the removal en bloc of the breast, the large and
small pectoral muscle, and the lymph nodes of the omolateral axillary excavation. This
technique, albeit very demolishing, at a time when the disease was only revealed
following clinical evidence, appeared rational and appropriate to ensure complete
removal of the tumor and its diffusion paths before it had time to extend to the whole
organism. In the last few decades, instead, thanks to the great progresses made in the
field of instrumental diagnostics, the hypothesis that cancer is a systemic disease from
the time of its inception, because it is very soon capable of producing micrometastases,
has been growing. Consequently, in the presence of an already widespread illness, it is
no longer meaningful to perform only a single district operation, moreover severely
mutilating: it appears justified, instead, an operation that only removes the tumor locally
but is associated and integrated with appropriate adjuvant therapies (chemotherapy,
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Ciro Comparetto and Franco Borruto
hormone-therapy, immune-therapy, radiotherapy, etc.) that can clean systemic
metastases. It has been also reinforced the notion that early diagnosis is essential because
it allows to remove small tumors that are therefore able to produce more limited
metastases than the bigger ones. In oncological surgery, and especially in breast cancer,
the choice of intervention is subordinated to the stage at which the disease is diagnosed.
Until some time ago, the diagnosis was almost exclusively clinical, based on the
symptoms and, above all, on clearly visible signs at breast examination and palpation.
These signs, punctually listed in breast cancer books, are: breast swelling, orange-peeling
or stingy or ulcerated skin, nipple deviation or retraction, hemorrhage from galactofor
ducts, etc., and they represent the obvious manifestation with which the disease, just
because in an advanced stage, gives a sign of itself. These are, fortunately, increasingly
rarer situations where the only surgical indication is a very aggressive operation that,
although associated with medical therapies, often fails to change a severe prognosis.
Today, however, the concept of preclinical diagnosis as the possibility to reveal the
tumor before it becomes apparent with visible manifestations has been stated. In these
cases, not only it is possible to have little or no demolitive surgery, but the survival and
healing percentages significantly increase. This has come thanks to various reasons: 1)
information and screening campaigns: targeted information campaigns have contributed
to widening the participation of women in breast cancer screening. Important study
groups against cancer, as the National Operational Force against Breast Cancer
(FONCAM), have prepared appropriate protocols that, by identifying “target
populations” (women over 40 years of age or with risk factors such as nulliparity,
obesity, premature menarche, etc.) foresee a series of investigations that consist of breast
examination, various instrumental investigations, etc.; 2) progress of instrumental
diagnostics: mammographic examination has been usefully accompanied by ultrasound
and the advent of increasingly sophisticated equipments allows to reveal tumors of a few
millimeters (mm) and thus in the very beginning phase; and 3) diagnostic protocols:
fundamental in the elaboration of the various therapeutic programs, they include a
number of required steps. They begin with the common clinical and instrumental
investigations that, in doubtful or positive cases, are followed by further examinations:
cytological [on cells taken by fine-needle aspiration (FNA)] or histological (on fragments
of tissue taken by biopsy). These samples, sometimes of a few mm and taken by the
internal glands, can be purchased because they are ultrasonically or radiographically
“guided” by sophisticated equipments designed for this purpose, such as the
Mammotome [Devicor Medical Products, Inc., Cincinnati, OH, United States (USA)] or
the Vacora system (Bard Biopsy Systems, Tempe, AZ, USA). By “classification” is
meant the identification of predetermined categories in which cancer may be inserted.
One of the best known and followed is the clinical (made at the time of diagnosis or at
certain post-therapeutic moments) or the pathological (made at the time of surgical
Preface
ix
intervention as it appears to the operator and especially to the pathologist who performs
the microscopic exams extemporaneously) Tumor-Node-Metastasis (TNM)
classification. It provides a large number of classes characterized by different values of:
1) T, that distinguishes primitive tumor whose size and nature is expressed by the value
that accompanies it (X – 0 – IS – 1mic, 1a, 1b, 1c, 1d – 2 – 3 – 4a, 4b, 4c, 4d): TX or T0
indicate a non-definable or undetectable tumor, T1c a tumor of size up to 2 centimeters
(cm), to progressively arrive to T4b, tumor of any size but already adherent to the skin in
which it causes an inflection or orange peel, and to T4d, indicating inflammatory
carcinoma; 2) N, indicating whether and to what extent breast lymph nodes are affected
by the tumor: also the values that accompany N are different (X – 0 – 1a – 1b1, 1b2, 1b3,
1b4 – 2 – 3) and go from N0, absence of metastasis, to N3, when there is metastatic
involvement of the lymph nodes belonging to the omolateral internal breast chain; and 3)
M, that refers to the presence of any metastases: MX indicates that it is impossible to
ascertain the presence of distant metastases, M0 excludes them, and M1 locates them in
distant organs. Some examples: 1) T1cN0M0 pathological indicates a tumor of the size
of 1-2 cm without metastatic involvement of local lymph nodes and without metastases
in distant organs; 2) T4bN2M0 indicates a cancer already adhering to the skin with
metastases in axillary lymph nodes (ALN) that are fixed and without peripheral
metastases; and 3) T1aN0M1 indicates a tumor less than 0.5 cm without local lymphatic
involvement but with metastases in distant organs. This big number of classes and
subclasses makes it easy to type a cancer. This is useful because it allows to accurately
integrate it into the most appropriate therapeutic protocol for that “type” of cancer
because it uniquely and universally identifies it, and because it allows healthcare
providers and other structures to monitor its evolution. Practical reasons and easy-tounderstand requirements have led to simplify the TNM system by choosing the most
homogeneous classes and incorporating them into only four groups or stages, including
some subcategories: 1) Stage 0: TisN0M0; 2) Stage I: T1N0M0; 3) Stage IIA: T0N1M0
or T1N1M0 or T2N0M0; 4) Stage IIB: T2N1M0 or T3N0M0; 5) Stage IIIA: T0N2M0 or
T1N2M0 or T2N2M0 or T3N*M0 (* N1 or N2); 6) Stage IIIB: T4N*M0 (* with any N
state) or T*N3M0 (* indicates any T state); and 7) Stage IV: T*N*M1 (* with any T and
any N state). Staging allows the setting of the most suitable therapy, and an objective
statistical evaluation of prognostic evolution. Breast cancer has been studied for many
decades and the great mass of data collected has made it possible to produce reliable
estimates of the outcome of the affected patients. This disease, the first cause of death
from malignancy in women, when treated in the preclinical phase, has a very high
survival rate at five and ten years, up to 95-98%. In contrast, at Stage IV, this percentage
dramatically drops below 5%. But staging has also other advantages: 1) it avoids a
difficult decision, to choose an intervention that may be more or less invasive and
mutilating, to the empathic relationship between surgeon and patient; 2) it represents an
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Ciro Comparetto and Franco Borruto
objective and acceptable discussion basis for the patient who understandably tends to
reject a mutilating intervention; and 3) it makes the therapeutic choice for that particular
situation univocal, regardless of the surgeon, the structure, and the country where surgery
is performed, with the exception, of course, of the operator’s professionalism and the
quality of the service that can be varied. Tumor classification and staging, along with
other general evaluations, allow the elaboration of therapeutic protocols indicating the
most suitable type of intervention and possible adjuvant and/or neoadjuvant therapies to
be associated. Current views on breast cancer surgical therapy generally suggest that
tumors initially revealed, and therefore small, can be treated with conservative
interventions, leaving the most destructive mastectomies to the bigger late-diagnosed
ones. It should be noted that since the prognosis is directly related to the disease stage,
women who will benefit from less mutilating interventions will also have a greater
probability of survival, while others will not only undergo heavier interventions but will
have a worse prognosis too. Guidelines for surgical breast cancer treatment include a
series of interventions in strictly framed protocols. The most common techniques are the
following: 1) breast biopsy and tumorectomy: the biopsy consists in the removing of
tissue whips. It may be incisional if it is limited to the removing of a small part of a
larger tumor, or excisional when it removes en bloc all the tumor. Biopsy is always
associated with the histological examination that may be extemporaneous if the
pathologist prepares the anatomical part at the freezer microtome examining it as soon as
it is sent to him by the surgeon, or deferred when he looks at it later. Tumorectomy is the
removal of the breast tissue with the tumor, with or without the skin covering it. It is a
really therapeutic intervention that is indicated for benign tumor forms or for very
limited malignant tumor forms. It is distinguished from excisional biopsy because while
this is an intervention aimed at diagnosis, tumorectomy is a therapeutic intervention; 2)
enlarged tumorectomy: it corresponds to the excision of the part of the breast gland
containing the tumor together with at least 1 cm of healthy surrounding parenchyma.
This operation is practiced for very small tumors. When they are not palpable, the
surgeon to locate them follows the path of a metallic tile previously introduced under
ultrasound or stereotactic guidance. In order to be sure to have made the complete
exeresis of the diseased area, the anatomical sample is subjected to a radiographic
control that allows the immediate comparison of the removed area (tissue around the
metallic tile) with the one recognizable in the radiogram made before the intervention; 3)
quadrantectomy: this operation has been proposed by Umberto Veronesi of the European
Institute of Oncology (IEO) in Milan for the initial stages. Quadrantectomy refers to the
removal of a piece of breast gland with the above skin and the underlying large pectoral
muscle fascia. In small breasts, the exeresis can coincide with one of the four quads in
which anatomically we can divide the breast. In the bigger ones, it corresponds to the
removal of a breast clot. It is a limited intervention that gives excellent aesthetic results
Preface
xi
comparable to those of a reductive mastoplasty that often require the remodeling of the
contralateral breast which has become asymmetrical as compared to the operated one;
and 4) mastectomy: there are some variants of this operation. Radical mastectomy is the
complete removal of the breast along with the large and small pectoral muscles and the
exeresis of the axillary lymphatic chain up to the third level. Surgery is the main but not
the only therapeutic moment. Additional adjuvant therapies, such as hormonal,
chemotherapy, radiotherapy, which help the body to fight the likely micrometastases
already present at surgery, may be associated to it based on a series of further
evaluations. The indications and the type of adjuvant therapy are evaluated based on the
state of involvement of lymph nodes (invasion or not), on the study of hormone
receptors, and on age and menopausal status of the woman. A separate case is
represented by tumors in a particularly advanced phase, corresponding to Stage IV,
which were very common in the past but still occur today. In these cases, it is advisable
to submit the patient to some chemotherapy cycles or to radiotherapy aimed at reducing
the tumor mass and hence only later, if in case, to radical mastectomy. Therapy made
before surgery is called “neoadjuvant therapy.” Plastic surgery has the purpose of
remedying some breast defects such as: 1) hypertrophy: it is the enlarging of one or both
breasts. It is corrected with reductive mastoplasty interventions, i.e., the removal of part
of the gland and of the excess skin in order to obtain the desired volume, followed by the
repositioning of the nipple-areola complex (NAC); 2) ptosis: it is the lowering of the
breast. Its correction consists of mastopexy techniques to restore the breast to the upper
position with repositioning of the NAC; 3) hypoplasia: it is the failure of the
development of one or both of the breasts. In these cases, breast augmentation
interventions are based on the insertion of breast implants (containing silicone gel) with
appropriate volume, shape, and profile; and 4) hypotrophy: it is the loss of tone and
volume of one or both breasts due to various causes: pregnancy, lactation, elderly age,
weight loss, etc. It can be corrected with mastopexy interventions associated with breast
augmentation. This kind of surgery, which in most cases responds to requests of a purely
aesthetic nature, is therefore also known as “aesthetic surgery.” Reconstructive surgery is
instead used to reconstruct the breast when it has been necessary to remove it for
neoplastic pathologies or when it has been destroyed by traumatic events. In general, the
first phase is the reconstruction of the mammary mass to which, after some time, follows
the reconstruction of the NAC. The choice of the surgical technique depends on several
factors, including, among the most important ones: age, degree of motivation of the
patient, and, in case of removal for cancer, the extent of the mutilation and the current
stage of the disease. Thus, it is worth to emphasize the importance of an ethically and
psychologically correct approach to the oncological patient. The therapist’s planning,
which could also include total mastectomy, and which must be thoroughly explained to
the woman, will have the urge to insert the reconstructive moment as the possible, if not
xii
Ciro Comparetto and Franco Borruto
natural, conclusion of the surgical path. In this way, he/she will get a more convinced
informed consent from the patient but, above all, will help her to overcome the
psychological, even before physical, trauma of the mutilation she is going to undergo.
The mode and time of the reconstruction are essentially related to the type and extent of
the loss: 1) quadrantectomy: it is a sort of reductive mastoplasty that requires only a few
simple technical measures during the wound closure. Rather, the volumetric reduction of
the operated breast creates a positional and shape asymmetry with respect to the
contralateral breast that is often remodeled in later times; 2) subcutaneous mastectomy: it
involves removing of the mammary gland by maintaining the muscular and skin planes.
The ideal surgery is a breast reconstruction that is carried out with the immediate
placement of a prosthesis; 3) Halsted’s radical mastectomy: it involves a severe
mutilation for the loss, together with the breast, of the two pectoral muscles. This makes
it impossible to insert a prosthesis and requires a real reconstruction that is obtained by
resorting to large muscle-skin edges, portions of the abdominal and large dorsal muscles
covered by the skin and provided with vascular peduncles that are moved from their
original site; and 4) radical mastectomy modified by Patey or Madden: these
mastectomies, compared to the previous one, retain partially or completely the muscular
plane. Madden’s technique, in particular, requires the immediate placing, below the large
pectoral muscle, of a skin expander that will progressively be inflated, helping to create a
space where, once the expander is removed, a definitive prosthesis can be inserted. Once
the breast is reconstructed, after some times, the NAC is reconstructed too. For this
purpose, it is possible to use some of the analogous contralateral structures or tissue
areas taken in other places of the body (inguinal bend, thigh root, large lips, etc.).
Keywords: breast cancer, breast surgery, plastic surgery, aesthetic surgery
Introduction
The obstetrician/gynecologist is the primary physician to women. The breast is an
organ of reproduction, and complete breast examination is part of the obstetric and
gynecological examination. In addition to history and physical examination, the
obstetrician/gynecologist should be prepared to undertake simple diagnostic studies.
Cancer, on the other hand, presents many challenges. The appropriate role for the
obstetrician/gynecologist is one of surveillance and as a resource for patients, including
the discussion of risk factors and treatment alternatives [1]. The American Board of
Obstetrics and Gynecology (ABOG) has recognized the special role of the
obstetrician/gynecologist in the diagnosis and treatment of breast disease and indicated
in 1985 that it would require a knowledge of breast disease in its certification process. It
was also recommended that the obstetrician/gynecologist provide adequate information
concerning screening and perform simple diagnostic studies including aspiration of cysts,
fine-needle aspiration (FNA), and appropriate follow-up studies for patients treated for
breast cancer. Because open biopsy often becomes part of the treatment for breast
cancer, the ABOG stopped short of recommending that every obstetrician/gynecologist
perform this procedure. The American College of Obstetricians and Gynecologists
(ACOG) also has increased its efforts to more clearly define the role of the
obstetrician/gynecologist in the diagnosis and treatment of breast disease. Questions
have been raised concerning the lack of national standards to evaluate training in the
diagnosis of breast disease surgery, and the ACOG has convened many workshops to
address these issues [2]. The designation of the obstetrician/gynecologist as a principal
physician for women may impose new responsibilities on them, but it merely reaffirms
what most obstetrician/gynecologists have long regarded as standard practice. The
gynecologist has always insisted that breast examination is an integral part of the
evaluation of every patient and the basic knowledge of breast disease is certainly as
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Ciro Comparetto and Franco Borruto
essential as any understanding of obstetric and gynecological problems. The
obstetrician/gynecologist should follow certain guidelines that will help achieve in
making an early diagnosis. These include:
1) integrate breast examination into the routine gynecological examination of all
patients;
2) instruct patients in the technique of life-long, periodic breast self-examination;
3) develop proper ambulatory surgical facilities suitable for performing breast
biopsies;
4) perform biopsy for all true, solid, and three-dimensional (3-D) masses: the final
diagnosis of a pathological condition rests on a careful histological examination
of a biopsy specimen;
5) encourage research, both basic and clinical, and etiology, diagnosis, and
treatment of breast lesions, including innovative screening programs for highrisk patients; and
6) include obstetric and gynecological residency programs with specific
instructions in early breast cancer detection techniques.
Previously, breast cancer was viewed as a stereotype disease that progressed from
the breast to the nodes to the systemic area. This has changed: breast cancer is now
viewed as a systemic disease, which spreads to local and distant sites at the same time.
Breast cancer is best viewed as occultly metastatic at the time of presentation. Therefore,
dissemination of tumor cells has occurred by the time of surgery in many patients, and it
is not surprising that radical mastectomy and local irradiation do not prevent metastatic
disease [3]. Breast cancer is the leading cause of death in women between the ages of 35
and 54. It is estimated that the specialist in obstetrics and gynecology provides health
care for more than half of the female population and should become familiar with both
benign and malignant breast conditions. Confronted with the misconception that the
disease appears in women “at risk” only and the estimate that one in every nine women
born in the United States (USA) will develop breast cancer, adequate education,
screening, examination, and documentation are essential in the field of breast disease [4].
Most gynecologists have accepted their role in reducing mortality from breast cancer
giving a thorough breast examination to all patients. They must also be involved in the
interpretation and treatment of symptoms, the use of diagnostic aids, the recognition and
understanding of pathology, and in following and counseling those who have been
treated for cancer. Many of the surgical procedures are within their technical abilities.
Specialty organizations and residency training programs must assist in bringing the
gynecologists’ educational level up to their degree of involvement [5].
Introduction
xv
An understanding of breast pathology is essential when caring for women with breast
disease [6]. Breast diseases are a common aspect of primary care practice [7]. There has
been significant improvement in breast health care over the past few decades, primarily
due to advances in health research by diverse teams of basic scientists, physicians,
pharmacists, industries, nurses, and social workers. This research has involved inquiries
about fundamental biological alterations in breast cancer, differences in diagnostic
modalities and treatment options, and various outcome studies. Increase in public
awareness of breast cancer, an interest in women’s health issues, advances in
radiological imaging, development of new chemotherapeutic agents, and the availability
of molecular genetic testings have brought remarkable opportunities to a new insight in
breast cancer. These efforts have resulted in earlier detection and prolonged disease-free
intervals. However, the overall survival time has remained the same. This is mainly
attributable to the wide range of individual therapy for breast cancer, which responds to a
range of disease curable by surgery alone to one refractory to treatment and marked by
rapid metastatic progression. Challenges remain in fostering adequate funding for
biomedical, as well as behavioral and social research. Attempts should also be made to
promote clinical and population-based studies and to emphasize the value of effective
delivery of health-care services to all women with benign, high-risk, premalignant, and
malignant breast disease [8]. Initial diagnostic errors are related to the presumption that
symptoms or findings are due to benign causes. Physical examination augmented by
mammographic study will disclose those benign-appearing lesions which may harbor a
carcinoma. All palpable lesions and mammographically suspicious areas require that
their identity is determined. The final resolution depends upon biopsy. Missing the tumor
also causes diagnostic error. An accurate biopsy or “sample” must be obtained for study.
Negative results of sampling techniques should be followed by formal biopsy. Failure to
eliminate the primary disease by leaving tumor or breast tissue behind increases the
incidence of recurrence. Total mastectomy reduces this risk. Removal of the axillary
lymph nodes (ALN) also aids in obtaining cure, as well as providing prognostic
information. Well intentioned attempts to obtain a better cosmetic appearance or to
reconstruct the breast are secondary to the patient’s chief need which is to achieve cure.
Complications of the surgical procedures are due to improper flap dissection, desiccation
and trauma to tissues, incomplete hemostasis, and inadequate drainage. Attention to
operative details and adherence to well established surgical principles will minimize
complications [9].
There have been many changes in the last 40 years in breasts surgery. Careful
consideration is given to minor points in operative technique and patient selection, which
will help to achieve consistently good results with minimal complication. Great emphasis
is placed on tailoring the operations to the needs of the patient [10]. Procedures for
management of breast disease are those that are done most commonly by the general
xvi
Ciro Comparetto and Franco Borruto
surgeon and for which the ambulatory surgical unit is apt to be the preferred site [11].
The function of the surgeon remains the same relative to the management of primary
breast cancer. What has changed is our perception of the biology of the disease and our
understanding of data evaluation and analysis [12]. Breast surgery has evolved as a
subspecialty of general surgery and requires a working knowledge of benign and
malignant diseases, surgical techniques, shared decision-making with patients,
collaboration with a multidisciplinary team, and a basic foundation in surgical ethics.
Rapid continuous changes in breast oncology practice have further substantiated
dedicated expertise in breast surgical oncology. Training programs are structured to
develop proficiency in fellows for advanced surgical techniques and clinical decisionmaking as well as exposure to the multidisciplinary aspects of breast cancer
management. Components of a successful program include an intense multidisciplinary
curriculum, engagement in clinical research, and attention to strong mentorship. National
curriculum and training requirements as well as supplemental resources assist in
standardizing the fellowship experience. As surgical training and the field of breast
oncology continues to evolve, so do fellowship training programs to ensure high quality
breast surgical oncologists equipped to deliver high quality evidence-based patient care
while continuing to drive future research and trainee education [13]. Ethics is defined as
the practice of analyzing, evaluating, and promoting best conduct based upon available
standards. As new information is obtained, or as cultural values change, best conduct
may be redefined. In 2014, the Ethics Committee of the American Society of Breast
Surgeons (ASBrS) acknowledged numerous ethical issues, specific to the practice of
breast surgery. This independent review of ethical concerns was created by the Ethics
Committee to provide a resource for ASBrS members as well as other surgeons who
perform breast surgery [14].
Breast cancer management requires a multidisciplinary approach that is tailored to
the patient’s stage at presentation, desire for breast conservation or reconstruction,
estimation of risk of recurrence, and assessment of the benefits and toxicities of potential
adjuvant therapies. Breast surgeons, plastic surgeons, radiation oncologists, and medical
oncologists staff the breast cancer treatment clinic (breast unit or breast center), and
work closely together to formulate treatment plans that will optimize the likelihood for
cure with an acceptable cosmetic result. This involves careful preoperative work-up,
surgical axillary staging, breast irradiation in the setting of breast conservation, and
selection of chemotherapy or hormonal therapy if appropriate. Newer aspects of breast
cancer care, including sentinel lymph node biopsy (SLNB), post-mastectomy radiation
therapy, expanded use of hormonal therapy in younger women, new agents and
chemotherapy combinations, and autogenous reconstruction techniques, have become an
essential part of the multidisciplinary clinical approach [15, 16]. The enormous burden
placed by this disease both on the population and on health care systems explains the
Introduction
xvii
increasing efforts and resources that have been devoted over the years to the search for a
systematic and optimized strategy in breast cancer diagnosis and treatment. Today, the
breast unit model is identified as the gold-standard to ensure optimized patient-centered
and research-based clinical services for breast cancer patients improving survival rates
and patients’ quality of life by a multidisciplinary approach in breast care [17]. The
European Society of Mastology (EUSOMA) Working Group published in 2000
guidelines for the development and operation of state-of-the-art multidisciplinary breast
units. The requirement of a breast unit was a quality assurance plan with the overall goal
of improving breast care for women with both benign and malignant disease. Moreover,
the European Parliament issued a report on breast cancer in 2003 demanding the
establishment of European guidelines for the certification of breast units to prevent an
inflation of breast units without the required quality standards [18]. Breast centers are
defined as focused multidisciplinary facilities of excellence, dealing with the complete
range of breast problems [19]. Comprehensive breast centers directed by full-time breast
imagers have a significant impact on medical care from the perspective of the patient, her
physicians, and the health care system [20]. The breast care continuum is characterized
by a wide variety of procedures and pathways leading to similar outcomes. This variation
leads to very substantial differences in costs and patient experience, dependant upon
physician choice of procedure or pathway. The breast center is uniquely positioned to
develop disease management for the breast, including subspecialized care, the adoption
of evidence-based protocols, and comprehensive management of outcome information.
This approach to disease management focuses on physician excellence and is the key to
increasing the quality of patient care, decreasing the overall cost of breast cancer, and
increasing reimbursement and practice satisfaction for breast physicians [21].
Over the last 40 years of breast center development, it has been found that for every
obstacle there is an option for resolution. The solutions are not uniform in each setting,
but rather they reflect the medical staff politics, interests, and strengths, the resources
and commitment of the institution, and the needs of the community. The most important
message is to validate local medical staff issues as legitimate concerns. The crucial
obstacle is the lack of cooperation among the medical specialties and the lack of trust
between the medical staff and management. The obstacles need to be appropriately
addressed by the creation of an effective organizational structure that is successful in the
local environment and by the programmatic development that reflects the medical staff’s
interests and strengths. This will ensure comprehensive breast center success in the local
political environment and ultimately translates into enhanced expertise, pride, and higher
quality patient care [22]. The pathologist’s contribution to the interdisciplinary team
approach in breast cancer management is a cornerstone for decision-making. Continuous
communication with the radiologist, surgeon, oncologist, and radiation oncologist is
essential. Preoperative diagnosis, surgical specimen work-up with size determination,
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SLNB, processing forms to facilitate the work-up, and diagnostic templates are some of
the items of the pathologist’s contribution to the interdisciplinary team in breast cancer.
Use of diagnostic templates or synoptic reports routinely provide the complete diagnostic
information required for treatment decisions [23]. However, surgeons retain the central
role in the multidisciplinary breast cancer patient care. In fact, the role of the surgeon
remains important in the diagnosis, staging, and treatment of disease, as well as in
educating the patient as to her best options. While technical details of the operations for
these patients remain important, effective evidence-based decision-making may be even
more so. Advances in the methods of breast cancer diagnosis, localization techniques,
and surgical therapies, as well as the expanded role of the surgeon in breast cancer
prevention, radiation therapy, and the treatment of distant disease, requires surgeons to
stay up to date with the available evidence [24, 25]. Several modalities and areas of
expertise are critical for optimal patient management. The basis for medical decisions
and recommendations must reflect outcomes and clinical trial data that are designed and
interpreted with broad input across different fields. Hence, there has been a trend for
specialization in breast disease in many large community and academic practices.
Furthermore, a system of communication and standardization of data values, procedures,
and protocols has begun, but needs much further development. There are many natural
barriers to the process of multidisciplinary care and research in terms of logistics,
finances, and education. The example of preoperative neoadjuvant therapy for earlystage locally advanced breast cancer is one that involves multiple disciplines in the
formulation of a treatment and in future research that will define the optimal
individualized approach. This process can also shed further light on biological principles
and potential for improved treatment. Solutions for overcoming barriers to
multidisciplinary care should include incentives for collaborative and coordinated
clinical care across disciplines. A model of increased efficiency because of pooled
resources and specialization in several fields should also be accompanied by a
demonstration of increased quality of care and patient satisfaction. Any process that adds
to cost or inconvenience needs to be justified in an evidence-based manner. Finally, these
initiatives need to be effectively communicated to the professional and policy-making
communities and to the public at large through well-conceived and unbiased educational
venues [26].
Chapter I
Historical Overview
Throughout documented history, man has admired physical beauty. Artistic works
such as the Venus de Milo and Michelangelo’s David and contemporary movie stars and
athletes emphasize the physical being. More than mere appreciation of corporeal
attributes, ours is a reverence that perceptually bestows a halo effect of associated
virtues. If certain physical criteria are met, the individual simultaneously is presumed
intelligent, strong, charming, good, or any of many other socially esteemed
characteristics. In a highly competitive society, it is no wonder we strive for the edge
which beauty bestows [27]. Throughout the Christian era, saints have been adopted as
patrons of countries and towns, trades and professions, and for protection against
disease. Although patronage is usually related to the saint’s most spectacular cure or
mode of death, sometimes it derives from a play on words, an unusual physiognomy, or
mistaken identity. Historical research has identified 295 patrons of specific diseases.
Thirteen of these saints are patrons of breast disease, St Agatha, who was martyred by
mastectomy, being the most famous [28]. An ex-voto (from the Latin for “from the
vow”) is an image made to express the patron’s gratitude for divine assistance in the face
of personal difficulty. A late 18th century Mexican painting shows Doña Josefa Peres
Maldonado undergoing a mastectomy, and, as an ex-voto, expresses her thanks for divine
aid in having survived the operation. As such, the painting manifests Doña Josefa’s
response to her disease, drawing on both medical and religious sources of support [29].
A Renaissance painting depicts a young woman with locally advanced breast cancer
reaching out towards a healing potion in the church of Santa Maria della Grazia in Milan,
that houses Leonardo da Vinci’s “Last supper.” Today’s potion may well contain
neoadjuvant systemic therapy including trastuzumab that may allow breast-conserving
surgery and targeted intraoperative radiotherapy [30].
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Ciro Comparetto and Franco Borruto
Cancer was known as a disease since prehistoric times. Breast cancer is known from
ancient time, and the treatment strategy evolved as our understanding of the disease
changed with time. Breast cancer, seen by Galen as the commonest cancer of his time,
was probably first mentioned by Hippocrates in the 5th century before Christ (BC). In 460
BC, Hippocrates described breast cancer as a humoral disease and presently, after a lot of
studies, breast cancer is considered as a local disease with systemic roots. Hippocrates
proposed that breast cancer, among other neoplasms, was a “systemic disease” caused by
an excess of black bile. The humoral theory was further supported by Galen and
dominated for centuries in medicine. A case history was described but no specific
treatment mentioned. For centuries, no further cases were described, until Cato, 2nd
century BC, advocated cabbage poultices for all tumors and breast cancer. Aëtius of
Amida probably first described Paget’s cancer of the nipple. By the 2 nd century anno
Domini (AD), treatment comprised a variety of local applications, systemic
medicaments, venesection, and surgery. Surgical resection, first described by Celsus and
subsequently by Leonidas (usually combined with cautery), proved curative when
applied early in the disease [31]. Management of breast cancer evolved slowly through
centuries in the ancient world up to the Renaissance. This period is marked by the
absence of any scientifically verifiable understanding of the true nature of cancer and its
natural history and consequently by a lack of effective treatment. Breast has been
considered as a symbol of femininity, fertility, and beauty. Fulguration and breast
amputation by using various instruments to achieve a rapid operation were widely used
up to the 18th century. The Renaissance was a revolutionary period, since it stimulated
medical practice: at that time, physicians started to scientifically study medicine.
Vesalius greatly contributed in the advancement of surgery, and he vigorously opposed
Galen’s doctrines. Many great surgeons of that time (including Paré, Cabrol, Servetto,
Scultetus, Tulp, Fabry von Hilded, etc.) advanced the science of surgery. Interestingly,
Bartoleny Gabrol (1590) in Montpellier advocated radical mastectomy, which was
popularized by William S. Halsted 300 years later. However, the lack of anesthesia and
the problem of wound infections (due to the lack of the aseptic techniques) generated
significance and often problems for the surgeons of that time. Surgery was often “heroic”
but primitive and even inhumane by current standards. Therapeutic nihilism was the
prevailing attitude regarding breast cancer, at least among the clear majority of surgeons
[32]. Today, we take for granted the blessing of anesthesia and it is almost impossible for
us to imagine the agonies that surgical patients underwent in the past. The description of
a mastectomy, performed in 1720 by Lorenz Heister, Professor of Surgery and Anatomy
in Altdorf in the republic of Nurnberg (now part of Germany), gives a vivid idea of
major surgery in those days. In the abstract from his lengthy report, which appears in the
1775 English edition of his textbook entitled “Medical, Chirurgical and Anatomical
cases and Observations” he discusses the preoperative preparation, the mastectomy itself,
Historical Overview
3
performed as quickly as possible and the tedious postoperative dressings of the
inevitably suppurating wound [33]. The lesion was probably a massive cystosarcoma
phyllodes rather than infiltrating carcinoma of the duct. His thorough description reveals
that patients and surgeons have changed little in three centuries [34]. Professor Bernard
Peyrilhe occupied the chairs of surgical chemistry and medical materia at the Faculty of
Medicine of Paris. He was a great surgeon, cancer specialist, and historian of medicine.
He led in-depth studies on cancer and realized the first experimental transmission of
cancer by injecting extracts of breast cancer into an animal [35].
During the 18th and 19th centuries, management of breast cancer was greatly
improved. The humoral theory of Galen, which dominated for centuries, was fallen into
disfavor. ALN involvement was recognized as an adverse prognostic factor, while
LeDran, in the middle of the 18th century, proposed the theory of lymphatic spread of
breast cancer. He also favored the idea that breast cancer at its earliest stage was a local
disease, which could be effectively treated by surgery. The need to excise enlarged ALN
was recognized by other surgeons of the 18th century, including Petit, who proposed a
procedure very similar to radical mastectomy. During the 19th century, significant
advances were noted, including the development of anesthesia and antisepsis, a better
understanding of the biology of cancer, and the introduction of microscopic examination.
Radical mastectomy was widely used in clinical practice by Halsted. However, this
radical procedure was used by other surgeons of that time, including Meyer. Halsted was
able to report very low local recurrence rates (approximately 6%), a very important
achievement given the advanced stages of breast cancer when diagnosed in women at
that time [36]. In 1804, Seishu Hanaoka performed the first successful surgical treatment
of breast cancer under general anesthesia in the world. It preceded by 38 years C.W.
Long’s trial of ether anesthesia in 1842. Hanaoka had made many efforts to develop the
optimal prescription of the anesthetic “Tsusensan (or Mafutsu-To)” for almost 20 years.
Finally, he succeeded in using it clinically for breast cancer surgery, on October 13 th,
1804. Hanaoka performed operations for breast cancer in a total of 156 cases, and for
many other kinds of surgical procedures. He also eagerly contrived and modified many
surgical instruments. Despite such a busy daily schedule, he eagerly trained and educated
many students, using his own philosophy for medical management [37].
Cooper in 1840 described mammary branches from the 2nd-6th intercostal nerves, and
noticed that the nipple was supplied by branches which lay close to the surface of the
gland. Eckhard (1850) divided the mammary branches into superficial branches to the
skin and nipple, and deep branches to the glandular tissue and nipple, but many later
authors ignored those findings. After the Second World War, cosmetic breast surgery
made further research critical, as surgeons strove to design operations which would
retain its shape and preserve postoperative sensation. Craig and Sykes (1970) described
mainly anterior branches from the 3rd, 4th, and 5th intercostal nerves passing through the
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Ciro Comparetto and Franco Borruto
breast glandular tissue and along the line of the ducts to the nipple. Farina et al. (1980)
concluded that the nipple was supplied solely by superficial lateral branches of the 4 th
nerve. Using improvements in dissecting technique learned from microsurgery, Sarhadi
et al. (1996) found that the nipple was innervated by the lateral cutaneous branch of the
4th intercostal nerve, by two branches, one passing superficial to the gland, and the other
through the retromammary space, and by variable lateral and medial additional branches
from the 2nd-5th nerves. These branches came to lie superficially and formed a subdermal
plexus under the areola. This account is uncannily close to Cooper’s original description:
it is a reassuring, if sobering, conclusion that his early account remains one of the most
reliable [38].
The understanding of the association of mammalian ovarian function with lactation
was common knowledge to dairymen early in the 19th century or earlier. Beatson of
Glasgow noted the cellular anatomical similarity between pregestational breast and
carcinoma in premenopausal women in 1895, leading to the monumental work of
Huggins in 1941 [39]. Dr. Wendell G. Scott hailed mammography as the first significant
contribution to the control of breast cancer since Halsted described the radical
mastectomy in 1903. Mammography has engendered innovative approaches and has
supplied new concepts of breast cancer. Through the tenacity of a few physicians
convinced something could be done for the breast cancer patient, the team against this
dread disease has gradually, but solidly, been built and continues to grow [40]. In the
early 20th century, surgeons and pathologists arrived at the conclusion that specific
anatomical and cytological changes in the breast are related to a heightened risk of
developing a malignancy in the future. This conclusion was directly related to a shift
from macroscopic to microscopic diagnosis of malignancies, and to the integration of the
frozen section into routine surgery for breast cancer. In the interwar era, conditions such
as “chronic mastitis” and “cystic breast disease” were defined as precancerous, and
women diagnosed with these conditions were advised to undergo mastectomy. In the
post-Second World War era, these entities were replaced by “carcinoma in situ” (CIS).
The recent development of tests for hereditary predisposition to breast cancer is a
continuation of attempts to detect an “embodied risk” of cancer and to eliminate this risk
by cutting it out [41]. The first modern case-control study was Janet Lane-Claypon’s
study of breast cancer in 1926, but the design was used only sporadically in medicine
and the social sciences until 1950, when four published case-control studies linked
smoking and lung cancer. These 1950 studies synthesized the essential elements of the
case-control comparison, produced a conceptual shift within epidemiology, and laid the
foundation for the rapid development of the case-control design in the subsequent half
century [42].
The history of carcinoma was for many centuries mainly the history of breast cancer.
Only when in the second half of the 19th century anesthesia and antisepsis had enabled
Historical Overview
5
surgery to treat certain internal carcinomas as well, interest in malignancies other than
those of the breast sprang into being [43]. The history of breast cancer treatment is
divided into periods in which different methods of treatment were dominant [44].
Surgical treatment of breast cancer has been marked by a constant evolution since the
Halsted’s radical mastectomy described in the late 19th century. Then, Madden’s radical
mastectomy, a breast surgery that involves the ablation of tissue with the axillary
lymphatic chain preserving both pectoral muscles, has become the current standard [45].
First, surgery was too radical, then radiation was overused, soon perhaps adjunctive
chemotherapy will be overused. We should continue to search for new methods such as
combinations of heat and radiation that might maintain or increase the immunological
resistance of the host [46]. Halsted is the 19th century surgeon whose name is most
frequently associated with the radical mastectomy procedure. Halsted’s radical
mastectomy was the “established and standardized operation for breast cancer in all
stages, early or late.” However, this type of surgery has been performed since the 16th
century. The development of radical mastectomy was a long process, and many surgeons
over time have contributed valuable insights and alterations to this fundamental
treatment for breast cancer. This procedure may be most commonly associated with
Halsted because he promoted a meticulous operative technique, synthesized the best
points in the techniques suggested by the most famous surgeons of the 19th century, and
provided a scientific basis for the performance of radical mastectomy, which became the
standard surgical treatment of breast cancer for nearly 100 years [47]. Later in this
period, theories suggesting that breast cancer was a systemic disease at inception were
championed by Bernard Fisher. This alternative hypothesis of biological predeterminism
was based upon results of randomized clinical trials (RCT) comparing breast-conserving
therapy with mastectomy, which showed similar overall survival outcomes. Nonetheless,
data from meta-analyses suggest that inadequate local therapy can increase risk of local
recurrence, which can subsequently increase mortality. Local therapy of breast cancer
has evolved in the face of improved adjuvant therapies and better understanding of
disease biology [48]. Misconceptions and illusions prevail in the management of breast
cancer. Historical review reminds us that medical practice is commonly rooted in
tradition rather than proof. The Halsted mastectomy inadvertently served the burgeoning
profession of surgery in the early 20th century more than it has benefited women with
breast cancer, yet more than 100 years later the operation continues to thrive. Despite
evidence that mastectomy, radiation following lumpectomy, ALN dissection (ALND), or
intensive follow-up surveillance have little impact on survival, these practices are
adhered to tenaciously. The extent to which current treatment for breast cancer succeeds
in prolonging life remains open to question. Many accepted ideas and interventions are
perilously disconnected from their true merit. The imperative for doctors to do something
sometimes contradicts their pledge to do no harm [49]. The operation described by
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Ciro Comparetto and Franco Borruto
Halsted in 1894 and called “radical mastectomy” represents a milestone in the treatment
of breast cancer. It consisted of removal of the breast, muscles, and ALN. The preHalsted era saw attitudes ranging from the willful abstention to brutal treatments by
cauterization or amputation. The introduction of anesthesia and asepsis enabled more
advanced surgical attempts. The stratification of patients into operable and non-operable
categories has improved surgical outcome. After attempts to extend Halsted procedure
(by extended or super-radical mastectomies) proved to be of little benefit, a minimallyinvasive trend emerged gradually. It started with modified radical mastectomy by
Madden or Patey that spares the muscles and was then followed by breast conservative
surgery that leaves breast tissue behind. Then, SLN mapping was introduced with the
hope of reducing the extent of ALND. Finally, skin-sparing mastectomy appeared to
conserve skin and facilitate breast reconstruction [50, 51].
The 20th century is marked by significant advances regarding the management of
breast cancer. A clear trend towards less aggressive surgical operation was constantly
noted. Modified radical mastectomy gradually replaced radical mastectomy during the
second half of the 20th century, while during the last two decades breast-conservation
therapy became the treatment of choice for the treatment of breast cancer. This type of
therapy includes segmental mastectomy (either quadrantectomy or lumpectomy) with
ALND, followed by postoperative irradiation. Other significant advances during the 20th
century include the introduction of systemic therapy (chemotherapy and hormonal
therapy) and radiation therapy. Better patient follow-up, statistical analysis, development
of staging systems and the introduction of frozen section, the development and wide use
of mammography (including screening mammography), breast reconstruction following
mastectomy, and the development of newer diagnostic methods [including breast
magnetic resonance imaging (MRI) and the advanced breast biopsy instrumentation
(ABBI)] are other advances that contributed to a better management of breast cancer
patients. SLNB has been introduced during the 1990s to reduce morbidity due to ALND.
Despite these advances, breast cancer remains a significant problem and represents a
field of active and intense research [52]. On January 7th, 1948, a meeting was held at the
Royal Society of Medicine (RSM) in London. Its purpose was to settle a controversy.
Robert McWhirter, an Edinburgh-based radiotherapist, had been invited to defend the
scandalous position advocated by Geoffrey Keynes ten years previously: that radical
mastectomy offered no survival advantage when compared to simple mastectomy plus
local radiotherapy. The negative publicity surrounding the meeting proved overwhelming
for Keynes and he abandoned his research. Indeed, the events of the meeting may have
been quietly buried were it not for McWhirter who, over the following decade, pursued
Keynes’ research. He refined his technique, sparing patients the disfiguring and painful
radical mastectomy without compromising overall survival. Later, he garnered support
from other researchers, which led to a series of papers confirming his original findings.
Historical Overview
7
Towards the end of his career, he also made contributions to service organization and
hormone therapy, eventually holding the Presidency of the Faculty of Radiologists. By
keeping the controversy alive, McWhirter was instrumental in overturning 60 years of
surgical dogma. He remains a pivotal figure in the history of breast cancer [53].
As we have said, since the 1950s the treatment of breast cancer has changed
substantially. This related surgery has become less disfiguring without either impairing
survival or increasing recurrences. Adjuvant chemotherapy has also contributed [54, 55].
Considerable controversy still exists regarding the correct management of breast cancer
[56]. In fact, during the past 100 years there have been two major controversies about the
treatment of primary breast cancer. The first controversy, which occurred approximately
40 years ago, questioned the performance of radical mastectomy, as originally proposed
by Halsted in the 1890s. That controversy was resolved using laboratory and clinical
research, hypothesis formulation, and evaluation of the efficacy of the latter through the
conduct of RCT. A second major controversy arose when MRI began to detect the
presence of tumor multicentricity in many breast cancer patients, resulting in a
resurgence in mastectomy in women who could have been treated with breast-preserving
surgery. Because the use of science resolved the first controversy, there was scientific
evidence to justify the current reversion to mastectomy. Extensive examination of the
vast amount of recent medical literature related to that subject, that is, individual articles,
review articles, and reports from the use of RCT, demonstrated that many physicians are
not familiar with the scientific method, and thus, were unable to present, in those
articles, credible evidence to support mastectomy in the presence of tumor cell
multicentricity. Aside from the RCT conducted by the National Surgical Adjuvant Breast
and Bowel Project (NSABP) begun in 1976, which demonstrated no statistically
significant difference in disease-free survival, distant disease-free survival, and overall
survival between mastectomy and lumpectomy with or without radiation therapy, there
has been no information in any of the few recently conducted studies involving
multicentricity to justify the current resurgence in mastectomy [57]. Until the 1960s, the
central public health message about breast cancer was that women should not delay
seeking medical attention for breast problems. Problematic assumptions about the natural
history of cancer, the efficacy of surgery, and individual responsibility for disease
contributed to the durability of the “do not delay” message. More important, the message
catalyzed or sustained changes in the routines of ordinary women, general practitioners,
surgeons, and pathologists, which led to the perception that the campaign against cancer
was working. Thus, a powerful set of reinforcing perceptions and behaviors maintained
the centrality of the “do not delay” campaign until the era of mammography [58].
Most of the period from 1900 to 1970 was governed by the “non-science” of
anecdotalism and classical inductivism and was marked by the absence of a scientific
gestalt. In keeping with the Halstedian concept that breast cancer was a local disease that
8
Ciro Comparetto and Franco Borruto
spread throughout the body by contiguous extension and could be cured by more
expansive surgery, the disease was treated with radical surgery. In 1950, however, a new
era of enlightenment began to emerge. The awareness that there was a scientific process
in which hypotheses generated from laboratory and clinical investigation could be tested
by means of RCT was a seminal advance, as were findings from studies that laid the
groundwork for the modern era of steroid hormone action, including identification of
estrogen receptors (ER). Expanding knowledge regarding tumor cell kinetics, tumor
heterogeneity, and technological advances related to mammography and radiation
therapy were also to play a role in making possible the advances in therapy that were
subsequently to occur. In the past 30 years, as a result of laboratory and clinical
investigation, the Halstedian thesis of cancer surgery was displaced by an alternative
hypothesis that was supported by findings from subsequent clinical trials. A new
paradigm governed surgery for breast cancer, and lumpectomy followed by radiation
therapy became accepted practice. A second paradigm that governed the use of adjuvant
systemic therapy arose because of laboratory and clinical investigation. Treating patients
who were free of identifiable metastatic disease with systemic adjuvant therapy because
some of them might develop distant disease in the future was a revolutionary departure
from prior treatment strategy and became a new exemplar. Not only did chemotherapy
favorably alter the outcome of breast cancer patients, but the antiestrogen tamoxifen
(TMX) benefited patients with all stages of the disease. TMX also reduced the incidence
of contralateral breast cancer, as well as tumor in the ipsilateral breast following
lumpectomy. The use of preoperative therapy was also found to enhance breastconserving surgery in women with large tumors, although its value in other
circumstances is still being defined. The observation that, because of TMX
administration, invasive and non-invasive breast cancers can be prevented in women who
are at increased risk for such tumors, and the finding that pathological entities such as
atypical hyperplasia, lobular CIS (LCIS), and intraductal CIS (DCIS) can identify
women who should be considered candidates for TMX serve as a fitting capstone to the
accomplishments of the 20th century. Breast cancer prevention has now become a reality.
Unfortunately, a variety of circumstances have arisen as the result of advances in the
understanding and treatment of breast cancer over the last 50 years that threaten to
nullify the progress that has been achieved. This distressing phenomenon may be
reviewed as a “paradox of accomplishment.” The numerous uncertainties, issues, and
questions that have arisen following the report of each advance in treatment, the surfeit
of new information that has not yet been integrated into treatment strategies, the
undesirable consequences of enhanced tumor detection, a reversion to Halstedianism and
anecdotalism, and the uncertainty of therapeutic decision making resulting from the
demonstration of small but statistically significant benefits, particularly in patients with
good prognosis, need to be addressed. Inappropriate interpretation of those
Historical Overview
9
circumstances threatens to deny women with breast cancer and those at high risk for the
disease the opportunity to benefit from treatments that have been proven to be of worth
[59].
Umberto Veronesi’s contribution was to offer the same possibility while
considerably reducing the mutilation that went with cure. Large-scale clinical trials
conducted by Veronesi’s group in Milan in the 1970s and 1980s to demonstrate the
efficacy of quadrantectomy, radiotherapy, and ALND (QUART) as conservative
treatment for small-size breast cancer set in motion the world-wide trend to conservative
surgery in all forms of cancer [60]. Breast conservation surgery has become established
but is always flanked by additional local treatment, and often by systemic therapy.
Studies conducted in Milan were the first to demonstrate that conservative surgery plus
an adjuvant therapy such as radiotherapy is efficacious in treating small-size breast
cancer. As the year 2000 is passed, it has become clear that breast cancer is curable in a
high proportion of cases and attention is turning to improving the aesthetic outcome of
surgery, and to investigating the biological and genetic factors that influence the disease
[61]. Today, the patient with newly diagnosed breast cancer and her surgeon have
significantly more varied treatment options. Radical surgical resection has been
supplanted by breast conservation therapy. Biopsy methods and the actual surgical
techniques continue to be refined. Further developments have emerged in the debates
over the efficacy of ALND and SLNB. Diverse differences are seen in breast cancer of
younger patients due to some fundamental distinctions in their disease. As we entered the
new millennium, breast cancer is curable in a large percentage of women. While
attention is turning to the investigation of the biological and genetic factors involved
with this disease, surgical regimens maintain a pre-eminent role in the overall quest for
cure [62].
As we have seen, the current management of breast carcinoma is very different than
it was a relatively few years ago. The improvements in care have been introduced into
practice because of RCT. From the non-randomized but controlled clinical trial of radical
mastectomy by Halsted demonstrating that loco-regional control could be dramatically
improved, trials have become considerably more sophisticated in both design and
analysis. RCT of breast conservation therapy were begun in Milan by Dr. Veronesi.
Trials by the NSABP headed by Dr. Bernard Fisher have, with other trials, defined the
benefits and techniques of this less morbid treatment approach. Improvements in survival
have also emerged from RCT of adjuvant systemic therapy. Although these
improvements are significant, they do not eliminate the risk of death from breast cancer.
Much remains to be answered in the clinical management of breast cancer. RCT will
assess new developments and introduce improvements to clinical practice. Funding for
research in breast cancer must support basic investigation into the biology of the disease
process, new approaches to control disease, and RCT to test therapeutic principles and
10
Ciro Comparetto and Franco Borruto
techniques [63]. The mastectomy that is performed today is a procedure born from
hundreds of years of discoveries, inventions, and amendments to existing surgical
techniques. The reasons for performing this extreme surgery have changed as well,
ranging from unilateral breast removal to allow greater upper limb functionality to
bilateral removal of the breasts or breast tissue in individuals predisposed to breast
cancer or in individuals who have already been diagnosed. The additions of surgical
tools and anesthetics to the field of medicine further transformed the surgical field in
general and had a large impact on the mastectomy. Halsted’s radical mastectomy served
as the basis of most future breast removal techniques, and is the method recognized
today as the “radical mastectomy.” Most radical surgeries are currently used for
prophylaxis, whereas less invasive lumpectomies have eclipsed breast removal surgeries
as of the latter half of the 20th century [64, 65].
Artificial X-rays were first produced in Germany in 1895 and used for cancer almost
immediately. During the century since this remarkable discovery, radiation therapy has
now become the most important non-surgical modality in cancer: over 50% of all cancer
patients now receive radiotherapy at some point during the illness. Radiation therapy has
increasingly replaced surgical resection for primary control of a variety of solid tumors,
particularly where surgical excision is accompanied by severe long-term tissue loss or
psychological morbidity. Frequent examples include breast cancers. Combinations of
surgery and radiotherapy are increasingly used, for example in the preferred management
of most breast cancers, by wide local surgical excision, breast preservation, and
postoperative radiotherapy. In other circumstances, radiation is routinely combined with
chemotherapy. In 1990, almost half a million patients were treated with radiation therapy
in the USA. Recent technical advances, both in imaging and therapy beam precision,
have greatly improved the therapeutic ratio and accuracy of modern radiotherapy [66].
The radiation treatment of breast cancer has evolved from 2-D to 3-D conformal and to
accelerated partial breast irradiation (PBI), aiming to reduce normal tissue toxicity and
overall treatment time. Systemic therapy in the form of hormone therapy, chemotherapy,
and biological agents is now a well-established modality in treatment of breast cancer.
The current perspective of breast cancer management is based on the rapidly evolving
and increasingly integrated study on the genetic, molecular, biochemical, and cellular
basis of disease [67].
Endocrine surgery includes excision of diseased or sometimes normal endocrine
glands and occasionally the transplantation of endocrine tissues. Male castration was
performed for social reasons in prehistoric times, and thyroid operations were described
during the 12th century. Until the end of the 19th century, most operations were
undertaken to relieve the local effects of pathological enlargement of the thyroid,
ovaries, pituitary, and adrenals, and with the development of anesthesia, antisepsis, and
effective hemostasis, thyroidectomy for benign, non-toxic goiter was perfected. After the
Historical Overview
11
discovery of hormones early last century, knowledge of endocrinology increased, and
many syndromes of hormonal excess were described. Surgeons began to operate to
relieve them. Results improved:
1) with mastery of surgical technique, especially for operations on the thyroid,
parathyroids, and pituitary;
2) with the development of methods for diagnosis of syndromes and the localization
of lesions;
3) with teamwork; and
4) with the use of hormones, drugs, and radiotherapy as alternative or additional
forms of therapy before, during, and after operation.
For about 60 years, increasing numbers of surgeons have specialized in endocrine
surgery as a discipline within general surgery, and results of treatment have improved
greatly [68]. Endocrine therapies for breast cancer have been used for more than a
century. The concept that changing the hormonal balance of the patient with breast
cancer could lead to changes in tumor growth and regression of metastatic disease was
recognized even before hormones and endocrine agents were available. Ablation of
ovaries, adrenals, or hypophysis was used in advanced disease to obtain tumor regression
and control of symptoms. Ovarian ablation was also tested for operable breast cancer
showing a significant beneficial treatment effect. Several endocrine agents have been
developed in recent years: estrogens, androgens, progestins, antiestrogens, aromatase
inhibitors, gonadotropin-releasing hormone (GnRH) analogues, antiprogestins, and
antiandrogens. The use of some of these agents in advanced disease led to investigations
in early breast cancer: TMX was the drug which was most extensively tested, showing a
significant long-term benefit for treated patients. Progestins [medroxyprogesterone
acetate (MAP)] and aromatase inhibitors (aminoglutethimide) were also tested in a few
clinical trials, but no conclusive recommendations for their use in patients with operable
disease may be formulated. The most important current challenges for the appropriate
use of endocrine therapies in breast cancer include:
1) understanding the effect of endocrine therapies and the mechanisms of resistance
associated with their use;
2) developing new agents with novel endocrine antitumor effect;
3) defining the best way to combine endocrine agents with cytotoxics or with other
endocrine manipulations; and
4) identifying long-term effects of endocrine agents in terms of disease control and
prevention, as well as desirable and undesirable side effects [69].
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Ciro Comparetto and Franco Borruto
One hundred years ago, ovarian ablation was shown to be an effective treatment for
advanced breast cancer in premenopausal women. Since that time, many different
treatment modalities have been advocated to improve patient survival. The value of
adjuvant ovarian ablation, however, has recently been established in the overview of
breast cancer clinical trials. In fact, comparison of the efficacy of combination
chemotherapy with earlier trials of oophorectomy demonstrate the superiority of
oophorectomy. The effectiveness of chemotherapy may largely be the result of partial
ovarian ablation produced in premenopausal patients. The use of TMX maintenance in
oophorectomized women might provide an optimal therapy for the control of breast
cancer recurrence [70]. After 100 years of using hormonal therapy for the treatment of
breast cancer, and developments since 1942 in chemotherapy, combining the two
modalities seemed a logical next step. However, trials using TMX plus
cyclophosphamide (CP), methotrexate (MTX), and 5-fluorouracil (5-FU), or
dibromodulcitol (DBD) and doxorubicin with TMX showed no improvement in survival,
and considerable toxicity. Nevertheless, it was learned from these trials that breast
cancers exhibit cellular heterogeneity about ER status and that hormonal therapy and
chemotherapy have different actions and toxicity. In addition, cell cycle specific agents
are most effective against rapidly dividing cells. Further trials utilizing these concepts
are warranted, although routine use of combined chemo-hormonal therapy is not yet
recommended [71].
In conclusion, this historical perspective on breast cancer tells us how and why
certain therapeutic eras have reached ascendancy and then declined. Therapeutic
revolutions occur after a crisis develops when there is a general recognition that clinical
interventions are not producing positive results predicted by the prevailing paradigm.
The attitude of premodern surgeons was influenced by the very real possibility of doing
more harm than good by operating upon women with breast cancer. Up until Halsted, the
consensus was clearly that, unless forced by the circumstances, surgical resection should
be avoided for disease much more advanced than very early-stage tumors (the
cacoethesis of Celsus). Twentieth century progress in antisepsis, anesthesia, and surgery
changed this point of view. The first three quarters of that century saw more and more
aggressive operations performed, while the last quarter century reversed this trend, with
reduction of the size of breast cancer operations based largely on the teachings of Fisher.
A new crisis is upon us now in that trials of early detection have resulted in unexpected
disadvantages to certain subgroups and there is previously unreported structure in early
hazard of relapse, clinical data that suggests the act of surgery might accelerate the
appearance of distant metastases. The explanation that agrees with these results, as well
as physicians of antiquity, is that surgery can induce angiogenesis and proliferation of
distant dormant micrometastases, especially in young patients with positive nodes [72].
Thus, breast cancer is a daunting disease and constitutes a continuing medical health
Historical Overview
13
problem through the ages for millions of women worldwide. Physicians, from the early
periods of recorded history have tried to heal breast cancer patients, with results that
were fairly promising at times and disappointing at others. The science of medicine
evolved through the ages under the scrutiny and critical thought of the many prominent
scholars and researchers of their times who constantly added to the therapeutic
armamentarium. Surgeons described new therapeutic approaches, and anatomists,
through their elaborate descriptions, added useful insights on the art of healing. Although
the Middle Ages hindered temporarily any progress in the field of medicine, the
Renaissance became the vaulting horse for science in its broadest sense. However, it was
not until the 19th century, with the discovery of anesthesia, the introduction of antisepsis,
and the establishment of microscopy that giant scientific leaps in the field of breast
cancer treatment occurred. The 20th century, with the development of chemotherapy and
radiation and the undertaking of numerous clinical trials, offered new insights regarding
breast cancer management [73]. In the history of the development of the treatment of
breast cancer over a 4000-year period, there have basically been three paradigms within
which we have studied and developed treatment for this disease. Clinical trials over the
last 40 years, as an expression of the scientific method in action, have demonstrated the
limited success of the contemporary paradigm with its therapeutic sequelae of breast
conserving surgery and adjuvant systemic therapy. At the same time, a critical review of
the natural history of breast cancer and the results of current treatments suggest logical
inconsistencies in the model. Therefore, a novel paradigm better fits the available
information by suggesting that metastases are not only a result of cellular transmission of
breast cancer, but subcellular transmission using the mechanism of in vivo transfection.
Although this may sound farfetched, there are a series of remarkable studies in the
literature which support this conceptual revolution. This is surely a fertile field for
research and the therapeutic consequences would be obvious. They might suggest that
more aggressive adjuvant systemic chemotherapy based on the conventional model is
unlikely to achieve any additional benefit, whereas therapy based on antiviral drugs
might produce the next therapeutic advance [74]. In the 1980s, breast-conserving surgery
was accepted in the surgical treatment of early breast cancer and during the last years of
last century SLNB has emerged as a method to avoid ALN clearance for node-negative
axillae. This will lead to a diminishing number of ALN clearance procedures. Breast
cancer surgery will increasingly be performed as day-case operations, under local
anesthesia. The real surgical challenges during the last decade has been immediate breast
reconstruction and oncoplastic breast-conserving procedures. Therefore, breast surgery
will increasingly be performed by plastic surgeons [75, 76].
Plastic surgeons have been performing operations to improve the aesthetic aspect of
the breast for centuries. The Amazon philosophy has been increasing in popularity
because of the evolving status of women in society. Many references point to
14
Ciro Comparetto and Franco Borruto
Themiscrya on the southern coast of the Black Sea in Anatolia as the Amazon homeland.
The hypotheses that have been proposed to explain the method of breast mutilation
include amputation, cauterization, breast searing, and breast pinching. It is generally
believed that the primary purpose was to facilitate the efficient use of a bow. Another
explanation would be that breast mutilation was performed for medical reasons,
including the prevention of breast pain, the development of a tender lump, or cancer.
There is another school of thought on this involving religious and sociological reasons
that breast mutilation was a badge of honor for warrior women and a sign that a woman
had become a real warrior and a sacrifice to Artemis as a sign of service. Much indirect
proof and archeological evidence point to their historical existence. The Amazons, who
lived in an autonomous and original social model, changed their image and function to
suit the needs of the society and the times [77]. Throughout ancient times, great
controversy produced many theories of how breast cancer occurred and the best
treatment. Because of beliefs that closure of mastectomy sites could conceal tumor
recurrence, breast reconstruction did not gain wide acceptance until the mid-1900s. In
fact, although the need for mastectomy has been evident for many years, postmastectomy reconstruction has been recognized as an achievable outcome for only a
little over a century.
Today, plastic surgeons have a variety of techniques to reconstruct the breast. The
earliest attempts at reconstruction used autologous techniques that were either
unsuccessful, not reproducible, or were associated with significant morbidity. The first
autologous muscle flap for breast reconstruction was the latissimus dorsi myocutaneous
flap, described in 1896 by Iginio Tansini. The introduction of Carl Hartrampf’s
transverse rectus abdominis myocutaneous (TRAM) flap and Robert J. Allen’s deep
inferior epigastric artery perforator (DIEP) flap have also provided excellent
reconstructive options. The myocutaneous flaps that are being used for breast
reconstruction have a long history, although the techniques of today are more
sophisticated than those of the past. Louis Ombredanne was the first to describe the
pectoralis muscle flap for immediate breast mound reconstruction in 1906. Breast
reconstruction was not encouraged in the early part of this century. Lately, the advances
in the myocutaneous flap have made breast reconstruction without a prosthesis possible.
The tissue that was transferred to reconstruct a breast using a tubed pedicle flap in
multiple stages can now be transferred in a single stage with a better result. Advances in
reconstructive surgery led to a revival in autologous techniques for breast reconstruction,
with microsurgical free-tissue transfer potentiating a new range of potential donor sites.
The abdominal wall became the donor site of choice, and with the advent of perforator
flaps, morbidity associated with flap harvest was minimized. In cases where the
abdominal wall is unsuitable, flaps such as the superior and inferior gluteal artery
perforator (GAP) flaps, the musculocutaneous gracilis flap, and the “stacked” DIEP flap
Historical Overview
15
are frequently used options. Recent developments in endoscopic instrumentation have
enabled surgeons to perform many types of procedures through small incisions located at
a distance from the surgical site. The transumbilical breast augmentation (TUBA) has
advantages over other methods, including a quicker recovery, less pain, and lower
chances of complications. The development of minimally invasive techniques for implant
placement and flap harvest, such as endoscopy, continue to evolve, and research in tissue
engineering offers a vision for a future without the need for a donor site.
About augmentation, Vincenz Czerny from Heidelberg attempted to enhance a
woman’s breast in 1895 with implantation of a lumbar lipoma. Soon after, surgeons used
paraffin injections and polyvinylic alcohol sponge implantation, which yielded disastrous
results. Prosthetic techniques became sought after, with silicone prostheses widely used
until concerns about potential adverse effects led to the investigation of alternate options.
With these concerns shown to be unfounded, silicone and saline prostheses evolved with
successive generations of implants. In 1961, Thomas Cronin and Frank Gerow promoted
the first silicone implant, paving the way for today’s silicone and saline prototypes.
Since then, a variety of non-silicone materials have been injected or implanted to
augment or to reconstruct the hypoplastic female breast, including autologous tissues,
intramammary- or submammary-injected alloplastic materials, and preformed alloplastic
materials other than silicone. For various reasons, none was fully acceptable. The
introduction of the medical-grade silicone bag prosthesis in the early 1960s improved the
results of mammary augmentation dramatically and reduced the incidence of fibrous
contracture and implant extrusion. Other methods of breast augmentation became
obsolete. The introduction of the silicone gel implant in 1962 began the modern era of
breast augmentation, and over the past 50 years, breast implants have evolved to
encompass a wide array of commercially available implants today. In April 1992, the
moratorium on silicone gel breast implants began, and much of the experience and
development of the cohesive shaped implants occurred outside the USA. During this
time, saline implants were used almost exclusively in North America, whereas silicone
implants continued to be used throughout the rest of the world. In 2001, cohesive gel
implants became available in the USA under an Investigational Device Exemption (IDE)
Study. Three companies have USA Food and Drug Administration (FDA) approval of
fifth-generation implants: Sientra (Sientra Inc., Santa Barbara, CA, USA), Allergan
(Allergan Inc., Irvine, CA, USA), and Mentor (Mentor Worldwide LLC, Irvine, CA,
USA). These implants are unique due to the texture of the shell, implant dimensions, gelshell interaction, gel fill ratio, degree of cross-linking, and form stability. Although form
stability is a relative term, it may best be reserved to describe the increased ability of the
implant to maintain its basic, intended shape. The cross-linking, form stability, and
cohesiveness of these fifth-generation implants provide surgeons with an innovative tool
to more closely create a natural breast in both shape and softness.
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Ciro Comparetto and Franco Borruto
Although reduction mammoplasty techniques had originated centuries earlier than
mastopexy methods, the advancements of both have largely paralleled one another. In
1949, the Wise pattern was introduced to preoperatively plan safer and predictable
outcomes in breast reductions. Efforts to minimize scars were achieved with Claude
Lassus’ introduction and Madeleine Lejour’s subsequent modification of the vertical scar
mammoplasty [78-82]. Erich Lexer wrote the first publication, in Spain in 1921, on the
correction of pendular breasts. This author was the first in the history of mammoplasty to
perform breast reduction with an “open” nipple-areola complex (NAC) transposition,
with preservation of the continuity of the skin to the remaining gland. This feature was
far ahead of its time, as the techniques based on this concept did not become popular
until after 1955. Lexer also was the first to propose subcutaneous mastectomy for
treatment of fibrocystic disease, to perform breast augmentation in the ptotic hypoplastic
breast with fat flaps, and to use free fat grafts taken from the abdomen or hips for
augmentation mammoplasty. In the early 1900s, the best method for enlarging small
breasts was to inject them with paraffin. Within 50 years, researchers turned to the free
grafting of autogenous material to achieve breast enlargement. Then came the fast and
easy silicone injections of the 1950s and 1960s. For the last 20 years, the surgical
implantation of alloplastic materials has been used for augmentation mammoplasty. The
management of the greatest complication, capsular contracture, is difficult because it is
the natural, enhanced scarring response of tissue that has been subjected to hosting a
foreign body, the prosthesis. There is no simple solution to this problem, only the
possibility that through manual manipulation of the augmented breast tissue, the intensity
of the contracture can be minimized [83].
Chapter II
Breast Biopsy
Breast symptoms are appropriately evaluated by a breast-oriented history and by the
diagnostic triad of clinical breast examination, FNA, and mammography. Detection and
management of a breast mass requires an optimal environment for interpretation, relevant
use of clinical information, technically excellent imaging procedures, proper
interpretation of the findings, and pertinent recommendations. Masses suspicious for
malignancy by only a single modality ideally should undergo some form of biopsy, as the
consequences of delayed diagnosis of breast cancer can be devastating. Early invasive
breast cancer can be identified and treated if the appropriate evaluation is performed
[84]. In the case of a palpable dominant mass, concordance of the diagnostic triad yields
a reliable clinical diagnosis. If there is not concordance, or if there is any doubt about the
diagnosis either on the part of the physician or the patient, open surgical biopsy provides
the definitive histological diagnosis. The goal in clinical practice is to detect nonpalpable cancers by ordering screening mammography for all patients eligible by age,
history, or both. The long-term cancer-free survival of women treated for non-palpable
breast cancer is excellent [85]. Biopsy techniques include aspiration for fluid, for
cytology, or for histology. The indications for each method depend on the physical
and/or mammographic findings. If a breast cancer is diagnosed, then treatment will
depend on the size and location of the lesion and the patient’s wishes [86]. Concepts
regarding the best methods for doing biopsies and the most appropriate methods for
treatment of patients with breast cancers have changed dramatically since the early
1970s. Currently, formal biopsies (incisional or excisional) are being done as two-step
procedures with reliance on permanent sections for diagnosis [87].
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Ciro Comparetto and Franco Borruto
Patients with a palpable mass often benefit most from aspiration. As the clinician
tries to aspirate, fluid may be obtained if the lesion is cystic. A solid lesion can be
assessed with FNA biopsy with a very high degree of accuracy. Excisional biopsy should
be used when a cystic lesion recurs, the mass does not disappear after the cyst is
aspirated, or if the fluid obtained is bloody. A solid lesion may need to be excised if the
aspirate is negative. The overall detection rate of breast cancer is approximately 20% for
excisional biopsies. Mammographically detected lesions can be evaluated with needlelocalization biopsies and stereotactic needle biopsies (SNB). The detection rates for
breast carcinoma averages approximately 30%, with at least 20% of these lesions being
non-invasive. The role of core needle biopsy (CNB) of palpable lesions is limited:
however, histological confirmation of positive cytological results from aspirate is
possible with this approach. SNB appears to correlate well with the specimen obtained at
incisional biopsy and may decrease the need for needle-localized excisional biopsy [88].
Mammography is an excellent screening tool for the detection of breast masses. One of
the goals of the radiologist is to separate benign breast masses warranting no intervention
from the indeterminate and malignant masses that require histological evaluation.
Thorough mammographic and sonographic work-up of lesions detected at screening will
reduce the number of biopsies performed and increase the true positive biopsy rate. By
systematically evaluating a breast mass as to its density location, size, margins, and
interval change, one can separate benign lesions from those requiring additional work-up
and those that will require a biopsy diagnosis. Any features suggesting malignancy
should prompt histological assessment. For many women, FNA biopsy (FNAB) or largeCNB, guided either stereotactically or sonographically, will not only reduce the
morbidity associated with excisional biopsy but also decrease the cost of evaluating
questionable lesions found at screening. Ultrasound examination will further reduce the
number of biopsies by separating cysts from solid and indeterminate lesions that require
further evaluation. The mammographer’s experience and confidence as well as patient’s
compliance with follow-up recommendations will help the mammographer reach this
goal [89].
In 1989, the Canadian Cancer Society (CCS) recommended that women over 50
years of age should undergo mammography as a test for breast cancer in centers
dedicated to such programs. This recommendation and others by American societies
have increased the number of mammographies done for screening purposes. As a result,
many mammographic abnormalities are reported by radiologists, who recommend
biopsy. The surgeon should review the films with the radiologist and ensure that the
anomaly is real. Attention should be given to specific signs of cancer, such as spiculated
lesions. However, non-specific signs of cancer, such as microcalcifications,
Breast Biopsy
19
microlobulation, and architectural distortion, should be evaluated carefully before biopsy
is carried out. Stereotactic FNA can decrease the number of surgical biopsies needed.
The surgical biopsy should be a one-step, segmental mastectomy done for diagnosis and
treatment. The specimen should be oriented, inked, and X-rayed and a definitive
diagnosis made on paraffin blocks. Frozen sections should not be made of
microcalcifications [90]. The development of mammography and that of breast specimen
radiography have paralleled one another. The preparation of radiographs of breast
specimens is obligatory when biopsy is performed for purely mammographic indications
and when no palpable mass is present. Such cases are being encountered with increasing
frequency because of the development of centers for breast cancer screening. Close
collaboration among pathologists, radiologists, and surgeons and precise attention to
procedural detail are necessities wherever this situation arises. The application of
specimen radiography as a routine to all breast specimens is regarded as an adjunct to
gross examination. While useful, its yield of otherwise undetected occult carcinoma is
low. Whether other advantages outweigh the cost appears to be a matter for individual
decision. Investigative uses of breast specimen radiography have received little attention
[91]. The increasing use of screening mammography, liability risks, and volume control
legislation by the federal government pose a major challenge to clinicians to safely select
patients for breast biopsy. Despite a normal mammogram, a palpable breast mass often
requires aspiration or excisional biopsy. Careful clinical judgment must prevail if
observation is elected. A biopsy should be performed on a clinically suspicious mass
whether the mammogram is suspicious or not. Thoughtful clinical judgment and
interdisciplinary cooperation promote an acceptable benign to malignant ratio for breast
biopsies [92]. As screening mammography has become more widespread, the urgency to
provide more sensitive and more specific interpretations has also increased. Although
many calcifications detected on mammograms are characteristically benign and need no
further evaluation, there are many microcalcifications that warrant further evaluation
with special views. The importance of their detection lies in the fact that many
malignancies are mammographically manifested solely as microcalcifications. Once
detected, radiologists have attempted to characterize and stratify microcalcifications by
their level of suspicion to improve the predictive value of biopsy recommendations. This
is an important endeavor because the cost to society, especially in this era of limited
resources, and the collective anxiety produced by benign breast biopsies are both great.
When a biopsy is recommended, the breast team should ensure that histopathological
correlation is achieved. Communication among colleagues from different specialties
should be encouraged and can be fostered by the use of the Breast Imaging Reporting
and Data System (BI-RADS) lexicon (Table 1) [93].
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Ciro Comparetto and Franco Borruto
Table 1. Breast imaging-reporting and data system (BI-RADS) classification
(adapted from radiopaedia.org, 2017)







BI-RADS 0:
o incomplete, further imaging or information is required, e.g.,
compression, magnification, special mammographic views, ultrasound;
o this is also used when requesting previous images not available at the
time of reading.
BI-RADS I: negative, symmetrical and no masses, architectural
disturbances or suspicious calcifications present.
BI-RADS II: benign findings, interpreter may wish to describe a benignappearing finding:
o calcified fibroadenomas;
o multiple secretory calcifications;
o fat-containing lesions such as:

oil cysts;

breast lipomas;

fibroadenolipoma or mixed density hamartomas;

galactoceles;
o simple breast cysts;
o these all should have characteristic appearances, and may be labeled
with confidence; the interpreter might wish to describe intra-mammary
lymph nodes, implants, etc. while still concluding that there is no
mammographic evidence suggesting malignancy.
BI-RADS III: probably benign, short interval follow-up suggested.
BI-RADS IV: suspicious abnormality:
o there is a mammographic appearance which is suspicious for
malignancy;
o biopsy should be considered for such a lesion;
o these can be further divided as:
 BI RADS IVa: low level of suspicion for malignancy;
 BI-RADS IVb: intermediate suspicion for malignancy;
 BI-RADS IVc: moderate suspicion for malignancy.
BI-RADS V: there is a mammographic appearance which is highly
suggestive of malignancy, action should be taken.
BI-RADS VI: known biopsy proven malignancy.
A palpable mass in a woman’s breast represents a potentially serious lesion and
requires evaluation by history taking, physical examination, and mammography. The
initial objective is to distinguish simple cysts from solid lesions, which can be
accomplished with FNA. A solid lesion requires a firm diagnosis, and this usually calls
for removing the lesion for histological examination. A positive result on cytological
examination after aspiration is sufficiently accurate to justify one-stage diagnosis and
Breast Biopsy
21
treatment, with confirmation by examination of a frozen section obtained during the
procedure. A negative or suspicious finding on cytological evaluation is inconclusive,
and outpatient biopsy is indicated. Perfection in diagnosis will require the removal of
every solid mass. This can be expected to result in the biopsy of many benign lesions, but
removal of many of them is desirable on other grounds. Although in some instances the
probability of cancer may be exceedingly small, it is never zero. If biopsy is not
recommended, the probability of cancer should be estimated so that the patient can
decide whether the level of risk is acceptable to her [94]. Increased public and
professional awareness has resulted in more women obtaining mammograms. As a result,
the surgeon is often called on to diagnose and treat occult breast lesions. Although
current controversy questions the earliest age at which screening mammography truly
lowers the death rate from breast cancer, that mammography does detect breast cancer
years before it might be discovered as a mass in the breast cannot be challenged.
Mammographic techniques have improved so that smaller and smaller areas of suspicion
may be identified, and mammographers have gained greater judgment in the
interpretation of these minute radiographic abnormalities. This has inevitably led to an
increase in procedures designed to explain them. The incurred costs, both emotional and
economical, of positive mammographic “calls” are considerable. Whether practicing
medicine as patients’ advocates or, as unfortunately currently seems to be of equal
importance, exercising politically correct and cost-effective mandates, the management
of non-palpable breast lesions certainly bears witness to the correlation of cognitive and
procedural skills and cooperation between physicians, as well as the technical
achievements of contemporary medicine [95]. The development of new diagnostic
modalities has changed the way such breast lesions are approached. Management
decisions are made in the context of new pressures applied by the growing managed care
imperative and increased medical-legal exposure [96]. The specimen excised for the
mammographically detected lesion is somewhat unique and requires special
consideration by the surgical pathologist. The biopsy, in most instances, contains no
grossly visible lesion and is relatively large, so that blocking in its entirety is not
practical. The pathologist needs to establish that the radiological abnormality is
contained in the biopsy and to this end specimen radiography is required. Established
prognostic parameters for breast carcinoma, such as tumor size, histological type, grade,
and hormone receptor status are equally applicable in the non-palpable breast lesion, but
consideration should also be given to the identification of epithelial proliferations which
have increased risk for subsequent carcinoma. In addition, the recognition of DCIS in the
biopsy indicates potential for widespread disease, and LCIS, a less commonly detected
lesion in mammography, is associated with multifocality and disease in the contralateral
breast. Both lesions are also associated with increased risk of recurrence in the remaining
breast tissue. Failure to observe the corresponding quantity of calcium seen in
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Ciro Comparetto and Franco Borruto
radiographs relates to the fact that calcium may occur, not only as calcium phosphate
[Ca3(PO4)2], but also as calcium oxalate (CaC2O4), the latter not being stained by
hematoxylin and eosin (H&E) but readily detected by its birefringent nature in polarized
light. Detailed correlation of serial thin slices of the specimen with radiographic features
is largely an educational exercise, but is the most time-consuming step in the
examination of the non-palpable breast lesion [97].
FNA cytology (FNAC) for breast tumors was first described and performed in 1930.
Thirty years later, it gained acceptance first in Europe and about a decade later in North
America. Since 1970, FNAC has grown in popularity and is now routinely used in the
initial diagnosis of palpable breast masses in the USA and in other parts of the world.
Fast staining methods of the aspirate enables reporting within ten minutes of the aspirate
being performed. Training and experience is important in obtaining satisfactory smears
for diagnosis, and pitfalls are false-negative and false-positive findings, which may have
dire consequences for the patient if cytological diagnosis is the final arbiter, and raise
questions regarding the diagnostic utility of FNA as a replacement for open biopsy in
many clinical situations. False-positive diagnoses may result from atypical epithelial
proliferations, fibroadenomas, or inflammatory lesions. False-negative aspirates may
occur because of technical errors, cystic lesions, and under-diagnosis of low-grade
neoplasms. Conditions such as benign mammary dysplasia and sclerosing adenosis are
the most common sources of highly cellular smears and often show marked atypia, which
makes distinction from carcinoma difficult. In addition, atypical papillary formations
present a diagnostic problem, and biopsy is indicated to exclude a papillary carcinoma.
FNA very seldom cause traumatic complications, and these are usually of a minor
degree. Seeding along the needle track has occurred, but in most cases with a largercaliber (18-gauge) needle. Aspiration itself has been shown to have no effect on the
survival rates in breast carcinoma. Contemporary reports show that around 90% of cases
of breast cancer can be detected with confidence by means of this procedure. The
reduction in scar formation facilitates future evaluation of the patient as scar tissue often
interferes with the interpretation of mammograms. Cost-effectiveness is evident in terms
of decreased use of anesthetics and operating time and a reduction in the use of frozen
section histology by about 80% [98]. The exact role of FNA in the diagnosis of palpable
breast lesions is still uncertain. The triple-diagnosis protocol has been suggested as a
replacement for open biopsy of palpable breast masses in many clinical situations.
Following this algorithm, the results of palpation, mammography, and cytology are
combined to guide management. Mammography should precede FNA or follow the
cytological procedure by two or more weeks. Patients with a positive triple diagnosis
should undergo open biopsy or confirmatory intraoperative frozen section. Positive FNA
results would be useful for preoperative counseling as well as serving as a diagnostic
procedure for clinically suspicious lesions in patients wishing a confirmatory test before
Breast Biopsy
23
open biopsy is performed. Patients with discordant triplet results should be referred for
open biopsy. The management of patients with negative triplet results is less clear. From
the available data, it appears that approximately 2% of patients with negative triplet
results have carcinoma. Based on these results, we cannot recommend replacing open
biopsy by the triple diagnosis method in most patients with a persistent dominant mass.
In most cases, a biopsy is indicated. Surgeons who plan to follow a breast mass with
clinical examination may be able to reduce their false-negative rate by performing FNA
[99]. Breast FNA has a reported mean specificity of 99%, and a reported sensitivity of
70-99%. The false-positive rate varies from 0-0.4% in most larger series, with a reported
false-negative rate ranging from 0.7-22%: however, higher false-negative rates have been
reported in tumors under 2 centimeters (cm) in diameter. The FNA technique uses a fine,
20-gauge or less, needle and is not associated with a significant risk of tumor growing
out the needle tract. FNAC is not effectively used if a breast mass cannot be palpated or
distinguished from fibrous tissue within the breast. The procedure can be applied to nonpalpable masses detected by mammography by employing stereotactic techniques. The
cytological samples obtained from FNA can be used to distinguish atypical ductal
hyperplasia from DCIS or invasive ductal carcinoma. However, cytological criteria to
effectively distinguish DCIS from invasive adenocarcinoma are not definitive in many
cases, and are dependent on variables related to the type of intraductal tumor, the size
and character of the cell groups, and the presence of single or disaggregated tumor cells.
Employing current cytological criteria, LCIS may be distinguished from invasive lobular
carcinoma in some cases: however, the individual LCIS cells are not morphologically
distinct from lobular carcinoma cells. Atypical lobular hyperplasia has cellular features
essentially the same as those seen in LCIS. FNAB employs larger needles of 14-16gauge, does not require surgery, and uses only a small amount of material [100]. FNAB
can also be used to acquire material for special studies. This is especially useful with
small tumors (≤ 1 cm) when most of the material is needed to make a histological
diagnosis. Immune-staining techniques can be used on FNAB to investigate proliferation
by bromodeoxyuridine (BrdU) uptake or Kiel-67 (Ki-67) labeling. Immune-staining
techniques can also be used to identify oncoprotein expression, such as of tumor protein
53 (p53). Fluorescence in situ hybridization (FISH) is a technique that can be used to
gather cytogenetic information directly from interphase tumor cells and is well suited for
use with FNAB material because the harvested nuclei are intact and no cumbersome
dissociation processing is needed. Flow cytometric techniques can be applied to FNAB
material to study deoxy-ribonucleic acid (DNA) content and synthesis (S)-phase fraction.
Material acquired by FNAB can also be analyzed by the polymerase chain reaction
(PCR) followed by mutation detection. It is essential that the FNAB harvest is
representative, ample, and well prepared for the success of these studies [101].
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Ciro Comparetto and Franco Borruto
Recently, there has been a considerable increase in the use of both FNAB (aspiration
cytology) and breast tissue-CNB. In patients with suspected breast cancer, needle biopsy
is frequently used to confirm the diagnosis before treatment is planned. This allows a
more thoughtful approach to the patient and full screening for possible metastatic disease
prior to definitive surgery. Needle biopsy techniques are simple, rapid, can be performed
in the doctor’s office, and save time, equipment, and hospital beds. Complications are
few. Aspiration cytology has the advantage that it is quick to perform, the preparation
can be examined almost immediately, and, in the event of an unsatisfactory smear, the
procedure can be repeated. However, the diagnosis is based on purely cytological
evaluation, and the information obtained is somewhat limited. Reported accuracy rates
range from 42-96%. False-positive reports are rare but have occurred in most centers,
and a high degree of accuracy will only be obtained by experienced practitioners. TissueCNB has the advantage that the diagnosis is based on histopathological assessment, but
the procedure is slightly more time-consuming, is more traumatic for the patient, and the
equipment is more expensive. Accuracy rates range from 67-98.5%. Studies comparing
the use of FNAC and tissue-CNB in the diagnosis of mammary carcinoma have produced
variable results. Both methods have advantages and disadvantages, and the choice of
technique must depend on the clinical situation and the preferences and skills of the
practitioners involved in the management of the patient [102].
In developed countries, in the last 20 years, mammographic screening programs,
which have been used extensively, are designed to detect the earliest possible breast
cancer. The FNAC report is extremely important because it gives the necessary
information for the management of patients, to proceed with more invasive diagnostic
methods or surgical treatment, and to decide what kind of operation to perform. In the
preoperative phase, FNAC has taken a fundamental role of both palpable and nonpalpable lesions, using ultrasound or stereotactic guidance. New developed techniques,
breast biopsy instrumentation (ABBI) and Mammotome (Devicor Medical Products, Inc.,
Cincinnati, OH, USA) have the advantage of complete removal of breast lesions, but this
is not possible in all the examined cases. In developing countries, economical restrictions
and low budget for health care and screening programs put the patients at a disadvantage
because of the prohibitive cost of sophisticated diagnostic methods, thus it is
recommended that FNAC be used as a routine diagnostic method because of its low cost
compared with the others and this policy maximizes the availability of health care to
women with breast cancer. FNAC plays an important and essential role in the
management of patients with breast lesions and offers a great potential for prediction of
patient outcome, disease response to therapy, and assessment of risk of developing breast
cancer. The reliability and efficiency of the method depends on the quality of the
samples and the experience of the medical staff that performs the aspiration [103].
However, the success of breast FNA is highly dependent on the adequate preparation of
Breast Biopsy
25
cytological conventional smears. The liquid-based cytology (LBC) technique consists of
an automated method for preparing thin-layer cytological samples from cell suspensions
collected in alcohol-based preservative. LBC is designed to improve conventional smears
by avoiding limiting factors such as obscuring material, air-drying, and smearing
artifacts. LBC preparations of breast aspirates demonstrated better cellular preservation,
less cell overlapping, and elimination of blood and excessive inflammation compared to
conventional smears. Conversely, alterations in architecture and cell morphology as well
as loss of myoepithelial cells and stromal elements have been described in LBC
specimens, requiring training before applying this technique for diagnosis. Studies have
shown a similar accuracy between LBC and conventional smears for the diagnosis of
breast lesions. LBC also permits the use of residual material for ancillary tests, which is
an important advantage compared to conventional smears. LBC can be safely applied to
breast FNA, showing a similar diagnostic accuracy to conventional smears [104].
CNB is increasingly being used in the investigation of breast disease whether this is
asymptomatic and suspected after screening mammography, or presents symptomatically
in the patient. In most cases, the result of the procedure provides a definitive diagnosis or
at least provides information that is used to plan the further management of the patient.
There are, however, many unresolved issues with the use of CNB: for example, with
regard to the amount of information that can be reliably derived from CNB or with
regard to the management of the patient after some CNB diagnoses. ER and progesterone
receptors (PR) and human epidermal receptor 2 (HER-2) are reported on both CNB and
excisional specimens, but there continues to be debate over which represents the more
appropriate specimen type on which to perform these tests. There are many possible
diagnoses after CNB for which the management is not straightforward and around which
there may be controversy, or just a lack of sufficient evidence to support a definite
management plan. These “lesions of uncertain malignant potential” include papillary
lesions, fibroepithelial lesions with cellular stroma, mucocoele-like lesions, and radial
scars. Currently, these are removed surgically but there may be an argument for more
conservative management including vacuum-assisted core biopsy (VACB) in some cases
[105]. CNB is an established alternative to surgical biopsy, and CNB can avoid excess
surgical biopsies in many patients. In addition to accurate histological diagnosis, there is
interest in obtaining prognostic information from CNB, especially for patients being
considered for preoperative (neoadjuvant) therapy. CNB provides useful information
about histological type and grade. However, an unavoidable problem of CNB is
underestimation of invasion. Several aspects of CNB remains controversial, such as
diagnosing papillary lesions by CNB, problems regarding tumor cell displacement after
CNB, and management of lobular neoplasia on CNB [106].
In the last decade, percutaneous breast biopsies have become a standard for the
management of breast diseases. Biopsy clips allow for precise lesion localization, thus
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Ciro Comparetto and Franco Borruto
minimizing the volume of breast to be resected at the time of surgery. With the
development of many imaging techniques (including mammography, sonography, and
breast MRI), one of the challenges of the multidisciplinary team became to synthesize all
informations obtained from the various imaging procedures. The use of biopsy markers
after percutaneous biopsy is one of the keys for optimal patient management, helping the
radiologist to deal with multiple lesions, to insure correlation across different imaging
modalities and to follow-up benign lesions, helping the oncologist by marking a tumor
prior to neoadjuvant chemotherapy, helping the surgeon by facilitating preoperative
needle localization, to precisely mark the margins of extensive disease and to guide
intraoperative tumor resection, and helping the pathologist to insure the lesion of interest
has been removed and to identify the region of interest in a mastectomy specimen. We
believe biopsy clip markers should be deployed after all percutaneous interventions
[107].
FNAB and CNB techniques require training and cytopathologist support. In contrast,
breast cyst aspiration using a 21- or 22-gauge needle is a simple, cost-effective, and
minimally invasive procedure. The technique is easy to learn and can be practiced on a
breast model. Breast cyst aspiration may be attempted in many women who present with
a palpable, dominant breast mass. If clear fluid is aspirated and the mass resolves,
malignancy is unlikely, and breast cyst is the probable diagnosis. In this situation, reevaluation in four to six weeks is appropriate: if the cyst has not recurred, only routine
mammographic surveillance is required. Referral for FNAB or excisional biopsy is
indicated if the aspirate is bloody or extremely tenacious, if no fluid can be aspirated, or
if there is residual mass after aspiration. Complications such as local discomfort,
bruising, and infection are uncommon [108].
Established methods of breast cancer detection have well-described limitations, and
new diagnostic techniques are evolving continually to improve diagnostic accuracy.
Studies to date suggest the presence of 5-12 independent ductal lobular systems per
breast, each harboring complex cellular fluids contributed by local and systemic
processes. The intraductal approach to breast cancer has been invigorated in the last
decade by a series of papers exploring ductal-based screening through nipple aspiration
and lavage and ductal exploration through endoscopy. The merging of these efforts to
define the earliest biological changes in the progression toward breast cancer is opening
new fields for both bench-translational and clinical research. These techniques have
already begun to show value in defining the presence and extent of proliferative disease
in high-risk patients, allowing for more informed therapeutic decision making [109].
Ductal lavage is a recently introduced technique for non-surgical breast epithelial
sampling of asymptomatic high-risk women. It is based on exfoliative cytology of duct
epithelial cells, obtained by cannulation and lavage of ducts that produce nipple fluid
after breast massage and nipple aspiration. The technique is performed with topical
Breast Biopsy
27
anesthesia and involves cannulation of any fluid-yielding nipple orifice with a speciallydesigned catheter for lavage and aspiration of the ductal system. Ductal lavage provides
information like that obtained by cytological examination of nipple aspiration fluid and
random periareolar FNA. Women who demonstrate cytologic atypia on these tests can be
assumed to be at higher risk for breast cancer and may benefit from prophylactic
medication. Ductal lavage promises to provide more reproducible sampling of the same
area of the breast, as opposed to methods of random sampling, such as random FNA, but
the degree of reproducibility remains to be demonstrated. If reproducibility is greater
than with random periareolar FNA, ductal lavage may represent an important advance in
the design of phase II chemoprevention trials, particularly because it also provides
another source of material for judging response to prevention agents (i.e., the protein
component of nipple aspiration fluid), which can be analyzed for levels of hormones,
specific proteins, and protein profiles obtained with proteomics [110, 111]. Ductal lavage
and cytological analysis of the effluent is a more sensitive and specific test than nipple
aspiration cytological analysis and random FNA. The dilemma lies in what should be
done after a ductal lavage yielding malignant or atypical cells [112]. The ductal approach
to breast cancer allows assessment of breast ductal epithelial cells and their local
microenvironment in a graded process of increasing invasiveness. Samples of ductal
epithelial cells sufficient for cytological diagnosis may be safely collected, titers of
individual proteins showing variation with breast cancer status may be measured, and
abnormal pathology within the breast ducts may be directly visualized. Identification of
surrogate molecular markers may facilitate early breast cancer detection, in conjunction
with cytological assessment, and be useful for individual prediction of breast cancer risk
and assessment of treatment response. The small quantities of nipple aspiration fluid
available for analysis, and difficulties in identifying and cannulating ducts remain
important limitations of these techniques [113-116].
To improve disease monitoring over time and to avoid painful procedure such as
tissue biopsy, liquid biopsy may represent a new precious tool. Indeed, it represents a
basin of “new generation” biomarkers that are spread into the bloodstream from both
primary and metastatic sites. Moreover, elevated concentrations of circulating tumor
DNA (ctDNA) as well as circulating tumor cells (CTC) have been found in blood plasma
of patients with various tumor types. Nowadays, several innovative approaches have
been introduced for the detection and characterization of CTC and ctDNA, allowing a
real-time monitoring of tumor evolution [117, 118].
Today, radiology is an essential step in the pathological analysis of breast biopsies. It
is determinant at each stage of the management of non-palpable lesions, clusters of
microcalcifications, and opacities, whether this concerns the needle biopsy or the
surgical excision. Firstly, an X-ray is necessary to ensure that the biopsy specimen has
been adequately sampled and when samples with microcalcifications are selected by the
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Ciro Comparetto and Franco Borruto
radiologist, management can be more specific and accurate. In the case of surgical
specimens, the X-ray confirms the presence of the radiographic abnormality or the clip
indicating the site of the surgical excision which guides sampling. Some radiographic
features also provide information on underlying pathologies allowing management to be
adapted accordingly. Radiographs are also important to ensure that microscopically
detected microcalcifications or lesions exactly correspond to the radiographic
abnormality in size and location. The paraffin block can also be X-rayed to select those
containing microcalcifications for additional slicing. It is also important to identify the
presence of modifications caused by the biopsy (fibrosis, hemorrhage, and inflammation)
and to carefully recognize displacement of epithelial cells and pseudoemboli resulting
from the needle procedure. Such correlation between radiology and pathology is
essential so that appropriate management of the specimen can be adapted and to avoid
pitfalls arising from preoperative procedures [119]. With the ability to perform good
diagnostic mammography, breast ultrasound, ductography, cyst aspiration, abscess
drainage, and stereotactic or ultrasound-guided percutaneous biopsy, the modern breast
radiologist should play the central role in breast diagnosis. The definitive diagnoses
afforded by percutaneous breast biopsy that obviate surgery entirely in benign lesions
and streamline the therapeutic surgery for malignant lesions now can be obtained
routinely. The future holds even more exciting challenges for the radiologist as
percutaneous lumpectomy becomes a reality. Thus, the breast radiologist, armed with the
technology and techniques of the 21st century, truly stands on the threshold of a new era
[120].
In summary, investigation of women with a breast lump or suspicious change in
breast texture starts with a history, physical examination, and usually mammography.
The clinical history should establish how long the lump has been noted, whether any
change has been observed, and whether there is a history of biopsy or breast cancer. Risk
factors for breast cancer should be noted, but their presence or absence should not
influence the decision to investigate a lump further. The breast physical examination
should aim to identify those features that distinguish malignant from benign lumps.
Mammography can often clarify the nature of the lump and detect clinically occult
lesions in either breast. FNA can establish whether the lump is solid or cystic. When a
tumor is solid, cells can be obtained for cytological examination. Ultrasonography is an
alternative method to FNA for distinguishing a cyst from a solid tumor. Whenever
reasonable doubt remains as to whether a lump is benign or malignant, a biopsy should
be carried out. When surgical biopsy is used, the aim is to remove the whole lump in one
piece along with a surrounding cuff of normal tissue. CNB, either clinically or imagingguided, can usually establish or exclude malignancy, thus reducing the need for surgical
biopsy. Thermography and light scanning are not recommended diagnostic procedures.
The value of MRI is progressly growing. The choice of procedure should consider the
Breast Biopsy
29
experience of the diagnostician and availability of the technology in question. The workup should be completed expeditiously and the patient kept fully informed throughout.
Even when malignancy is not found, it may be prudent, in some cases, to arrange followup surveillance [121]. For the evaluation of non-palpable breast lesions, imaging-guided
large-CNB are increasingly replacing needle-localized open breast biopsies. The
sensitivity rate of large-CNB for the diagnosis of breast cancer is high (97%). The
reclassified agreement rate between CNB and subsequent surgical biopsy or long-term
mammographic follow-up is also high (94%). In case of 20% breast cancer prevalence
among women referred after screening (as in the USA), the risk of breast cancer despite
benign large-CNB result is less than 1%. In European countries, however, prevalence of
breast cancer among referred women is 60-70%. This would result in a risk of breast
cancer despite benign large-CNB result of 4-6%. The imaging-guided large-CNB is a
promising alternative for the needle-localized breast biopsy. However, additional
research is needed to explore the limiting factors of the technique. Without such detailed
knowledge, a benign histological diagnosis on large-CNB in countries with high
prevalence of malignancy among referred women should be interpreted with caution
[122]. Most countries have now adopted a triple assessment approach, i.e., clinical,
imaging, and pathology, to breast diagnosis, with FNAC as the first-line pathological
investigation in both screening and symptomatic populations, except for
microcalcifications. Pathologists specialized in cytopathology are best qualified to
collect and interpret FNAC samples, but this is not always possible or practical.
Radiologists involved in breast imaging should ensure that they have the necessary skills
to carry out FNAC under all forms of image guidance. Best results are achieved by a
combination of both techniques, as shown in the imaging-guided FNAC in the presence
of the cytopathologist. Most of European countries use similar reporting systems for
breast FNAC, in keeping with European Guidelines for Quality Assurance in Breast
Cancer Screening and Diagnosis, although some still prefer descriptive reporting only.
When triple assessment is concordant, final treatment may proceed based on FNAC,
without a tissue biopsy. ER and PR assessment can be done safely on FNAC material.
However, not all institutions may have expertise in doing this. HER-2 protein expression
on direct cytological preparations is insufficiently reliable for clinical use, although its
use for FISH is possible, if expertise is available. Most clinicians practise a degree of
one-step diagnosis with a cytopathologist present in the out-patient clinic. Formal
recognition of the importance of the time spent outside the laboratory, both for
cytopathologist and cytotechnologist, is necessary to ensure appropriate resourcing. The
use of CNB has increased, although not always for evidence-based reasons. CNB and
FNAC are not mutually exclusive. FNAC should be used in diagnosis of benign,
symptomatic lesions and CNB in microcalcifications, suspicious FNAC findings, and
malignancies where radiology cannot guarantee stromal invasion [123-136].
Chapter III
Benign Breast Diseases
Benign breast diseases can be divided into congenital, developmental, inflammatory,
neoplastic, “fibrocystic,” and miscellaneous categories [137]. The relevant medical
literature does not reflect the entire spectrum of benign breast diseases or the appropriate
treatment. Most textbooks on breast disease emphasize breast cancer and the late
manifestations of benign breast disease that often require surgical treatment. More than
180,000 cases of breast cancer occur each year in the USA. The number of women with
benign breast disease is far greater and can be counted in the millions. For these patients,
the well-trained primary care physician can provide appropriate evaluation and
treatment, including recommendations for referral. For most patients with breast
symptomatology, the goal is relief of symptoms and resolution of the problem. To
accomplish this requires a contemporary knowledgebase combined with adequate time
spent with the patient [138]. Thus, breast health means more than breast cancer. At least
50% of patients seen at a multidisciplinary breast center have benign conditions [139].
The most common breast problems for which women consult a physician are breast pain,
nipple discharge, and a palpable mass. Most women with these complaints have benign
breast disease. Breast pain alone is rarely a presenting symptom of cancer, and imaging
studies should be reserved for use in women who fall within usual screening guidelines.
A nipple discharge can be characterized as physiological or pathological based on the
findings of the history and physical examination. A pathological discharge is an
indication for terminal duct excision. A dominant breast mass requires histological
diagnosis. A breast cyst can be diagnosed and treated by aspiration. The management of
a solid mass depends on the degree of clinical suspicion and the patient’s age [140].
When faced with a suspicious clinical or mammographic finding, patients may be
anxious about the possibility of breast cancer. Because many of these findings are
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Ciro Comparetto and Franco Borruto
benign, clinicians attempt to make a rapid and accurate diagnosis to definitively rule out
carcinoma. Imaging plays a key role in diagnostic strategies [141].
Benign breast disorders, classified by the aberrations of normal development and
involution (ANDI) system, constitute the major workload in breast clinics (Table 2).
Breast pain (mastalgia) is classified as cyclical, and non-cyclical extra-mammary causes
such as ribircage pain must be identified. Most patients need reassurance alone, but those
with moderate/severe pain present for more than six months may need treatment: RCT
have shown danazol, bromocriptine, and TMX to be effective. Fibroadenoma is the
commonest benign solid lump in women aged 15-30 years. The diagnosis must be
confirmed by triple assessment. Cysts occur usually in women of middle to late
reproductive life. After ultrasound has confirmed the lump as cystic, it can be aspirated.
Nipple discharge should be tested for the presence of hemoglobin (Hb). Those with Hb+
discharge may require microdochectomy for treatment and diagnosis, common causes
being duct papilloma and duct ectasia. Breast abscesses may occur during lactation or
in women with duct ectasia and are treated by incision or aspiration together with
antibiotics [142]. Benign breast disorders can be considered from four points of
view: clinical presentations, clinical significance, management, and pathogenesis.
Understanding the pathogenesis is important for rational management and for assessing
clinical significance. Clearly understood nomenclature is also important. Clinicians have
tended to concentrate on the condition usually known as fibrocystic disease, a clinical
condition (painful nodularity), but a terminology which relates to a histological picture
of fibrosis, cyst formation, and epithelial hyperplasia, now known to occur in both
asymptomatic and symptomatic breasts. To address these problems, the ANDI concept
has been proposed as a framework for benign breast disorders which is comprehensive,
accurate in terminology, and based on pathogenesis. For each disorder, there is a
spectrum from normal through mild abnormality (aberration) and in some cases (only) to
disease. This concept encompasses pathogenesis, clinical and histological significance,
and general principles of management. It has proved particularly useful in giving an
understanding of benign breast disorders to doctors in training [143].
Several large-scale prospective RCT establish the validity of managing probably
benign breast lesions with periodic mammographic surveillance as a safe and effective
alternative to immediate tissue diagnosis. This approach to mammographic interpretation
is now very widely accepted: the American College of Radiology (ACR) indeed includes
“probably benign – short interval follow-up suggested” as one of the five final
assessment categories in the BI-RADS, which all American radiologists are encouraged
to use. There is also consensus that probably benign interpretations should involve:
1) cases restricted to non-palpable lesions;
2) use of the specific imaging criteria described in the prospective RCT; and
Benign Breast Diseases
33
3) preinterpretation comparison with prior mammograms, if available, to ensure
that new or progressing lesions undergo prompt biopsy (it makes no sense to
recommend follow-up for a lesion that has already demonstrated interval
progression when the very demonstration of progression during surveillance is
what prompts biopsy instead of continued follow-up).
Table 2. Aberrations of normal development and involution (ANDI) system
classification (adapted from radiopaedia.org, 2017)
Disorders of development:
 polymastia and polythelia;
 accessory axillary breast tissue;
 congenital nipple retraction;
 macromastia;
 fibroadenoma;
 phyllodes tumor;
 adolescent hypertrophy.
Disorders of cyclical change:
 mastalgia;
 nodularity.
Disorders of involution:
 fibrocystic change:
o cysts;
o fibrosis;
o sclerosing adenosis.
 periductal mastitis.
Yet, unresolved issues concerning probably benign lesions include whether initial
full problem-solving imaging should be performed in all cases, whether to use patient
age and lesion size (for solitary masses) as additional criteria in deciding between the
management alternatives of mammographic follow-up and immediate tissue diagnosis,
and what should be the specific timing, frequency, and duration of the follow-up
examinations that constitute the surveillance protocol [144]. The discussion of abnormal
results of breast imaging and abnormal pathological findings can be challenging for
health care professionals and often is stressful for patients. Although most imaging
findings and biopsy results are negative and do not infer a substantial increase in breast
cancer risk, the subsequent conversation between the patient and her practitioner is more
effective and informative with a thorough review of the pathological results and an
appreciation of the importance of radiological-histological concordance [145]. The
strategies of treating breast benign conditions depend upon the need to relieve symptoms,
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Ciro Comparetto and Franco Borruto
to prevent recurrence, and to guard against malignancy which vary according to the
diagnosis. Morbidity also must be prevented [146, 147].
Disorders of the female breast in the pediatric age group are a relatively common
finding: however, there is limited information in the current literature. The plastic
surgeon treating these patients is faced with a wide range of reconstructive problems. By
understanding the various breast disorders, the plastic surgeon can better diagnose and
treat this patient population appropriately [148]. Pediatric chest wall and breast
deformities present as a wide spectrum of anomalies, and often occur coincidentally.
Chest wall abnormalities fall into two categories: congenital (which are largely
hypoplastic) and deformational (including both chest wall malignancies and
postoperative abnormalities). Breast abnormalities can be categorized into three groups,
including hypoplastic, hyperplastic, and deformational anomalies. Hypoplastic breast
anomalies require reconstruction with augmentation techniques and are often associated
with significant reoperative rates, as are deformational anomalies. Hyperplastic
abnormalities require reduction techniques and are less likely to require re-operation.
Considerations about surgical correction of pediatric chest wall and breast deformities
often require coordinated efforts between pediatricians and pediatric plastic surgeons
with anticipation of continued growth of the child and careful timing for treatment to
maximize functional and aesthetic outcomes [149, 150].
Breast lesions, including mastalgia, benign proliferative changes, and benign masses,
including fibroadenomas, are common in adolescents and young adult women. Breast
cancer is rare in women less than 20 years old and uncommon in women less than 30
years old. Discrete masses in women less than 30 years old that do not feel suspicious on
examination can be observed for one or two months. If they persist, then a FNA can
differentiate those that are benign and can be observed versus those that need either an
excisional biopsy or definitive surgery. Mammography has little role in the diagnosis of
women less than 30 years old except in those individuals with highly suspicious lesions
on examination [151]. So, though females may develop breast masses early in life, the
risk of malignancy is extremely low. Therefore, most breast masses in the young can be
managed conservatively without surgery. Breast masses in young girls may represent
thelarche or tumors of adjacent structures, but are unlikely to be malignant. The most
common form of bilateral breast enlargement in prepubertal girls is premature thelarche,
a benign, transient, and incomplete form of precocious puberty. Fibroadenoma is the
most common cause of breast mass in female adolescents. In the rare case in which a
breast mass in this population is malignant, it is more likely to be a non-carcinomatous or
metastatic cancer. Because of the low risk of malignancy and the relatively different
composition of the adolescent as compared to the adult breast, mammography is not
recommended for routine screening or routine imaging of breast masses in adolescents.
The role of breast self-examination should be further studied [152]. Anyway, although
Benign Breast Diseases
35
99% of breast lesions in female adolescents are benign tumors, surgical intervention is
commonly required [153]. Breast disease in the adolescent female encompasses an
expansive array of topics. Benign disease overwhelmingly dominates the differential
diagnosis and dictates a different protocol for care in the adolescent compared with the
adult patient to avoid inappropriately high assessments of risk and unnecessary
diagnostic procedures and surgery. There are also emerging issues pertaining to the care
of the adolescent breast, such as breast augmentation, nipple piercing, and management
of the adolescent patient with a family history of breast cancer [154, 155].
Macromastia is a rare psychologically and physically disabling condition of
abnormal breast tissue enlargement more than the normal proportion characterized by
excessive breast growth. The condition may be caused by glandular hypertrophy,
excessive fatty tissue, or combination of both. The usual physiological enlargement of
female breast occurs over three to five years and the female breast size is related to body
habitus and hereditary characteristics. The etiology of macromastia is usually
undetermined, however, hormonal excesses and hypersensitivity of the target organ have
been found in some cases. It is safe to surmise that the pathological condition is multifactorial, with both inherited and acquired aspects. Cases of hyperprolactinemia have
been reported by some workers. Immunological risk factors for development of
macromastia have also been seen in some groups of patients with myasthenia gravis,
chronic arthritis, and Hashimoto thyroiditis. Ultrasonography may show no breast
parenchyma abnormalities, while mammography may be indicated in some patients who
are 40 years or older. Hormonal assay can be done but its value in treatment is doubtful.
Drugs are only marginally effective in reversing gigantomastia: therefore, surgery
remains the mainstay of treatment. Management of macromastia can be physically,
socially, and psychologically satisfying to both the patients and the surgeons [156]. To
date, there is no universal classification or accepted definition for this condition. Many
authors cite gigantomastia as breast enlargement that requires reduction of over 1500
grams (g) per breast. However, there is discordance in the literature with the weight of
reduction ranging from 0.8-2 kilograms (kg). Practically, this is a postoperative
definition which is of little use to the clinician in terms of patient management or
prognosis [157]. Macromastia is a deforming, disabling, and painful condition, especially
in the adolescent. Multiple procedures have been advocated and are successful for the
reduction of breast tissue. In addition, adjunctive therapy with hormones may prevent
relapse. In the various techniques for reduction, it is important to have a clear
understanding of breast vascular and neural innervation, to maintain maximum security
in reduction without loss of excessive vital tissue. Although both sensory ability and
lactation function are diminished with most procedures and eliminated with some,
careful planning and patient counseling in all cases should lead to maximal benefit and
optimal results [158]. Currently, there are no patient- or disease-oriented evidence-based
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Ciro Comparetto and Franco Borruto
guidelines for the treatment of this condition. A significant relationship was found (p <
0.01), as was an odds ratio (OR) of 7.0, for the likelihood of recurrence using a reduction
mammoplasty as opposed to a mastectomy. Based on the evidence, certain interventions
are more effective for the treatment of virginal mammary hypertrophy. On diagnosis of
virginal mammary hypertrophy, TMX therapy may be considered based on previous
literature, barring any medical contraindications. A subcutaneous mastectomy with
complete removal of breast tissue is the procedure least likely to lead to recurrence but is
more deforming. Reduction mammoplasty gives an improved aesthetic breast, but it is
important to counsel the patient on the likelihood of increased recurrence. TMX therapy
following surgery may decrease the recurrence rate [159].
Pain is one of the most common breast symptoms experienced by women. It can be
severe enough to interfere with usual daily activities, but the etiology and optimal
treatment remain undefined. Breast pain (mastalgia) is the commonest breast symptom
presenting to general practitioners and breast surgeons alike. To make a full assessment
of the cause, all patients require a full history, physical examination and, sometimes,
radiological investigations. Diary cards are often helpful. Breast pain is typically
approached according to its classification as cyclical mastalgia, non-cyclical mastalgia,
and extramammary (non-breast) pain. The commonest cause is cyclical mastalgia.
Cyclical mastalgia is breast pain that has a clear relationship to the menstrual cycle. Noncyclical mastalgia may be constant or intermittent but is not associated with the
menstrual cycle and often occurs after menopause. Extramammary pain arises from the
chest wall or other sources and is interpreted as having a cause within the breast. The
risk of cancer in a woman presenting with breast pain as her only symptom is extremely
low. Mastalgia is a common cause of anxiety among women and frequently leads to a
primary care clinic for consultation. Fortunately, mild premenstrual breast discomfort
lasting for one to four days can be considered “normal.” However, moderate-to-severe
breast pain lasting over five days can interfere with usual activities, lead to unnecessary
medical tests, and potentially invite the use of ineffective, occasionally harmful
medications. Despite the severity of some patients’ symptoms, mastalgia is still
considered a trivial complaint by many physicians: often, it is felt to be psychological in
nature. After appropriate clinical evaluation, most patients with breast pain respond
favorably to a combination of reassurance and non-pharmacological measures. For the
remainder 15% of mastalgia patients who have life-altering pain and still request
treatment, simple lifestyle changes should be suggested initially, such as well-fitting
wearing, weight reduction, regular exercise, a decrease in dietary fat intake, a reduction
in caffeine intake, and discontinuance of oral contraceptives or hormone replacement
therapy (HRT). Unfortunately, there is a paucity of evidence for the usefulness of these
measures. In a few patients, however, mastalgia is severe enough to deserve further
evaluation and treatment. Overall, 92% of patients with cyclical mastalgia and 64% with
Benign Breast Diseases
37
non-cyclical mastalgia can obtain relief of their pain with the judicious use of several
available therapies. If pain is persistent or severe, a variety of pharmacological agents
exist. The most effective with least side effects is a three-six-month course of low-dose
TMX [10 milligrams (mg)]. Other proven agents include evening primrose oil
supplements, danazol, bromocriptine, or GnRH analogues, but these have a higher sideeffect profile and are rarely indicated nowadays. The potentially serious adverse effects
of these medications limit their use to selected patients with severe, sustained breast
pain. Newer treatments include lisuride maleate and topical non-steroidal antiinflammatory (NSAI) preparations [160-162]. Predicting which treatment will be most
useful for any woman may be challenging. No differences in success rates were found to
be associated with factors such as reproductive history, presenting complaint, personal or
family history of breast disease, or subsequent need for breast surgery. The peak (but not
basal) serum prolactin (PRL) levels in response to thyrotropin releasing hormone (TRH)
stimulus has been predictive of success for hormonal treatment but is relatively invasive.
The prognosis for women with breast pain is not always predictable. Women with
cyclical breast pain often are relieved by events that alter their hormonal milieu, whereas
non-cyclical breast pain may last only one to two years [163]. Differentiation into
cyclical and non-cyclical patterns on a simple pain chart is useful for objective
assessment of pain severity and for selection of appropriate drug therapy and subsequent
monitoring of response. About 85% of new patients will be satisfied with adequate
reassurance, but some 15% will have persistent pain and warrant medical treatment. No
ideal agent exists, and the choice of drug will depend on efficacy, side effects, and cost.
Non-cyclical pain has a lower response rate compared to cyclical mastalgia, but
differentiation of a subgroup with chest wall pain leads to an overall 90% response to
treatment by local infiltration with steroids and lignocaine. Newer agents such as
luteinizing hormone-RH (LHRH) agonists are currently undergoing evaluation in doubleblind RCT against placebo. The management of nodularity is based on the clinical
differentiation of the normal spectrum of physiological change within the breast (ANDI),
requiring simple reassurance, from a true dominant breast nodule that will require
excisional biopsy to exclude malignancy. When pain and lumpiness coexist, some
reduction in overall nodularity (with the use of agents given for mastalgia) may occur
[164].
Congenital breast and chest wall anomalies represent a relatively common set of
disorders frequently encountered by breast and pediatric plastic surgeons with a
spectrum of severity that ranges widely from the relatively benign polythelia to the very
complex disorders such as Poland’s syndrome and tuberous breast deformities. While the
former can be treated in a single surgical setting with minimal morbidity, the more
complicated disorders often require a staged reconstructive algorithm. The treatment for
many of these conditions includes surgical correction. If the child is still growing,
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treatment timing is crucial and many of the surgical corrective procedures require more
than one operation over many years. Some disorders also require a multidisciplinary
management for both workup and treatment [165]. Although these deformities have less
impact on functional capacity, the psychological consequences can be serious in
adolescent patients. They can experience embarrassment, social isolation, and
complexities during sexual development, and this results in problems with relationships
[166].
Poland’s syndrome is characterized by hypoplasia or absence of the breast or nipple,
hypoplasia of subcutaneous tissue, absence of the costosternal portion of the pectoralis
major muscle, absence of the pectoralis minor muscle, and absence of costal cartilages or
ribs 2, 3, and 4 or 3, 4, and 5. The chest wall defect is often associated with a lung
hernia. Clinical manifestations are extremely variable and rarely are all the features
recognized in one individual. Fortunately, it is invariably unilateral, allowing for an
easier reconstruction. Single-stage reconstruction of the chest wall combined with
simultaneous augmentation mammoplasty and transfer of an island pedicle
myocutaneous flap of latissimus dorsi muscle are major improvements over previous
multiple-stage procedures that provide less satisfactory cosmetic results in management
of patients with Poland’s syndrome [167]. The main purpose of surgical correction in
Poland’s syndrome is to improve chest wall symmetry and correct breast hypoplasia.
Creation of an anterior axillary fold and smoothing out the infraclavicular defect greatly
improves the result. Cardiorespiratory function may be impaired, but serious conditions
requiring early operative correction are rare. When present, unilateral costochondral
agenesis involves one to three segments in the mid-anterior chest and sternal depression
to that side. Operative planning in such cases includes a multilayered approach to
provide a solid base for soft tissue reconstruction of the more superficial layers [168].
The presence of accessory breast tissue such as extra nipples (polythelia) and extra
breast (polymastia) is relatively common, with a high incidence of being misdiagnosed in
clinical medicine. Although polythelia is congenital in origin and is identifiable at
childhood, polymastia may not be evident until the influence of sex hormones during
puberty [169]. The common congenital anomalies of the nipple include inversion, clefts,
and supernumerary nipples. Supernumerary nipples are common anomalies, and their
significance is usually limited to cosmetic concerns. However, a high index of suspicion
should be maintained during physical examinations, because any disease process that
involves anatomically normal breasts may affect aberrantly located breasts or nipples as
well. These anomalies may be associated with several systemic disorders, particularly
urinary tract abnormalities [170, 171]. Several different techniques have been developed
and currently are in use for correction of the inverted nipple. The diversity of techniques
indicates the lack of a good, sustainable, and durable solution for this quite widespread
problem. In a new technique, two flaps are inserted beneath the nipple through a small
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39
tunnel. The advantages of this procedure are its simplicity, the creation of a durable
support for the nipple, and the lack of transverse scars in the areola surrounding the
nipple. The follow-up period up to four years demonstrates the validity of this technique
[172]. The tuberous breast classification proposed by Grolleau does not account for a
minor form of the deformity characterized by isolated NAC protrusion with a normal
breast base. The breast is subjected to hormonal influences as early as the prepubertal
period. These influences result in thrusting forces with both horizontal (estrogen) and
vertical (progesterone) vectors, unfortunately not always balanced and harmonious.
Close observation of the anomaly substantiates the basic anatomical defect, namely, the
structural congenital dermal weakness of the NAC already described in all forms of
tuberous breast deformity. This weakness explains the morphological anomaly and
confirms that all types of tuberous breast deformity constitute a spectrum of a single
entity. It indicates also that the tuberous breasts classification should include, in addition
to the three types (types I-III) already described, a fourth type (type 0) to describe
isolated simple areola protrusion, either permanent or intermittent, that is associated with
a normal mammary base (Table 3). The revised classification of tuberous breasts and the
proposed hypothesis of breast development allow better assessment of all possible
variants of breast morphological anomalies. In the cases of isolated herniated NAC, the
deformity is corrected through a perinipple approach (not circumareolar), with adequate
stable correction of the deformity and minimal scarring [173].
Many terms, including duct ectasia, secretory disease, periductal mastitis, and
plasmacell mastitis, have been used about a variety of clinical conditions associated with
nipple discharge, non-puerperal sepsis, and nipple retraction. The confused nomenclature
reflects the uncertainties regarding the singularity or inter-relationships of the main
elements – dilated ducts, periductal inflammation, bacterial infection, and nipple
retraction. Recent clinical studies combined with new histological and bacteriological
information have set the scene for better understanding of the pathogenesis and
management of these clinical conditions [174]. Skin conditions affecting the nipple
include eczema, which, while like eczema occurring elsewhere on the body, poses unique
aspects in terms of diagnosis and treatment. The benign abnormalities that develop
within the nipple include intraductal papilloma and nipple adenoma [175, 176]. Nipple
adenoma can pose a diagnostic problem for both clinicians and pathologists. It can be
confused clinically with nipple Paget’s disease and histologically with carcinoma.
Syringomatous nipple adenoma is often misdiagnosed because clinical examination and
mammographic findings of syringomatous nipple adenoma mimic carcinoma. Most
nipple adenomas are entirely benign, although rare examples have shown malignant
changes. Despite its benign behavior, syringomatous nipple adenoma usually shows
infiltrative expansile proliferation into adjacent tissue and underlying breast tissue. Up
until now, to our knowledge, there has been no reported case of regional or distant
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metastasis. Histologically and clinically, syringomatous nipple adenoma is often
confused with tubular carcinoma as well as low-grade adenosquamous breast carcinoma.
Special attention given to this tumor by pathologists and clinicians can avoid
misdiagnosis and unnecessary treatment. Limited surgical excision is the appropriate
treatment [177, 178].
Table 3. Tuberous breasts classification
(adapted from mybreastaugmentation.info, 2017)
Type I – Underdevelopment (hypoplasia) of the lower medial quadrant.
Type II – Underdevelopment of the lower medial and the lower lateral
quadrants, but with sufficient skin in the region below the areola.
Type III – Underdevelopment of the lower medial and the lower lateral
quadrants, but with a deficiency of skin in the region below the areola
(this is like Type II but with less skin below the areola, and a tight
inframammary fold).
Type IV – Severe breast constriction, with a very minimal breast base.
Papillary secretion is a common symptom in the breast clinic with many different
underlying causes like intraductal papilloma, mammary duct ectasia, infected cysts and
abscesses, breast cancer/ CIS, and rarely pituitary adenoma. The association with
cancer/CIS is one of the two main concerns of the patient and must always be ruled out.
The second item is that spontaneous and ongoing discharge causes embarrassment due to
staining the clothes. Nipple discharge accounts for approximately 5% of visits to a breast
specialist surgical practice and may be encountered as the chief complaint by many other
types of physicians. The clear majority of breast cancers originate in the ductal system,
which prompted interest in the evaluation of the intraductal approach to breast cancer.
Three evolving minimally invasive techniques for the evaluation of high-risk patients
include ductoscopy, nipple aspiration, and ductal lavage. These have emerged as
innovative fields of study that may have clinical applications. Nipple aspiration and
ductal lavage fluid may be assayed for cytology, genomic, gene expression, and
proteomic studies. Several different translational approaches are being undertaken to
investigate the local microenvironment associated with the development and progression
of breast carcinoma. Nipple aspiration fluid and ductal lavage offer the opportunity to
study the local microenvironment of the ductal system, which is where most breast
cancers originate. These powerful approaches to biomarker analysis could be applied to
the prevention and treatment of breast cancer [179]. Nipple discharge disorders is a field
in which there has been both increasing awareness on the part of patients and advances
in management. Today, secretion from nipples can be classified according to its color,
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41
cellularity, and biology. To be significant, a discharge should be true, spontaneous,
persistent, and non-lactational. Moreover, there are methods to differentiate patients who
require surgical intervention from those who do not. Surgically significant nipple
discharges are watery, serous (yellow), serosanguineous, and bloody. Cytology smears of
discharge material have helped to classify the cellular material, providing information
about normality, atypia, and malignancy and about papillary formation of the exfoliated
cells. Tests such as Hemoccult (Beckman Coulter, Inc., Brea, CA, USA) help to discover
occult blood in the secreted fluid. Modern immunological tests can be performed on
cytology smears where occurrence of high levels of carcino-embryonic antigen (CEA)
could indicate a latent malignancy. Galactography investigation is today the state-of-theart approach to investigate patients with nipple discharge disorders and this examination
can demonstrate the size, location, and extent of an intraductal abnormality. Modern
high-resolution ultrasound techniques are helpful in visualizing intraductal disorders and
are becoming a good complementary approach if not an alternative to traditional
radiology techniques. Recently, even MRI galactography has been shown to be of
diagnostic value, but not as informative as regular galactography. The most sophisticated
investigation method, which can also be used therapeutically, is fiber-ductoscopy of the
concerned duct in a breast. This technique, although expensive and in its infancy, is a
fascinating and promising approach for inspecting the intraductal lumina [180].
Traditional treatment is surgical excision of the involved ductal system from which the
discharge emanates. Ductal excision has been the only reliable procedure in establishing
a certain diagnosis and in controlling the bloody discharge. The early success reported
with imaging-guided excision of papilloma and duct endoscopy promises a significant
improvement in our diagnostic accuracy from minimally invasive emerging technology
[181, 182]. Surgery (when undertaken) due to benign discharge should aim for radical
excision of the underlying cause of the discharge, sometimes only a dilated single duct
with or without a papilloma or excision of the central ducts as in case of mammary duct
ectasia. Discharge should be consistent, spontaneous, and disturbing otherwise surgery
should not be recommended in the absence of a suspicion of malignancy (negative triple
test) [183].
The benefits of breast-feeding are well known, and the World Health Organization
(WHO) recommends exclusive breast-feeding for the first six months of life and
continuing breast-feeding to age two. However, many women stop breast-feeding due to
lactational breast abscesses. A breast abscess is a localized accumulation of infected
fluid in breast tissue. Abscesses are commonly treated with antibiotics, incision and
drainage (I&D), or ultrasound-guided needle aspiration, but there is no consensus on the
optimal treatment. There is insufficient evidence to determine whether needle aspiration
is a more effective option to I&D for lactational breast abscesses, or whether an
antibiotic should be routinely added to women undergoing I&D for lactational breast
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abscesses [184, 185]. Periductal mastitis/duct ectasia affects major breast ducts and is
poorly understood. A variety of different terms has been used for this condition and these
probably reflect different stages in one disease process. It appears to be responsible for
1-2% of all symptomatic breast conditions. Although the incidence is higher in postmortem studies, much of what is included as so-called “periductal mastitis” or “duct
ectasia” in these studies is duct dilatation, which occurs as part of normal breast
involution. Periductal mastitis appears to be the primary condition, with duct ectasia
being the outcome. The cause of this periductal mastitis is uncertain, although bacteria,
particularly anaerobic organisms, appear to play some role. Clinically, this condition can
present with non-cyclical mastalgia, nipple discharge, nipple retraction, a subareolar
breast mass with or without overlying breast inflammation, a periareolar abscess, or a
mammillary fistula. Antibiotics against the organisms isolated from this condition are
effective in resolving periareolar inflammation and are useful when combined with
surgery in mammillary fistula [186].
Idiopathic granulomatous mastitis is a rare chronic inflammatory condition of the
breast which predominantly occurs in premenopausal women shortly after their last
childbirth, and which although benign can mimic carcinoma. Its etiology is unclear,
however, the disease has been shown to be correlated with breast-feeding and the use of
oral contraceptives. An autoimmune component has also been discussed. It presents with
the clinical symptoms of galactorrhea, inflammation, breast mass, tumorous indurations,
and ulcerations of the skin. In mammography and sonography, nodular opacities and
hypoechoic nodules are found. Very often, clinical and radiological findings mimic
breast cancer. The diagnosis is made by histopathology. Histological features in
granulomatous mastitis include signs of a chronic granulomatous inflammation with noncaseating granulomas which are of a lobulocentric pattern, giant cells, leucocytes,
epitheloid cells, and macrophages as well as abscesses. Therapy of granulomatous
mastitis consists of complete surgical excision combined with oral steroid therapy,
eventually in combination with anti-inflammatory drugs or colchicine. Use of MTX has
also been successful. In case of formation of abscesses, antibiotic therapy should be
applied before steroid therapy. Immune-suppressive therapy should be performed until
complete remission, as rates of recurrence can be up to 50% [187]. Management of
confirmed cases remains controversial with proponents of initial surgical or medical
therapies – each has its associated problems which can be worse than the original
symptoms of granulomatous mastitis. However, many patients require more than one
modality of treatment to completely resolve granulomatous mastitis lesions and careful
judgment is necessary to ensure optimal type and sequencing of treatments [188].
Tubercular mastitis is a rare clinical entity as mammary gland tissue, like spleen and
skeletal muscle, resists the survival and multiplication of the tubercle bacillus. Breast
tuberculosis can mimic carcinoma, whereas in young patients it can be mistaken for a
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43
pyogenic breast abscess, thus labeled a “great masquerade” in recognition of its
multifaceted presentation. Breast tuberculosis commonly affects women in the
reproductive age group, between 21 and 30 years, and is rare in prepubescent females
and elderly women. FNAC is very useful and it is a promising technique in expert hands.
In tuberculosis-endemic countries, the finding of granuloma on FNAC warrants
empirical treatment for tuberculosis even in the absence of positive acid-fast bacilli and
without culture results [189].
Approximately 25% of all “discrete” breast lesions are fibroadenomas or breast cysts
and they more commonly cause a breast lump than breast cancer. Despite their
frequency, their natural history and relationship to subsequent breast cancer have not
been clearly defined, although palpable breast cysts, but not fibroadenomas, are
associated with some increased risk of breast cancer. The diagnosis of these two entities
is now possible by FNA and excision of these lesions is only indicated in certain
circumstances [190]. Fibroadenomas of the breast are common, accounting for 50% of
all breast biopsies performed. Fibroadenomas are benign tumors which commonly
present in late adolescence and are the most common breast masses in adolescent
women, therefore it is important that health providers understand their assessment and
management. They are classified according to their histology and size. Simple
fibroadenomas are the most common type and usually present as smooth mobile masses
up to 3 cm in diameter. Giant fibroadenomas are more uncommon but typically present
in adolescence. Multiple, giant fibroadenomas are histological and clinical variants of
“juvenile” or “giant” fibroadenomas. These tumors are rare and occur mainly in
adolescent and young adult black females. The individual lesions are well encapsulated
with a histological pattern primarily of the “juvenile” type, although cases of the “adult”
type have been reported. Fibroadenomas associated with other soft-tissue masses should
raise the possibility of an inherited syndrome. Assessment of breast masses in this age
group generally involves clinical assessment through history and physical examination
and, when imaging is needed, ultrasonography. As the incidence of primary breast
malignancy is very low in this age group, CNB is not routinely recommended.
Transformation from fibroadenoma to cancer is rare, regression or resolution is frequent,
supporting conservative approaches to follow-up and management. Large or rapidly
growing tumors, or those associated with suspicious features, warrant surgical excision.
New minimally invasive excision techniques are being introduced which are associated
with high initial success rates. A high incidence of recurrence is noted upon local
excision, although this may decrease as the patient becomes older. Management options
include local excision with reconstruction, reduction mammoplasty, and simple
mastectomy with reconstruction. Whereas the clear majority of fibroadenomas in
teenagers may be monitored with surveillance alone, new minimally invasive techniques
may play an important role in the management of selected patients [191-193].
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Breast fibromatosis is a rare benign tumor that should be included in the differential
diagnosis for breast cancer. It is usually indistinguishable from malignancy on
ultrasound, mammography, physical examination, and on gross evaluation. Distinction is
easily made by histological findings. This benign tumor does not metastasize, but is
locally aggressive and tends to recur postoperatively, which accounts for considerable
morbidity [194, 195]. Most women have fibrocystic changes in their breasts. Patients
with proliferative changes with atypia are at an increased risk of breast cancer. The
management of mastalgia is the challenge most frequently encountered in patients with
fibrocystic changes. Clinically, the types and variants of fibrocystic changes are
sometimes difficult to distinguish. When the diagnosis of fibrocystic changes is unclear,
a histological evaluation biopsy, open surgical biopsy, should be performed [196]. The
prominence of breast fibrocystic change mandates knowledge of pathophysiology,
diagnosis, and treatment on the part of all providing primary care to women [197].
Human breast cystic disease is a common premenopausal benign breast condition.
Apocrine metaplasia of normal breast epithelium is the lesion that allows cysts to
develop. Apocrine metaplasia is a very common finding in the female breast after the age
of 25. It is so common that many people regard it as a normal component of the breast.
This, however, is only really the case in apocrine sweat glands of the axilla and in the
periareolar apocrine glands. The apocrine cell does, however, contribute to many
different breast lesions, some of which are very taxing diagnostically: apocrine variants
of both in-situ and invasive cancer are encountered [198]. Apocrine metaplasia and
breast cysts occur frequently in association with other proliferative changes in breast
epithelium, especially breast epithelial hyperplasia. Clinical follow-up studies of women
with breast cystic disease indicate an increased risk of subsequent development of breast
carcinoma. This risk is enhanced when multiple cysts occur. A positive family history of
breast carcinoma adds to the increased risk that is associated with breast cystic disease.
Biochemical analysis of breast cystic disease fluid shows a unique protein profile. Gross
cystic disease fluid protein 15 (GCDFP-15) in breast cystic disease fluid is also found by
immune-peroxidase staining to be present in approximately 50% of all breast
carcinomas. Enhanced production of GCDFP-15 by breast carcinomas has been shown
experimentally and clinically with the use of androgens [199]. Most evidence on
management of breast cysts was obtained from cohort studies. Family physicians can
manage women presenting with breast lumps if they have skill in breast cyst aspiration.
Most breast cysts can be cured in minutes, thus avoiding unwarranted anxiety and
eliminating unnecessary additional investigations and referrals. Women presenting with
solid lesions should be referred to a surgeon. Breast cyst aspiration is a simple technique
that family physicians can use to either cure breast lumps or define appropriate cases for
referral [200].
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45
Papillary breast lesions encompass a wide spectrum of pathologies ranging from
benign lesions, such as solitary intraductal papilloma, to the uncommon papillary
carcinoma, whose hallmark is the formation of either papillary tufts composed only of
epithelium, or true papillary structures with fibrovascular support and epithelium. The
precise diagnosis has significance because of the variability in treatment modalities.
These lesions have various clinical presentations and diverse radiological features.
Differentiating benign and malignant papillary lesions based on imaging features may
often be difficult. Other benign and malignant pathologies can also mimic papillary
lesions on imaging, and tissue diagnosis is essential. Imaging plays a key role in lesion
identification, assessment of extent, tissue sampling, and follow-up. Surgical excision
has been recommended for all papillary lesions due to an increased incidence of highrisk lesions and neoplasia even with percutaneous, biopsy-proven benign papillomas
[201, 202]. The condition of multiple breast duct papillomas, although relatively
common in adult women, is not a well recognized clinical entity in adolescent females.
The risk of adolescents with this condition developing carcinoma is presently unknown,
although in adulthood it is regarded by some authorities as a precancerous condition
[203]. The assessment and categorization of papillary lesions remains one of the most
challenging areas in breast pathology. Several diagnostic and management issues related
to papillary breast lesions that are frequently encountered in daily practice include:
1) the distinctions among papillomas with atypia (atypical papillomas), papillomas
with DCIS, and papillary DCIS;
2) recent developments in our understanding of encapsulated (“intracystic”)
papillary carcinomas and solid papillary carcinomas; and
3) the impact of CNB on management decisions and specimen evaluation [204].
Obtaining a balance between overtreatment and undertreatment of these lesions is
also challenging. Knowledge of the clinical presentation, histology, immune-profile, and
behavior of papillary breast lesions will assist pathologists with the diagnosis and
optimal management of patients with papillary breast lesions [205]. Interpretation of
breast papillary lesions remains a challenging task because of the wide morphologic
spectrum encountered in the benign, atypical, and malignant subtypes. Data on clinical
significance and outcome of papillary lesions, with superimposed atypia or areas like
DCIS partially replacing the benign elements, are sparse. Furthermore, complete excision
of even a fully developed papillary carcinoma confined to a dilated or cystic duct is
associated with an excellent prognosis, whereas a complex papilloma extending into
multiple branches of a duct may ultimately recur as a carcinoma because of incomplete
excision of microscopic foci. This makes an outcome-based classification difficult. It
would be prudent to completely excise any papillary lesion that has not been entirely
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Ciro Comparetto and Franco Borruto
removed by the initial CNB. The optimal management of localized papillary lesions is
complete excision with a small rim of uninvolved breast tissue without any prior needle
instrumentation when the papillary nature can be determined by imaging. Thus managed,
most of these lesions behave indolently, and outcome is usually excellent [206].
The pathologist evaluating breast biopsy specimens sometimes encounters nonneoplastic alterations of the mammary epithelium that raise the differential diagnosis of
atypia. Because the identification of breast atypical ductal hyperplasia has significant
clinical implications, it is important to correctly recognize its non-neoplastic
morphological mimics. Among physiological alterations of the ductal epithelium, lutealphase changes and secretory changes can sometimes be overinterpreted as atypical.
Treatment-related changes, secondary to chemotherapy and radiation, can pose a major
diagnostic challenge and their misinterpretation as neoplastic carries major clinical
consequences. Familiarity with the morphology of both physiological and treatmentrelated alterations of the mammary epithelium is essential to avoid misdiagnosis [207].
High-risk benign breast lesions can create confusion for both the patient and the clinician
and offer varying degrees of increased risk for the future development of breast cancer.
Chemoprevention may be used to help decrease the risks from some lesions. The
management of high-risk benign breast lesions can be confusing. Clinicians should
assess the risk of future breast cancer and develop a proper screening and prevention
strategy for each individual patient [208].
During the last several years, increased public awareness, advances in breast
imaging, and enhanced screening programs have led to early breast cancer detection and
attention to cancer prevention. The number of imaging-detected biopsies has increased,
and pathologists are expected to provide more information with smaller tissue samples.
These biopsies have resulted in detection of increasing numbers of high-risk proliferative
breast disease and in-situ cancers. Atypical epithelial hyperplasia, LCIS (lobular
neoplasia), radial scar, and DCIS are considered high-risk lesions that predispose toward
the future development of non-invasive or invasive breast cancer. The general hypothesis
is that some forms of breast cancers may arise from established forms of DCIS and
atypical ductal hyperplasia, and possibly from more common forms of ductal
hyperplasia. However, this is an oversimplification of a very complex process given the
fact that most breast cancers appear to arise de novo or from a yet unknown precursor
lesion. Currently, atypical ductal hyperplasia and DCIS are considered as morphological
risk factors and precursor lesions for breast cancer. However, morphological distinction
between these two entities has remained a real issue that continues to lead to
overdiagnosis and overtreatment. Aside from morphological similarities between
atypical ductal hyperplasia and low-grade DCIS, biomarker studies and molecular
genetic testing have shown that morphological overlaps are reflected at the molecular
level and raise questions about the validity of separating these two entities. It is hoped
Benign Breast Diseases
47
that as we better understand the genetic basis of these entities in relation to ultimate
patient outcome, the suggested use of the term “borderline breast disease” can minimize
the number of patients who are subject to overtreatment [209]. Generally, those women
with atypical epithelial hyperplasia, radial scar, or LCIS can be managed conservatively
by close surveillance. The minority of women may consider prophylactic mastectomy.
DCIS can usually be managed by lumpectomy with or without radiation, with some
patients requiring mastectomy due to extensive disease [210]. This progress, however,
has created a challenge for pathologists. In lieu of the fact that these entities are difficult
to diagnose even in tissue sections taken from surgically excised lesions, pathologists are
now expected to diagnose them in small and often fragmented tissue/cellular samples
obtained from imaging-guided biopsies. In addition, some proliferative lesions are
associated with an increased risk of finding neighboring malignancy when diagnosed on
minimally invasive procedures. Therefore, classifying these lesions in small biopsies is
difficult and risky. Some of the most challenging areas in diagnostic pathology includes
the differentiation between atypical ductal hyperplasia and low-grade DCIS, lobular
neoplasia versus solid low-grade DCIS, the correct interpretation of papillary lesions
with atypia, and classifying the spectrum of columnar cell changes. Although these
issues have been recognized for years, consensus criteria and uniform terminology for
the diagnosis of these problematic lesions are far from being achieved [211].
Intraductal proliferative lesions (intraductal hyperplasia, atypical intraductal
hyperplasia, and DCIS) should be classified as “mammary intraepithelial neoplasia
(MIN), ductal type” or as “ductal intraepithelial neoplasia” (DIN). This approach
obviates the current separation of atypical intraductal hyperplasia and low-grade DCIS
into two very drastically distinct categories of cancer and non-cancer without interfering
with appropriate management of the various lesions [212]. Breast atypical epithelial
hyperplasia is considered a benign histological lesion with breast cancer risk. Clinical
signification and management of atypical epithelial hyperplasia remain controversial.
Data from immune-histochemistry (IHC) and molecular studies suggest atypical
epithelial hyperplasia is a precursor of breast cancer. Epidemiological studies
demonstrate low rate of breast cancer in women with atypical epithelial hyperplasia.
Surgical excision is necessary after diagnosis of atypical epithelial hyperplasia, such as
LCIS or atypical ductal hyperplasia, on CNB. Although current recommendations are
evolving to fewer (if not no) excisions for flat epithelial with atypia and classic lobular
neoplasia found on percutaneous biopsy (without radiological indications for excision),
atypical epithelial hyperplasia management steel need prospective evidences, but recent
retrospective data give some clue for less invasive management for some of atypical
epithelial hyperplasia [213]. “Flat epithelial atypia” is the adopted term by the WHO
working group on breast tumor referring to an early neoplastic breast lesion affecting the
terminal duct-lobular units. Pathologists have described this lesion under a variety of
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Ciro Comparetto and Franco Borruto
names, including columnar cell lesions and low-grade clinging CIS. It is usually
encountered on breast biopsies performed for mammographically-identified
microcalcifications. Because of its relatively frequent association with carcinomas, its
recognition in biopsy specimens is important [214]. Flat epithelial atypia is a presumably
neoplastic alteration that is characterized by the replacement of the native luminal
epithelium by ductal cells demonstrating low-grade cytologic atypia. The atypical cells
maintain a “flat” pattern of growth without evidence of architectural atypicality.
Morphologic IHC and molecular investigations support that flat epithelial atypia
represents an early step in the evolution of low-grade ductal carcinomas. It is frequently
seen in association with atypical ductal hyperplasia, low-grade DCIS, invasive tubular
carcinoma, and lobular neoplasia. The risk for subsequent breast carcinoma remains to
be defined, but flat epithelial atypia likely represents a non-obligate precursor with an
extended time course to progression. Certain benign alterations may superficially mimic
its appearance: careful attention to cytological and architectural characteristics can help
one distinguish these unrelated entities from flat epithelial atypia [215, 216]. Breast
columnar cell lesions refer to the morphological spectrum of alterations of the epithelial
lining of variably dilated acini of the terminal duct lobular unit (TDLU), lined by one to
several layers of tightly packed, columnar-shaped epithelial cells, often related to
secretions and calcifications. After decades of varied terminologies, the term of “flat
epithelial atypia” by the WHO consensus group encompasses the part of the spectrum
where columnar cell change or columnar cell hyperplasia acquires low-grade cytological
atypia, merging with atypical ductal hyperplasia and low-grade DCIS. Its association
with low-grade invasive carcinoma and lobular neoplasia, whether by proximity to these
lesions, or by similar molecular expressions, has prompted greater scrutiny into its
clinical significance. Although recent literature attempts to refine the term “flat epithelial
atypia,” the applicability of its morphological criteria in routine diagnostic practice
remains to be seen, and interobserver variability is highly possible. This poses even
greater challenges especially in limited samples of breast tissue, such as in CNB, for
preoperative decision-making [217-219].
Lobular neoplasia broadly defines the spectrum of changes within the lobule, ranging
from atypical lobular hyperplasia to LCIS. This continuum of lesions is associated with
an increased risk for developing subsequent invasive breast cancer, with the magnitude
of that risk corresponding to the degree of proliferative change. The associated risk for
developing invasive breast cancer after a diagnosis of lobular neoplasia is multicentric,
bilateral, and equal in both breasts. Lobular neoplasia itself may transform into invasive
carcinoma, although the frequency of this occurrence is unknown. Thus, lobular
neoplasia is a risk factor for invasive breast cancer and may be a precursor lesion in
unusual circumstances. Although classic forms of lobular neoplasia are predominantly
heralded as a risk marker, the pleomorphic form of LCIS is generally regarded as a more
Benign Breast Diseases
49
aggressive subtype and a possible cancer precursor, and thus is treated in a manner more
like DCS than classic forms of lobular neoplasia. Correct classification of classic lobular
neoplasia and pleomorphic LCIS is critical because of differences in clinical
management, with current treatment strategies focused on risk reduction for patients with
classic lobular neoplasia and eradication of the lesion for those with pleomorphic LCIS
[220]. The management of atypical lobular hyperplasia and LCIS depends on the setting
in which they are encountered. When atypical lobular hyperplasia and LCIS are
diagnosed after breast CNB, wire localization for surgical excision is required for
definitive diagnosis because rates of histological underestimation approach those of
atypical ductal hyperplasia. When diagnosed on surgical biopsy, atypical lobular
hyperplasia and LCIS generally do not require further intervention, even when present at
a surgical margin. However, bilateral breast cancer risk must be considered, especially
when patients have a family history of breast cancer. In selected situations, bilateral
prophylactic mastectomy with or without reconstruction may be considered when
atypical hyperplasia or LCIS is diagnosed. Although this reduces risk for developing
subsequent breast carcinoma by 90%, patients selected for prophylactic mastectomy
represent a small subgroup of lobular neoplasia patients and generally have other risk
factors, such as strong family history or evidence of genetic predisposition [221].
Lobular neoplasia is a relatively uncommon lesion, which is frequently diagnosed in
biopsy specimens taken for other reasons. Although the histological features of this
lesion are well known, its biological significance as a “risk indicator” or “breast cancer
precursor” has been a matter of debate. Recent clinical-pathological and genetic
molecular data on lobular neoplasia have changed the way these lesions are perceived
and, most importantly, managed [222-224]. However, this opportunity comes with the
possibility of overdiagnosis and overtreatment, necessitating risk-based intervention.
Notably, despite the progress in defining the molecular changes associated with
carcinogenesis, alterations identifying the individuals with high-risk lesions that will
progress to invasive carcinoma remain to be identified. Thus, until reproducible clinicalpathological or molecular features predicting an individual’s risk of breast cancer are
found, management strategies must be defined by population-level risks as determined by
models such as the Gail or the International Breast Cancer Intervention Study (IBIS)
models, as well as patient attitudes toward the risks and benefits of interventions.
Progress in this area will ultimately be dependent on the ability to individualize risk
prediction through better definition of the key drivers in the carcinogenic process [225].
Histopathologists are encountering intralobular epithelial proliferations more frequently
in CNB taken from lesions identified in mammographic breast screening programs.
Columnar cell lesions are increasingly being seen in CNB taken for the histological
assessment of mammographically detected microcalcifications. Of the biopsies
performed because of microcalcifications on mammograms, 70-90% are unnecessary.
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Ciro Comparetto and Franco Borruto
Most of the time descriptions of diagnostic criteria are irrelevant and vague. It is
confusing that LCIS is considered a real cancer, as happens frequently, and that
histologically dissimilar ductal carcinomas and benign abnormalities of different origin
are simply considered as “malignant” or “benign” and subsequently reported as such.
The number of needless biopsies can be reduced drastically [226]. The morphological
features of lobular neoplasia are relatively well known, but columnar cell lesions,
particularly forms with atypical features, are less widely recognized. Lobular
intraepithelial neoplasia (LIN) and DIN reflect proliferations of immune-phenotypically
variable, biologically and morphologically diverse cells with a potential, not always
realized, for progression to carcinoma by breaking through the barriers of the
myoepithelial cell layer and basement membrane, ultimately invading the stroma [227].
The biological and clinical significance of these intralobular processes is controversial:
1) as indicators of adjacent malignancy when encountered in CNB;
2) the relative risk (RR) conferred of development of subsequent malignancy; and
3) their precursor behavior.
For this reason, the optimal clinical management of these lesions, particularly when
encountered on CNB, is unclear [228, 229].
Radial scar is a benign, well recognized, radiological and pathological entity.
Histologically, it is characterized by a fibroelastotic core with entrapped ducts and
surrounding radiating ducts and lobules. Post-mortem studies indicate that these lesions
are present commonly in the population, especially in association with benign breast
disease. In recent years, their clinical relevance has assumed more importance with the
introduction of population-based screening programs. The exact pathogenesis of radial
scar is unknown. Accumulating evidence indicates that they are associated with atypia
and/or malignancy and, in addition, may be an independent risk factor for the
development of carcinoma in either breast. In view of the association with atypia and
malignancy, excisional biopsy is justified in radial scar, although it has been argued that
CNB evaluation and surveillance may be appropriate in selected patients [230].
The management of precancerous lesions of the breast has become a considerable
clinical problem in the past 20 years. It is not possible to identify with absolute certainty
which of these lesions will progress to invasive carcinoma, and tailoring the treatment
according to each individual case remains a challenge. There is a dilemma for surgeons,
who must balance the risk of resecting too much and causing unnecessary cosmetic
damage, or resecting too little and leaving an increased risk of recurrence. Further
knowledge in the field of predictive and prognostic factors together with the
development of gene-profiling techniques will, hopefully, provide answers to these
questions. Nearly all possible combinations of surgery, radiotherapy, and medical
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51
treatments (antiestrogens) have been tested in different clinical trials, but the situation is
far from satisfactory. An important contribution can come from oncoplastic surgery,
which is the application of plastic and reconstructive surgical techniques to ensure both
radical excision of the disease and acceptable cosmetic outcomes. Although the
relationship of various breast lesions and cancer risk is complex, and is compounded by
the uniqueness of each patient, numerous clinical investigations have validated the
implications of specific lesions and future risk. While variations in lesion cytology,
histology, and molecular biology present a challenge to the clinician in determining
disease risk and formulating a management strategy for individual patients, research has
yielded several guidelines. These include patient variables, such as age and menopausal
status, as well as information concerning the lesion itself [231-235].
Pseudoangiomatous stromal breast hyperplasia is a benign, proliferative
mesenchymal lesion with possible hormonal etiology. It typically affects women in the
reproductive age group. The exact etiology of pseudoangiomatous stromal hyperplasia is
still controversial, but a neoplastic process of the stromal myofibroblasts, with a
hormonal stimulus in its development and progression, is the favored theory.
Pseudoangiomatous stromal hyperplasia is frequently an incidental histological finding
in breast biopsies performed for other benign or malignant lesions. Rarely, it can present
as a firm, painless breast mass, which has been referred to as nodular or tumorous
pseudoangiomatous stromal hyperplasia. Grossly, tumorous pseudoangiomatous stromal
hyperplasia is a well-circumscribed, firm, and rubbery mass with solid, homogenous, and
gray-white cut surface. On histological examination, it is characterized by the presence
of open slit-like spaces in dense collagenous stroma. The spaces are lined by a
discontinuous layer of flat, spindle-shaped myofibroblasts with bland nuclei. The spindle
cells express PR and are positive for vimentin, actin, and cluster D 34 (CD34). The
clinical, radiological, and cytological findings can resemble those of fibroadenoma. The
most important differential diagnosis on histopathology is angiosarcoma.
Pseudoangiomatous stromal hyperplasia discovered incidentally does not require any
additional specific treatment. Tumorous pseudoangiomatous stromal hyperplasia is
treated by local surgical excision with clear margins and the prognosis is excellent, with
minimal risk of recurrence after adequate surgical excision [236, 237].
Phyllodes tumors is a rare fibroepithelial lesion that accounts for less than 1% of all
breast neoplasms with a very variable, but usually benign, course. Formerly known as
cystosarcoma phyllodes, the designation “phyllodes tumor” with appropriate
qualification regarding malignant potential based on pathological features is now the
agreed-upon term. The most important diagnostic distinction is from fibroadenoma –
phyllodes tumors require complete excision with free margins even when pathological
features suggest benignity because of a proclivity to local recurrence. As CNB cannot
always distinguish the two, assessing radiological-pathological concordance is essential
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Ciro Comparetto and Franco Borruto
to guide appropriate clinical management. With the non-operative management of
fibroadenomas widely adopted, the importance of phyllodes tumors today lies in the need
to differentiate them from other benign breast lesions. All breast lumps should be tripleassessed and the diagnosis of a phyllodes tumor considered in women, particularly over
the age of 35 years, who present with a rapidly growing “benign” breast lump. The main
prognostic factor is the histotype of the phyllodes tumor (benign, borderline, or
malignant). The role of the pathologist in the preoperative diagnosis of breast phyllodes
tumors is critical to appropriate surgical planning. However, reliable differentiation of
phyllodes tumor from cellular fibroadenoma remains difficult. Preoperative diagnostic
accuracy allows correct surgical treatment, avoiding the pitfalls of re-operation because
of inadequate excision, or surgical overtreatment. Specific clinical indices may arouse
diagnostic suspicion but are unreliable for confirmation, as with current imaging modes.
FNAC has a high false-negative rate. Few studies have evaluated the role of CNB, but it
may prove a useful adjunct. Both diagnostic and prognostic information may in future be
gained from application of IHC and other techniques assessing the expression of
proliferative markers including p53, Ki-67, and others. Treatment can be by either wide
excision or mastectomy provided histologically clear specimen margins are ensured.
While the surgical management of these relatively uncommon tumors has been addressed
in the literature, few reports have commented on the surgical approach to tumors greater
than 10 cm in diameter – the giant phyllodes tumor. Management of the giant phyllodes
tumor presents the surgeon with unique challenges. Nodal metastases are rare and routine
ALND is not recommended. Few reliable clinical and histological prognostic factors
have been identified. Local recurrence occurs in approximately 15% of patients and is
more common after incomplete excision. It can usually be controlled by further surgery.
Repeated local recurrence has been reported without the development of distant
metastases or reduced survival. Approximately 20% of patients with malignant phyllodes
tumors develop distant metastases. Long-term survival with distant metastases is rare.
The role of chemotherapy, radiotherapy, and hormonal manipulation in both the adjuvant
and palliative settings remains to be defined. At present, there is no consensus that
patients with high-grade phyllodes tumors of the breast will benefit from either of these
modalities [238-243].
Breast myofibroblastoma is an unusual benign tumor that belongs to the family of
the “benign spindle cell tumors of the mammary stroma.” The name myofibroblastoma
reflects its cellular composition, comprising mainly stromal cells with myofibroblastic
and, less frequently, myoid differentiation. Since the original description, the
morphologic spectrum of myofibroblastoma has been expanded by the recognition of
several unusual morphological variants, such as the cellular, infiltrative, epithelioid,
deciduoid-like,
lipomatous,
collagenized/fibrous,
and
myxoid
variants.
Myofibroblastoma may show alarming morphological features, which can lead to a
Benign Breast Diseases
53
misdiagnosis of malignancy. The incidence of myofibroblastoma diagnosis has increased
in recent years, likely due to the mammographic screening. Accordingly, this unusual
benign tumor may represent a potential diagnostic pitfall, especially when interpreting
FNA and/or CNB. Pathologists should be aware of the wide morphological spectrum
exhibited by myofibroblastoma to avoid a misdiagnosis of malignancy [244]. Fat breast
necrosis is a benign condition that most frequently affects perimenopausal women. It can
mimic breast cancer clinically or radiologically. In other cases, it can obscure malignant
lesions. Fat breast necrosis is a complex process. Therefore, a systematic review of this
condition will enable surgeons, radiologists, and oncologists working in the field of
breast disease to understand it better and improve its management [245]. Hibernoma
arising in the breast is rare and may present as an asymptomatic mass or may be detected
by screening mammography. Four histological types have been identified: typical,
myxoid variant, spindle-cell variant, and the lipoma-like variant. The most common
“typical variant” is composed of pale to eosinophilic multivacuolated cells with
interspersed univacuolar cells. Hibernomas are universally benign and are not known to
recur or have an aggressive behavior, even in incompletely excised lesions. Hence, their
clinical importance lies in distinguishing them from other benign and malignant breast
neoplasms as well as inflammatory conditions that come into the histological or
radiological differential [246].
Sclerosing lymphocytic lobulitis is strongly associated with long standing type 1
diabetes, then it is known as “diabetic mastopathy,” but may occur occasionally in its
absence. This very rare benign condition tends to present in premenopausal women,
often with diabetic complications, particularly retinopathy and neuropathy, but more
research is needed to verify this association. Patients present with clinically suspicious
fibrous breast lumps: these are commonly multiple, bilateral, and recurrent, usually in a
subareolar site, but may appear equally in any part of the breast. Mammograms show
asymmetric densities and no focal mass and ultrasound investigation tends to show illdefined hypoechoic attenuation with strong posterior acoustic shadowing.
Mammographically and morphologically, this lesion simulates cancer. MRI can be used
to further differentiate the lesion from malignancy. However, a CNB or excisional biopsy
is essential so that a pathological diagnosis can be made. The constellation of
pathological findings is: lymphocytic lobulitis and ductitis with glandular atrophy,
lymphocytic/mononuclear perivascular inflammation which is predominantly B-cell, and
dense often keloid-like fibrosis, with or without epithelioid-like fibroblasts. The
etiopathogenesis is unknown and the disorder does not seem to predispose to breast
carcinoma or lymphoma. The lesion may recur after excision in the same site or in
another location of the ipsilateral or the contralateral breast. Awareness of this entity,
establishment of the diagnosis by open biopsy or by CNB may spare the need for
repeated wide excisions and the resulting distortion of the breast architecture [247-249].
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Ciro Comparetto and Franco Borruto
In conclusion, the purpose of breast screening is to identify early cancers with the
aim of reducing mortality from the disease. However, the specificity of mammography is
such that a considerable number of women will require assessment for benign disease,
particularly in the prevalent round. Knowledge of the types of benign breast disease
which are commonly seen in screening, together with careful assessment using the
techniques which have been described, will allow the benign to malignant biopsy rates to
be kept acceptable without missing the very lesions which screening hopes to identify
[250].
Chapter IV
Breast Cancer
Breast cancer, while often lumped together as one disease, represents a diverse group
of malignancies with different imaging findings, histological appearances, and behavior.
While most invasive primary breast cancers are epithelial derived adenocarcinomas, rare
neoplasms may arise from mesenchymal tissue. Breast cancer has become the top
malignant neoplasm in women with an increasing risk of morbidity and mortality. As a
crucial part of comprehensive treatment of breast cancer, breast surgical technique is
ceaselessly ameliorating and enriching its features. With the purpose of achieving
minimal surgical intervention and satisfactory cosmetic results, the trend of mammary
surgery is focusing on minimally invasive treatment and aesthetics in the 21st century
[251-253]. Personalized medicine is emerging as an important guiding principle in
diagnosis and treatment. This means not just doing more for some, but safely doing less
for others. The lessons learned about the biology of breast cancer over the last two
decades have enabled us to understand the incredible heterogeneity of breast cancer and
its associated behavior. Although much work remains, there is an emerging opportunity
to identify and recognize more indolent forms of breast cancer, made more prevalent
through the widespread adoption of screening. With improving systemic therapies and
improved molecular tools, we now have the opportunity to reduce the burden of
treatment in women with lower-risk tumors. Surgical treatments have evolved, with less
morbid and more cosmetic procedures [254]. Although controversy has emerged in
recent years regarding the diagnosis and treatment of this disease, it remains important to
detect and treat breast cancer before it has metastasized [255, 256].
The surgical management of breast cancer has undergone continuous and profound
changes over the last 40 years. The evolution from aggressive and mutilating treatment to
conservative approach has been long, but constant, despite the controversies that
appeared every time a new procedure came to light. Today, the aesthetic satisfaction of
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Ciro Comparetto and Franco Borruto
breast cancer patients coupled with the oncological safety is the goal of the modern
breast surgeon. Breast-conserving surgery with adjuvant radiotherapy is considered the
gold standard approach for patients with early-stage breast cancer and the recent
introduction of “oncoplastic techniques” has furtherly increased the use of breastconserving procedures. Mastectomy remains a valid surgical alternative in selected cases
and is usually associated with immediate reconstructive procedures. New surgical
procedures called “conservative mastectomies” are emerging as techniques that combine
oncological safety and cosmesis by entirely removing the breast parenchyma sparing the
breast skin and NAC. Staging of the axilla has also gradually evolved toward less
aggressive approaches with the adoption of SLNB and new therapeutic strategies are
emerging in patients with a pathological positivity in SLNB [257]. Local treatment of
breast cancer with tumor-free surgical margins is the standard procedure in the treatment
of T1 and small T2 breast cancers. Surgery is followed by radiation therapy, and
adjuvant systemic therapy is offered depending on primary tumor characteristics, such as
tumor size, grade of differentiation, number of involved ALN, the status of ER and PR,
and the expression of the HER-2 receptor. Although this approach implies a higher risk
of ipsilateral breast tumor recurrence, the total risk of recurrence is low (1% per year),
with rates of overall survival similar to that after radical procedures. The most peripheral
part of epithelial tumors, the tumor margin, is the part which is most likely to remain in
loco after surgical resection. Thus, understanding the biology of the invasion front is
important as these tumor cells have been reported to lose epithelial properties, such as
cohesiveness and keratin expression, and to acquire features of mesenchymal cells. The
parallel appearance of tumor cells in different states of cell dedifferentiation implicates a
dynamic equilibrium that is determined by the induction of epithelial-mesenchymal
transition (EMT). EMT has been suggested to be of prime importance for tissue and
vessel invasion. Furthermore, features of EMT are associated with the activity of tumor
stem cells (TSC). TSC exist in breast cancer and their appearance varies depending on
the used marker profile. Consequently, intratumoral heterogeneity is reflected by the
grade of EMT activation. A specific function at the invasion front is hypothesized but
has not yet been proven. Nevertheless, the molecular differentiation between the tumor
center and the invasion front enhances the importance of tumor-free surgical margins
[258-261].
The recent history of operations for breast cancer indicates a growing trend toward
conservatism. The modified radical mastectomy achieves the goal of removing all
evidence of cancer in the breast involved and removes the regional lymph nodes (RLN)
for accurate staging of the disease. In addition, it provides a cosmetic result superior to
that of the standard radical mastectomy. Breast reconstruction may be undertaken later
with excellent result [262]. The surgical management of breast cancer continues to
evolve in an attempt to define the ideal line between therapeutic efficacy and morbidity.
Breast Cancer
57
It is clear that breast cancer is a biologically heterogeneous group of diseases, and no
single hypothesis explains its behavior. The surgical options proposed to the individual
patient must draw from the experience of retrospective clinical studies and prospective
RCT in an attempt to optimize the treatment plan. Most patients without distant disease
are eligible to consider mastectomy, which can accomplish excellent local control and
significantly improve survival for earlier stages of disease. However, breast conservation
remains an appropriate alternative for a carefully defined subset of patients. Today, with
early-stage disease, no patient need leave the operating room without a breast. Recent
advances in reconstructive surgery make mastectomy with immediate reconstruction or
limited resection plus ALND with postoperative radiation therapy the two principal
treatment choices available. Studies focus on the integration of other treatment
modalities. Clinical research into the use of preoperative chemotherapy to downstage the
disease to permit less extensive surgery is of interest. Recent application of molecular
biological techniques such as oncogene analysis, cytogenetic studies, proliferative
indices, and the highly sensitive detection of distant micrometastases using monoclonal
antibodies may assist in the design of innovative approaches to surgery, radiation
therapy, and systemic drug treatment. These advances show great promise for improving
the quality of life and the cure rate for patients with breast cancer. Today, surgical
treatment options have evolved that fulfill some of the objectives outlined by Dr. James
Ewing of Memorial Hospital some 80 years ago. His concerns about breast cancer
remain as relevant today as they were almost a century ago: “I have drawn the
impression that in dealing with mammary cancer, surgery meets with more peculiar
difficulties and uncertainties than with almost any other form of the disease. The
anatomical types are so numerous, the variations in clinical course so wide, the paths of
dissemination so free and diverse, the difficulties of determining the actual conditions so
complex, and the sacrifice of tissues so great, as to render impossible in the majority of
cases a reasonably accurate adjustment of a means to an end” [263].
A very satisfying concept of treatment is not easy to formulate from the complex and
often conflicting results of local therapeutic interventions for breast cancer. It seems
evident that clinically occult cancer is often beyond the pale of both resection and
irradiation at primary treatment, particularly when cancer is found in RLN. Despite all
combinations of local treatment, the ultimate risk of failure correlates more closely with
the stage of the disease at the time of treatment than with the particular form of
treatment. Thus, the extent of disease must be considered the major, perhaps the ultimate
determinant of prognosis. Since, under controlled conditions, several therapeutic
alternatives have appeared to provide virtually identical results in terms of survival and
ultimate dissemination of the disease, the adequacy of control within the field of
treatment, in fact, may be the most meaningful result of local treatment. The experience
that has accumulated with treatment of breast cancer supports the thesis that removal of
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Ciro Comparetto and Franco Borruto
the breast accomplishes all that can be achieved in terms of curing the disease, and wider
treatment with surgery or irradiation serves only to improve the prospects for local
control. Halsted demonstrated this principle with his radical mastectomy and it still
seems to be the case. This fact provides further impetus for detecting and treating cancer
while it is still localized to the breast. With these generalizations in mind, some empirical
observations can be added. An anatomical fact is that multiple microscopic foci of cancer
that are not evident clinically are often present in the mammary parenchyma.
Undisturbed, at least some, and perhaps eventually all, of these foci of cancer progress to
become clinical cancers. Thorough removal of the entire breast (the entire mammary
parenchyma) eliminates this particular hazard and, one may presume, terminates the
disease if it is still limited to the breast. Removal of the underlying pectoralis major
muscle provides additional margin around the tissues primarily involved, but sacrifice of
the muscle is apparently needless unless it is directly invaded by cancer. Microscopic
metastases are also often present in RLN without being clinically detectable and, left
untreated, have the capacity to enlarge and become clinically apparent. Routine wide
removal of RLN improves the control of cancer at these sites when metastases are
present, but whether it improves the chances for cure is doubtful. The fact is that
approximately 25% of patients with ALN metastases enjoy prolonged survival free of
recurrence, some remaining well even after 30 years. Whether they would survive as well
without removal of the metastases is uncertain. Disease-free survival is highest if
metastases are removed while still microscopic, but this phenomenon may simply reflect
treatment at an earlier phase in the evolution of the disease [264, 265]. The clinical
assessment of patients with Stage I and II breast cancer is limited to a history and
physical examination supplemented by a breast radiograph and serum alkaline
phosphatase (ALP) determination. If the serum ALP is abnormal in the presence of
otherwise normal liver function studies, a bone scan, liver scan, and CEA should be
obtained. Areas of increased radioactivity on bone scan are always evaluated by
additional radiographs and tomograms. The majority of focal areas of increased
radioactivity will demonstrate radiographic evidence of benign bone lesions,
predominantly degenerative joint disease. Only those focal areas of increased
radioactivity that are normal on X-ray film or show radiographic evidence of metastases
are considered to be positive for metastatic disease. The results of the liver scan are
correlated with the level of CEA. Focal areas of decreased radioactivity associated with a
CEA greater than 5 nanograms/milliliter (ng/ml) are considered to be metastases. In the
absence of elevation of the CEA, focal areas of increased radioactivity should be
biopsied prior to any further considerations as to definitive therapy. In the absence of
positive clinical findings or elevation of the ALP, routine scintigraphy of the skeletal
system and liver is not indicated. Patients with Stage III disease have a much greater
chance of having clinically occult metastases of sufficient size to be detected by chest X-
Breast Cancer
59
ray film, serum ALP, and bone scan. In contrast, routine scintigraphy of the skeletal
system and liver is indicated in patients with Stage III disease, even in the absence of
clinical evidence of systemic metastasis. If the serum ALP is abnormal, a liver scan and
CEA are obtained in an effort to detect liver metastases. The same sequence of events is
then followed as suggested for patients with Stages I and II disease. Several new
techniques of detecting occult metastases are being evaluated. Biomarkers are the subject
of several studies. The use of computed tomography (CT) is also being utilized as a
means of detecting lung, liver, and mediastinal metastases. The results of clinical trials
should be carefully followed [266, 267].
CIS of the breast is divided into DCIS and LCIS. These two entities have different
morphological appearances and natural histories. The traditional treatment of DCIS has
been mastectomy, which has been shown to yield a very high cure rate. Other options
include excision with or without radiotherapy. Preliminary evidence suggests that these
techniques can be successful in the great majority of patients, with most treatment
failures being manageable by salvage mastectomy. Careful observation of these patients
appears associated with a low risk of breast cancer mortality and is generally the
recommended policy [268]. Both DCIS and LCIS are forerunners of invasive breast
cancer but with different behavior. Neither condition is fatal but management can be
difficult. After 20 years follow-up of LCIS, the cumulative risk of ipsilateral invasive
cancer is 18%, and 14% for contralateral disease. Of the cancers that occur, 40% are
invasive lobular and 60% invasive ductal. Standard management of LCIS is surveillance,
with no attempt to perform a wide excision or a mastectomy. Many cases of DCIS are
detected because of microcalcification on mammograms: 20% of screen-detected cancers
are of this type. DCIS is a forerunner of ipsilateral invasive disease, so complete excision
is necessary. Subsequent relapse or progression to invasive disease can be reduced by
breast irradiation. Because of the extent of DCIS, a significant proportion of patients will
need a total mastectomy with or without immediate reconstruction [269-271]. The
clinical expression of in-situ cancer varies widely but is usually occult. Diagnosis can be
made by a variety of minimally invasive techniques. Treatment of LCIS is patientdirected but generally requires only close follow-up. Mastectomy is the gold standard for
DCIS and is associated with low recurrence rates. Breast conservation therapy has
become an acceptable alternative. This choice of definitive therapy for DCIS depends
largely on the ability to obtain negative margins. Any attempt at breast conservation
therapy should be coupled with the caveat of close postoperative long-term follow-up.
Patients diagnosed with LCIS or who have a history of DCIS should be given the options
for the use of TMX for the reduction of subsequent development of invasive breast
cancer. Risk versus benefits should be clearly defined [272].
DCIS is an early localized stage of mammary malignancy that has an especially
favorable prognosis with appropriate management. It seems to be a direct precursor to
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Ciro Comparetto and Franco Borruto
invasive carcinoma of the breast and has the same therapeutic options. There are still
many outstanding issues to be resolved before the intriguing potential of this disease can
be fully realized [273]. DCIS is increasing in frequency, primarily because of the
increasing use of routine screening mammography. The management of DCIS has
become one of the more controversial aspects in the treatment of breast cancer. Although
total mastectomy provides local control and long-term survival approaching 100%, the
move to breast conservation with early invasive breast cancer has forced a re-evaluation
of the treatment of in-situ breast cancer. Recent advances in the evaluation and
subclassification of DCIS according to histological subgroupings and sizings have
provided valuable insight into the biology of the disease. These biological parameters
may help to identify those lesions amenable to breast conservation. In properly selected
patients, breast conservation affords a 1%/year local failure rate, with approximately
one-half of the recurrences being invasive [274, 275].
DCIS of the breast represents a disease process that continues to increase in
incidence with treatment paradigms that continue to evolve. Greater access to long-term
data from large observational studies addressing the natural history of the disease has
contributed to changes in treatment paradigms and put into question traditional
management strategies. While recent analyses have suggested that a more conservative
approach to the management of DCIS without surgical intervention or radiation therapy
may be advisable based on breast cancer mortality data, there is a lack of level 1 or
prospective evidence to support the widespread adoption of these approaches. Currently,
surgery remains the standard of care for the initial treatment of DCIS. Adjuvant radiation
therapy has consistently demonstrated a reduction in the risk of local recurrence
following breast-conserving surgery, even in “low-risk” populations of patients. Invasive
recurrences following breast-conserving surgery are associated with increases in breast
cancer mortality. Surgery and radiotherapy remain standard of care treatment options in
the management of DCIS. Future studies are required to identify cohorts of patients in
which radiotherapy can be safely omitted as well as to evaluate whether short-course
radiotherapy alone may represent a better option than endocrine therapy with respect to
compliance, toxic effects, cost, and local control following breast-conserving surgery
[276]. DCIS accounts for approximately 20% of mammographically diagnosed breast
cancers. Currently, there is a trend to consider DCIS as a lesion for which treatment deescalation is advocated to avoid overtreatment, that is, radiotherapy in addition to breastconserving surgery or even surgery at all. The long-term follow-up updates of the firstgeneration RCT comparing lumpectomy with and without radiation therapy have
confirmed that radiation halves the local failure rates. However, radiotherapy is not
associated with a survival benefit just as affirmed by the recently published evaluation of
the Surveillance, Epidemiology, and End Results (SEER) registries database.
Nevertheless, the risk of dying of breast cancer increases about factor 18 after experience
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61
of an invasive local recurrence. That means at least some DCIS have the potential to
progress to a life-threatening disease. At the same time, none of the recently updated
prospective trials that tested the outcome after excision alone in low-risk DCIS achieved
a ten-year local failure rate below 10%. DCIS is not a uniform disease. Its clinical
behavior is heterogeneous, but up to date no criteria are available that allow a precise
identification of patients with low or very low progression risk who do not need
irradiation. Therefore, excision followed by radiotherapy is still the standard of care in
patients undergoing breast conservation. Promising new approaches for risk estimation
have to be validated prospectively before their use in daily practice can be recommended
[277, 278].
LCIS of the breast is a well-defined pathological entity that is found in about 2.5% of
all specimens of the breast taken for biopsy and most commonly occurs in
premenopausal females. Its diagnosis is virtually always incidental due to the absence of
any clinical indication of its presence. This lesion carries a significant risk for
development of subsequent invasive carcinoma which applies equally to both breasts and
which appears to increase with time. The appropriate treatment of this disease remains a
controversial issue. There is certainly a perception that LCIS represents the early form of
a malignant process that can be cured or prevented if appropriately treated at this stage.
At the very least, an understanding of this lesion holds the potential for broadening our
understanding of the physiological basis of carcinoma of the breast as a whole [279].
Although recorded studies emphasize that patients with LCIS are “at risk” for the
development of invasive cancer, it has not been unequivocally demonstrated whether
such an event represents a persistence of cancer due to inadequate excision or a de novo
lesion. In support of the latter is the contention that lobular carcinoma exhibits a
propensity for multicentricity and bilaterality. The recognition that the histological types
of the subsequent invasive cancers are not universally lobular invasive might also be
cited in this regard. This information also bears upon views purporting a stepwise
development of lobular invasive carcinoma from its in-situ analogue. Analysis fails to
confirm any significant association between invasive lobular carcinoma and multicentric
lesions. The diagnostic difficulty in distinguishing lobular hyperplasia from LCIS and
the inadvisability of frozen sections for this purpose is noted. Although the results of
some electron microscopic studies of the in-situ lesion challenge the propriety of its
“pure in-situ” nature, this criticism does not appear valid from both a pathological as
well as pragmatic standpoints. Various schemes have been proposed concerning the
surgical management of patients with LCIS. Certain biological principles prompt
consideration of segmental mastectomy and ALN sampling as an alternative,
commodious form of treatment for such lesions. There does not appear to be any unique
reason to invoke any different treatment regimen for lobular invasive carcinoma than has
been utilized for other invasive breast cancers [280, 281].
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LCIS of the breast is commonly identified as an incidental finding in breast biopsies
performed because of either a mammographic abnormality or a palpable mass. Although
long recognized as an entity, the significance and optimal treatment of LCIS remains
controversial. Initially regarded as a preinvasive form of breast cancer analogous to
DCIS, LCIS was treated by mastectomy. As evidence mounted for an equal risk of
invasive carcinoma in both breasts, bilateral mastectomy was advocated by some. More
recent studies suggest that LCIS is a marker for increased risk rather than a true
precursor of invasive carcinoma, and this allows a more conservative approach [282].
The incidence of LCIS and invasive lobular carcinoma of the breast is increasing. Recent
data suggest that LCIS is an indolent precursor for breast cancer, rather than a pure risk
factor. This could imply free surgical margins become important. The risk of
contralateral carcinoma and of multifocality of invasive lobular carcinoma is higher than
for invasive ductal carcinoma. Therefore, the need for mastectomy, or even for
preventative contralateral mastectomy is questioned. Conventional mammography or
ultrasonography cannot always give useful preoperative information about the extent of
lobular cancers. The value of dynamic contrast-enhanced MRI needs to be established
for these patients. The risk of invasive carcinoma after LCIS is increased. Invasive
carcinoma is usually located at the index point of LCIS and is of lobular histology.
Dynamic contrast-enhanced MRI can be useful in the detection and preoperative staging
of invasive lobular carcinoma. The risk of local recurrence is high in patients with
invasive lobular carcinoma. Mastectomy and breast reconstruction could be an option in
selected patients. The response to preoperative chemotherapy is worse for invasive
lobular carcinoma compared with invasive ductal carcinoma, with a greater need for
rescue mastectomy. LCIS and invasive lobular carcinoma are different entities from
DCIS and invasive lobular carcinoma. Their biological profile should be studied further
in order to make the fine tuning of treatment possible [283-285].
We can draw the following conclusions about minimal breast cancer: the concept of
minimal breast cancer as a stage of cancer that is 95% curable is a valid one, if minimal
breast cancer is defined by strict parameters. Both 0.5 and 1.0 cm have been defined as
the upper limit of size for minimal invasive cancer. Some data indicate that 0.5 cm is the
preferable dividing line and that 1-cm cancers are no longer minimal. Other data suggest
that the most important factor is ALN status. One-centimeter cancers are probably 95%
curable if ALN are negative. Cancers of 0.5 cm and smaller in size are probably not 95%
curable if ALN are involved. CIS appears to be curable, even if ALN are involved.
Minimal breast cancer should include LCIS (lobular neoplasia) and DCIS regardless of
nodal status, and (tentatively) invasive carcinoma smaller than 1 cm in total diameter, if
ALN are not involved. Many cases of minimal breast cancer are asymptomatic. If special
screening is not used, less than 10% of women with breast cancer will be at the minimal
stage when diagnosed. Screening programs can increase this ratio to as much as one third
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of patients, perhaps even more. While serious questions about cost-effectiveness of mass
screening remain, screening programs appear to represent the best way of detecting
minimal breast cancer. Screening programs should include careful history and physical
examination, of course. It is probable that at least 50% of all minimal cancers would be
missed without mammography. After a period of significant worry about the risk of
radiation, opinion seems to be changing now and many authors are willing to accept the
fact that mammography is of more benefit than risk for younger women. The Health
Insurance Plan (HIP) study indicated that the risk/benefit ratio becomes favorable at age
50. Many authorities would now comfortably include mammography in the screening of
women age 40 or older. Some authors believe that the benefits of mammography
outweight the risks for patients of all ages. The legitimate worry over the risks of
mammography should not obscure a very important fact [286].
The increasingly widespread implementation of breast screening programs,
combined with the use of advanced imaging modalities, such as MRI, will further
increase the numbers of patients diagnosed with this disease. The current standard
management for non-palpable breast cancer is localized surgical excision combined with
axillary staging, using SLNB in the clinically and radiologically normal axilla. Wireguided localization (WGL) during mammography is a method that was developed over
40 years ago to enable lesion localization preoperatively: this technique became the
standard of care in the absence of a better alternative. Over the past 20 years, however,
other technologies have been developed as alternatives to WGL in order to overcome the
technical and outcome-related limitations of this technique [287, 288]. Current
recommendations for surgical management of early-stage breast cancer include breastconserving surgery with postoperative irradiation. However, studies show that
mastectomy is still being used by women with early-stage breast cancer. The following
patient characteristics affect the surgical decision-making process in early-stage breast
cancer: age, socio-economical factors, geographic area in which the patient lives,
proximity to a radiation therapy center, testing for breast cancer susceptibility gene
(BRCA), breast imaging, and decision aids. Of increasing importance in the decision
making about treatment of women with early-stage breast cancer are the woman’s
perception of having a surgical choice and the influence of that choice on postoperative
quality of life [289].
Adoption of urbanized lifestyles together with changes in reproductive behavior
might partly underlie the continued rise in worldwide incidence of breast cancer.
Widespread mammographic screening and effective systemic therapies have led to a
stage shift at presentation and mortality reductions in the past two decades. Locoregional control of the disease seems to affect long-term survival, and attention to
surgical margins together with improved radiotherapy techniques could further
contribute to mortality gains. Developments in oncoplastic surgery and partial breast
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reconstruction have improved cosmetic outcomes after breast-conservation surgery.
Optimum approaches for delivering chest-wall radiotherapy in the context of immediate
breast reconstruction present special challenges. Accurate methods for intraoperative
assessment of SLN remain a clinical priority. Clinical trials are investigating
combinatorial therapies that use novel agents targeting growth factor receptors, signal
transduction pathways, and tumor angiogenesis. Gene-expression profiling offers the
potential to provide accurate prognostic and predictive information, with selection of
best possible therapy for individuals and avoidance of overtreatment and undertreatment
of patients with conventional chemotherapy. Short-term presurgical studies in the
neoadjuvant setting allow monitoring of proliferative indices, and changes in geneexpression patterns can be predictive of response to therapies and long-term outcome
[290-292].
The therapy of early breast cancer has been changing during the last decennia. It
requires a multidisciplinary approach and in each of these disciplines, improvements
have been implemented. The result is that treatment schedules can now be adapted to
specific subgroups. Early breast cancer is defined as operable disease, using the criteria
set out by Haagensen. The new developments in prognostic criteria form the basis for
creating subgroups for specific treatment schedules. Data on screening promises a
beneficial effect of the implementation of screening in national health care programs.
Important shifts are seen in treatment schedules: the place of postoperative radiotherapy
after classic ablative treatment is being challenged, whereas it plays a major role in the
new breast conserving therapy schedules. The data suggest that a large proportion of
“operable” cases can be treated with breast conservation. They form a major part of the
prospective studies in breast cancer. Improvements in reconstruction techniques, creating
better cosmetic results, make reconstruction more competitive with breast-conserving
therapy. The use of chemotherapy and endocrine manipulation in early breast cancer has
now been clearly confirmed by the overview technique by the Peto group, thanks to all
efforts of individual trialists together [293]. As understanding of the natural history of
breast cancer has increased, radical mastectomy has given way to a preference for breastsparing surgery and greater reliance on radiation therapy and chemotherapy. Probably,
the most important factor for selection of treatment is consultation with a
multidisciplinary team skilled in the various procedures and techniques that might be
efficacious. The key to successful management is selection of an appropriate course of
treatment with which the patient feels comfortable [294].
Occult breast cancer presenting with ALN metastases is an unusual presentation and
can be a diagnostic and therapeutic challenge. A comprehensive work-up, including
high-quality mammography is required to decrease the false-negative rates. A number of
other imaging methods have been proposed in the diagnostic evaluation of these women,
including breast ultrasonography, color Doppler ultrasonography, breast MRI, positron
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65
emission tomography (PET), and scinti-mammography. Among them, MRI may be
particularly helpful, since it has a high sensitivity and may enable preoperative
localization of the primary, thus allowing the surgeon to perform a breast-conserving
procedure. Even pathological examination of the mastectomy specimen may not disclose
the primary tumor in up to one third of patients. Treatment options include surgery,
radiotherapy, and watchful waiting (followed by mastectomy when a breast tumor is
detected). Traditionally, occult breast cancer is treated with total mastectomy and
ALND, but accumulating data suggest that primary breast irradiation following ALND
may provide an equivalent survival with the advantage of breast conservation. Occult
breast cancer patients are eligible for adjuvant chemotherapy and radiation as stage II/III
node-positive patients would be treated. Overall, the prognosis for occult breast cancer is
equivalent to or slightly better than staged counterparts with detectable primary breast
tumors [295, 296].
Breast preservation has focused attention on the extent and distribution of cancer in
the breast. Recent studies suggest that there is spread from the primary tumor rather than
a random distribution of cancer throughout the breast. As a result, the term multicentric
has largely been replaced by multifocal. Evidence that there is a geographic relationship
of secondary deposits to the primary lesions opens the way to wide excision as definitive
treatment for selected patients with both invasive and in-situ breast cancer [297]. Interest
in the presence and management of synchronous multiple ipsilateral breast cancer has
been reported since the early 1920s. The demonstration of multiple foci of breast cancer
has been reported in 9-75% of breast cancer related specimens. The large difference in
reported incidence is multifactorial and related to the definitions applied, mode of
detection, and pathological assessment. However, RCT comparing total mastectomy and
segmental mastectomy with or without radiation over many years have shown no
difference in distant disease-free survival or overall survival in patients with
synchronous multiple ipsilateral breast cancer compared with unifocal breast cancer
[298, 299].
Conventional indications for mastectomy reflect circumstances where breastconserving therapy could compromise oncological or cosmetic outcome. Mastectomy
continues to be recommended for the majority of women with multiple lesions within the
same breast. Published studies have reported divergent results regarding the oncological
adequacy of breast-conserving therapy in the management of multifocal or multicentric
disease. Earlier studies demonstrated high rates of local recurrence for breast-conserving
therapy. More recent series have found breast-conserving therapy to be comparable to
mastectomy in terms of local recurrence, distant failure, and disease-free and overall
survival. Few studies have adequately evaluated cosmetic outcomes following breastconserving therapy for multifocal or multicentric breast cancer. Contemporary
oncoplastic techniques have extended the clinical utility of breast-conserving therapy and
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are of particular relevance to breast conservation in the context of multifocal or
multicentric lesions. Appropriate case selection, preoperative oncological and aesthetic
planning, satisfactory clearance of the surgical margins, and adjuvant radiotherapy are of
paramount importance. In the absence of level 1 guidance concerning the management of
women with multifocal or multicentric disease, each case requires discussion with regard
to tumor- and patient-related factors in the context of the multidisciplinary team. In
selected patients with multifocal or multicentric disease, breast-conserving therapy is
oncologically safe and cosmetically acceptable [300-302]. The critical question is
whether multicentricity makes a difference clinically and especially to women who do
not have their entire breast removed. Radical mastectomy results in a severe cosmetic
and functional problem for patients. According to many authors, the goal of the treatment
should be the removal of breast cancer by conservative surgical techniques (lumpectomy,
subcutaneous mastectomy, and quadrantectomy), using adjuvant radiotherapy and/or
chemotherapy. The use of radiotherapy as primary treatment of early breast cancer has
been also suggested. There is disagreement about surgical management of breast cancer.
In fact, some investigators emphasize that the natural biological history of multicentric
cancers has not been documented by any adequate follow-up series in women who do not
have their entire breast removed. Thus far, no difference has been seen in disease-free or
overall survival between groups of patients with early breast cancer treated by an
alternative therapeutic procedure and patients treated by radical mastectomy [303].
An increasingly large proportion of women with unilateral breast cancer are treated
with bilateral mastectomy. The rationale behind bilateral surgery is to prevent a second
primary breast cancer and thereby to avoid the resultant therapy and eliminate the risk of
death from contralateral breast cancer. Bilateral mastectomy has been proposed to
benefit women at high risk of contralateral cancer, such as carriers of BRCA1 and
BRCA2 mutations, but for women without such mutations, the decision to remove the
contralateral breast is controversial. It is important to evaluate the risk of contralateral
breast cancer on an individual basis, and to tailor surgical treatment accordingly. On
average, the annual risk of contralateral breast cancer is approximately 0.5%, but
increases to 3% in carriers of a BRCA1 or BRCA2 mutation. Risk factors for
contralateral breast cancer include a young age at first diagnosis of breast cancer and a
family history of breast cancer. Contralateral mastectomy has not been proven to reduce
mortality from breast cancer, but the benefit of such surgery is not expected to become
apparent until the second decade after treatment. An alternative to contralateral
mastectomy is adjuvant hormonal therapy (such as TMX), but the extent of risk
reduction is smaller (approximately 50%) compared to 95% or more for contralateral
mastectomy. Bilateral mastectomy might reduce mortality in patients with unilateral
breast cancer [304]. Bilateral breast cancer has a cumulative incidence of 7-20% in
patients with primary operable breast cancer, and the majority of these lesions are
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metachronous. A consensus on the management of the contralateral breast has been
elusive. Much of the confusion arises from the fact that there exist marked differences of
opinion regarding the impact of a second primary breast cancer on the overall prognosis.
The risk of developing a contralateral breast cancer is influenced by the age of the
patient, the presence of in-situ disease, lobular histology of this new lesion,
multicentricity, exposure to certain types of ionizing irradiation, and, possibly, family
history of breast cancer. Management options include observation (clinical and
mammographic surveillance), contralateral biopsy, and, rarely, prophylactic mastectomy.
It is hoped that trials of breast cancer prevention, employing drugs such as TMX, will
identify agents capable of abrogating the risk of contralateral breast cancer and improve
the ultimate outcome [305].
The true incidence of bilateral breast cancer, both simultaneous and subsequent, is
higher than older statistics indicate, and the frequency can be expected to increase as
more efficient methods of detection and treatment become commonplace. Furthermore,
there is a subgroup of patients who have an especially high risk for having a second
primary cancer in the other breast: if such a cancer develops, it deleteriously influences
the survival of the patient. A rational approach to the management of the other breast
uses contralateral biopsy as an added modality for detection and reserves prophylatic
mastectomy of the other breast for those patients who are at high risk for developing
cancer in it [306]. Despite extensive publications reviewing contralateral breast cancer,
the role of screening and preventative measures for contralateral tumors is controversial
and optimal clinical management remains undefined. Retrospective studies suggest that
contralateral mammographic surveillance results in the early detection of breast cancer,
but no clear survival benefit has been demonstrated. Trials of adjuvant TMX in breast
cancer patients have shown a reduction in the incidence of contralateral breast cancer in
both pre- and post-menopausal women. In addition, breast cancer patients treated with
ovarian ablation and prednisone have significantly reduced contralateral breast cancer
versus controls. In patients with primary breast cancer, there is no evidence that
contralateral breast biopsies or contralateral prophylactic mastectomy reduce mortality.
Based on the published literature, contralateral breast surveillance in breast cancer
patients reasonably includes breast self-examination, regular physical examinations, and
annual mammography. In women who have no evidence of distant metastasis at the time
of contralateral breast cancer diagnosis, it is recommended that the contralateral breast
cancer be treated in the same manner as a first breast cancer, taking into account prior
local and systemic therapy [307].
Locally advanced breast cancer represents the most advanced stage breast cancer that
is still potentially curable with surgery, radiation, and systemic therapy. There is no one
encompassing definition for this disease, but in general cancers of the breast are
considered to be locally advanced if they are large and/or have infiltrated into adjacent
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tissues (the overlying skin or underlying muscles) and/or are found to have extensive
loco-RNL involvement. It is not surprising, therefore, that locally advanced breast cancer
can cause significant morbidity and mortality. Recent advances in our understanding of
the biology of breast cancer have made it clear that locally advanced breast cancer does
not represent a single clinical entity but rather a heterogeneous group of breast tumors
that share a common theme of extensive loco-regional spread without overt evidence of
distant metastatic disease. Despite advances in breast cancer screening and treatment,
locally advanced breast cancer remains a significant global healthcare issue [308]. In
locally advanced breast cancer, treatment typically includes neoadjuvant chemotherapy,
surgery, and radiation therapy. Neoadjuvant chemotherapy allows in vivo assessment of
primary tumor response to chemotherapy and is achieved the early control of
micrometastatic disease. It also significantly improves surgical outcomes. Patients
achieving pathological complete response after neoadjuvant chemotherapy have a better
survival. Tumor downsizing can make breast-conserving therapy by allowing for smaller
resections and improving cosmesis. Tumor downstaging with chemotherapy can allow
breast-conserving surgery in patients who are initially candidate for mastectomy. SLNB
is an appropriate alternative to routine staging ALND for early-stage breast cancer
patients with clinically negative ALN. During the last years, there have been a number of
clinical studies on effectiveness and role of SLNB in patients receiving neoadjuvant
chemotherapy. The use of SLNB is an alternative approach to ALND in patients with
neoadjuvant therapy [309]. By judicious selection of patients and operative procedures,
the surgeon has an opportunity to improve the quality of life and to enhance disease-free
survival in specific patient subgroups, despite the fact that the local breast cancer may be
advanced and untreated [310, 311].
Although relative survival for breast cancer has improved in recent years, patients
who present with metastatic disease have a less than 30% five-year survival. Thus,
improvements in treatment for these patients have the potential to have a significant
impact on outcomes. Historically, removal of the primary breast tumor has been offered
to these patients only for palliation. However, there have been recent reports that
removal of the primary tumor may improve survival. Although the definitive role of
removal of the primary tumor in metastatic breast cancer is not settled, it is critical to
understand the complexities of this debate in order to make further gains in breast cancer
survivorship [312]. The intact primary in patients diagnosed with Stage IV breast cancer
is generally reserved for palliative indications. Haagensen and Stout’s 1943 criteria of
inoperability for breast cancer, including tumor fixation to the chest wall, ulceration, and
peau d’orange, hold true. Surgery alone is unlikely to prolong life in such patients.
Improvements in breast cancer screening and awareness mean fewer patients having
inoperable breast cancer. The current problem is that imagining studies reveal some
patients to have oligometastatic disease with an intact primary. Several challenges to
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previous dogma to never operate on Stage IV breast cancer patients except with
palliative intent have arisen [313-318]. Chest wall involvement by breast cancer remains
a difficult clinical challenge that may occur at the time of the primary diagnosis or later
as a result of loco-regional breast cancer recurrence. A case-by-case multidisciplinary
approach is strongly recommended, and a multimodality therapy should be always
considered. Full-thickness resection of the chest wall can be done with acceptable
morbidity and mortality, providing a good palliation and a better quality of life even to
patients with poor prognosis. Moreover, in well-selected cases, chest wall resection
results in loco-regional control of disease and prolongation of life [319, 320].
Inflammatory breast cancer is the most aggressive breast neoplasm and one of the
most ominous solid tumors, characterized by involvement of the skin and rapid
progression of the disease. Because of distinct clinical characteristics, diagnosis can
usually be made on clinical grounds. Biopsy including the overlying skin may
demonstrate dermal lymphatic invasion, although the absence of dermal lymphatic
invasions should not deter aggressive therapy. Surgery or irradiation alone has little
effect on the natural history of this disease, since lymphatic invasion and distant
metastases are often present at presentation. Inflammatory breast cancer should be
considered a systemic disease [321]. Management involves careful coordination of
multidisciplinary modalities, including imaging, systemic chemotherapy, surgery, and
radiation therapy. The use of neoadjuvant chemotherapy has contributed significantly to
improvement in overall survival since the first descriptions of this entity, and has made
the role of loco-regional therapy, including surgery and radiation, critical to continued
improvements in this disease [322]. Of all malignancies in women, perhaps none is as
lethal or as frustrating to the surgeon as inflammatory breast cancer. No significant
progress in curing or controlling inflammatory breast cancer was made until the last
decades, when investigators, noting the futility of local therapies, applied systemic
therapies with some significant improvement in survival [323]. Significant advances in
imaging, including digital mammography, high-resolution ultrasonography with Doppler
capabilities, MRI, and PET-CT, have improved the diagnosis and staging of
inflammatory breast cancer. There are currently no established molecular criteria for
distinguishing inflammatory breast cancer from non-inflammatory breast cancer. Such
criteria would be helpful for the diagnosis and development of novel targeted therapies.
Combinations of neoadjuvant systemic chemotherapy, surgery, and radiation therapy
have led to an improved prognosis: however, the overall five-year survival rate for
patients with inflammatory breast cancer remains very low (∼30%). SLNB and skinsparing mastectomy are not recommended. Optimal management of inflammatory breast
cancer requires close coordination among medical, surgical, and radiation oncologists, as
well as radiologists and pathologists. There is a need to identify molecular changes that
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define the pathogenesis of inflammatory breast cancer to enable eradication of it with the
use of specific targeted therapies [324, 325].
Solid papillary carcinomas are tumors morphologically characterized by round, welldefined nodules composed of low-grade ductal cells separated by fibrovascular cores.
These tumors are rare and affect predominantly older women. Although they are
considered CIS, debate and uncertainty still exist regarding their true nature, because
IHC for myoepithelial cells has shown absence of myoepithelial cell layer along the
epithelial-stromal interface of the tumor in many cases. Clinically, these tumors present
as a palpable, centrally located mass or as bloody nipple discharge. Pathologically, solid
papillary carcinomas exhibit low-grade features, and often the tumors display
neuroendocrine and mucinous differentiation. In the majority of cases an associated
invasive carcinoma is present, with colloid and neuroendocrine carcinomas being the
most common. The pathological differential diagnosis is broad and ranges from benign
to malignant lesions. The treatment for solid papillary carcinomas is surgical excision.
When invasive carcinoma is not present, the prognosis is excellent [326]. Any papillary
growth of the breast presents both a diagnostic and a therapeutic challenge: For each one
of them a diagnosis of whether they are malignant or benign in nature is required as well
as appropriate staging and suitable treatment. In the international literature, we find a
considerable amount of different terms being used for papillary breast growths. As a
result, pathological and clinical evaluation is somewhat problematic. Encapsulated
papillary carcinoma is an interesting subgroup of breast papillary tumors. Because of its
rarity, there have been only a limited number of large clinical studies that safely assess
its appropriate treatment and expected outcome. However, more safe data exist in terms
of prognosis – which seems to be excellent, as almost all published studies regarding
these tumors have confirmed so far [327].
Paget’s disease, described by Sir James Paget in 1874, is classified as mammary and
extramammary. The mammary type is rare and often associated with intraductal cancer
(93-100% of cases). It is more prevalent in postmenopausal women and it appears as an
eczematoid, erythematous, moist, or crusted lesion, with or without fine scaling,
infiltration, and inversion of the nipple. It must be distinguished from erosive
adenomatosis of the nipple, cutaneous extension of breast carcinoma, psoriasis, atopic
dermatitis, contact dermatitis, chronic eczema, lactiferous ducts ectasia, Bowen’s
disease, basal cell carcinoma, melanoma, and intraductal papilloma. Diagnosis is
histological and prognosis and treatment depend on the type of underlying breast cancer
[328]. Paget’s disease of the breast is a disorder of the NAC that, while rare, is often
associated with an underlying in-situ or invasive carcinoma. It is characterized by
eczematoid changes and persistent soreness or itching of the NAC. The histogenesis of
Paget’s disease of the breast continues to be debated and is important when considering
treatment options. Two theories have been proposed to explain the pathogenesis of
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Paget’s disease. The epidermotropic theory suggests that Paget’s cells are ductal
carcinoma cells that have migrated from an underlying carcinoma of the breast
parenchyma to the epidermis of the nipple. It is supported by the predominance of breast
cancer markers found in Paget’s disease [329, 330]. The in-situ transformation theory
has been proposed to explain the development of this disorder in patients in whom an
underlying mammary carcinoma is not found or when there is an underlying carcinoma
anatomically remote from the NAC. Paget’s cells are believed to arise as malignant cells
in the epidermis of the nipple independent from any other pathologic process within the
breast parenchyma [331, 332]. The histogenesis of Paget’s disease has been hotly
debated, and only recently has epidermotropic theory become widely accepted. With the
evolution of our understanding of breast cancer, it became apparent that the prognosis of
Paget’s disease was more a reflection of that of the underlying carcinoma, be it
intraductal or infiltrating. The current standard treatment of Paget’s disease remains
mastectomy with or without ALND. In this era of breast-conserving surgery, however,
there is much evidence to suggest that conservative treatment of Paget’s disease of the
breast is possible for patients in whom an underlying breast cancer cannot be located
[333].
Breast sarcomas are a rare group of heterogeneous mesenchymal tumors accounting
for less than 1% of all breast malignancies. Primary sarcoma of the breast accounts for
less than 5% of all soft-tissue sarcomas. As experience with breast sarcoma has
increased, the perceived differences with other soft-tissue sarcomas has decreased.
Outcome is predicated upon histological type, degree of differentiation, and tumor size.
Recurrences are primarily local as an early event and distant to the lung somewhat later
in the course of the disease. Owing to the rarity of the disease, current knowledge is
mostly based on numerous case reports and relatively small retrospective series. Unlike
epithelial breast cancer, there is no high-level evidence to support a standard of care for
primary and/or adjuvant therapy. To overcome this relative shortage of data, most
therapeutic strategies for breast sarcoma are extrapolated from current treatment for soft
tissue sarcoma in other locations, mainly of the extremities and thoracic wall. In general,
the therapeutic approach to sarcoma of the breast should be based on a multidisciplinary
strategy necessitating experienced surgeons, pathologists, radiotherapists, and medical
oncologists and including surgery, radiation to improve local control, and systemic
chemotherapy in selected patients [334, 335]. Whether chemotherapy is indicated is
primarily determined by tumor size. There is evidence that tumors larger than 5 cm are
associated with an elevated risk of systemic failure and a poor prognosis. Negative
surgical margins are more important for local recurrence and overall survival than is the
extent of surgical resection. Thus, neoadjuvant chemotherapy should be considered in
order to shrink the tumor and help obtain negative surgical margins. After surgical
resection, patients with chemosensitive tumors should undergo additional adjuvant
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chemotherapy to treat micrometastatic disease. Patients with tumors less than 5 cm that
are easily resectable should undergo complete resection to the extent required to provide
negative surgical margins. Radiation therapy should be used to improve local control in
cases in which the tumor is larger than 5 cm and in cases with positive surgical margins
[336]. Further advances in treatment should follow the assembly of breast sarcoma
patients in specific cancer networks in specialized sarcoma referral centers. The
characterization of molecular pathways active in tumorogenesis of these tumors may
pave the way for the application of novel therapeutic agents [337-339].
Breast carcinoma is increasingly treated by conservation therapy. This includes wide
local excision and ALN clearance followed by radiotherapy to the remaining breast.
Therapeutic irradiation may be complicated by several problems, including the
development of other malignant tumors [340]. Postradiation vascular tumors fall into two
categories:
1) postradiation cutaneous angiosarcoma, malignant vascular neoplasms with
significant morbidity and mortality; and
2) atypical vascular lesions, vascular tumors that reportedly behave in a benign
manner.
Postradiation vascular tumors not only present a therapeutic problem for clinicians,
but they present an increasingly common diagnostic dilemma for pathologists. Although
first described separately 25 years ago, the relationship between postradiation cutaneous
angiosarcoma and atypical vascular lesions remains controversial. It appears that, in at
least some cases, angiosarcoma can arise in the context of atypical vascular lesions,
suggesting that these lesions are part of a spectrum of the same disease process. This
latter view point is supported by the significant clinical and histological overlap found
between both tumors [341].
Breast angiosarcoma following surgery and radiotherapy for breast cancer is a rare
but important clinical entity. Breast angiosarcoma remains challenging clinically,
radiologically, and histologically, and thus a high index of suspicion is required in
susceptible patients. Surgery is the primary treatment option and there are an increasing
number of studies on the use of radiotherapy and chemotherapy, each with variable
success. There have been recent reports of patients with metastatic disease responding to
taxane chemotherapy, and there might be a future role for targeted agents given the
expression of tyrosine kinase receptor (c-KIT) in a subset of angiosarcomas. Overall
survival, however, remains poor [342, 343]. Leiomyosarcoma of the breast was an almost
unknown tumor until some 40 years ago, and the few previously published cases lacked
detailed information [344-346].
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Metaplastic breast carcinoma is a rare but aggressive type of breast cancer that has
been recognized as a unique pathologic entity by the WHO, characterized by various
combinations of mesenchymal, adenocarcinoma, and other epithelial components.
Metaplastic breast carcinoma often manifests as a large mass, with low ALN
involvement and poor prognosis. Morphologically, it is characterized by the
differentiation of neoplastic epithelium into squamous cells and/or mesenchymal-looking
elements (squamous cells, spindle cells, cartilage or bone, etc.). It shares many
similarities with invasive ductal carcinoma and benign lesions on mammography, which
further complicates the diagnosis. Knowledge and treatment patterns about metaplastic
breast carcinoma demographics, presentation, and tumor characteristics are very limited.
In clinical practice, metaplastic breast carcinoma is usually treated based on the
guidelines developed for infiltrating ductal carcinoma. The ideal treatment paradigm for
metaplastic breast carcinoma is unknown due to its low incidence and pathological
variability, so potential predictors of treatment efficacy need to be explored, but studies
suggest that removal of the tumor and adjuvant radiation therapy has the greatest benefit
[347, 348].
Primary malignant fibrous histiocytoma of the breast proper is a very rare tumor.
From the limited number of cases reported so far, it seems that a rather high rate of local
recurrence and lung metastasis might be expected, and that there is still uncertainty as to
the most adequate treatment of the tumor. Therefore, the need for RLN dissection
(RLND) appears justified [349, 350].
Cystosarcoma phyllodes constitutes only 0.3-0.9% of all breast tumors. The term
“sarcoma” was initially used because of its fleshy appearance, a more modern term is
phyllodes tumor. The behavior of phyllodes tumor constitutes a spectrum from benign
and locally recurrent to malignant and metastatic. In a general surgical series, 6.2% of
the tumors were malignant. The microscopic appearance of phyllodes tumor is that of
epithelial elements and connective tissue stroma. Malignancy is determined by
characteristics of the stroma. The metastatic spread of malignant phyllodes tumor is
mainly hematogenous to lung, with infrequent lymphatic involvement. Compared to
breast adenocarcinoma, phyllodes tumor tends to affect a younger population, follows a
different clinical course, is associated with different imaging and histological findings
and is managed distinctively. There may be difficulty in differentiating the phyllodes
tumor from a large fibroadenoma, but the mammographer plays a key role in reviewing
the clinical and imaging data in order to arrive at the correct diagnosis. Early diagnosis
with proper surgical management can often cure non-metastatic phyllodes tumors.
However, in rare cases where metastasis occurs, prognosis tends to be poor. Wide local
excision with 2 cm margins is the treatment of choice. In 20% of both benign and
malignant cases, phyllodes tumor will locally recur. There is no proven benefit of
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Ciro Comparetto and Franco Borruto
radiation or chemotherapy, although radiotherapy may be useful in selected cases [351,
352].
Primary squamous cell carcinoma (SCC) of the breast is a rare tumor that presents a
unique biological behavior. Thus, it challenges the justification for routine ALND and
adjuvant therapy. SCC has several unique biological characteristics: it is associated with
a lower rate of lymph node metastasis at presentation (22% vs. 40-60% for infiltrating
ductal carcinoma) and a significant rate of distant metastasis without lymph node
involvement. ER and PR receptor levels are usually very low. Because lymph node
involvement plays a lesser prognostic and therapeutic role in this disease, a more
selective approach (i.e., SLNB) has been proposed. The issue of adjuvant treatment
remains unresolved, owing to lack of data. Surgical and medical treatment of SCC of the
breast should be tailored to fit its distinct biological characteristics. The 5-FUdoxorubicin-cisplatin (CDDP) combination may be warranted in lieu of the combinations
used for infiltrating ductal carcinoma [353].
Primary small cell carcinoma of the breast is an uncommon neoplasm that accounts
for less than 1% of primary breast cancers. Histologically, these tumors have striking
similarities to small cell carcinoma of the lung, usually with evidence of associated DCIS
with areas of ductal, lobular, or papillary differentiation. Immune-reactivity for
neuroendocrine markers is documented in two thirds of cases, while 33% to 50% are
positive for ER or PR. HER-2 expression has not been reported in small cell carcinoma
of the breast. Because of its rarity, its biological and clinical characteristics are still not
fully understood and, to date, no standard therapy has been developed. Primary small cell
carcinoma of the breast differs from more common types of breast cancer in its
biological features. Treatment, which may include surgery, radiotherapy, and
combination chemotherapy, is based on clinical stage and the presence of metastases.
Prognosis is variable and is dependent on the initial stage of disease. An improved
understanding of the clinical characteristics of this tumor will result in the development
of new therapeutic modalities, which would improve its prognosis [354, 355].
Subtyping of breast cancers by means of DNA microarray analyses has given rise to
the new concept of the basal-like subtype: this subtype is in effect the equivalent of socalled “triple-negative” breast cancer. Basal-like breast cancer has aggressive
characteristics, such as high histological grade, mutation of the p53 gene, and negative
hormone receptors. It tends to occur in relatively young women and is highly correlated
with suppression of BRCA1 function. The epidermal growth factor receptor (EGFR)
gene is often overexpressed in this subtype [356].
Primary neuroendocrine carcinomas of the breast are extremely rare. Tumors can
only be considered small cell neuroendocrine tumor of the breast if non-mammary sites
are excluded. These tumors form a diagnostic and therapeutic challenge [357-359].
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75
The presence of ectopic breast tissue is reported in 2-6% of the general population
with most cases being located in the axillary region. Although the same pathology occurs
in both eutopic and ectopic breast tissue, primary carcinoma of ectopic breast tissue has
been reported only in a small number of cases. Because an overlying accessory areola or
nipple is often missing and because of a general lack of awareness among physicians and
patients concerning these unsuspicious nodules, clinical diagnosis is frequently delayed.
Histological diagnosis can also be delayed if ectopic breast tissue is not present or
screened for in the biopsy specimens as apocrine glands of the breast and skin,
respectively, exhibit striking similarities and IHC is of limited help. Two thirds of
reported cases of primary ectopic breast carcinoma arose within the axillae [360, 361].
Metastases to the breast from extra-mammary tumors are infrequent. The main
challenge in diagnosis is differentiating them from primary breast cancer. Radiologically,
this can be difficult as there are no specific imaging characteristics for metastases to the
breast. Cytopathological evaluation, as well as full radiological assessment, is vital to
avoid unnecessary surgery. Sources of primary tumors include a wide variety of cancers.
The commonest sources of primary tumors include lymphoma, lung, ovarian and cervical
carcinoma, intestinal carcinoid, and rare cases of Ewing’s sarcoma and malignant
pigmented melanocytic schwannoma (low-grade malignant melanoma) [362].
With the improvements in imaging techniques that have allowed the earlier detection
of smaller breast cancers and the desire for improvements in cosmetic outcome, a
number of minimally invasive techniques for the treatment of early stage breast cancers
are being investigated. Minimally invasive therapy has been explored as a potential
means of treating breast tumors with minimal disruption to adjacent soft tissues. The
purpose of this is to facilitate improved cosmesis and to offer treatment to women who
are unfit for surgery. A number of treatment modalities including thermal therapies
(interstitial laser photocoagulation, radiofrequency, focused ultrasound, microwave
ablation, and cryotherapy), percutaneous excision, and interstitial radiotherapy are being
developed. All of these techniques have shown promise in the treatment of small cancers
of the breast. However, additional research is needed to determine the efficacy of these
techniques when they are used as the sole therapy and to determine the long-term local
recurrence rates and survival associated with these treatment strategies [363, 364]. The
carbon dioxide (CO2) laser has several properties which make it advantageous for breast
surgery. Experimental evidence documents a marked reduction of local tumor recurrence
following surgery with lasers. Preliminary human studies suggest that laser use lengthens
the disease-free interval and may decrease local recurrence. Interstitial laser therapy
holds promise for use in the treatment of locally advanced breast tumors and has been
suggested by some as a potential modality for the primary therapy of breast cancer. The
clinical use of lasers in the treatment of breast cancer is justified [365].
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Ciro Comparetto and Franco Borruto
It is well established that the development and homeostasis of the mammary gland
are highly dependent upon the actions of ovarian hormones progesterone and estrogen, as
well as the availability of PRL for the pregnant and lactating gland. More recently, it has
become apparent that immune system cells and cytokines play essential roles in both
mammary gland development as well as breast cancer. Hormonal control of the immune
system may contribute to mammary development at each stage via cytokine secretion and
recruitment of macrophages, eosinophils, mast cells, and lymphocytes. Collectively,
these alterations may create an immune-tolerant or inflammatory immune environment at
specific developmental stages or phases of the menstrual cycle. Of particular interest for
further research is investigation of the combinatorial actions of progesterone and
estrogen during the luteal phase of the menstrual cycle and key developmental points
where the immune system may play an active role both in mammary development as well
as in the creation of an immune-tolerant environment, thereby affecting breast cancer
risk [366]. It has been claimed that the timing of surgery in relation to the menstrual
cycle can significantly influence the prognosis among premenopausal women with
primary operable breast cancer. Those undergoing surgery at a time of unopposed
estrogen (days 3-12) had a significantly worse prognosis than those who had operations
at other phases of the menstrual cycle. This was also borne-out by another study that
indicated that progesterone levels at the time of surgery had prognostic significance, with
node positive patients in the luteal phase (progesterone more than 1.5 ng/ml) having a
significantly better outcome. A meta-analysis has shown a highly significant
heterogeneity of results, which do not overall show an effect. The results are
heterogeneous, and the quality of the studies is in general low. Many studies suffer from
statistical problems concerning small sample sizes and subgroup analyses. In all, the
scientific basis for the hypothesis seems weak [367, 368].
As genetic and biological treatment modalities are developed that can be customdesigned for individual patients, the possibility that breast cancer can be managed as a
chronic long-term disease becomes more real, and the requirement for minimally
invasive surgical intervention used as part of a multidisciplinary treatment approach
becomes more pressing [369]. Over recent decades, breast carcinoma surgery has
witnessed a considerable evolution. The extent of surgery undertaken has progressively
reduced, leading to less disfigurement and a significant improvement in quality of life,
thereby offering women considerable motivation to seek early diagnosis. From an
oncological perspective, outcome was found to be equally effective, and this key
observation provided us with significant impetus to investigate the effects of reducing
the radiotherapy field. Conservative surgery of breast carcinoma, both in the breast and
in the ALN, has yielded very good results in terms of overall survival and impact on
quality of life [370].
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77
A survey of controlled RCT of orthodox therapy directed to the breast and ALN has
indicated that:
1) if radical mastectomy is performed, postoperative radiotherapy gives no
advantage over a watching policy; and
2) if postoperative radical radiotherapy is given, there is no need for other than a
simple mastectomy.
A large multicenter trial has also indicated that simple mastectomy alone with
reservation of radiotherapy for treating local recurrent disease is a safe initial treatment.
These results refer to survival: postoperative radiotherapy reduces the incidence of local
recurrence, but this apparently can be equally well treated when it occurs. Local excision
of the tumor, followed by radiotherapy, has been reported to give inferior results to a
radical approach in Stage II tumors. Recognition that all these methods of local treatment
fail to cure the majority of patients has emphasized the need to define the extent of the
disease and to apply treatment according to that extent. A policy of selective local
therapy based on this principal in which total mastectomy is combined with biopsy of the
pectoral lymph nodes and further treatment by radiotherapy given only if these nodes are
involved by tumor has been studied. This policy has been compared with a standard
radical approach and gave similar results [371]. Subcutaneous mastectomy appears to
remain a valid procedure. A 50-year experience indicated that it is feasible in at least
80% of selected patients to successfully remove the breast parenchyma and subsequently
reconstruct the breast without serious complications. It is reasonable to assume that as
surgical technique and experience improve, the complication rate will diminish.
Furthermore, it is essential that better breast implants be devised and developed in the
future. This would clearly enhance all forms of cosmetic breast surgery. The use of
subcutaneous mastectomy as a prophylactic cancer procedure will parallel the
improvement of implant breast reconstruction. Whether subcutaneous mastectomy will
measurably reduce the mortality rate of breast cancer, of course, will take a generation to
determine. However, it is a justifiable and valuable surgical tool in the treatment of
breast disease. The concept of almost total breast biopsy has great merit in the discovery
of occult carcinoma. Clearly, caution should be exercised in the selection of cases for
this modality, and further study must be devoted to develop diagnostic guidelines of
ever-increasing precision to determine which breasts are potentially malignant and
should be afforded the procedure [372].
Skin-sparing mastectomy is an oncologically safe technique in selected cases,
including invasive breast cancer less than 5 cm, multicentric tumors, DCIS, and
prophylactic risk-reduction surgery. The high risk of local recurrence excludes
inflammatory breast cancers and tumors with extensive involvement of the skin. Skin-
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Ciro Comparetto and Franco Borruto
sparing mastectomy can facilitate immediate breast reconstruction and is associated with
an excellent aesthetic result. Prior breast irradiation or the need for postmastectomy
radiotherapy do not preclude skin-sparing mastectomy, however the cosmetic outcome
may be affected. NAC preservation is possible for remote tumors, employing a frozen
section protocol for the retroareolar tissue. There is limited data available for endoscopic
mastectomy and superiority over conventional skin-sparing mastectomy has not been
established. In appropriately selected cases, skin-sparing mastectomy is oncologically
adequate. There are several patient-centered advantages over conventional mastectomy,
including aesthetic outcome and the avoidance of multiple staged procedures [373].
Nipple-sparing mastectomy is a surgical procedure that allows the preservation of the
skin and NAC in breast cancer patients or in patients with prophylactic mastectomy.
However, the oncological safety and patient selection criteria associated with nipplesparing mastectomy are still under debate. The incidence of NAC involvement of breast
cancer in recent studies ranges from 9.5-24.6%, which can be decreased through careful
patient selection. Tumor-nipple distance, tumor size, lymph node involvement, and
molecular characteristics can be evaluated preoperatively by clinical examinations,
imaging studies, and biopsies to predict the risk of NAC involvement. Currently, there is
no available standard protocol for surgical approaches to nipple-sparing mastectomy or
pathological examination of nipple-sparing mastectomy specimens. The local recurrence
(ranges from 0-24%) of nipple-sparing mastectomy is not significantly higher than that
of traditional mastectomy in selected patients based on long-term follow-up. The role of
radiotherapy in nipple-sparing mastectomy is still controversial and is not universally
accepted. Nipple-sparing mastectomy appears to be oncologically safe following careful
patient selection and assessment of margins [374, 375].
Breast-conserving therapy is the best method for breast cancer treatment when
concerning the psychological sequelae to the patient, so it has become the standard of
care, and survival is now excellent. Cosmetic results after conservative surgery are not
always acceptable: about 20% of patients need a revision operation and correcting the
residual defect of the breast or asymmetry of the breasts afterwards. Consequently, the
focus of breast-conserving therapy has increasingly shifted to cosmetic outcome, quality
of life, and patient satisfaction. Nonetheless, excision of certain tumors still presents a
considerable challenge. Specialized approaches combining oncological surgery and
plastic surgery techniques are collectively referred to as oncoplastic breast surgery.
Oncoplastic surgery means that the methods familiar to plastic surgeon are used to
increase the number of patients treated with conservative surgery without compromising
the oncological results. Even wider margins than in normal breast conservation can be
gained, if local glandular flaps, musculocutaneous latissimus dorsi flaps, or
microvascular free TRAM flaps are used to immediately preserve the shape and
symmetry of the breasts. With plastic surgery it is possible to reshape the breast, replace
Breast Cancer
79
the nipple, and gain breast symmetry. As we know, every tenth woman will have a breast
cancer during her lifetime, and 80% of breast cancer women will survive. It is important
to operate breast cancer immediately to save costs and help a patient feel that her breasts
are still a part of her own body. Using oncoplastic surgical techniques for breast
preservation, breast surgeons can achieve widened surgical margins at the same time that
the shape and appearance of the breast is preserved and sometimes rejuvenated.
Oncoplastic surgical resection is designed to follow the cancer’s contour, which
generally follows the segmental anatomy of the breast, which has been well understood
since the mid 19th century because of pioneering anatomic studies performed by Sir
Astley Paston Cooper. The quadrantectomy, developed by Veronesi and colleagues in
the 1970’s, follows these same anatomic principles of wide segmental resection. The
more surgically narrow lumpectomy as popularized in the USA uses a smaller, scooplike non-anatomic resection of cancer. With negative surgical margins, the lumpectomy
is equivalent to the quadrantectomy in achieving the goals of breast conservation as
measured by local recurrence and survival. However, the lumpectomy is less versatile for
resection of larger cancers, and can be more prone to creating suboptimal cosmetic
defects. Cancers with large in-situ components can be particularly problematic for
resection with the standard lumpectomy, when they extend both centrally toward the
nipple and peripherally to distal terminal ductulo-lobular units, which typically occur in
a pie-shaped segmental distribution. Ductal segments, each of which ultimately drains to
a single major lactiferous sinus at the nipple, vary in size and depth in the breast. Breast
surgeons should carefully evaluate the cancer distribution and extent in the breast before
operation. A combination of imaging methods (mammography with magnification views,
ultrasonography, MRI, or all) may yield the best estimates of overall tumor extent.
Multiple bracketing wires afford the greater help to complete surgical excision. Those
tumors with segmental spreading are best excised by oncoplastic resections according to
their distribution. A summary of oncoplastic breast surgery outcomes would facilitate
decision-making and best treatment selection by both clinicians and patients. In these
studies, 80-93% of the tumors were invasive. Tumor-free resection margins were
observed in 78-93%, resulting in a 3-16% mastectomy rate. Local recurrence was
observed in 0-7% of the patients. Good cosmetic outcome was obtained in 84-89% of
patients. However, most studies showed significant weaknesses including lack of robust
design and important methodological shortcomings, negatively influencing
generalizability. Current evidence supporting the efficacy of oncoplastic breast surgery is
based on poorly designed and underpowered studies. Given the increasing importance
and application of oncoplastic breast surgery, there is a pressing need for robust
comparative studies, including both RCT and well-designed, multicenter prospective
longitudinal studies [376-381].
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The management of patients with early-stage breast cancer has evolved over time,
with the understanding that tumor biology, and not just disease burden, impact local
control. Local control is greatly improved with systemic therapy, providing an
opportunity to decrease the morbidity of local therapy in women with invasive breast
cancer. In women undergoing breast-conserving therapy, which consists of lumpectomy
and whole-breast irradiation (WBI), there has been a lack of consensus as to what
constitutes a negative margin [382]. Team work is the key to successful breastconservation therapy. Patient education and the informed consent process should include
a discussion about the importance of margin status. Specimen management is critically
important to obtain the highest quality information about margins. Operating technique
should avoid trauma to or disruption of the specimen surface. The specimen should be
oriented for the pathologist using standard techniques including sutures, clips, or colored
inks. Specimen radiography is mandatory to confirm complete resection of the target
tissues and can be used to direct additional margin resections during the initial
procedure. With a well-designed and oriented specimen, the pathologist can give an
accurate description of the margin distance for both the invasive and in-situ components
of the cancer. In most cases, decision-making about margins will be straightforward.
When margins are positive, approaches include re-excision, mastectomy, or, as secondline treatment, radiotherapy with a high boost dose. When margins are negative, boost
administration and its dose depend on the risk of local recurrence, which is linked to
biopathological tumor features and surgical margin width. Clear margins (more than 5
mm) require no further surgical therapy. “Close” margins (1-4 mm) will remain a point
of controversy because of conflicting reports from clinical series. At UAB, decision for
re-excision is made on a case-by-case basis. Routinely, 2 mm is considered adequate,
however, volume of disease and intraductal component are important considerations
when making recommendations. Current evidence indicates that wider margins do not
reduce local recurrence compared to “no tumor on ink.” Although margin status does not
affect the choice of systemic therapy, it may delay the start of chemotherapy when
further surgery is required [383]. Despite the widespread conservative management of
breast cancer, the pathologists’ examination of these specimens is far from uniform.
Pathologists sample margins differently, and even disagree on what constitutes a positive
margin. This variability in the pathological examination of the lumpectomy creates
tremendous problems in analyzing the existing literature on the importance of positive
margins. Only by adopting a uniform system of margin assessment we can begin to
critically evaluate the importance of positive margins in segmental resections of the
breast [384-388].
The standard treatment for early breast cancer comprises wide local excision, SLNB
or ALND, adjuvant medical treatment, and external beam radiation therapy (EBRT) to
the whole breast. Many studies suggest that local control plays a crucial role in overall
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81
survival. The local recurrence rate is estimated to be 1% per year and varies between 47% after five years and up to 10-20% in the long-term follow-up. On the basis of low
local recurrence rates, the concept of WBI comes up for discussion, and PBI is
increasingly under consideration. A policy of EBRT for every patient undergoing breastconserving surgery is in fact associated with a number of practical difficulties, acute
radiation side effects, and longer-term toxicity, all of which detract from the obvious
benefits of EBRT. In addition, with a disease as common as early breast cancer and a
treatment program typically requiring sophisticated radiation planning and many
fractions of treatment, the policy of breast-conserving surgery plus EBRT has enormous
resource implications within departments of oncology, greatly contributing to lengthy
pretreatment delays. For all these reasons, an increasing interest developed in techniques
of PBI, with an emphasis on the emerging technique of intraoperative radiotherapy
(IORT), which was initially employed as a boost to the tumor bed for use in conjunction
with EBRT to the whole breast. Intraoperative radiotherapy (IORT) is thus referred to as
the delivery of a single high dose of irradiation directly to the tumor bed (confined
target) during surgery. PBI [limited field radiation therapy, accelerated PBI (APBI)] is
the irradiation exclusively confined to a breast volume, the tumor-surrounding tissue
(tumor bed) either during surgery or after surgery without WBI. The advantage of a very
short radiation time or the integration of the complete radiation treatment into the
surgical procedure convinces at a first glance. Local recurrence rates could probably
increase and furthermore give rise to distant metastases and a reduction in overall
survival. The combination of IORT in boost modality and WBI has the ability to reduce
local recurrence rates, and overall survival figures have improved during the past
decades, with the advent of more effective systemic endocrine- and chemotherapy [389,
390]. IORT, in addition to WBI, has yielded excellent long-term results. Under the
assumption that the majority of in-breast tumor recurrences occur in the originally
affected site, APBI as the sole treatment modality was initiated in several studies and
with different techniques, one of which was IORT first with electrons, later also with
conventional X-rays. The question whether and for whom the gold standard of may be
replaced by APBI – especially IORT – alone has recently been one of the most
controversial issues of adjuvant therapy for breast cancer. Two recently published
studies by Veronesi et al. and Vaidya et al. presenting short-term results of single shot
IORT with electrons (ELIOT) and with an orthovoltage system (TARGIT), respectively,
have further invigorated this discussion [391]. APBI is increasingly used in the hope of
increasing convenience, decreasing sequelae, and maintaining cure rates. ELIOT is an
attractive APBI technique because collimator placement is under the direct control of the
surgeon who removes the tumor, the skin is spared, shielding protects the chest wall, and
complete irradiation can be given in a single intraoperative session (avoiding five-seven
weeks of WBI). ELIOT seems as safe as WBI, however, long-term results on local
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control and survival are not available yet [392]. Potential future directions of IORT
include novel IORT techniques utilizing intraoperative brachytherapy with in-room
imaging and rapid treatment planning [393].
The rapid patient accrual observed in the European breast IORT studies reported
since 2000 indicates that surgeons, radiation oncologists, and women who have breast
cancer are no longer content to continue to travel down the well-worn path of disfiguring
ablative treatment. Breast conservation is currently viewed as the preferred mode of
therapy for early-stage breast cancer in most clinical situations. Determination of the
optimal combination of whole-breast EBRT and localized IORT, for dose and
fractionation, is a critical issue that only recently has been addressed. Clearly, such
clinical investigative endeavors should be regarded as high priority. The very low
incidence of local in-breast recurrence of cancer to date suggests that another avenue for
investigation might be the determination of the extent to which the lumpectomy
procedure can be safely minimized when used in conjunction with IORT. Another
question remaining to be addressed pertains to the utility of IORT in the management of
in-breast recurrence of cancer following conservative therapy. The incidence of local
failure after organ-conserving treatment is generally reported to be approximately 5-10%.
Currently, the preferred mode of salvage therapy in such a clinical situation is
mastectomy. The proven efficacy of IORT concurrent with lumpectomy in the primary
treatment of early-stage breast cancer suggests that even local recurrences following
conventional conservative treatment might be dealt with effectively and expeditiously by
means of local excision plus IORT. Such treatment, if safe and effective, could prove to
be much less disfiguring than mastectomy. Because breast irradiation routinely produces
a desmoplastic tissue response in the breast, there seems to be an opportunity here to
address local recurrences of breast cancer with local surgical extirpation enhanced by
IORT. The remarkably low incidence of local recurrence of breast malignancy observed
in every breast IORT study reported to date may portend an important advancement in
physicians’ ability to better achieve local control of mammary carcinoma. It is hoped that
such a putative improvement in the local control of breast cancer will soon translate into
improved patient survival rates for this common malignancy [394-398].
With widespread use of mammography for breast cancer screening, the number of
surgical procedures has also increased. Overlapping with radiographic signs of
malignancy, including masses, areas of asymmetric density and architectural distortion,
microcalcifications, and skin thickening, postsurgical changes may make mammographic
evaluation difficult. After tumor excision and irradiation where breast alterations are
more profound and prolonged, the task of distinguishing recurrent tumor from scarring or
fat necrosis is even more challenging. Mammograms after breast conservation therapy
for carcinoma or after cosmetic surgery require correlation with physical findings and the
surgical procedures that were performed. Responses of tissue to lumpectomy and
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83
radiation, such as breast edema and skin thickening, are most pronounced six to 12
months after treatment, gradually resolving within one to three years. Carefully tailored
mammographic studies will promote the dual goal of early detection of local tumor
recurrence and avoidance of misinterpreting postoperative and irradiation changes as
malignancy. Sequential examinations should begin with a postoperative preradiation
mammogram for residual carcinoma, particularly when microcalcifications have been
present, followed by the baseline postradiation examination at six months with the next
study six months later (one year after initial treatment). Mammograms of the treated
breast may be performed at intervals of six months until radiographic stability has been
recognized. The contralateral, unaffected breast should be evaluated mammographically
according to screening guidelines or clinical concerns. Mammograms performed after
cosmetic and reconstructive procedures should be correlated with the surgical techniques
and clinical history. Modified views for silicone implants can maximize visualization of
breast parenchyma. Ultrasonography is a useful complement to mammography in
demonstrating the origin of a palpable mass either within the implant or the breast
parenchyma. In reduction mammoplasty, distorted architecture, parenchymal bands,
tissue redistribution, and fat necrosis should be recognized. After mastectomy,
myocutaneous reconstruction may be performed. Masses that develop within flap
reconstructions most frequently represent fat necrosis, which, when calcifying oil cysts
are seen, may have a characteristic radiographic appearance [399]. Many breast cancer
patients undergo cross-sectional imaging at some point during or after treatment.
Thoracic CT is an important modality performed for staging and surveillance. Thoracic
CT examinations often show findings related to patients’ surgical or adjuvant treatment.
The postsurgical changes visible on thoracic CT may include those related to
lumpectomy, mastectomy, breast reconstruction, and ALN surgery. Postsurgical
complications may also be seen, including fluid collections, infection, fat necrosis, and
lymphedema. Recognition and appropriate interpretation of the post-therapeutic
spectrum of findings are important to avoid unnecessary diagnostic imaging and
minimize patient anxiety [400].
Chapter V
Imaging-Guided Breast Surgery
Achieving the maximum yield of breast cancers detected by mammography has
required particular changes in tissue handling and examination of the mammographically
directed breast biopsy. This radiographic technique, increased use of breast-conserving
surgical approaches for the treatment of breast cancer, more enlightened and demanding
patients, and increasing medical-legal exposure have all contributed to changes in the
way surgical pathologists should process and sample breast biopsy specimens [401]. The
capability to provide histological diagnoses of non-palpable lesions by performance of
percutaneous needle biopsy has revolutionized breast imaging in the past decades. The
radiologist who performs percutaneous breast biopsies assumes an increased level of
responsibility for the patient regarding patient selection, lesion selection, performance of
the biopsy procedure, interpretation of results, and patient follow-up. With variable and
increasingly numerous options for the biopsy of breast lesions, careful attention must be
paid to the selection of patients and types of lesions for different procedures. Critical
technical considerations affect whether biopsy of a lesion can be optimally performed
percutaneously, and these considerations must be factored into the recommendations for
patient treatment. In addition, a limited preprocedural clinical assessment of the patient
will allow a safer procedure to be performed expeditiously. Most breast abnormalities
classified by using the American College of Radiology (ACR) Lexicon as 4 (suggestive)
or 5 (highly suggestive, likely malignant) are suitable for either percutaneous breast
needle biopsy or needle localization and excisional biopsy. In general, those lesions
classified as 3 (probably benign) carry a recommendation for early follow-up and not
biopsy, because the likelihood of malignancy is small. A particular advantage of
percutaneous biopsy is in the diagnosis of multicentric breast cancer. CNB is less
invasive and less costly than surgical biopsy, and it can be used to demonstrate
multicentric disease, saving the patient a two-step surgery. However, several lesions are
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better treated by excision than by percutaneous biopsy. Among these are architectural
distortion or loosely arranged, segmental, or regional microcalcifications. For nonpalpable breast lesions visualized on mammography, sonography, or both, imagingguided localization is required for precise needle placement either for wire localization
or for percutaneous breast biopsy. The selection of which modality to use for guidance
depends on:
1)
2)
3)
4)
5)
6)
7)
the adequacy of visualization of the lesion by the modality used;
the position of the lesion;
the ease of positioning the patient;
the skill of the operator;
the need to reduce radiation exposure;
the overall patient condition; and
the size of the lesion.
FNAB has a high sensitivity and specificity in the diagnosis of palpable breast
lesions when the procedure is properly performed and interpreted. Variable results have
been achieved with FNAB of non-palpable breast lesions under imaging guidance. Three
critical components are necessary to achieve reliable results by using FNAB. These
include the following:
1) accuracy in needle placement;
2) skill in performance of FNAB; and
3) expert cytopathological analysis.
Accurate preoperative needle localization of non-palpable breast lesions allows the
radiologist to guide the surgeon performing an open biopsy and helps to ensure that the
surgical procedure can be performed quickly and can be accomplished with the best
possible cosmetic result for the patient. Lesions selected for needle localization and
biopsy should undergo a complete tailored imaging evaluation before the needle
localization is scheduled. Specimen radiography should be performed for all nonpalpable lesions. Once the lesion has been identified on specimen radiography, the
radiologist can assist the pathologist in identifying the lesion microscopically by marking
the lesion within the surgical specimen [402, 403]. Only 10-20% of non-palpable breast
lesions are malignant, yet all suspicious lesions must undergo biopsy. For many women
with breast abnormalities, needle biopsy is a less expensive, quicker, and better tolerated
alternative to surgical excisional biopsy. Localization techniques that may be used during
needle biopsy include clinical guidance, the grid coordinate system, ultrasound guidance,
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and stereotactic guidance. Of these four options, only stereotactic guidance permits 3-D
localization of a lesion [404].
Localization of breast lesions with specialized, computerized stereotactic
radiographic equipment or ultrasound imaging with subsequent use of this image to
guide percutaneous core sampling of the abnormal area is less invasive, less painful,
highly accurate, and less expensive than incisional breast biopsy with preoperative
needle localization. These imaging-guided techniques have progressively matured in
recent years, are used regularly by more and more surgeons, and are areas of clinical care
and technology [405]. In particular, mammographically-guided needle biopsy is an
accurate technique for the evaluation of non-palpable breast lesions that should lead to
less discomfort and anxiety, fewer complications, and less cosmetic disfigurement.
Moreover, this method is done on an outpatient basis with local anesthesia, and with a
significant decrease in cost when compared with conventional surgical biopsy, so that it
can decrease the expense of breast cancer screening programs.
The use of FNAB should lead to surgery on a much more highly selected group of
patients, thus producing higher true positive surgical biopsy rates for breast cancer than
has been previously possible. These incentives should serve to increase compliance with
screening mammography guidelines by women and their physicians. SNB of the breast is
a diagnostic technique to obtain samples of a non-palpable area deemed suspicious for
malignancy on mammography. This procedure, when performed with a large core biopsy
needle, appears to be about as accurate as surgical biopsy [406, 407]. Nevertheless, it is
likely that stereotactic FNAB will be best suited to high volume practices in which a
large number of biopsies are performed and in which experienced mammographers,
cytopathologists, and breast surgeons use a team approach to manage each patient [408].
SNB should not be used to biopsy lesions that would otherwise not undergo biopsy. The
radiologist who performs this procedure must understand the implications of the
resultant histological diagnosis and be certain that the pathological and radiological
findings are concordant. The performance of this procedure by a radiologist is important
for accurate positioning and needle placement in the breast, allowing accurate diagnosis,
and in minimizing the number of exposures required for the procedure, thereby keeping
the radiation dose to the patient at a minimum. In addition to understanding the guidance
system used in this procedure, the radiologist also should understand the needles and
guns used and be able to select the most appropriate method for each patient. Patients
undergoing SNB should be told that, in some instances, surgical biopsy may still be
necessary. They should know that major complications are rare but possible. Before
initiating an SNB program, the radiologist performing SNB should develop a mechanism
for surgical referral of woman who have a complication or an SNB diagnosis requiring
surgery [409]. A specific pathological diagnosis, as well as determination of
invasiveness, can be achieved for mass lesions. Microcalcification can also be sampled
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to diagnose in-situ cancer, although the use of CNB for non-comedo intraductal cancer is
still evolving. The procedure demands meticulous technique to assure accurate needle
placement, and careful correlation of biopsy results and patient follow-up is mandatory.
Accuracy relative to surgical biopsy of non-palpable lesions has been excellent in
published series [410]. Major complications, such as hemorrhage and infection, are
extremely rare, although postbiopsy ecchymosis and tenderness are not unusual. Because
less tissue is removed, postbiopsy cosmetic deformity does not occur. SNB is performed
by triangulating the position of a breast lesion and by obtaining views angled equally off
a central axis. This can be done using dedicated tables or add-on equipment. SNB has a
reported accuracy of at least 90%. All lesions for which biopsy would ordinarily be
recommended are amenable to stereotactic techniques, but those near the chest wall or in
the axilla may be more difficult to biopsy with some equipment. Lesions characterized
by calcifications are sometimes more difficult to sample. A biopsy diagnosis of ductal
atypia, because of its histological heterogeneity, requires surgical excision to exclude
coexistent carcinoma, which has been found in half of women at subsequent surgical
excision. A CNB diagnosis of DCIS does not preclude the discovery of invasive
carcinoma at surgery. In rare instances, the small tissue volume removed at stereotactic
biopsy does not permit a final diagnosis to be made: this occurs most commonly when
differentiating phyllodes tumor from fibroadenoma [411]. An important component of a
stereotactic core breast biopsy procedure is the mammographic and pathological
correlation of findings to plan optimal patient management. The level of suspicion of a
mammographic lesion, the accuracy of stereotactic targeting, and the confirmation of
microcalcifications in specimen radiographs for calcified lesions must be considered
carefully and correlated with the histopathological findings. Meticulous operator
technique is essential to provide representative samples of the mammographic
abnormality. As we have said, properly performed, imaging-guided percutaneous core
breast biopsy has reduced the morbidity of surgical breast biopsy and the overall cost of
breast cancer diagnosis. Recent work has demonstrated that stereotactic core breast
biopsy can reduce the cost of diagnosing mammographically detected breast lesions by
more than 50%. At a time when health-care policy and reimbursement decisions are
influenced by cost considerations, increased use of stereotactic core breast biopsy is
anticipated. Meticulous attention to technique allows maximal realization of the benefits
of this procedure [412, 413].
Recently, there have been a number of new devices introduced for SNB of nonpalpable, mammographically detected lesions. The vacuum-assisted core biopsy (VACB)
[Minimal Invasive Breast Biopsy (MIBB), USA Surgical Corporation, Norwalk, CT,
USA; Mammotome, Biopsys Medical, Cincinnati, OH, USA] obtains multiple tissue
cores (11-gauge) in a circumferential manner around the biopsy probe, inserted under
stereotactic guidance. It provides more complete sampling of mammographic lesions
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than the conventional 14-gauge SNB, reducing the number of unsatisfactory biopsies.
The ABBI system utilizes stereotactic technique and an oscillating blade-cutting
mechanism to obtain a single large diameter (5-20 mm) tissue core, with the aim of
obtaining an intact lesion in its entirety for histological assessment [414]. Percutaneous
core biopsy is most often used for evaluation of BI-RADS category 4 lesions, but may
also be helpful in the evaluation of some BI-RADS category 5 lesions. Stereotactic
guidance is particularly useful for calcifications: for masses that can be seen with
ultrasound, ultrasound guidance may be preferable because of the absence of radiation
and lower cost. The automated CNB is excellent for mass lesions, but directional VACB
is superior for calcifications. Directional VACB may also be preferable for small lesions
that may require placement of a localizing clip and lesions that are superficial or in thin
breasts. The more expensive ABBI device has substantial limitations. Complete removal
of the mammographic target can occur at percutaneous biopsy, and is a more frequent
event when the larger tissue acquisition devices are used. Complete removal of the
mammographic target does not ensure complete excision of the histological process.
Epithelial displacement can occur during all breast needling procedures, but may be less
frequent at directional VACB than at FNA or automated core biopsy. There is no
evidence that displaced cells are of biological significance, but displaced DCIS can
mimic infiltrating carcinoma. The pathologist should be aware of the findings of
epithelial displacement, to avoid misdiagnosing DCIS as infiltrating ductal carcinoma.
Some lesions warrant repeat biopsy or surgical excision after percutaneous core biopsy.
Repeat biopsy is warranted if histological findings and imaging findings are discordant.
Surgical excision is warranted for lesions yielding a percutaneous diagnosis of atypical
ductal hyperplasia or possible phyllodes tumor. Controversy exists regarding the need for
surgical excision after percutaneous diagnosis of radial scar, papillary lesion, atypical
lobular hyperplasia, or LCIS. Follow-up is necessary if percutaneous biopsy yields
benign findings concordant with imaging characteristics. Follow-up protocols vary, but
all require substantial commitment of time and resources. It can be estimated that
approximately one million breast biopsies will be performed every year to diagnose
approximately 200,000 breast cancers. Percutaneous core biopsy may spare many of
these women the need for a more deforming, invasive, and expensive surgical biopsy
[415, 416].
Ultrasound provides a versatile approach for guiding biopsies and other breast
interventions. The wide availability, real-time capability, technical improvements, and
increasing user experience have greatly expanded the role of ultrasound-guided
interventions in the diagnosis and management of breast disease [417]. The use of
ultrasonographic guidance for such procedures provides a safe and effective real-time
technique to sample tissue while the patient lies in a comfortable supine position. The
operator who has a good understanding of the procedure will be able to obtain reliable
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specimens efficiently and consistently [418]. High-frequency ultrasonography offers
several distinct advantages over stereotaxy and is the technique of choice for guiding the
drainage of cysts and fluid collections and the biopsy of any solid mass that can be
identified on sonograms. Ultrasonography also can be used for localizing such lesions
preoperatively [419-422]. Pathologist-performed, ultrasound-guided FNAB is one of the
frontiers of pathology. There is little training in ultrasound-guided biopsy of breast
masses. To successfully perform an imaging-guided biopsy of the breast, pathologists
should understand the basics of mammography and breast ultrasound. The heart of early
breast cancer detection is the screening mammogram. Abnormalities detected on
screening, such as masses, densities, architectural distortions, nipple retraction, skin
thickening, abnormal lymph nodes, and microcalcifications, will lead to a diagnostic
mammogram and/or breast ultrasound. Lesions classified as BI-RADS 4 or 5, and a few
classified as 3 lesions, require biopsy. If the lesion is visible on ultrasound, ultrasoundguided FNAB and/or CNB is the procedure of choice. Suspicious lesions visible only on
mammogram require stereotactic X-ray-guided biopsy [423] For breast masses,
interventional breast sonography has become the standard for guiding needle biopsy,
whether a fine aspiration or a core biopsy needle is used. Ultrasonography has also
become the preferred method for guiding insertion of various localization devices for
non-palpable masses, and ultrasonography’s intraoperative use for this purpose is
expanding. Recently, ultrasonography has been used to monitor the placement of
percutaneous ablation devices, such as radiofrequency ablation needle-electrodes, into
breast masses, including carcinomas. Ultrasonography is not indicated for the routine
evaluation of microcalcifications. However, on occasion, clusters of microcalcifications
without a mass can be visualized on sonograms with sufficient clarity to undertake a
ultrasonography-guided core biopsy if stereotactically-guided biopsy cannot be
performed for technical reasons [424-426]. Portable ultrasound is now used in a variety
of clinical settings by specialties outside of radiology. Despite increased accessibility to
ultrasound, the overall performance of ultrasound by breast surgeons is consistently low.
Intraoperative ultrasound performed by surgeons reduces re-excision rates in breastconserving surgery. Outpatient-based ultrasound performed by surgeons frees up the
resources of radiology departments, allowing them to focus upon patients requiring more
complex diagnostic and interventional procedures, such as lumpectomy, percutaneous
excision of benign masses, and ablation of cancers. For surgeons to competently perform
intraoperative and outpatient-based ultrasound, a period of formal ultrasound training is
necessary to acquire knowledge of ultrasound skills and techniques. This should be
followed by a period of mentorship and supervised training with an experienced breast
radiologist. Breast surgeon-performed ultrasound is beneficial to the multidisciplinary
care of breast cancer patients. To further improve multidisciplinary care, breast surgeons
and radiologists should work more collaboratively to optimize imaging applications both
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in the operating theater and outpatient department. Current advances in therapeutic
percutaneous techniques are of interest to both surgeons and radiologists. In future, a
hybrid specialization should be considered to incorporate accreditation in both
specialties for breast interventional procedures [427].
Techniques and instrumentation are now widely available that enable interventional
MRI-guided preoperative needle localization and lesion marking. Minimally invasive
MRI-guided core biopsy techniques have been demonstrated but remain limited for small
lesions and will be facilitated by the development of biopsy instruments that can be
directly visualized using MRI. MRI-guided tumor ablation is beginning to be evaluated
in a few centers. It holds promise as new treatment modality in the continuing trend
toward greater breast conservation in the local therapy of breast cancer. Further studies
are needed to document the ability of MRI-guided ablation to control the margins of a
tumor as effectively as surgery. Patients with an extensive in-situ intraductal component
may pose a significant hurdle because the extent of DCIS maybe underestimated on
breast MRI. Ultimately, the success of MRI-guided thermal ablation depends on the
ability of MRI to map the extent of heating during the procedure, so that the procedure
can be performed to achieve complete control of the tumor margins. It is unfortunate that
the conventional method for MRI thermometry – the proton resonance frequency (PRF)
shift method – does not work in fat or in voxels with a mix of fat and glandular tissue
and, hence, has limited applicability in the breast. Other methods, including
measurement of T1 and T2, are being investigated as alternatives [428]. Thus, despite the
proven high sensitivity of MRI for invasive breast cancer, MRI has lagged behind
mammography and sonography as an imaging modality for guiding interventional
procedures because of the lack of suitable techniques. New imaging apparatuses, pulse
sequences, and MRI-compatible devices are beginning to enable MRI-guided breast
interventions, including preoperative lesion localization and minimally invasive biopsy.
MRI-guided tumor ablation holds promise as a future therapy for breast cancer because
of the ability of MRI to reveal the progress of heating and freezing, as well as the extent
of ablated tissue [429, 430]. In fact, MRI imaging of the breast has high sensitivity for
the detection of invasive breast cancer. However, not all enhancing lesions are
malignant. A needle localization or biopsy system is necessary to differentiate falsepositive benign enhancing lesions from the true carcinomas [431]. Technical obstacles in
the integration of breast MRI-minimally invasive therapy for breast tumors include
accurate determination of margins, DCIS, and localization methods. Treatment methods
are cryotherapy, interstitial hyperthermia, and focused ultrasound. Other subjects include
the amount of minimally invasive therapy performed to date and the ethical dilemma of
clinical trials [432, 433]. However, the use of breast MRI in the diagnosis, staging, and
management of breast cancer is rapidly increasing. MRI has the ability to detect
malignancy that is occult to physical exam, ultrasound, and mammography. These
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qualities necessitate methods for MRI-guided tissue sampling [434]. For the histological
verification of such lesions, percutaneous MRI-guided biopsy techniques can now be
offered as an alternative to open breast biopsy [435, 436]. However, the specificity of
MRI is moderate. These attributes necessitate methods for MRI-guided tissue sampling
to determine the histology of MRI-detected lesions [437-440]. The majority of MRIguided breast biopsies yield benign pathology. Proper radiological-pathological
correlation is an integral component of MRI-guided breast biopsy. Familiarity with the
spectrum of MRI findings and key histopathological features of common benign entities
will enhance the radiologist’s confidence in determining concordance and lead to
improved patient management recommendations [441].
Histological work-up of just MRI-detected breast lesions has become essential with
increasing use of contrast-enhanced MRI. The different MRI-guided breast interventions
are performed since 1990. Presently, for reasons of costs and image quality closed
magnets are most widely used. The following approaches have been described: MRIguided freehand localization in supine position, stereotactic localization in supine
position, and most frequently used localization in the prone position by means of a
compression device that immobilizes the breast to prevent tissue shift during
intervention. Only limited experience exists with interventions on open magnets. MRIguided wire localization is a well-established procedure. Recently, percutaneous vacuum
biopsy of enhancing breast lesions has become possible under MRI guidance. The new
system allows accurate and safe access to lesions in any location of the breast and direct
check-up of representative excision by visualization of the cavity. Thus, reliable
histological evaluation of lesions smaller than 10 mm is possible with this approach
[442, 443]. VACB is an imaging-guided technique introduced in 1995 that is thought to
be superior to 14-gauge automated-needle biopsy for the evaluation of non-palpable
breast lesions. VACB can decrease the high risk and DCIS underestimate rates, but it is
unclear whether it can also decrease the miss-rates of cancer [444, 445]. The vacuumassisted biopsy device was originally introduced as a diagnostic tool. However,
improvement in technology (by production of larger caliber tools) has now extended the
role of VACB to therapeutic procedures. VACB has an expanding role in the surgical
treatment of benign breast diseases, and improvement in technology may further extend
its therapeutic role to the excision of small malignant lesions [446]. Quite a number of
radiologists indicate that complete removal of an imaged lesion in the breast by
transdermal tissue acquisition is beneficial for the patient. Although this claim is
technologically feasible with the vacuum-assisted biopsy devices and, by virtue of a
similar technology of aspiration, liposuction, there is no scientific or clinical proof that
the extended procedure is indeed valuable for the patient. The optimal treatment of
malignant or premalignant lesions remains open surgery with the goal to obtain
pathologically free margins whenever possible. Complete removal by imaging is quite
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different from complete pathological removal. Hence, VACB elimination of suspect or
malignant lesions can be considered less optimal and even malpractice in many cases. In
addition, there is no evidence that complete removal of benign lesions is good for the
patient. When benign lesions can be considered precursors for malignancy, they should
be surgically removed as for other premalignant lesions. Most benign lesions can be
treated medically as they are usually dispersed in the breast and hormone-dependent. The
rest of benign breast lesions need removal only to relieve the patient of psychological
stress or because of symptoms. Evidence indicates furthermore that increase in cancer
risk is related to the number and extent of breast interventions in the past. VACB and
other large core biopsy devices remain a useful tool in the diagnosis of breast cancer but
not for treatment purposes [447].
Diagnostic trends in medicine are being directed toward cellular and molecular
processes, where treatment regimens are more amenable for cure. Optical imaging is
capable of performing cellular and molecular imaging using the short wavelengths and
spectroscopic properties of light. Diffuse optical tomography is an optical imaging
technique that has been pursued as an alternative to X-ray mammography. While this
technique permits non-invasive optical imaging of the whole breast, to date it is
incapable of resolving features at the cellular level. Optical coherence tomography
(OCT) is an emerging high-resolution biomedical imaging technology that for larger and
undifferentiated cells can perform cellular-level imaging at the expense of imaging
depth. OCT performs optical ranging in tissue and is analogous to ultrasound except
reflections of near-infrared (NIR) light are detected rather than sound. OCT images of a
well-established carcinogen-induced rat mammary tumor experimental model show
strong correlation with corresponding histopathology. These results illustrate the
potential of OCT for a wide range of basic research studies and for intraoperative
imaging-guidance to identify foci of tumor cells within surgical margins during the
treatment of breast cancer [448].
The area of breast interventions has benefited from recent advances in devices and
imaging quality. As we have seen, ultrasound, MRI, stereotactic-guided vacuum-assisted,
and mechanical rotating stick freeze biopsy are the preferred methods for histological
diagnosis of breast lesions. Ablation techniques are available for the treatment of benign
and malignant breast disease. The MammoSite (Marlborough, MA, USA) balloon
catheter can be placed percutaneously for delivering high dose short term brachytherapy
[449]. The integration of imaging and thermal therapy can provide a minimally invasive
or even non-invasive alternative to breast surgery for small tumors. To be successful,
these therapies must achieve equivalent or even greater efficacy as surgical outcomes and
must demonstrate total ablation of the dominant lesion with negative margins, while
sparing normal tissue beyond the target tissue. Procedures have been validated by
histopathology subsequent to resection [450]. The various techniques used for
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percutaneous ablation of breast cancer include thermotherapy (radiofrequency ablation,
laser irradiation, microwave irradiation, and insonation with high-intensity focused
ultrasound waves), cryotherapy, and irreversible electroporation. The techniques used for
percutaneous ablation of breast cancer raise many questions and issues that must be
addressed before percutaneous ablation can be adopted for the treatment of early breast
cancer [451-453]. Although percutaneous ablation techniques have some promising
potential for less-invasive treatment of breast cancer, larger multicenter trials are needed
to confirm their efficacy, especially in comparison with the reference standard of
lumpectomy. The use of these techniques also leads to other remaining unanswered
questions, including how to manage the axilla and which patients are the best candidates
for these treatments [454].
Intraoperative evaluation of breast tissue has changed as newer imaging techniques
and surgical approaches to the treatment of breast cancer have placed the pathologist in a
pivotal role in the management of this disease. Assessment of the index lesion and
surgical margins are but two of the many tasks to face when the specimen arrives in the
surgical pathology laboratory. Pathologists are also called on to correlate changes in the
mammogram with the gross pathology, particularly in those cases in which the lesion is
non-palpable. Careful assessment of the gross specimen coupled with prudent utilization
of frozen sections is pivotal to reducing intraoperative error rates and preventing
needless anxiety for the patient [455, 456]. In breast-conserving surgery, the tumor
should be removed with a clean margin, a rim of healthy tissue surrounding. Failure to
achieve clean margins in the initial surgery results in a re-excision procedure. Reexcision rates are reported as being 11-46% for invasive carcinoma and DCIS. Reexcisions can have negative consequences such as increased postoperative infections,
negative impact on cosmesis, patient anxiety, and increased medical costs. Therefore, the
surgical margin of invasive and intraductal (DCIS) breast tissue is a subject of intense
discussion. Different options for intraoperative assessment are available, but all in all,
they are unsatisfying. Frozen section margin examination is possible but is timeconsuming and restricted to the assessment of invasive carcinoma. In the case of DCIS,
there is no procedure for intraoperative margin assessment. Thus, a solution for efficient
intraoperative surgical margin assessment is needed. For this purpose, an innovative,
real-time, intraoperative margin-assessment device (MarginProbe, Dune Medical
Devices, Caesarea, Israel) was designed, and recent published clinical data reported a
reduction of re-excisions by more than 50% [457-460]. Also several other techniques
such as WGL, intraoperative ultrasound-guided resection, radio-guided occult lesion
localization, and radioactive seed localization have been described and applied. The two
commonly used localization techniques are radio-guided occult lesion localization and
WGL [461].
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The majority of patients with non-palpable breast lesions are eligible for breastconserving surgery guided by some kind of lesion localization. The current standard is
WGL even though it has several disadvantages, the most important one being the
considerable proportion of patients with insufficient resection margin. These patients
require a reoperation. New methods in the field of radio-guided surgery have been
developed, including radio-guided occult lesion localization (ROLL) and radioactive
seed localization (RSL). Especially RSL is a very promising technique. Guided by
ultrasound, a small titanium seed containing typically 1-10 megabecquerels (MBq) of
radioactive iodine-125 (125I) is placed in the center of the non-palpable breast lesion.
During the operation, the seed is located with a hand-held gamma probe. To date, only
few cohort studies exist on the feasibility of RSL, and the method has only been tested in
one RCT. The results are either equal to or superior to those obtained with WGL, with
regards to achieving free margins and low reoperation rates. Additionally, the RSL
technique is less unpleasant for the patient and more flexible regarding preoperative
logistics. The seed can be placed a few days before surgery, in contrast to the wire used
in WGL, which has to be placed within few hours of surgery. RSL has quickly become
popular in surgical and radiological teams that have used the technique and will probably
become an important tool for preoperative localization of non-palpable breast lesions in
the near future [462]. ROLL is a possible alternative to the commonly used WGL of nonpalpable breast lesions. Intratumoral injection of a radiotracer identifies both the primary
tumor and the SLN for intraoperative gamma probe-guided dissection. The studies that
combined ROLL and the SLN procedure mentioned high percentages of radically
excised specimens ranging from 90-95% and an identification rate of SLN up to 100%.
ROLL seems a promising technique, which appears to be more radical than WGL.
Localization tends to be more accurate and faster, the excision procedure is more elegant
and simple to perform, and the cosmetic result seems to be better [463, 464]. A variety of
optical techniques utilizing NIR light are being proposed for intraoperative breast tumor
margin assessment. Immediately following a lumpectomy excision, the margins are
inked, which preserves the orientation of the specimen but prevents optical interrogation
of the tissue margins. A workflow allows for both NIR optical assessment following full
specimen marking using molecular dyes which have negligible absorption and scattering
in the NIR. The effect of standard surgical inks in contrast to molecular dyes for a NIR
signal is shown. Further, the workflow is demonstrated with full specimen intraoperative
imaging on all margins directly after the lumpectomy has been excised and completely
marked [465, 466]. Intraoperative breast margin assessment techniques have failed to
penetrate routine practice due to limitations, including slow reporting times, technical
demands, and logistics. Nevertheless, emerging intraoperative margin assessment
technologies are being developed to reduce positive margin and re-excision rates. Pooled
data suggest that frozen section and cytology have the greatest diagnostic accuracy.
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However, these methods are resource intensive and turnaround times for results have
prevented widespread international adoption. Emerging technologies need to compete
with the diagnostic accuracy of existing techniques while offering advantages in terms of
speed, cost, and reliability [467].
In summary, the institution of screening mammography protocols has increased the
number of suspicious breast abnormalities requiring diagnostic intervention. Up to 80%
of these lesions are benign, forcing the medical community to devise minimally invasive
techniques for tissue sampling. A reduction in the number of needle-localized open
breast biopsies reduces the morbidity and cost associated with imaging-detected breast
masses. Ultrasound, stereotaxis, and MRI are excellent modalities for detection of breast
cancers. Imaging-guided, large-CNB systems have been developed for each of these
imaging modalities, enabling successful and accurate tissue sampling and, ultimately,
diagnosis of a suspicious lesion. Care must be taken to ensure correlation between
imaging findings and pathological diagnosis: if the two are discordant, further
investigation is mandatory. There remains a role for needle-localized open breast biopsy,
although is has been reduced significantly. Some patients prefer this method of
diagnosis, and in others further investigation is required because of discordant findings.
When the documented pathology of the breast abnormality is atypical ductal hyperplasia,
atypical lobular hyperplasia, or LCIS, the patient should undergo surgical excision
because of the possibility of DCIS or invasive disease in the same area. Some lesions are
inaccessible with the current imaging modalities and biopsy systems available [468]. The
aim of the breast team is to obtain a definitive, non-operative diagnosis of all potential
breast abnormalities in a timely and cost-effective way. Percutaneous needle biopsy with
its high sensitivity and specificity should now be standard practice, removing the need
for open surgical biopsy or frozen section. For patients with cancer, needle biopsy
provides a cost-effective and rapid way of providing not only a definitive diagnosis but
prognostic information, allowing prompt discussion of treatment options, be they
surgical or medical. Early removal of uncertainty also allows better psychosocial
adjustment to the disease. Patients with benign conditions found either by themselves or
as a result of population or opportunistic screening can be promptly reassured and
discharged, removing the health care and psychological costs of surgical biopsy or
repeated follow-up. Radiologists involved in breast imaging should ensure that they have
the necessary skills to carry out core biopsy and/or FNA under all forms of imaging
guidance. Minimally invasive, imaging-guided biopsy for breast masses promises to
continue to evolve, enabling physicians to diagnose breast cancer with a high degree of
accuracy without significant morbidity [469-471].
Chapter VI
Breast Lymphadenectomy
Enlargement of breast RLN can be due to a variety of benign and malignant causes.
The most common malignant cause is invasive ductal carcinoma, which is usually
visualized with mammography. Excluding breast cancer, other causes of abnormal lymph
nodes that produce a negative mammogram include lymphoma, metastases from other
malignancies, and benign etiologies such as inflammatory processes, infectious diseases,
collagen vascular diseases, and miscellaneous causes [472]. ALN status is an important
prognostic indicator for women with breast cancer and ALND provides accurate
information regarding nodal status. In addition, local control of axillary disease and
allocation of adjuvant systemic therapy are dependent on appropriate axillary surgery.
The survival benefit of an ALND remains controversial. A technique of complete
axillary clearance includes levels I, II, and III. In the axilla, the lymphatic system usually
first drains into a group of low ALN (level I). The validity, as a staging procedure, of a
four-node axillary sample was demonstrated 40 years ago by Prof. Sir Patrick Forrest
[473].
This technique is associated with no additional morbidity to patients and incurs
minimal prolongation of operative time compared with a level II dissection. Other
operative descriptions of axillary surgery generally do not adequately describe a method
that clearly and consistently identifies the boundaries, anatomical landmarks, and
neurovascular structures that traverse the axilla. This technique, with relative ease,
allows the identification and preservation of these structures in their original anatomical
planes and avoids the division of the pectoralis minor muscle. The assumption that
routine level III axillary clearance, as opposed to level I or level II dissection, is
associated with greater morbidity warrants further evaluation [474]. The word “sentinel”
is defined in The Oxford English Dictionary as “a guard, one who keeps watch or a
sentry.” When translated to the concept of a tumor and its lymph node drainage, the SLN
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could be interpreted to mean the lymph node that guards or keeps watch over a tumor.
The SLN can thus be defined as the first lymph node that drains a primary tumor within
the regional lymphatic basin of that tumor. We know that tumor progression in breast
cancer often occurs in an orderly, progressive fashion. So, in theory, if the SLN is tumorfree, then the rest of the nodes in the lymphatic basin should also be uninvolved by the
tumor [475]. The concept of SLNB in breast cancer surgery relates to the fact that the
tumor drains in a logical way through the lymphatic system, from the first to upper
levels. Therefore, the first lymph node met (the SLN) will most likely be the first to be
affected by metastasis, and a negative SLN makes it highly unlikely that other nodes are
affected. Because ALND does not improve prognosis of patients with breast cancer
(being important only to stage the axilla), SLNB might replace complete ALND to stage
the axilla in clinically node-negative (N0) patients. SLNB would represent a significant
advantage as a minimally invasive procedure, considering that, after surgery, about 70%
of patients are found to be free from metastatic disease, yet ALND can lead to significant
morbidity. Furthermore, histological sampling errors can be reduced if a single SLN is
assessed extensively rather than few histological sections in a high number of lymph
nodes per patient. Although the pattern of lymph drainage from breast cancer can be
variable, the mammary gland and the overlying skin can be considered as a biological
unit in which lymphatics tend to follow the vasculature. Therefore, considering that
tumor lymphatics are disorganized and relatively ineffective, subdermal and peritumoral
injection of small aliquots of radiotracer, as we will see, is preferred to intratumoral
administration. Technetium-99m (99mTc)-labeled colloids with most of the particles in the
100- to 200 nanometers (nm) size range would be ideal for radio-guided SLNB in breast
cancer. Lympho-scintigraphy is an essential part of radio-guided SLNB because images
are used to direct the surgeon to the site of the node. The SLN should have a
significantly higher count than that of background (at least 10:1 intraoperatively). After
removal of the SLN, the axilla must be re-examined to ensure that all radioactive sites
are identified and removed for analysis. The SLN should be processed for intraoperative
frozen section examination in its entirety, based on conventional histopathology and,
when needed, immune staining with anticytokeratin antibody. The success rate of radioguidance in localizing the SLN in breast cancer surgery is about 94-97% in institutions
where a high number of procedures are performed and approaches 99% when combined
with the vital blue dye technique [476, 477]. The detection of metastases in SLN is
facilitated by the, now relatively routine, enhanced histopathological examination via
step-sectioning and IHC. In clinical terms, the finding of a metastatic deposit that
measures between 0.2-2 mm, that is “micrometastasis” in a SLN is largely noncontroversial. However, the presence of smaller metastatic foci detected either by routine
H&E stain or by cytokeratin immune-stain [less than 0.2 mm, i.e., so-called “isolated
tumor cells (ITC)”] has remained problematic since the advent of the SLNB. A broad
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morphological range of metastatic disease in SLN may be placed in the category of ITC.
To facilitate the reproducible classification of the various strata of minimal metastasis in
SLN, it is recommended the following:
1) the term “ITC” (in singular form) be restricted to cases that show the presence of
only a single tumor cell;
2) in situations where there are multiple isolated single cells and/or cell cluster(s)
present and each cluster measures less than 0.2 mm, the term “submicroscopic
metastasis” be adopted and an actual count of tumor cells present may be given;
and
3) restrict the use of the term micrometastasis to cases wherein the largest
metastatic focus is larger than 0.2 mm but smaller than 2.0 mm [478].
Metastatic foci to SLN have been classified into macrometastasis, micrometastasis,
and ITC in 2002, and the definition of ITC was modified in 2010. Clinical significance
of occult SLN metastases, being mostly composed of micrometastasis and ITC, has been
clarified in terms of predictive factors for non-SLN metastasis and patient prognosis by
large-scale retrospective studies and prospective RCT [479]. WHO reclassification of
axillary metastases into macrometastases, micrometastases, and ITC has highlighted the
issues of sampling and further histological examination of the initially negative SLNB.
Molecular detection of metastatic breast cancer cells in lymph nodes is now available as
a commercial kit for intraoperative use and can resolve the sampling issue [480]. ITC
and micrometastases represent low-volume or minimal disease in the RLN of breast
cancer patients as compared to macrometastases. SLNB is a functional selection and
removal of the most likely site of regional metastasis, and gives pathologists the
opportunity to concentrate detection techniques on a limited number of lymph nodes.
Consequently, more lesions belonging in the two mentioned staging categories are
discovered in SLN. Despite some publications contradicting stochastic models of breast
cancer, micrometastases seem to reflect a prognosis intermediate between the nodenegative and macrometastatic nodal status, and they also reflect a risk of non-SLN
involvement slightly higher than that associated with a node-negative status. Data are
more contradictory as concerns ITC [481].
Knowledge of the anatomy and physiology of the lymphatic system is helpful when
considering a particular SLNB technique. The delicate balance between internal and
external pressures in a lymphatic channel can be influenced by the injection volume and
by massage in a negative or positive way. The narrow openings in the interendothelial
junctions determine the speed of clearance of particles with a certain size, and this has
implications for the timing of lympho-scintigraphy and surgery. Tracer uptake and lymph
flow are highly variable and depend on a number of factors, some of which are beyond
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our control. The lymphatic anatomy is not completely understood despite numerous
studies since the end of the 18th century. Several topics have been elucidated in more
recent studies and through experience with SLNB. First, although axillary drainage is the
principal lymphatic path of the breast, any drainage pattern from any quadrant of the
breast can occur. Second, most lymph from the breast flows to the nodal basins with a
direct course, not passing through the subareolar plexus. Another relevant point is that
gentle massage encourages lymph flow and facilitates SLN detection. The optimum size
and number of labeled colloid particles remain to be established. The optimum volume of
the tracer also remains to be determined. But the main controversy concerns the injection
site. Although the intradermal injection technique has attractive practical features, there
is currently insufficient certainty that drainage of tracer injected anywhere in or
underneath the skin of the breast reflects drainage from the cancer. Connections between
collecting lymphatic vessels from the tumor site and the collecting vessels from the skin
and subdermal lymphatics can explain the concordance between intraparenchymal and
superficial injections in most patients. To determine the technique that yields the best
SLN identification rate with the lowest possible false-negative rate would require a large
RCT with all patients undergoing a complete lymph node dissection and evaluation of all
other ALN with serial sections and IHC. Current knowledge about sensitivity is based on
examination of the other ALN with H&E staining and not with IHC. In addition, a
complete level I to III dissection may not have been done in all patients, and it is not
certain that pathologists removed and examined all the nodes from the specimens. The
proposed study seems impossible now that routine ALND has been abandoned by the
larger centers around the world. Choosing the most attractive approach requires
determining the aim of lymphatic mapping. A superficial injection technique may be
adequate when the purpose is to spare patients without lymph node metastases in the
axilla an unnecessary ALND. An intraparenchymal injection technique should be used
when the additional purpose is to determine the stage as accurately as possible and to
identify SLN elsewhere [482, 483]. So-called “occult” micrometastases detected by such
methods have led to speculation that some may have reached the SLN by benign
mechanical transport (BMT) rather than a metastatic process. Two potential modes of
BMT are: lymphatic transport of epithelial cells displaced by biopsy of the primary
breast tumor and by breast massage-assisted SLN localization. The biopsy techniques
under most scrutiny include FNA and large-gauge CNB. The evidence implicating breast
massage prior to SLN biopsy as a mode of BMT has been supported by statistical
analysis. However, no method of distinguishing massage-associated cells in SLN from
true occult micrometastases is available. The significance of small epithelial clusters in
SLN is currently unknown. Thus, deviation from current biopsy and SLN-localizing
practices is unwarranted [484].
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Experimental evidence suggests that RLN are important in the initiation and possibly
the maintenance of tumor immunity. “Negative” nodes denote strong tumor immunity
and “positive” nodes low. The latter also serve as markers of systemic disease. From
histological and immunological studies, and mostly from recent clinical studies in breast
cancer, the following practical recommendations are made:
1) clinically positive ALN are best eliminated by surgery;
2) resection of positive internal mammary lymph nodes (IMLN) appears to increase
survival of patients with central and inner quadrant lesions, however, destruction
of these nodes by irradiation, although improving local disease control, may
decrease survival; and
3) negative RLN should be preserved, as they appear to prevent lymph node
metastases and stimulate systemic immunity.
Only a small fraction of unresected RLN harboring micrometastases will ultimately
develop palpable disease, and their elimination at that late phase yields the same results
as when these nodes are treated prophylactically [485]. The prime objectives of axillary
surgery in the management of breast cancer are:
1) accurate staging;
2) treatment to cure; and
3) quantitative information of metastatic lymph nodes for prognostic purposes and
allocation to adjuvant protocols.
It is generally agreed that ALN status in potentially curable breast cancer is
considered the single best predictor of outcome and the main determinant of allocation to
adjuvant therapy. No physical examination, no imaging techniques, and no molecular
biological markers can today replace ALN surgery for staging purposes. The objectives
of ALN surgery are best obtained by carrying out a complete ALN clearance.
Nonetheless, less radical surgery is generally performed by carrying out a sampling
procedure with a yield of about four nodes or a partial ALND level I-II and Rotter’s
nodes, without level III nodes, with at least ten nodes recovered. Understaging the axilla
is detrimental to outcome and, furthermore, loco-regional tumor control is important for
survival. Accuracy of staging is enhanced by IHC staining of micrometastases, which
pathologists can easily perform for one to three SLN, but not for 20 to 30 nodes, using
ALND procedure. Optimum methodology for performing SLN imaging is important for
accurate identification of SLN [486]. ALN surgery should therefore be conducted in
accordance with high professional standards [487].
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Lympho-scintigraphy has allowed the detection of alternate drainage patterns to
internal mammary, infraclavicular, and supraclavicular lymph nodes. Although patients
are occasionally identified who have metastases to these basins but not the axilla, this
information will not impact the decision for chemotherapy in most cases [488].
Metastases to the ALN, the IMLN, or both, define a group of patients at very high risk of
having systemic micrometastases leading to recurrent disease and death if surgical
therapy alone is used. In patients with breast cancer in whom both ALN and IMLN were
examined histologically, 5-10% had IMLN metastases in the absence of ALN metastases.
With the availability of effective systemic therapy that can improve the survival of
patients with operable breast cancer who have lymph node metastases, information
obtained from IMLN biopsies assumes practical significance. The management of IMLN
in breast cancer is controversial. IMLN are frequent mostly benign incidental findings.
However, they are clinically important because they can be the primary sites of
metastasis and SLN. Surgical series from the 1950s showed that one third of breast
cancer patients had IMLN involvement, with a higher risk in patients with medial tumors
and/or positive axillary nodes. Although, like the axilla, the IMLN are a first-echelon
nodal drainage site in breast cancer, the importance of their treatment has long been
debated. Seminal RCT have failed to demonstrate a survival benefit from surgical IMLN
dissection (IMLND), and several retrospective studies have shown that IMLN are rarely
the first site of recurrence. However, the recent widespread adoption of SLNB has
stimulated a critical reappraisal of such early results. Furthermore, the higher proportion
of screening-detected cancers, improved imaging and techniques (i.e., lymphoscintigraphy for radioguided SLNB) make it possible to visualize lymphatic drainage to
the IMLN. The virtually systematic application of adjuvant systemic and/or loco-regional
radiotherapy encourages re-examination of the significance of IMLN metastases.
Moreover, RCT testing the value of postmastectomy irradiation and a meta-analysis of
RCT have provided high levels of evidence that loco-regional tumor control is associated
with long-term survival improvements. This benefit was limited to trials that used
systemic chemotherapy, which was not routinely administered in the earlier studies.
However, the contribution from IMLN treatment is unclear. Lympho-scintigraphic
studies have shown that a significant proportion of breast cancers have primary drainage
to the IMLN, including approximately 30% of medial tumors and 15% of lateral tumors.
In the few studies where IMLN biopsy was performed, 20% of sentinel IMLN were
metastatic. The risk of IMLN involvement is higher in patients with medial tumors and
positive ALN. IMLN metastasis has prognostic significance, as recognized by its
inclusion in the American Joint Committee on Cancer (AJCC) staging criteria, and seems
to have similar prognostic importance as ALN involvement. Although routine IMLN
evaluation might be indicated, it has not been routinely performed, perhaps because
IMLN drainage with lympho-scintigraphy is more difficult to demonstrate than axillary
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drainage. This difference is due to technical reasons and not the absence of lymphatics to
the IMLN. Recent anatomical studies have confirmed a model of breast lymphatic
drainage that comprises superficial, deep, and perforating systems. The superficial
system drains to the axilla, usually to a lymph node posterior to the pectoralis minor
muscle. The deep system drains to the axilla and also anastomoses with the perforating
system which drains to the IMLN. The perforating system does not connect with the
superficial system. The prevalence of IMLN drainage tends to reflect the method of
lympho-scintigraphy, where peritumoral (deep lymphatic system) injections have a much
higher likelihood of IMLN drainage than subareolar or subdermal (superficial lymphatic
system) injections. The fused single-photon emission CT (SPECT)/CT images represent
a further technical solution to increase the identification of IMLN and consequently can
significantly reduce the false-negative rate of SLNB. Before mature results from current
and future RCT assessing the benefit of IMLN irradiation become available, lymphoscintigraphy and IMLN biopsy (IMLNB) may be used to guide decisions regarding
systemic and loco-regional treatment. However, even in patients with visualized primary
IMLN drainage, the potential benefit of treatment should be balanced against the risk of
added morbidity [489-498].
Although ALND is an excellent procedure for both staging and local control,
particularly in the clinically positive axilla, it has considerable morbidity and may
understage a significant proportion of patients, because it will usually miss
micrometastases that can occur in approximately 10% of “node-negative” patients. An
increasing number of patients whose tumors are either non-invasive (DCIS),
microinvasive, tubular cancers, or low-grade Stage I tumors without lympho-vascular
invasion may be spared axillary surgery because the risk of ALN disease is 0-3%. Many
studies, both prospective trials and large retrospective series, show that axillary
radiotherapy alone provides similar local control rates to axillary dissection in patients
with clinically negative axillas. Primary treatment of the axilla with radiotherapy alone,
however, does not allow appropriate staging and carries the same morbidity of surgery.
SLNB is being increasingly used in patients with breast cancer to provide this
information. When a SLN is identified, it is equal to or better than ALND for staging the
axilla and, if the node is positive, it will help select patients who should then proceed to
further axillary surgery or axillary radiotherapy [499]. So, a better understanding of the
loco-regional and systemic approaches to breast cancer over the past decades has altered
the perspective on surgical management of the axilla. An increased awareness of the
importance of early diagnosis and appropriate staging has focused further attention on
the extent of resection of ALN [500].
The diagnosis of ALN metastases remains a challenge in the management of breast
cancer and is a subject of controversy. Clinical node staging clearly is limited in the
assessment of ALN. Axillary mammography, ultrasonography, and CT do not provide
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histological information. Although nuclear MRI may have considerable value in the
diagnosis of ALN metastases, it does not detect micrometastases. The use of biological
markers in the assessment of ALN metastases remains a subject of investigation. On the
other hand, biopsy of selected ALN or tissue with examination of histology or cytology
generally would not identify a significant percentage of patients with ALN involvement.
SLNB, however, is useful for assessing ALN metastases [501]. Although the concept of
the SLN has existed for most of the 20th century, it was only in the last decades that,
developed initially for the treatment of malignant melanoma, lymphatic mapping and
SLNB have been introduced into the treatment of early breast cancer. This technique will
avoid the morbidity associated with more extensive axillary dissection. A wide range of
different methods and materials has been employed for lymphatic mapping, but there has
been little consensus on the most reliable and reproducible technique. Nuclear medicine
procedures have revealed a very interesting diagnostic potential in recent years. The
different approaches proposed in the literature for lymph node visualization are:
1)
2)
3)
4)
imaging with gamma-emitting tumor seeking agents;
radioimmune-scintigraphy intravenous (i.v.) or by the interstitial route;
lympho-scintigraphy with colloids and gamma probe SLNB; and
PET.
At present, lympho-scintigraphy with gamma probe SLNB and fluorodeoxyglucose18 (18FDG)-PET are the nuclear medicine approaches with the best diagnostic
performance. In addition, a final statement today should consider also the increasing
need to carry out an economical analysis by evaluating the cost-effectiveness of the
examinations [502]. Among the recently developed imaging modalities, (18FDG)-PET
has in particular been applied to the study of lymph node metastases in cancer patients.
Several clinical studies have been carried out to evaluate the accuracy of PET in the
axillary staging of operable primary breast cancer. These studies have sometimes
provided conflicting results, either supporting the possibility of using ( 18FDG)-PET to
select patients who need ALND or questioning whether (18FDG)-PET can accurately
assess the axillary status in primary breast cancer. Comparing ( 18FDG)-PET with SLNB
in the same series of patients, the results seem to indicate that the lower sensitivity of
PET is restricted to micrometastases. Of course, this limitation of PET has to be analyzed
in relation to the importance of such small axillary metastases for the outcome of patients
with breast cancer. The added value offered by PET in breast cancer staging in
comparison with intraoperative detection of the SLN lies in the fact that (18FDG)-PET is
a non-invasive procedure that allows, within a single examination, the biological
characterization of breast cancer and viewing of the entire body [503]. In the gamma
probe-guided method, the use of a large-sized radiotracer (particle size, 200-1000 nm)
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may be preferred because only one or two SLN are identified. To increase the chance of
finding metastases in SLN, it is desirable to make step sections with H&E staining on
permanent and frozen sections. The addition of IHC may improve the accuracy of SLN
diagnosis [504].
Knowledge of the important anatomical landmarks of the axilla is important in
finding and accurately reporting suspicious lymph nodes. The pathological features of
nodal metastases illuminate the imaging appearances of these nodes, as depicted with all
modalities. Preoperative axillary ultrasound and FNAC has recently been shown to
improve patient selection for SLNB [505]. Ultrasonography is the primary imaging
modality for evaluating ALN. Morphological criteria, such as cortical thickening, hilar
effacement, and non-hilar cortical blood flow, are more important than size criteria in the
identification of metastases. Ultrasound-guided lymph node sampling, especially with
CNB, is invaluable in confirming the presence of a metastasis in a suspicious node. So,
axillary ultrasound has increasingly been used to determine nodal status prior to surgery.
It has been shown to be a sensitive and specific modality in the detection of nodal
metastases. When combined with FNA, the specificity of this modality significantly
increases [506]. CNB has been shown to be equal in safety to FNA and has a
significantly lower false-negative rate. MRI is also useful, with the added benefit of
providing a global view of both axillae. CT and radionuclide imaging play a lesser role in
imaging the axilla. Non-invasive techniques such as paramagnetic iron oxide contrastenhanced MRI may provide genuine alternatives to axillary staging and should be
evaluated within clinical trials. Selective axillary surgery could then be offered based on
imaging findings and for therapeutic intent. This non-operative approach would reduce
morbidity further and facilitate interpretation of follow-up imaging. Modern imaging and
biopsy greatly help the axillary staging of breast cancer. Super-paramagnetic iron oxide
(SPIO)-enhanced MRI offers a further advance. SLNB may become redundant with
SPIO-enhanced MRI [507]. SPIO-enhanced MRI for the detection of metastases in SLN
localized by CT-lymphography (CT-LG) in patients with breast cancer is a useful
method of detecting metastases in SLN localized by CT-LG in patients with breast
cancer. Patients with clinically negative nodes may be spared even SLNB when the SLN
is diagnosed as disease-free using SPIO-enhanced MRI [508].
One of the most exciting current roles of SLNB is the ability to stage patients
intraoperatively, allowing a one-step ALND if the SLN contains metastatic carcinoma.
Furthermore, intraoperative assessment of SLN can now be performed rapidly and
accurately using the real-time GeneSearch Breast Lymph Node (BLN) Assay (Raritan,
NJ, USA). Currently, intraoperative evaluation of SLN is performed using imprint
cytology with or without rapid cytokeratin staining, frozen sectioning with or without
rapid cytokeratin staining, scrape preparations, or some combination of these techniques
[509]. Intraoperative imprint cytology (IIC) in the assessment of SLN allows immediate,
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cost-effective ALND. IIC diagnosis is accurate in up to 100% of grossly abnormal SLN.
Despite overall low sensitivity for grossly negative SLN, the benefits of immediate
complete ALND offset the increased risk of missing micrometastases or loss of ITC by
performing frozen section. IIC of the lumpectomy margins is rapid, accurate, and costeffective. It allows re-excision during initial surgery if needed with better cosmetic
result. It is a useful adjunct to and frequently a replacement for frozen section in many
centers [510]. However, many technical problems are correlated with the intraoperative
examination of the SLN and its sensitivity and specificity. In order to avoid the incidence
of false-positive or false-negative intraoperative diagnoses, the examination of SLN
under local anesthesia, awaiting its definitive analysis before carrying out tumorectomy
and/or axillary lymphadenectomy has been proposed [511].
There are two current techniques used to identify the SLN: radiopharmaceutical,
99m
Tc-sulfur colloid and isosulfan blue dye (used in the USA), and 99mTc-labeled albumin
and patent blue dye, used in Europe (the labeled albumin is not FDA-approved in the
USA). There is an ongoing debate over the best tracer injection technique in lymphatic
mapping for breast cancer. Excision of radioactivity that remains at the injection site in
the breast cancer prevents the gamma ray scatter that may hamper retrieval of a SLN.
The intralesional injection technique avoids potential injection of tracer fluid across a
lymphatic watershed, it enables identification of extra-axillary SLN and allows probeguided excision of non-palpable tumors [512]. There are reported side-effects from the
parenteral administration of dyes, which range from minor to life-threatening in severity.
There are differences between the dyes as regards their effects. Many dyes have been
used for SLNB with acceptable identification rates. There are variable side-effects for
each of those dyes [513]. Recently, methylene blue dye has been shown to be an
efficacious and cost-effective alternative to isosulfan blue. With the increasing
popularity of SLNB, the potential complications of isosulfan blue use must be
appreciated. The use of isosulfan blue due for SLNB is associated with a significant
number of allergic reactions, some of which are life-threatening. Because methylene blue
dye has been shown to be equally effective and does not pose a serious risk of allergic
reactions, it offers an improved technique above isosulfan blue dye for SLNB [514].
Furthermore, methylene blue is superior to isosulfan blue and Patent Blue V with respect
to false-negative rates. In order to standardize the SLNB technique, comparative trials to
determine the most effective blue dye and national guidelines are required [515].
However, blue dyes and radioactive colloids used for clinical SLN mapping are
associated with a few issues such as adverse side-effects and short retention time in SLN.
In recent years, nanoscale probes for non-invasive SLN mapping have received attention
due to their adaptable synthesis methods, adjustable optical properties, and good
biocompatibility. The aim is to understand the status of nanomaterials for SLN mapping,
challenging work and potential clinical translation in the future [516].
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SLN tissue can be studied by systematic serial sectioning technique designed to find
metastases of given diameters with specific probabilities. A procedure whereby three
microsections are prepared repeatedly at intervals of 250 micrometers (mcm) appears to
be practical. Two sections from each level can be examined by routine staining and the
third by IHC stain. The latter is recommended particularly for infiltrating lobular
carcinoma. This method will find metastases of 0.25 mm diameter with theoretical
probability of one, and metastases of 0.10 mm diameter with probability of 0.46, with
reasonable costs. Metastases of these sizes are consequential and worth finding on
biological and clinical grounds [517]. In the actual tumor, node, and metastasis (TNM)
classification, it was recently introduced a definition of a “pN0” patient based on SLNB
[518]. IHC and serial sectioning as used in the SLN procedure indeed induce a shift from
pN0 to pN1a (according to TNM). By the thorough pathological examination of the
SLN, isolated tumor cells and micrometastases are more frequently detected. It has been
proposed to classify small micrometastases (less than 0.5 mm) in a separate pN1a
minimal (min) category to prevent stage migration [519].
The limited number of SLN compared with an ALND has prompted more
comprehensive lymph node analysis increasing detection of micrometastases. National
data show that many women previously classified node-negative are now classified
minimally node-positive. As a result, our nodal classification and cancer staging have
evolved to recognize the continuum of nodal tumor burden rather than a simplistic
dichotomous stratification. It is quite clear that the more sections we evaluate from SLN
the more metastases we identify. However, it is impractical to expect the practicing
pathologist to mount, stain, and microscopically examine every section through the SLN
paraffin blocks. Despite recommendations from the College of American Pathologists
(CAP) and the American Society of Clinical Oncology (ASCO), heterogeneity in the
approach to SLN evaluation exists. What is needed is adherence to a standardized
evaluation protocol. The most important aspect of the SLN examination is careful
attention to slicing the SLN no thicker than 2.0 mm and correct embedding of the slices
to assure we identify all macrometastases larger than 2.0 mm. A single section from
blocks prepared in this manner will identify all macrometastases present but smaller
metastases will be missed. The prognostic significance of these missed micrometastases
is still being evaluated as we await SLN outcome studies. In the context of the new
molecular classification of breast cancer, subgroups may be identified where detection of
micrometastases has clinical significance. It is critical that both clinicians and
pathologists understand there is a random component to micrometastasis distribution
within the 3-D paraffin tissue blocks. If we ultimately adopt more comprehensive
microscopic evaluation of SLN, the candidate sampling strategies need to be carefully
considered in the context of statistically valid sampling strategies [520]. Several
guidelines relating to the histopathology of SLN, including the recent European Working
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Ciro Comparetto and Franco Borruto
Group for Breast Screening Pathology (EWGBSP) guidelines, advocate multilevel
assessment of grossly or intraoperatively negative SLN with levels separated by a
maximum of 1 mm and allow IHC in their assessment, although this latter method is not
mandatory. Both methods of intraoperative evaluation are allowable. There are also
minimum requirements for the reports on SLN histology. For example, the reports should
include the extent of nodal involvement, the method used for their identification, and
preferably the method used for investigating the SLN, even if the results are negative.
These guidelines are intended to form the basis for national guidelines in European
countries [521].
Radiotracer techniques play an important role in the preoperative and intraoperative
localization of the SLN. Optimal localization of the SLN requires the use of both
preoperative lympho-scintigraphy and intraoperative radiosensitive probes. Lymphoscintigraphy also identifies patients with lymphatic drainage to sites other than the axilla,
thereby allowing more appropriate treatment and follow-up in this subset of patients.
Procedures for localizing SLN require an understanding of the kinetics of the
radiopharmaceuticals or other tracers used and the detection devices employed in each
institution. Both surgical and nuclear medicine personnel should understand these
principles, and close cooperation between surgeons, nuclear medicine physicians, and
pathologists is essential for the application of SLN techniques [522]. Using radioisotope,
blue dye, or both methods, experienced surgeons can successfully localize SLN in more
than 90% of cases. The effects of isotope and blue dye may be additive. SLNB reliably
predicts ALN status in 98% of all patients and 95% of those who are node-positive. The
operation is best learned under a formalized protocol in which a backup ALND is
performed to validate the technique during the surgeon’s early experience. Enhanced
pathological analysis, including serial sections and IHC staining, is an essential element
of the procedure [523]. The optimal technique of lymphatic mapping utilizes a
combination of vital blue dye and radiolabeled colloid. In breast cancer patients,
harvested SLN are evaluated more thoroughly by detailed pathological examination
using serial sectioning, IHC, flow cytometry, and reverse transcriptase (RT)-PCR
techniques. This allows for the detection of smaller tumor volumes and leads to more
accurate staging. Lymphatic mapping has a 68-98% success rate in identifying the SLN.
The false-negative rate (defined as a negative SLN while a higher node or nodes in the
axilla are positive) is between 0-2%. The morbidity associated with this procedure is
minimal [524, 525].
SLNB to replace axillary dissection should only be performed by surgeons and
patient management teams with appropriate training and experience. Although both
radiocolloid and blue dye are used together by most surgeons, and training should be in
both techniques, some experienced surgeons use one or the other almost exclusively.
Imaging SLN with preoperative lympho-scintigraphy effectively assures successful SLN
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identification. However, SLN are still identified in the majority of imaging-negative
patients. Given the logistics and cost required to perform preoperative lymphoscintigraphy, its routine use may not be justified. It may be valuable for surgeons in the
learning phase and in obese patients who have increased risk of intraoperative failed
localization. A negative preoperative lympho-scintiscan predicts inability to localize with
the hand-held gamma probe. Patients with no “hot node” on the lympho-scintiscan are
more likely to have failed localization using the gamma probe only. Therefore, blue dye
should be used along with the gamma probe to optimize the localization rate in these
patients [526]. The central problem is that it is not possible to preoperatively predict
whether the SNB will be positive, and it is even more difficult to determine the
likelihood of non-SLN positivity. Various histopathological features indicate increased
risk of non-SLN metastasis, including size of SNB metastasis, presence of lymphovascular invasion, multifocality, number of involved SLN, and, conversely, the number
of negative SLN. These features have been combined to produce predictive nomograms
but, understandably, these still lack precision. Presently, the decision to avoid ALND
will depend upon both the clinician and the patient’s impression of risk, but if either
requires assurance that no residual axillary disease remains, a completion clearance will
be required [527]. In fact, although delayed ALND is the gold standard for evaluating
axillary status after identification of a positive SLN, between 40-70% of SLN-positive
patients will have negative non-SLN and undergo a non-therapeutic ALND. Accurate
estimates of the likelihood of additional disease in the axilla can assist decision-making
about further treatment. To predict non-SLN metastases in patients with a positive
SLNB, four different nomograms have been created. There are several published scoring
systems that contain different parameters to estimate the rate of non-SLN metastases in
SLN-positive patients. Despite having some limitations, the Memorial Sloan-Kettering
Cancer Center (MSKCC) nomogram is the most validated model to predict non-SLN
status accurately [528]. In addition, surgical pathologists must recognize the need to
examine these small specimens with great care, using a generally adopted protocol.
Imprint cytology or frozen sections may be used, followed by additional sections for
light microscopy. Immune-chemical staining with cytokeratin or other techniques to
identify “submicroscopic” metastasis is often used, but the results should not be used to
influence clinical decisions with respect to adjuvant therapy. “Failed” SLNB implies the
surgeon’s failure to identify the SLN, in which case a complete dissection is performed.
A “false-negative” SLNB implies the finding of metastasis in the excised SLN by light
microscopy after a negative frozen section examination. Whether a false-negative SLNB
mandates completion ALND is controversial, with clinical trials currently under way to
answer this question. Although SLNB was initiated to accompany breast-conserving
treatment, it is equally useful in patients undergoing mastectomy. It is more difficult to
perform with mastectomy. When using blue dye only, SLNB may require a separate
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incision because of time constraints between injection and identification of the bluestained nodes: radiocolloid usually does not. Completion ALND after false-negative
SLNB is more difficult after mastectomy. SLNB is a useful procedure that may save 70%
of women with clinically negative (N0) axillae and all of those with pathologically
negative axillae from the morbidity of complete ALND. Ideally, the SLN should be able
to be identified in more than 95% of patients, with a false-negative rate of less than 5%,
that is the target set by the 2005 guidelines of the ASCO. Until these rates can be
achieved consistently, however, surgeons should not abandon traditional axillary
dissection [529, 530]. Complementary use of radionuclide imaging before surgery,
intraoperative probe detection, and blue dye have yielded the best reported sensitivities
for finding a SLN (94%). The learning curve phenomenon, which applies to the surgeon
and the nuclear medicine physician, has been recognized: measures to minimize it are
being implemented. Radiation exposure to operating room and pathology personnel is
very low: estimates of exposure to the surgeon’s hands are 0.2% of the annual wholebody dose received by every human being from natural background and cosmic sources
[531].
The optimal route of injection of radiocolloids and dye is controversial. Despite the
accepted status of SLNB as the standard for axillary staging in breast cancer patients
with clinically and radiologically negative axillae preoperatively, there is surprisingly
still a lack of consensus on the most appropriate site of injection of radioactive tracer
with or without blue dye. When comparing intraoperative SLN identification and
concordance rates, it is not possible to compare “like with like” at different injection
sites (deep radioactive tracer vs superficial radioactive tracer, superficial blue dye vs
deep blue dye). This leads to inaccurate conclusions due to the different properties of
these materials. The only way to determine the optimal injection site of radioactive tracer
and blue dye for SLN identification intraoperatively and accurate concordance rates is by
direct comparisons of “like with like” when it comes to injected materials at different
injection sites [532]. Based on the classic definition of the breast lymphatic drainage and
recently published articles addressing the issue of peritumoral and intradermal injections,
a possible new and simplified approach using intradermal injection may identify the
axillary SLN more quickly and reliably [533]. Intradermal injection of tracers has
reported to be successful, suggesting that dermal and parenchymal lymphatics drain to
the same SLN. Extra-axillary drainage is only seen after peri- or intra-tumoral injection
[534]. Intradermal injection offers superior identification rates compared with
peritumoral injection, with comparable false-negative rates [535]. Although
controversial, current evidence suggests that subareolar or intradermal/subdermal
injection will map the same axillary SLN as peritumoral injection in the vast majority of
cases, is at least as successful, and is better logistically. Peritumoral, but not alternative
routes, identify extra-axillary SLN, which are important in a minority of patients. It is
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recommended that at least some of the radiocolloid be injected peritumorally to avoid
missing those SLN not located in the ipsilateral axilla. Injection of the dye and a portion
of radiocolloid in an intradermal/subdermal location is reasonable to take advantage of
the general ease and accuracy of intradermal/subdermal injections in identifying axillary
SLN [536]. A combination of peritumoral injection with radioisotopes and subdermal or
subareolar injection with blue dye may result in enhanced success rates of SLN
identification [537].
A complementary way forward is to analyze the primary breast cancer for molecular
markers with prognostic significance with reference to the risk for metastatic capacity
and thereby obtain a “biological staging” and identify those patients in need of systemic
adjuvant therapy. A large number of molecular biological factors have been shown to
have prognostic significance in breast cancer, e.g., c-erbB-2, p53, urokinase-type
plasminogen activator (uPA), plasminogen-activator inhibitor-1 (PAI-1), and vascular
endothelial growth factor (VEGF) [538]. Other parameters as molecular markers, nuclear
grading, patient age, and tumor size, are not able to predict the ALN status and
consequent local therapeutic approach similar to those provided by SLNB. The extent of
SLN metastatic involvement, the extracapsular spread, the size of primary tumor, and
peritumoral lympho-vascular infiltration are the four characteristics shown to be
significant, if considered in association and not separately as predictors of the extent of
axillary involvement in presence of a positive SLN. However, so far, specific studies did
not confirm concordant and reproducible results. Therefore, apart from controlled
studies, ALND is always required in presence of a metastatic SLN [539].
Conventional lympho-scintigraphy does not always define the exact anatomical
location of a SLN. The lymphatic drainage pattern may be unusual or may not be shown
at all. The recently introduced hybrid SPECT/CT imaging could help overcome these
difficulties. SPECT is a tomographic version of conventional lympho-scintigraphy and
the images have better contrast and resolution. When fused with the anatomical details
provided by CT into one image, a meaningful surgical “roadmap” can be created. So far,
there is little literature on the use of hybrid SPECT/CT in lymphatic mapping in patients
with breast cancer. All studies demonstrated an improved anatomical localization by
performing additional SPECT/CT: SLN outside the axilla or nodes close to the injection
site were especially easier to identify. SLN were visualized in 89-100% by combined
conventional imaging and SPECT/CT, with SLN depicted only by SPECT/CT in up to
14%. Limitations for SLN detection with SPECT/CT include extra time and
inconvenience for the patient and additional radiation dose. SPECT/CT is a valuable tool
for SLND, especially in difficult cases, when planar lympho-scintigraphy shows no SLN
or unexpected lymphatic drainage. It is concluded that SPECT/CT shows the exact
anatomical location of SLN, detects SLN not depicted by conventional imaging, and
therefore facilitates surgical exploration. The hybrid SPECT/CT has the potential to
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make image fusion a routine clinical tool that improves lymphatic mapping in patients
with breast cancer [540, 541].
One-step nucleic acid amplification (OSNA) is a novel method introduced for the
lymph node staging of breast cancer and has been tested in multiple series. The results of
this automated molecular assay based on the quantification of cytokeratin-19 (CK-19)
messenger ribonucleic acid (mRNA) show a 96% concordance rate with detailed
histopathology complemented with IHC when alternative slices of the same lymph node
are used for the two tests. The low false-negative rate makes OSNA suitable for the
intraoperative evaluation of SLN. The false-positive rate also seems very low. Most
discordant cases are explainable by low volume metastases (micrometastases), which
may be missing from the material submitted for one test, but not from the different part
used for the other test. It is tempting to change the gold standard for comparisons
between the methods, and if this is done, histology seems to come out as a weaker test
for the identification of metastases. OSNA detects more low volume nodal involvement,
but it is uncertain whether these require further axillary treatment, and this will be a
subject for future investigations. Therefore, it is also uncertain whether the advantage of
OSNA of detecting practically all metastases due to complete sampling of lymph node
tissue is clinically more important than the exclusion of metastases greater than
micrometastasis that can be reliably done by intraoperative microscopy followed by
permanent section histology [542]. Pooled analysis of recent studies comparing OSNA
with pathology indicated that OSNA is as accurate as pathology (96.3% concordance
rate) and is useful for making the decision to omit axillary dissection for OSNA-negative
patients [97.4% negative predictive value (NPV)]. The advantage of OSNA over
pathology is that the former allows the semiquantitative evaluation of total tumor volume
in the node when a whole node is examined. OSNA is expected to be a powerful tool for
the estimation of risk of non-SLN metastasis and also patient prognosis, though further
studies about this issue with larger numbers of patients is needed [543].
In conclusion, modern breast surgery, as the primary treatment of invasive breast
carcinoma, has been evolving over the last century. Aggressive radical surgery, which
included chest wall resection, complete axillary clearance, and IMLND, has slowly
changed to a less aggressive approach. This has been based on an improved
understanding of the biology of the disease. Over the years, prospective RCT, performed
at centers all over the world, have demonstrated that ALND does not impact on the
overall survival while it helps with loco-regional control of breast cancer. Its major role,
at the present time, is limited to staging and prognostication, functions that are equally
well served by the limited approach of a SLNB. There is no therapeutic role for extended
ALND at the current time [544]. In fact, the development of the dynamic technique of
intraoperative lymphatic mapping in the 1990s resulted in general acceptance of the SLN
concept. Most breast cancer patients are suitable for SLNB, and the large majority
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reported to date has had clinical stage T1-2N0 invasive breast cancers. SLNB will play a
growing role in patients having prophylactic mastectomy, and in those with “high-risk”
DCIS, microinvasive cancers, T3 disease, multifocal/multicentric disease and large
tumors, neoadjuvant chemotherapy, and male breast cancer. SLNB for the first time
makes enhanced pathological analysis of lymph nodes logistically feasible, at once
allowing greater staging accuracy and less morbidity than standard methods [545-547].
Most of the initially identified potential contraindications towards the procedure, such as
non-palpability, large tumor size, pregnancy, and being previously operated in the breast
or axilla, have been ruled out, whereas multifocality represents an unsolved problem.
There is no consensus about the best use of the technique in patients receiving
neoadjuvant treatment. There is no place for SLNB in pure DCIS, but it can be used for
large high-grade in-situ cancer diagnosed through CNB, especially if a mastectomy is
planned. Morbidity is low, and the recurrence rates reported so far are reassuring [548].
It is ironic that the extent, morbidity, and cost of a staging procedure (ALND) is more
than that of the surgical treatment of the primary tumor [549]. The SLN data in breast
cancer is so convincing that SLN information has been incorporated into the new AJCC
classification of breast cancer. After the revision of the AJCC staging system for breast
cancer in 2002, the evaluation of IMLN and determination of micrometastases by H&E
or by IHC have become increasingly important in staging of patients. The therapeutic
value of additional lymph node dissection after a positive SLN for breast cancer is still
controversial. Follow-up data from breast cancer patients is somewhat limited, but
available information shows that patients with negative SLN fare much better. In
summary, several important patterns of metastasis can be established based on the
current SLN experience:
1) the earlier the breast cancer is found, the less the metastatic potential;
2) in most cases, breast cancer follows an orderly progression of metastasis to the
SLN; and
3) a small subgroup of patients may develop systemic dissemination without SLN
involvement.
Since metastatic cancer is usually incurable, it is important for oncologists to detect
and resect an early breast cancer without delay. The challenge in the future will be to
dissect these different patterns of metastasis based on molecular or genetic markers.
Such information will be critical to select high-risk patients for adjuvant therapy [550,
551].
The SLN concept agrees with the modern principles of surgical oncology in breast
cancer, which are related to lymphatic dissection, accurate axillary study, and less
traumatic surgery. After publication of many series, it has proven its capacity to correctly
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stage axilla and select patients who need ALND. However, the transportation of new
surgical techniques from research to practice always occurs with some ethical dilemmas
related to its introduction in clinical practice [552]. If a patient requests or is offered
SLNB, the benefits and risks as well as what is and is not known about the procedure
should be outlined. Patients should be informed of the number of SLNB performed by
the surgeon and the surgeon’s success rate with the procedure, as determined by the
identification of the SLN and the false-negative rate (the presence of tumor cells in the
ALN when the SLNB result is negative). Before surgeons replace ALND by SLNB as
the staging procedure at their institution, they should:
1) familiarize themselves with the literature on the topic and the techniques needed
to perform the procedure;
2) follow a defined protocol for all three aspects of the procedure (nuclear
medicine, surgery, and pathology); and
3) perform backup ALND until an acceptable success rate (as determined by the
identification of the SLN and the false-negative rate) is achieved.
A surgeon who performs breast cancer surgery infrequently should not perform
SLNB. There is considerable argument concerning the number of SLNB cases with
ALND that surgeons should perform before they are eligible on abandoning ALND in
negative SLN patients. The number of procedures of the learning curve can not be fixed
for all surgeons. Only surgeons in specialized breast cancer centers can succeed in
meeting current recommendations with 20-30 cases. Surgeons from affiliated community
hospitals will need more than 30 cases, whereas broad-based surgeons might need as
many as 60 cases with their current caseload. Not all surgeons will be able to offer the
procedure to their patients by the current recommendations. Women without SLN
metastases should not receive ALND. Women with one to two metastatic SLN planning
to undergo breast-conserving surgery with WBI should not undergo ALND (in most
cases). Women with SLN metastases who will undergo mastectomy should be offered
ALND. These three recommendations are based on RCT. Women with operable breast
cancer and multicentric tumors, with DCIS who will undergo mastectomy, who
previously underwent breast and/or axillary surgery, or who received
preoperative/neoadjuvant systemic therapy may be offered SLNB. Women who have
large or locally advanced invasive breast cancer (tumor size T3/T4), inflammatory breast
cancer, or DCIS (when breast-conserving surgery is planned) or are pregnant should not
undergo SLNB. These recommendations are based on cohort studies and/or informal
consensus. In some cases, updated evidence was insufficient to update previous
recommendations [553, 554]. Recent studies have shown that it is not only the absolute
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number of involved SLN, but also the ratio of metastatic to examined SLN [or SLN ratio
(SLNR)] that confers prognostic information [555].
There is no consensus regarding the strategy for managing the RLN in patients with
local breast cancer recurrence. The success rate of re-SLNB after previous surgery
depends on the method used for the previous axillary surgery and the number of lymph
nodes harvested. Re-SLNB may be feasible even after mastectomy. A longer disease-free
interval may correlate with a lower identification rate, but this finding is not definitive.
Based on data regarding back-up dissection after re-SLNB, the accuracy of re-SLNB may
be as good as SLNB in primary cases. Because the altered lymphatic drainage can be
detected only by lympho-scintigraphy, the radioisotope method, followed by lymphoscintigraphy, should be used. There are not many reported cases of axillary recurrence
after re-SLNB, and the follow-up periods have been short. Because re-SLNB cases have
a wide variety of backgrounds, it is necessary to accumulate a larger number of cases and
to obtain data from longer follow-up period in order to make clear recommendations
[556]. The increasing use of neoadjuvant chemotherapy for operable breast cancer has
raised questions about optimal local therapy for the axilla. SLNB after neoadjuvant
chemotherapy in patients presenting with clinically negative nodes has an accuracy
similar to upfront SLNB and reduces the need for ALND compared with SLNB prior to
neoadjuvant chemotherapy. In patients presenting with node-positive disease, clinical
trials demonstrate that SLNB after neoadjuvant chemotherapy is accurate when three or
more SLN are obtained, but long-term outcomes are lacking. The relative importance of
pre- and post-neoadjuvant chemotherapy stage in predicting risk of loco-regional
recurrence remains an area of controversy. Neoadjuvant chemotherapy reduces the need
for ALND, and SLNB is an accurate method of determining nodal status after
neoadjuvant chemotherapy [557-565].
Chapter VII
Endoscopic Breast Surgery
Endoscopic surgery has been extensively used for many surgical conditions and has
gained acceptance as an alternative and less invasive approach to open surgery.
However, minimal access endoscopic techniques have yet to be translated into
mainstream clinical practice in breast surgery. More recently, technical innovations have
made it feasible to conduct endoscopic breast cancer resection, with or without breast
reconstruction, through wounds inconspicuously hidden in the axilla and periareolar
region. Several clinical trials have now been conducted to demonstrate technical
feasibility, assess safety, and provide follow-up data regarding oncological success of
endoscopic breast surgery. Initial results have demonstrated that endoscopic breast
surgery is safe and technically feasible. Early data suggests that it is possible to achieve
disease control with high rates of overall survival and low rates of local relapse,
recurrence, and/or distant metastases [566]. Since 1992, video-assisted surgery for the
breast has been developed mainly in the field of plastic surgery, notably in breast
augmentation surgery. The surgical technique for mammary reconstruction using tissue
expander with endoscopic approach, associated to partial detachment of the pectoralis
muscle at the fourth rib and complete or nearly complete intraoperative expansion is a
well-honored technique that provides satisfying aesthetic outcomes, with minimal
morbidity for the patient. Nevertheless, this technique has some potential problems:
1) wound dehiscence with extrusion of the expander;
2) patient discomfort during the expansion process (weekly visits for the refill of
the expander); and
3) the poor definition of the lower pole of the breast and cranial migration of the
expander with excessive roundness of the upper pole.
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By using intraoperative tissue expansion, these drawbacks can be avoided [567].
Today, video-assisted surgery, indicating partial or total endoscopic surgery, can be
performed for the treatment of both benign and malignant breast tumors to improve the
cosmetic outcome. Although, in some respects, this kind of surgery for malignant tumors
is still experimental, it is feasible enough for clinical use, and is expected to become one
of the standard operations for breast cancer [568]. Mammoscopy seems to be a very
promising technique that allows evaluation of implant integrity and documentation of the
condition of breast implants in-situ. It is a useful tool in the evaluation of intercapsular
conditions in the augmented and reconstructed breast. Because of the limitations of
capsular space, however, there is a greater possibility of implant disruption when
multiple manipulations are attempted through separate ports of entry. It is best to use the
endoscope for visualization and documentation and to minimize the amount of
manipulation that has to be done through other ports for fear of rupturing the implant.
Endoscopy is a limited procedure best suited for documentation and evaluation rather
than endoscopic surgical procedures, particularly when capsulotomy and capsulectomy
can be done more readily under direct vision through a slightly larger incision [569]. The
use of subcutaneous endoscopy has allowed to dissect and perform sophisticated
procedures in the subcutaneous space [570].
Genetic analysis using comparative genetic hybridization has shown evidence that
the majority of benign and malignant lesions of the breast, approximately 85%, arise
from the epithelium of the terminal duct-lobular unit with normal cells progressing to
atypia and finally to carcinoma. Although modern mammography, ultrasound, and MRI
have improved diagnosis, a final pathological diagnosis currently relies on percutaneous
methods of sampling breast lesions. Mammography, which is currently the main
screening modality for early detection, has a low positive predictive value (PPV) of only
25%, especially in young women with very dense breasts. Therefore, new screening
approaches are needed for the early detection of breast cancer in all age groups. Two
related techniques of breast epithelial sampling have emerged in the past several years:
ductal lavage, in which fluid-yielding nipple ducts are cannulated at their orifices and
lavaged with saline while the breast is intermittently massaged, and ductoscopy, in which
discharging or fluid-yielding duct orifices are dilated, intubated with a microendoscope,
and the lumen directly visualized. This may aid in detection of breast masses long before
they are palpable or visible via mammography. Both of these techniques have significant
potential in terms of allowing the repeated sampling of ductal epithelium over time and,
as such, have generated considerable enthusiasm. However, data regarding the impact of
these techniques on the detection of significant breast disease is very scant. It is
important at the outset of the assessment of this new technology that breast cancer
clinicians and clinical researchers think carefully about the standards of evidence that
need to be met regarding the benefits of these procedures before they are widely adopted
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[571, 572]. Mammary ductoscopy has been used as a tool to evaluate the breast for
cancer for over 20 years. It allows direct visualization of the mammary ductal system
where most cancers originate using submillimeter fiberoptic microendoscopes inserted
through the ductal opening onto the nipple surface, and that produces sharp and clear
video images and ductal washings for cytological analysis, providing a more targeted
approach to the diagnosis of disease arising in the ductal system, since the lesion can be
visualized and samples collected in the area of interest. Mammary ductoscopy is a useful
diagnostic adjunct in patients with pathological nipple discharge. The procedure can be
performed under local anesthesia in the rapid intervention and outpatient setting.
Furthermore, it can reduce the number and extent of duct excision operations for
pathological nipple discharge. Abnormalities can be identified successfully by mammary
ductoscopy, and intraductal biopsy can be used when the tumor is a polypoid type.
Ductal lavage using microcatheters is effective in identifying malignant cells in high-risk
women and this has stimulated interest in exploring the role of mammary ductoscopy in
breast cancer screening. There is a growing body of evidence that mammary ductoscopy
combined with ductal lavage may have a role in the management of women with
pathological nipple discharge, the guiding of breast conserving surgery for cancer, and
the screening of high-risk women. The addition of molecular and genetic analysis of cells
obtained by mammary ductoscopy are likely to enhance the use of this technique.
Mammary ductoscopy techniques are safe and appear useful for detecting abnormalities
in the breast. The additional molecular biological study or ductal lavage may enhance the
ability to direct and limit subsequent surgery when removing the offending lesions.
However, its potential use in the early detection of breast cancer, guiding breastconserving surgery for cancer, therapeutic ablation of intraductal disease, and guiding
risk-reducing strategies among high-risk women requires further research and evaluation.
Cytological assessment of mammary ductoscopy is highly specific but less sensitive in
the detection of breast cancer. Nonetheless, a mammary ductoscopy sample from a breast
with pathological nipple discharge may rarely undergo cytological review and be
interpreted as consistent with malignancy, only later to undergo surgical resection
demonstrating benign pathology. For this reason, pathological nipple discharge
specimens interpreted as malignant on cytological review require histopathological
confirmation prior to instituting therapy. Additional sample evaluation using image or
molecular analysis may improve the sensitivity and specificity of mammary ductoscopy
in breast cancer detection. The development of a biopsy kit that obtains adequate
microbiopsy samples for histological diagnosis under direct visualization, combining
mammary ductoscopy with molecular diagnostic markers and real-time optical biopsy
system for the diagnosis of premalignant and early malignant disease and radiofrequency
for curative ablation of intraductal lesions, will enhance the use of this technique by
breast surgeons and radiologists. Further research is required to confirm these potential
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applications. Furthermore, the addition of molecular and genetic analysis of cells
obtained by mammary ductoscopy for diagnostic markers and the emergence of newer
generations of microendoscopes with optical biopsy systems for the diagnosis of
premalignant and early malignant disease are likely to enhance the use of this technique
[573-578].
The intraductal approach to breast cancer and premalignant lesions has now
developed to yield substantial cytological samples of exfoliated cells. Standard cytology
is still inadequate in sensitivity and specificity to accurately interpret the majority of
samples. As techniques evolve using ductoscopic biopsy and molecular marker panels to
increase accuracy of cytological interpretation, these tools will be able to unravel the
breast carcinogenesis pathways. They will also offer considerable benefit in screening
for premalignant changes and developing effective chemoprevention strategies [579,
580]. Recent technical development of ductoscopes and microinstruments is shifting
research interest from diagnostic to interventional ductoscopy. Diagnostic ductoscopy is
performed by many breast physicians worldwide. Interventional ductoscopy, however,
depends on an additional working channel and a variety of microinstruments of 0.4-0.8
mm for procedures inside the breast duct. Autofluorescence ductoscopy is a new imaging
technique used on an experimental base for clinical evaluation to identify intraductal
lesions. Laser ductoscopy for removal of intraductal papillomas and 3-D intraductal
tracking systems are future projects. Technical innovation and further miniaturization of
instruments is supporting a change from diagnostic to interventional ductoscopy. A
therapeutic intraductal approach as well as autofluorescence endoscopy could potentially
eliminate unnecessary biopsies and offer better identification of intraductal lesions [581].
The advantage of mammary ductoscopy is that it is possible to gain direct access to the
ductal system via the nipple. Direct visualization of the duct epithelium allows the
operator to precisely locate intraductal lesions, enabling accurate tissue sampling and
providing guidance to the surgeon during excision. The intraductal approach may also
have a role in screening individuals who are at high risk of breast cancer. Finally, in
spontaneous nipple discharge, as biopsy instruments improve and intraductal
therapeutics, such as intraductal excision and laser ablation, become a possibility, normal
or benign ductoscopic findings may help minimize surgery in selected patients. Duct
endoscopes have become smaller in diameter with working channels and improved
optical definition. Currently, the role of mammary ductoscopy is best defined in the
management of spontaneous nipple discharge facilitating targeted surgical excision,
potentially avoiding unnecessary surgery, and limiting the extent of surgical resection for
benign disease. Few prospective RCT exist in the literature, and these would be crucial
to validate current opinion, not only in the benign setting but also in breast oncological
surgery [582].
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In summary, endoscopy is a new tool in the armamentarium for surgery of the breast.
Endoscopic techniques may offer decreased scarring and morbidity rates for a variety of
aesthetic and reconstructive procedures. Whereas initial clinical experiences are
encouraging, most endoscopic procedures of the breast remain developmental, both in
technique and instrumentation. Additional development, refinement, and experience will
be required to define fully the utility of endoscopic techniques [583].
Chapter VIII
Prophylactic Breast Surgery
Increased understanding of risk factors for breast cancer, especially the identification
of genes associated with a predisposition to breast cancer, has focused attention on the
issue of breast cancer prevention [584]. Multiple factors which increase a women’s
breast cancer risk have been identified. These range from conditions such as LCIS,
which increase risk to relatively high levels, to reproductive factors such as nulliparity,
which are associated with only a small increase in risk. When determining an
individual’s risk, all her potential breast cancer risk factors must be considered. In order
for risk information to be meaningful to a woman, risk must be expressed as absolute risk
over a defined time interval, since there is no uniform agreement on what risk level is
high enough to require intervention. At present, careful follow-up or prophylactic
mastectomy are the best management options available for the woman at increased risk.
The efficacy of follow-up including breast self-exam, physician exams, and screening
mammography for early detection of cancer in a high-risk population is known.
Prophylactic mastectomy, while highly effective, does not provide complete protection
from breast cancer and is more radical than the surgery done for established cancer in
many cases. Which of these options is chosen by an individual woman is dependent on
how much risk she is willing to assume [585]. Therefore, at present, the care of women
at increased risk of developing breast cancer poses a clinical dilemma and remains an
area of controversy. A number of investigators have addressed the pros and cons of
prophylactic mastectomy versus close follow-up, utilizing annual mammography, semiannual or even more frequent physical examinations of the breast, and proficient monthly
breast self-examinations. Recent efforts to isolate a gene (BRCA1) on chromosome
17q12-21 raise additional concerns about the management of women testing positive for
BRCA1 mutations. These women are estimated to have an 85% lifetime risk of
developing breast cancer. In addition, women with a strong family history opting against
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testing for BRCA1 mutations may express interest in surgery [586]. Five to 10% of
breast cancer is attributable to the autosomal dominant inheritance of a high-risk
susceptibility gene. There are a number of known inherited cancer syndromes that confer
a higher risk of breast cancer. In 1994, the BRCA1 gene, which is responsible for 45% of
hereditary early-onset breast cancer and for the majority of coinheritance of breast and
ovarian cancer, has been cloned and, since 1996, genetic testing for these mutations has
been clinically available. Another gene that confers an increased risk of breast cancer is
the BRCA2 gene, which maps to the long arm of chromosome 13 by linkage analysis.
Mutations in BRCA2 account for approximately 40% of hereditary early-onset breast
cancer. In addition, at least 7% of breast cancer may occur in women who are
heterozygous for mutations in a gene for ataxia-telangiectasia (ATM), an autosomal
recessive chromosome instability syndrome. Predictive testing for some predisposing
conditions is possible through indirect or direct mutation testing [587].
Molecular alterations in proto-oncogenes, tumor-suppressor genes, and genes that
function in DNA damage recognition and repair are considered to be hallmarks of a
carcinogenic process, including breast carcinogenesis. The functions of the BRCA
proteins are not fully understood, although it is clear that they play a role in the control
of transcription, regulation of the cell cycle, and management of DNA damage. Genetic
risk factors and family history play an important role in breast cancer development.
Inherited genetic susceptibility to breast cancer can be due both to genes which confer a
high degree of risk and to polygenes which have a smaller effect on disease risk.
Although a greater proportion of inherited breast/ovarian cancers are due to the BRCA1
and BRCA2 mutations, a number of new genes have emerged as susceptibility
candidates, including rare germline mutations in high penetrance genes, such as p53 (LiFraumeni syndrome) and phosphatase and tensin homolog (PTEN, Cowden disease), and
more frequent mutations in moderate/low penetrance genes, such as partner and localizer
of BRCA2 (PALB2), checkpoint kinase 2 (CHEK2), ATM, DNA mismatch repair
adenosine 5’-triphosphatase (ATPase) 1 (MSH1) or mutL homolog 2 (MLH2)
[hereditary non-polyposis colo-rectal cancer (HNPCC) or Lynch syndrome], CHEK2,
caspase 8 (CASP8), peripheral-type benzodiazepine receptor (PBRL), and BRCA1interacting protein 1 (BRIP1). Moderate-risk genes associated with syndromes that are
inherited in an autosomal dominant pattern (such as Cowden disease, HNPCC, MuirTorre syndrome, and Peutz-Jeghers syndrome) exhibit lower penetrance and thus less
risk of breast and/or ovarian cancer. Several other less frequently occurring
predisposition genes such as Harvey rat sarcoma (HRAS) or the ER gene, the androgen
receptor (AR) gene, and cytosine-adenine-guanine (CAG) repeats of AR, as well as
reproductive and hormonal factors may also be involved and may therefore modify
cancer risk, but to a lesser extent. Other cancer-related genes [including
myelocytomatosis (myc), c-erbB2, tumor susceptibility gene 101 (TSG101), and
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mammary-derived growth inhibitor (MDGI)] are involved in breast carcinogenesis, but
they do not give rise to familial breast cancer syndromes. Multi-gene testing, if used
appropriately, is generally a more cost- and time-effective method than single-gene
testing, and may increase the number of patients who can be offered personal
surveillance, risk-reduction options, and testing of high-risk family members. Recent
advances in molecular genetics testing have identified a number of susceptibility genes
related to hereditary breast and/or ovarian cancers other than BRCA1 and BRCA2. The
introduction of multi-gene testing for hereditary cancer has revolutionized the clinical
management of high-risk patients and their families. Individuals with hereditary
breast/ovarian cancer will benefit from genetic counseling/testing [588]. Thus, the
hereditary breast and ovarian cancer (HBOC) syndrome includes genetic alterations of
various susceptibility genes such as p53, ATM, PTEN or MSH2, MLH1, protein
homolog mismatch repair system component (PMS)1, PMS2, MSH3 and MSH6, and
BRCA1 and BRCA2. Germline mutations of the cancer-susceptibility genes BRCA1 and
BRCA2 seem to be the major etiology of the HBOC. Male carriers have a moderately
increased risk of prostate cancer. Genetic counseling and identification of high-risk
families may be essential:
1) to provide the best method for genetic testing by explaining the sensitivity and
specificity of the methods;
2) to offer the opportunity to participate in specific early cancer detection programs
[breast (self) palpation, ultrasound, mammography, and MRI tomography for
breast cancer, and vaginal exploration and ultrasound for ovarian cancer];
3) to inform them about prophylactic medication (oral contraceptive pill),
chemoprevention (TMX, raloxifen, and aromatase inhibitors) or surgery
(bilateral prophylactic mastectomy or salpingo-oophorectomy); and
4) to provide individualized psychological support.
To fulfill these broad demands, an interdisciplinary counseling approach
(gynecological oncology, human genetics, molecular biology, and psychotherapy) in the
setting of a cancer genetic clinic seems the most appropriate. There, participation in
predictive genetic testing or the use of preventive or therapeutic options may be
discussed extensively with the subjects. In particular, preventive options are emotionally
disturbing for the subjects, and in cases of previous cancer. Breast cancer
chemoprevention for high-risk women does not seem to be as effective as expected.
However, oral contraceptive pill reduces the risk for ovarian cancer. For prophylactic
surgery, various points have to be considered, including:
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1)
2)
3)
4)
individual risk assessment and gain in life expectancy;
value of screening and early detection methods or medical prevention;
disease characteristics and prognosis; and
anxiety and quality of life.
Decisions regarding these options have to be individualized and psychological
support must be offered during the period of decision and follow-up [589]. The risk of
breast and ovarian cancer by age 70 in a BRCA1 mutation carrier is estimated at 55-75%
and 16-26%, respectively, overall, and as high as 87% and 44% in those with a strong
family history. The cancer risks associated with BRCA2 mutations appear to be
somewhat lower than those of BRCA1. BRCA mutations show a strong founder effect.
This is best recognized in the Ashkenazi Jewish community, in which the incidence of
one of three characteristic mutations is about 2%. In other ethnic groups, the pattern of
mutations is different, with over 100 distinct mutations throughout the genes having been
described. Most mutations so far have been frame-shift or mis-sense mutations, although
large deletions have also been described. Thus, in most situations, assessment of the
whole coding sequence is required to confirm or exclude a mutation. Microarray geneexpression studies show that breast tumors from BRCA1 carriers are predominantly of
basal subtype (i.e., triple-negative) and BRCA2 carriers are of luminal subtype (i.e., ERpositive). Guidelines to suggest who is likely to be a mutation carrier are being clarified,
but the appropriate management of someone who tests positive remains difficult.
Prophylactic mastectomy and salpingo-oophorectomy are likely to offer substantial gains
in life expectancy to mutation carriers, especially for young women with a strong family
history. Unfortunately, there are no currently available strategies to eliminate the risk of
breast or ovarian cancer. The psychological impact of testing also remains poorly
understood, and the danger of various forms of discrimination remains too. These factors
must be clearly understood by all parties prior to testing. The process of a dynamic,
interactive informed consent – much more than a simple printed document – and also
counseling is central to the testing process [590]. Yet, many women with a personal or
family history suggestive of a hereditary susceptibility to breast cancer undergo genetic
testing and no significant genetic alteration is found. Thus, there are other susceptibility
genes that have not been identified, and it is likely that the remaining familial
contribution to breast cancer will be explained by the presence of multiple low
penetrance alleles that coexist to confer high penetrance risks (a polygenic model). The
American Cancer Society (ACS) has identified cancer prevention as a key component of
cancer management and there is interest in developing individualized cancer prevention
focused on identifying high-risk individuals who are most likely to benefit from more
aggressive risk-reduction measures. Breast cancer risk assessment and genetic counseling
are currently provided by genetic counselors, oncology nurse specialists, geneticists,
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medical and surgical oncologists, gynecologists, and other health care professionals,
often working within a multidisciplinary clinical setting. Current methods for risk
assessment and predictive genetic testing have limitations and improvements in
molecular testing and risk assessment tools is necessary to maximize individual breast
cancer risk assessment and to fulfill the promise of cancer prevention [591].
Low-risk genes likely require significant environmental exposure, and although they
are associated with the lowest risk of cancer, they account for more cancer than highand moderate-risk genes. Lifetime risks for breast or ovarian cancer can be estimated.
The Gail and Claus models are the more widely utilized models for calculation of
lifetime breast cancer risk. Models are also available for determining the likelihood of
finding a BRCA1/2 mutation (the BRCAPRO and Myriad models). Appropriate
candidates for testing include affected individuals (women, but occasionally men) who
are most likely to have a hereditary form of cancer. Testing should proceed only after a
thorough discussion of the risks, benefits, and limitations of testing. Risk-reducing
options are available to women with a strong family history of breast and ovarian cancer.
These options include high-risk screening, chemoprevention, and prophylactic surgery
[592]. Women at particularly high risk of developing breast cancer represent a group in
whom expensive and rigorous screening programs are cost-effective and who may
benefit from trials of chemoprevention. There are only preliminary data on the efficacy
of increased surveillance and on risk reduction due to prophylactic surgery. However, for
chemoprevention to be equivalent to prophylactic mastectomy, it will be necessary to
strive for an equivalent reduction. The efficacy of chemoprevention in this high-risk
population is unknown. Existing and new agents for chemoprevention need to be
carefully assessed in properly designed clinical trials among such women. In the process,
other factors modifying the penetrance in mutation carriers need to be taken into account
in order to evaluate the true effect of the chemopreventive agents. Polygenes confer
much lower levels of risk and may be relevant for risk assessment when the effects of
multiple loci, possibly in conjunction with environmental factors, are understood and
quantified. At present, it seems unlikely that the genetic information at single polygenes
will be clinically relevant for risk assessment and management [593].
Breast cancer occurs in hereditary and sporadic form. However, not all mutations
will lead to breast cancer, and to prevent unnecessary surgery, assays to determine which
mutations adversely affect the functions of the protein encoded by the BRCA genes are
being developed. The functions of BRCA1 are mediated by numerous interactions that
are required for cell-cycle and centrosome control, transcriptional regulation, and the
DNA damage response. Mis-sense mutations that perturb the interactions of BRCA1 will
adversely affect these functions and are, therefore, likely to lead to breast cancer [594].
BRCA1 mutations are rare in sporadic cancers, but loss of BRCA1 resulting from
reduced expression or incorrect subcellular localization is postulated to be important in
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non-familial breast cancers. More than 300 germline mutations have been identified so
far in patients with familial breast and/or ovarian cancer, however, only a few somatic
mutations have been identified in sporadic breast cancer. The decreased expression of
BRCA1 in sporadic breast cancer is thought to be caused by other mechanisms, such as
5’-cytosine-phosphate-guanine-3’ (CpG) methylation. BRCA1 expression may play an
important role in the pathogenesis and prognosis of sporadic breast carcinoma [595]. The
“cancer stem cell” (CSC) hypothesis proposes that tumors arise in stem or progenitor
cells generating in tumors driven by a subcomponent that retains CSC properties. Recent
evidence supports the hypothesis that the BRCA1 gene involved in hereditary breast
cancer plays a role in breast stem cell (BSC) function. Furthermore, studies using mouse
BRCA1 knockout models provide evidence for the existence of heterogeneous CSC
populations in tumors generated in these mice. Although these populations may arise
from different stem/progenitor cells, they share the expression of a common set of stem
cell regulatory genes and show similar characteristics in in-vitro mammosphere assays
and xenograft models. Furthermore, these CSC display resistance to chemotherapeutic
agents. These studies suggest that breast tumors may display intertumor stem cell
heterogeneity. Despite this heterogeneity, CSC may share common characteristics that
can be used for their identification and for therapeutic targeting [596].
Basal-like breast cancers are characterized by their unique expression profile, with
the frequent loss of BRCA1, caused by such mechanisms as promoter methylation and
the overexpression of high-mobility group proteins of the A type 1 (HMGB1) or
inhibitor of differentiation 4 (ID4). Clinical-pathologically, basal-like cancers are ER-,
PR-, and HER-2-negative: they are of high grade and have a poor prognosis. The
fundamental similarity between BRCA1-mutated and basal-like cancers indicates that
disruption of BRCA1 may be an essential common initial pathogenic event. Furthermore,
p53 mutation and EGFR overexpression occur similarly in BRCA1-mutated and basallike cancers: these shared alterations provide very important information for
understanding not only the genetic and epigenetic carcinogenic pathways in these tumors
but also therapeutic strategies. Despite the limited available clinical data about response
to chemotherapy, anthracycline-based chemotherapy seems to be effective in a distinct
subset of basal-like cancers. Both disrupted BRCA1 and overexpressed topoisomerase IIalpha (TOP2A) possibly found in basal-like cancers are speculated to be associated with
their increased sensitivity to anthracyclines. If these tumors respond to this
chemotherapy, a favorable prognosis might be expected: however, in patients who do not
respond, the prognosis is poor. Currently, the sensitivity of basal-like cancers to taxanes
is not clear, but considering that these tumors have disrupted mitotic checkpoint
function, a poor response may be suggested. On the basis of in-vitro studies, BRCA1disrupted basal-like cancers may be sensitive to DNA-damaging agents including
platinum-based compounds, TOP1 and TOP2 inhibitors, and alkylating agents. In future,
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new therapeutic approaches for patients with basal-like cancers that are unlikely to
respond to chemotherapy should focus on molecules that are involved in the pathogenic
pathways of this disease [597]. Genome-wide association studies have already identified
novel risk alleles with a series of tumor-initiating single-nucleotide polymorphisms
(SNP). Some of these variants and other novel SNP and copy-number variants (CNV)
may also be relevant for local failures (ipsilateral breast cancer/contralateral breast
cancer). Beyond established risk factors, genetic testing allows identification of high-risk
patients (BRCA mutation carriers) who may benefit from bilateral mastectomy rather
than breast-conserving surgery. Human genetic variation (SNP/CNV) and DNA
methylation may be relevant for local failures assessment. Technological revolution has
opened a new avenue but multiple challenges should be overcome to integrate SNP/CNV
as markers for ipsilateral breast cancer/contralateral breast cancer risk-stratificationbased personalized surgery [598]. It has now been well documented that MRI of the
breast has a higher sensitivity than mammography for the diagnosis of breast cancer in
patients predisposed to breast cancer. A new diagnostic device, molecular breast imaging
(MBI), is now available and may be as sensitive as MRI. To date, this exciting
technology, MBI, has not been used in studies of patients with BRCA1/2 genes. Female
BRCA1/2 mutation carriers face unique choices regarding management of their high risk
for breast and ovarian cancer that impact their reproductive options. Despite their high
levels of concern, few female BRCA1/2 mutation carriers consider assisted reproduction
technologies (ART) such as pregnancy surrogate, cryopreservation of oocytes or
embryos, or implantation genetic diagnosis to select embryos without BRCA1/2
mutation. Further research must be undertaken to explore the risk management of
patients with inherited cancer predisposition and to incorporate these preferences into
clinical care [599].
Risk estimation is the most important clinical implication. Despite inadequate
knowledge about the genetic predisposition to breast cancer and its clinical implications,
the demand for genetic testing is likely to expand rapidly. In addition to risk estimation,
cancer surveillance, and preventive strategies, gene therapy offers a new and
theoretically attractive approach to breast cancer management [600]. Because of the
complex nature of genetic testing, mutation analysis is not presently routinely available
outside genetic counseling clinics. The need to provide comprehensive counseling for
women with an inherited predisposition to breast cancer has seen the evolution of the
familial cancer clinic, involving a multidisciplinary specialist team approach. Familial
cancer clinics will provide individuals with information about their risk of developing
breast cancer and offer advice regarding further management strategies. It is important
that surgeons, who have traditionally played a key role in breast cancer treatment, remain
cognizant of these advances in genetic molecular biology, and in so doing continue to
remain key participants in the conduct of breast cancer management [601].
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The USA National Comprehensive Cancer Network (NCCN), the United Kingdom
(UK) National Institute for Health and Care Excellence (NICE), and the ASCO have
recently updated relevant guidelines that inform practice on breast cancer screening and
prevention strategies for women at high risk of the disease. In the recently published
literature, there have been several important findings. A meta-analysis of RCT of
selective ER modulators (SERM) further support the use of SERM and aromatase
inhibitors in the primary prevention of breast cancer. A large observational study has
provided evidence that the SERM TMX may be efficacious for breast cancer prevention
in women who carry mutations in the breast cancer predisposition genes, BRCA1 and
BRCA2. Several observational studies have suggested that contralateral risk-reducing
mastectomy, following a diagnosis of breast cancer, may reduce mortality [602]. The
USA Preventive Services Task Force (USPSTF) recommends that primary care providers
screen women who have family members with breast, ovarian, tubal, or peritoneal cancer
with one of several screening tools designed to identify a family history that may be
associated with an increased risk for potentially harmful mutations in breast cancer
susceptibility genes (BRCA1 or BRCA2). Women with positive screening results should
receive genetic counseling and, if indicated after counseling, BRCA testing. The
USPSTF recommends against routine genetic counseling or BRCA testing for women
whose family history is not associated with an increased risk for potentially harmful
mutations in the BRCA1 or BRCA2 genes [603].
The concept of prophylactic mastectomy was nurtured in the shadow of the radical
mastectomy. It evolved as preferable to the mutilation caused by the procedure. It
developed during a time when the difference between benignancy and malignancy was
not as clear and when patients with benign disease were thought to be at significant risk.
The idea of surgical prophylaxis accompanied by a superior cosmetic result, in
comparison to the radical mastectomy, is a noble one. In retrospect, however, it is clear
that the indications were ill-defined, based often on unfounded risk, and predicated on
patient and physician anxiety. The scope of risk in breast cancer has been narrowed, with
new information identifying only specific subsets of women with proliferative types of
benign disease as more susceptible to the subsequent development of carcinoma.
Extensive reviews of material taken at biopsy that had been validated longitudinally have
provided data to substantiate this contention. The concept of familial high risk must take
into account the number of affected family members, age at diagnosis, menopausal
status, and bilaterality. The majority of indicants that motivated and propitiated the
performance of the bulk of prophylactic mastectomies have lost their relevance.
Prophylactic mastectomy for carcinoma, therefore, can perhaps be reserved for women
with biopsy-proved, high-risk lesions or an exceptional familial risk, or both, or
hereditary risk. Such women must choose for themselves and accept the uncertainty of
hypothetic risk reduction, life-long continued surveillance, and an altered body image.
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Guiding patients in the decision should involve a multidisciplinary team composed of a
surgical oncologist, geneticist, pathologist, psychotherapist, and plastic surgeon. As a
concept, the reduction of risk is appealing, but remains yet to prove itself superior to
rigorous clinical surveillance with high-quality mammography. The experience reflected
in the literature of a seemingly low rate of subsequent carcinoma cannot be judged,
because it seems that operations were applied indiscriminately to patients selected by
unknown means and from an unknown population pool. Success based on protecting
those not at increased risk only invalidates the operation further. Most surgical and
medical oncologists recognize that breast cancer is either localized or disseminated at the
time of the initial diagnosis [604]. Bilateral prophylactic mastectomy is effective in
reducing the risk of breast cancer in women with a well-defined family history or in
women with BRCA 1 or 2 mutations. Evaluating patient-reported outcomes following
bilateral prophylactic mastectomy are thus essential for evaluating success of bilateral
prophylactic mastectomy from patient’s perspective. Postbilateral prophylactic
mastectomy, patients are satisfied with the outcomes and report high psychosocial wellbeing and positive body image. Sexual well-being and somatosensory function are most
negatively affected. Vulnerability, psychological distress, and preoperative cancer
distress are significant negative predictors of quality of life and body image postbilateral
prophylactic mastectomy. There is a paucity of high-quality data on outcomes of
different health-related quality of life domains postbilateral prophylactic mastectomy.
Future studies should strive to use validated and breast-specific instruments for
measuring health-related quality of life. This will facilitate shared decision-making by
enabling surgeons to provide evidence-based answers to women contemplating bilateral
prophylactic mastectomy [605].
Mastectomy rates have significantly increased over the last decades, likely due to the
rising trend of risk-reducing mastectomies in the treatment and prevention of breast
cancer. Growing evidence suggests that aggressive risk-reducing surgical strategies are
only justified in high-risk breast cancer situations. Notably, in this selected cohort of
women, prophylactic mastectomies offer evident benefit for local and contralateral
disease control, and may also provide a survival benefit. Nevertheless, the extent of the
increasing frequency of this operation is not explained by the broadening of the medical
indications alone [606]. The Society of Surgical Oncology (SSO) has developed a
position statement that lists conditions warranting consideration of prophylactic
mastectomy. It must be stressed that there are no absolute indications for prophylactic
mastectomy. The data are limited about the efficacy of prophylactic mastectomy in
humans, but recent studies suggest that it results in up to 90% reduction in the risk for
breast cancer. Total mastectomy is technically a more definitive procedure, although
reported series have had a predominance of patients undergoing subcutaneous, nipplesparing procedures. Prophylactic mastectomy may improve longevity in BRCA mutation
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carriers, but this must be balanced against the impact on quality of life. The benefits of
prophylactic mastectomy relative to chemoprevention are unclear because there are no
prospective RCT comparing these two strategies. Contralateral prophylactic mastectomy
in patients with a unilateral cancer is unlikely to improve survival, but this approach may
be considered for high-risk or difficult-to-observe patients, to facilitate breast
reconstruction, and for the psychological benefits. Patients considering prophylactic
mastectomy should be well informed of risk-reduction alternatives and the limitations in
the efficacy and cosmetic results of the procedure [607]. The surgical technique should
aim at removing substantially all at-risk breast tissue. However, there is an obvious
balance between reduction of cancer risk and cosmetic outcome. The surgical technique
involves several operations to include the risk-reducing mastectomy as well as breast
reconstructive procedures. Skin-sparing mastectomy represents a new surgical approach
that allows a mastectomy, whereas preserving the natural skin envelope of the breast.
Breast reconstruction will involve several operations, especially if the NAC is resected
and is subsequently reconstructed. The contraindications to risk-reducing mastectomy
include the following:
1) the status of the family history or Munchausen’s syndrome has not been
confirmed;
2) the risk-reducing mastectomy is not the women’s own choice;
3) the patient has a current psychiatric disorder including clinical depression,
cancer phobia, or body dysmorphic syndrome;
4) if the comorbidity outweighs the clinical benefits, surgery should not be
undertaken; and
5) finally, the patient must not have unrealistic expectations of the benefits of
surgery: she must understand the subsequent risk-reducing mastectomy may
significantly reduce, but not eliminate the risk of subsequent breast cancer [608].
Because the cosmetic result of immediate breast reconstruction may not be optimal,
nipple sensation is lost, and capsule contraction may cause problems when silicon
prostheses are used, the patients should be well informed of risks and other preventive
methods. Surveillance or chemoprevention are suggested as alternatives to risk-reduction
mastectomy, but there is lack of prospective RCT comparing these options. Because
BRCA1 and BRCA2 gene mutations also increase risk of ovarian cancer, management of
these patients should be shared by the breast surgeon and gynecologist [609]. For the
majority of high-risk women, however, bilateral prophylactic mastectomy is not an
acceptable option for primary prevention of breast cancer. Several epidemiological
follow-up studies have indicated that there may be a substantial reduction in breast
cancer risk among women who have undergone breast reduction surgery. Although such
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observational studies cannot demonstrate definitively that reduction mammoplasty
reduces the risk of breast cancer, the evidence from these studies is sufficiently strong to
warrant the evaluation of breast reduction surgery as an option for primary prevention in
clinical studies of women at increased risk of breast cancer. The availability of a more
acceptable surgical option for primary prevention of breast cancer could increase the
number of women willing to choose risk-reduction surgery and thus may result in an
overall reduction in breast cancer mortality among high-risk women [610]. First, a risky
condition is not a disease and prevention does not improve well-being. The benefits are
only statistical and make sense at the population level. Secondly, the cause of the risk is
a genetic factor and some might argue about genetic “exceptionalism.” Thirdly, there is
no organ as connected to femininity, sensuality, sexuality, adulthood, and motherhood as
the breast. Lastly, making tough and complex choices requires assistance from ethics.
Among ethical principles, western countries often rely on autonomy. The physician has
to deliver all the relevant information: based on this “knowledge” and using their own
values, patients will take a decision. In 1998, in France national recommendations set a
list of criteria to fulfill, reducing autonomy. It might be expected that this tough issue
will be solved, thanks to the improvement of prevention and therapeutic efficacy [611].
Finally, there must be a balance in the reduction in risk against cosmetic outcome, with
subsequent quality of life issues. Women should be offered risk-reduction mastectomy
only on the basis of a strict selection and management plan, like that used in Manchester
protocol. This protocol involves a minimum of two sessions with a geneticist/oncologist,
a session with a psychiatrist, and two sessions with a plastic and reconstructive surgeon
with the support of a breast care nurse. A simple formula to calculate the life-time risk of
contralateral breast cancer has been devised. This allows stratification of breast cancer
patients into different risk groups: low, above average, moderate, and high risk.
Recommendations vary according to different risk groups. These guidelines are a useful
tool for clinicians counseling women requesting contralateral risk-reducing mastectomy.
Risk assessment is mandatory in this group of patients, and this formula allows evidencebased recommendations to be made [612].
In conclusion, the new genetics is having an impact on many areas of healthcare.
Diversity in the genetic code accounts for differences in phenotypes between populations
and it is becoming apparent that genetic differences may have a role in predisposition to
and behavior of disease. Genetic models suggest that there are two types of genetic
predisposition to disease: the so-called high- and low-penetrance genes. At present, most
of the impact on medicine has been from highly penetrant genes, and genetic testing for
disease predisposition, particularly for diseases of late onset (e.g., certain cancers) is in
its infancy. As a general statement, approximately 5-10% of common cancers are due to
such highly penetrant genes. The category of genes that will become of increasing
interest is that of the low-penetrance genes. Often, these are normal variations in genes
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that result in a slightly increased risk of disease. These are analogous to high blood
pressure patients carrying an increased risk of cardiovascular disease. Once rapid genetic
analysis is available for these types of genes, such analysis would be analogous to taking
someone’s blood pressure by a general practitioner to identify individuals at increased
risk of cardiovascular disease. This will produce a revolutionary change in the way we
practice medicine. Genetic analysis will become faster and may therefore be more
commonplace. It is possible to envisage an era when genetic analysis will become a
routine part of primary care to identify changes in low penetrance genes that will confer
a “risk profile” for patients. This will then enable their primary care physicians to advise
about primary prevention and even prescribe certain preventive drugs to decrease the risk
of certain diseases occurring. This proactive rather than reactive style of practicing
medicine is potentially exciting, however it carries with it ethical, legal, and social
implications for how we deal with this new knowledge [613]. The surgical option which
should be reserved for patients with BRCA1/2 mutation and breast cancer diagnosis is
still debated. Several aspects should be considered before the surgical decision-making:
the risk of ipsilateral breast recurrence, the risk of contralateral breast cancer, the
potential survival benefit of prophylactic mastectomy, and the possible risk factors that
could either increase or decrease the risk for ipsilateral breast recurrence or contralateral
breast cancer. Breast conservative treatment does not increase the risk for ipsilateral
breast recurrence in BRCA mutation carriers compared to non-carriers in short term
follow-up. However, an increased risk for ipsilateral breast recurrence in carriers was
observed in studies with long follow-up. In spite of the increased risk for ipsilateral
breast recurrence in patients who underwent breast conservative treatment than patients
with mastectomy, no significant difference in breast-cancer specific or overall survival
was observed by local treatment type at 15 years. Patients with BRCA mutation had a
higher risk for contralateral breast cancer compared with non-carriers and BRCA1mutation carriers had an increased risk for contralateral breast cancer compared to
BRCA2-mutation carriers. Bilateral mastectomy is intended to prevent contralateral
breast cancer in BRCA mutation carriers, however, no difference in survival was found if
a contralateral prophylactic mastectomy was performed or not. For higher-risk groups of
BRCA mutated patients, a more aggressive surgical approach may be preferable, but
there are some aspects that should be considered in the surgical decision-making process.
The use of adjuvant chemotherapy and performing salpingo-oophorectomy are associated
with a decreased risk for ipsilateral breast recurrence. When considering the risk for
contralateral breast cancer, three risk factors were associated with significantly
decreased risk: the use of adjuvant TMX, performing salpingo-oophorectomy, and older
age at first breast cancer diagnosis. As a result, we can identify a group of patients that
might benefit from a more aggressive surgical approach (unilateral mastectomy or
unilateral therapeutic mastectomy with concomitant contralateral prophylactic
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mastectomy). For women with BRCA mutations candidate to mastectomy, preservation
of the NAC may be highly important due to the generally younger age at time of surgery.
Concerning the oncological safety, nipple-sparing mastectomy is an acceptable option,
with no evidence of compromise to oncological safety at short-term follow-up. The
evaluation of surgical treatment in breast cancer patients with BRCA 1/2 mutation
should include several issues, namely the current evidence of adequate oncological
safety of breast conservative treatment in BRCA-mutated patients, the increased risk for
contralateral breast cancer especially in BRCA1 carriers, the feasibility on nipple-sparing
mastectomy with a greater patient’s satisfaction for cosmetic results with no evidence of
compromised oncological safety, and, finally, the awareness that breast radiotherapy
might increase the risk of complications in a possible subsequent mastectomy with
immediate breast reconstruction [614-622].
Chapter IX
Breast Reconstruction
Breast cancer is now treated either by conservative therapy or by mastectomy. In the
first case, no reconstruction is usually necessary, although some patients require
additional surgery for asymmetry, distortion, or even severe damage, by surgery or
radiotherapy, of the treated breast. In these cases, reconstructive surgery should be
performed very carefully, taking full account of the risk of operating in irradiated tissues.
Minor procedures are usually adequate, but major surgery, reconstruction with
abdominal flap, is sometimes the only solution to solve difficult postradiotherapy
disasters. When a mastectomy is the choice of the patient and the surgeon, immediate
reconstruction is now performed more often than before, as expansive prostheses are
now available, allowing immediate implantation without endangering the skin flaps. In
most cases of mastectomy, however, reconstruction has been performed as a secondary
procedure, in two stages if possible (volume and symmetry after the first and areola after
the second). Most of the reconstructions are done by simple implantation of a prosthesis.
When local conditions require a flap, the latissimus dorsi musculocutaneous has been the
best choice for years, but the lower rectus flap is now taking over, as it gives the
advantage of reconstructing a breast with autologous tissue [623]. Breast reconstruction
is not a new idea. Techniques have been developing since the late 1800s.
Postmastectomy breast reconstruction now is an integral and valuable part of the
management of patients with breast cancer. It offers hope and restitution for the patient
while lessening the ablation and psychological trauma of mastectomy. Present surgical
techniques and prostheses now permit any woman who has had a mastectomy to be
reconstructed. Whether a woman should have breast reconstruction must be decided only
after full discussion of prognosis and attainable goals with the woman herself. A variety
of choices of procedure, timing, and extent of surgery are available [624].
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Breast reconstruction after mastectomy for breast cancer has usually been performed
as a delayed procedure, often not less than one year after completion of postoperative
radiation therapy and cytotoxic chemotherapy. The reason for delaying the procedure has
been the increased risk of wound complications after the adjuvant therapy. The
reconstruction has been even further delayed for patients with increased risk of
recurrence in order to avoid a reconstruction “in vain” for a patient, who will succumb to
the disease within a couple of years after the reconstruction. Breast reconstruction can
also be performed immediately in conjunction with the mastectomy. The rather slow
acceptance of this procedure has mainly been for practical reasons. The mastectomies are
usually performed by general surgeons. The operation has not been centralized to larger
hospitals, and the patients usually want to have the operation performed as soon as
possible. It is therefore often difficult to arrange a joint operation by the general and the
plastic surgeons. In addition, suspicions have been raised that enlargement of the
dissection area could spread cancer and increase the risk of local metastases. The same
types of operation can be used for delayed and immediate breast reconstruction. There
are basically two possible ways of creating a new breast mound. One entails transferring
muscle, subcutaneous fat, and skin into the area of reconstruction in sufficient quantity to
shape a breast mound. The other possibility is to shape the breast mound mainly by
inserting a prosthesis, similar in consistency to breast tissue into the area of
reconstruction. For practical reasons, the implant has to be covered by a sufficient
amount of soft tissue, and for this purpose a number of pedicled flaps can be used. The
implant most commonly used is made of silicone gel and covered by a membrane to
prevent the gel from oozing into the surrounding tissues. A recent innovation is an
implant with textured surface in order to diminish capsule formation around the
prosthesis [625]. The techniques available today allow reconstruction of the breast in
almost all the cases even in poor local conditions. In 60-70% of the cases, the
reconstruction can be performed with an implant inserted behind the pectoralis muscle.
Special implants called expanders are inflatable progressively in the postoperative course
thanks to a reservoir located subcutaneously. They provide a progressive distention of
the teguments and a more natural shape after substitution of the expander with a
definitive implant. The symmetry is usually obtained thanks to a contralateral plastic
surgery, which allows at the same time histological check-up of the glandular tissue of
the opposite breast. The NAC is usually reconstructed in a second stage under local
anesthesia, using local flaps for the nipple and a tattoo for the color of the areola. In 30%
of the cases, especially after radiotherapy when a salvage mastectomy is required, a flap
reconstruction is preferred. The autologous tissue reconstruction with the rectus
myocutaneous flap gives excellent cosmetic results and the most natural shape for the
breast, but it is a more demanding technique requiring a good experience. In some
occasions, the reconstruction with the latissimus flap can also be autologous but usually
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requires the addition of prosthesis. As we have said, in most cases, the reconstruction can
be performed immediately. The delayed reconstruction is usually preferred when the
adjuvant chemotherapy should be delivered as soon as possible after the mastectomy.
Complications of the reconstruction such as local necrosis or infections, leading to
implant removal or revision of the flap could be detrimental to the patient in delaying the
start of the chemotherapy. It is not recommended to reconstruct the breast immediately in
case of locally advanced breast cancer. Partial breast reconstruction using plastic surgery
procedures can also be performed in case of quadrantectomy in order to obtain a better
cosmetic result. Local glandular flaps, as well as specific incisions according to the
location of the tumor in the breast allow the reshaping of the breast even in case of large
resection and, therefore, provide an opportunity to increase the number of conservative
treatment indications, especially in case of CIS [626].
The advantages of breast reconstruction are well understood: it helps to eliminate
many of the psychological burdens with which mastectomy patients must contend and
allows patients to participate in a normal lifestyle. Immediate breast reconstruction eases
much of the initial psychological trauma of mastectomy. For patients who require
postoperative radiation, reconstruction is often far less complex if done immediately than
if delayed, even though radiation increases the chances of capsular contracture. The
knowledge that immediate breast reconstruction is available may reduce patient’s
reluctance to seek medical advice when they find a breast lump [627]. Postmastectomy
radiotherapy is well known in the plastic surgery community for having a negative
impact on expander-implant-based immediate breast reconstruction, although recently
some technical improvements allow better results. Very recent papers would suggest that
there is no difference in postoperative complications in patients receiving
postmastectomy radiotherapy using modern techniques. However, study results are often
biased by small groups of patients and by heterogeneity of radiotherapy timing, different
surgical techniques, and measured outcomes. Papers amenable to plastic surgeons
highlighted the highest rate of undesired results, although with recent advances such as
delayed-immediate reconstruction or protective lipofilling. Postmastectomy radiotherapy
remains an undesired event when pursuing an implant-based breast reconstruction,
although it does not represent an absolute contraindication. The higher rate of
complications reported by plastic surgeons and not by other specialists can be explained
with the greater attention to aesthetic details, such as capsular contractures. Technical
strategies to prevent complications now allow better results, should be well known, and
improved if possible in the future [628]. Neoadjuvant radio-chemotherapy and immediate
reconstruction for breast cancer are still under debate. But there are recent abstracts and
articles which show that neoadjuvant radio-chemotherapy is feasible and could improve
the clinical outcome of breast cancer patients. It seems that the concept of immediate
implant delayed autologous breast reconstruction could be a safe procedure that is at
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least equivalent to primary autologous reconstruction [629]. Due to increasing
indications for postmastectomy radiotherapy and a growing demand for breast
reconstruction or augmentation, increasing numbers of patients are currently being
exposed to both these treatments. In view of the wide range of available techniques for
breast reconstruction, either prosthetic or autologous, and their various sequencing in
relation to radiotherapy, physicians can be faced with numerous clinical situations
requiring comprehensive knowledge of the topic. The available data indicate the
feasibility of such combinations, although at the expense of increased risk of
complications and less satisfactory cosmesis. Of the two methods of breast
reconstruction: using autologous tissue or prosthesis, the former seems to provide better
cosmesis and a lower risk of complications in conjunction with radiotherapy. To
minimize the risk of unfavorable outcome, the techniques and timing of both breast
reconstruction and radiotherapy should be given meticulous attention [630]. A lack of
consistent data is available about optimizing cosmetic outcomes, reducing potential
treatment-related toxicities, and defining important prognostic factors for women
undergoing postmastectomy radiation therapy following breast reconstruction.
Autologous tissue reconstructions represent less than 20% of all breast reconstructions
and include several techniques. A multitude of small studies have suggested that
autologous tissue reconstruction is associated with improved cosmetic outcomes and
similar rates of complications compared with expander/implant reconstructions. With
regards to autologous tissue reconstructions, the addition of postmastectomy radiation
therapy has been suggested but not definitively associated with a decrement in cosmetic
outcome compared with patients not receiving radiation. Expander/implant-based
reconstruction appears to be the most common form of breast reconstruction with large,
prospective, and retrospective series demonstrating that 20-30% of patients may require
some type of revision/replacement with long-term follow-up based on large series.
Whereas postmastectomy radiation therapy and the addition of regional irradiation has
been traditionally associated with increased complications and worse outcomes with
expander/implant-based reconstruction, recent data suggest that no difference in
perioperative complications exists in patients receiving postmastectomy radiation
therapy using modern techniques [631-634].
While the surgical emphasis remains on a cure for the cancer, experience with breast
reconstruction has not demonstrated any increased rate of cancer recurrence, even when
reconstruction is performed immediately following tumor resection. Advances in surgical
technique and biotechnology have made postmastectomy reconstruction possible. The
development of silicone gel and saline-filled implants as well as tissue expanders has
revolutionized breast reconstruction. The elucidation of musculocutaneous flaps now
provides the surgeon with the ability to transfer adequate quantities of vascularized
tissue to reconstruct the surgical defects. The advent of microsurgical techniques has
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provided an additional reconstructive option, with free tissue transfer allowing the plastic
surgeon to move musculocutaneous flaps from remote or distant sites to reconstruct the
defect. The option of having the reconstruction immediately following the mastectomy
procedure is now available to the patient. When reviewing the anatomy of the breast
region, the surgeon must consider the mammary gland, its vascular supply, and its
lymphatic system [635]. Anatomists and surgeons have underestimated the importance of
understanding the anatomical connective frame of the inframammary region. The
submammary fold does not originate as a self-governing unit but depends on breast
mould and on a fine superficial fascial system suspension. A reliable and fine correction
of inframammary fold contour in breast reconstruction may only be achieved by an
empirical surgical procedure that exclusively concerns the restoration of the superficial
fascial system [636]. Many surgeons are under the impression that the blood supply is
clearly defined in textbooks. Unfortunately, the majority of textbooks supply inadequate
information and illustrations can be misleading in many instances. None of the textbooks
describe a segmental pattern of blood supply when in actual fact a basic segmental
pattern does exist. The reason for inadequate information is the perpetuation of facts
since the work of the pioneers Cooper and Manchot from one textbook to another. A
paucity of research studies thereafter and the fact that the results of some of these studies
did not find their way into textbooks is another contributing factor. Researchers
concurred on the main sources of blood supply: these are internal thoracic, lateral
thoracic, anterior intercostal, and acromiothoracic (thoracoacromial) arteries. However,
the different research studies showed considerable variation in the branches from the
main sources to supply the NAC. Even though the locations of the main sources of blood
supply are constant, partial or complete absence of branches from the main sources does
occur and therefore the blood supply to the NAC is unpredictable. Cognizance of the
basic segmental pattern and the variations resulting from embryological development
will be helpful for the surgeon to use or adapt a technique to minimize the risk of nipple
necrosis [637].
Breast reconstruction procedures can be categorized as implant reconstruction, local
tissue with implant, autologous tissue, and free flaps. Implant reconstruction, immediate
or delayed, has been the easiest and most fulfilling experience for the surgeon and the
patient. Local tissue with implant and autologous tissue are usually available to those
patients with anterior chest tissue deficiency or those who prefer autologous tissue
without the fear of implant material. Free flap reconstruction is often selected when no
other procedures are appropriate for the patient. Individual procedures must be familiar
to the patient and the surgeon. Refinement and NAC reconstruction are an intimate part
of breast reconstruction, but these are usually the decisions made by the patient that must
be respected [638]. The state-of-the-art is such that the knowledge of its availability and
success has significant effect on the willingness of women to seek earlier diagnosis and
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treatment. However, reconstruction is not for everyone. Some issues involved are
financial, others have to do with cosmetic appearance, and still others involve the
medical and psychological affects. Identifying and understanding the issues from the
point of view of the patient is important in providing support for the patient with breast
cancer [639]. The goal of breast reconstruction is to reconstruct breasts which meet the
patient’s expectations both psychologically and aesthetically, while adhering to the
principles of sound oncological management. Breast reconstruction is usually started
around three to nine months after mastectomy. The simplest method of reconstruction
uses tissue available after mastectomy and a silicone implant. Breast reconstruction has
undergone a steady evolution since the introduction of the silicone gel prosthesis in the
early 1960s. Current restrictions of the use of breast implants have increased the reliance
on autologous tissue reconstruction. The improvement in the quality of breast
reconstruction can be attributed in part to a refinement in mastectomy technique. There is
an increasing emphasis on skin preservation, which makes it easier to match the
remaining breast. Local recurrence after breast conservation generally necessitates a total
mastectomy. Radiation fibrosis and endarteritis interfere with skin blood supply and
impair wound healing. Reconstruction in this setting has a potential for increased
operative morbidity [640].
In a large study, Lee and colleagues report that women receiving implants after
mastectomies for early-stage breast cancer experience lower breast cancer mortality than
women not receiving implants. Assessment of survival patterns among women receiving
reconstructive implants is complex given unique patient characteristics, disease
attributes, and treatment patterns. The interpretation of reduced mortality from breast
cancer must be assessed in light of significantly reduced risks of death from most other
causes. In contrast, patients receiving postmastectomy implants had elevated rates of
suicide, consistent with findings among women with cosmetic implants. Additional welldesigned investigations are needed to clarify survival patterns among women receiving
reconstructive implants [641-644]. Mesh use in surgical breast reconstruction is
becoming increasingly common. However, there is still no consensus on whether
synthetic matrices or biological matrices produce the best outcomes. Breast
reconstruction with a synthetic matrix produces comparable aesthetic outcomes to a
biological matrix, with lower costs and complication rates. The individual results for
complication rates show that biological matrixes are associated with lower infection rates
and slightly lower capsular contracture, but higher hematoma rates, and slightly higher
rates of skin necrosis and explantation – although many had postoperative radiotherapy.
The majority of the studies used biological matrices, and there are no RCT directly
comparing the two types of meshes: definite conclusions cannot be drawn from the
available evidence. A RCT comparing these outcomes in synthetic and biological matrix
use is needed [645]. Prosthetic-based breast reconstruction commonly involves device
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placement in either a total submuscular pocket or a partial subpectoral position for just
superior pole coverage, with various possible strategies for inferior pole coverage.
Historically, the pectoralis major muscle is managed either by suturing the muscle to the
inferior flap or with marionette sutures. Alternatively, the device is placed under total
muscle/fascia coverage (under the pectoralis major, plus the serratus anterior and rectus
abdominis muscles or fascia). For many plastic surgeons, acellular dermal matrix (ADM)
is now used instead to function as a sling or “hammock” supporting the periprosthetic
pocket and thus covering the inferior pole of the device, attached to the pectoralis major
muscle above and to the inframammary fold below. In addition to its added soft-tissue
support in the inferior pole, ADM may help to stabilize the pectoralis major muscle
along its inferolateral margin, create a well-defined inframammary fold, provide the
opportunity to significantly increase intraoperative fill volume of the tissue expander,
and reduce the incidence or severity of significant or symptomatic capsular contracture,
particularly in a patient whose breast has been treated with radiation. In addition to its
indications in primary breast reconstruction, ADM has been increasingly used in
secondary revision reconstruction cases. It can be used to buttress capsulorrhapy and
capsulotomy sites and it can be used to replace periprosthetic capsule following
capsulectomy. While clinical experience is accruing for these indications, ADM
continues to be used in primary and secondary breast reconstruction [646]. Combining
the use of tissue expanders and implants with autogenous tissue techniques of breast
reconstruction (the “bioengineered breast” concept) takes maximal advantage of the
benefits associated with each method. This approach provides an additional
reconstructive option that is particularly useful in patients who are not ideal candidates
for either method alone. Reconstruction may be performed in an immediate or delayed
fashion, and the aesthetic results are excellent [647, 648].
There have been numerous advances in breast reconstruction techniques of the past
decades. The disappearance of the radical mastectomy, along with the increased
frequency of smaller tumor detection, have contributed significantly to these changes.
Furthermore, reliable studies have shown that breast reconstruction does not interfere
with extirpative surgery or delay postoperative adjuvant therapy if indicated. Studies
such as these have led increasing numbers of women to elect immediate breast
reconstruction as opposed to delaying that reconstruction for months or even years after
the tumor extirpation. The advent of successful breast reconstruction using autogenous
tissue provided the most radical change to reconstructive techniques over the past 40
years. The TRAM flap was the first of these techniques to be introduced, in 1982, and
has rapidly assumed a position of prominence among those techniques chosen for breast
reconstruction. The lateral transverse thigh flap (LTTF) and the buttock flap, while
requiring microsurgical technique, are important alternatives for those patients who
choose autogenous tissue breast reconstruction and should be presented to women during
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the discussion of alternatives for breast reconstruction. Implant technology has continued
to improve with the introduction of the tissue expander, the most important addition in
the past decades. Investigations are currently underway to provide a long-term tissue
expander that does not have to be removed and replaced by a permanent implant. The
ultimate end result would be to create a more normal breast shape without firmness, and
the use of stacked or directional expanders may allow more freedom in creation of the
new breast shape to conform to the opposite side. Finally, NAC reconstruction has
improved significantly as the tissues of the breast mound itself are used for the new
NAC, thereby avoiding the transfer of grafts from distant sites which do not generally
maintain their size or projection over time [649, 650]. Breast reconstruction with
autologous tissue achieves more natural results and a better simulation of a real breast
than reconstruction based on prosthetic implants. Unlike implant-based reconstructions,
which tend to develop capsular contractures, the results of autologous tissue
reconstruction tend to improve with time. In the long run, the costs of autologous breast
reconstruction with TRAM flaps are equal to or lower than those of reconstruction with
tissue expansion and implants. Consequently, autologous tissue is preferable for most
patients, provided they are suitable candidates for the surgery required by autologous
reconstruction [651]. While autologous fat grafting provides a natural filler and seems
easy to harvest, autologous fat grafting in breast surgery is still problematic especially
due to the high resorption rate associated with megavolume transfer. Despite this
pending issue, there is growing interest in this method, which is becoming more and
more widespread, as can be seen by the recent increase in the number of clinical studies.
Recent studies have concentrated on new techniques to improve fat viability and graft
intake. However, all of these studies use different protocols at each step of the procedure.
Furthermore, results may vary depending on the technique used for fat harvesting and
processing [652, 653].
The optimal method for breast reconstruction should be safe, reliable, and accessible
for every patient, and it should display little or no donor-site morbidity. After comparing
mammary implants, it has been found that autogenous breast reconstruction can create a
ptotic, soft, symmetrical breast mound. Detailed analysis of the vascular anatomy of the
abdominal wall has extended the uses of the TRAM flap to major chest-wall
reconstruction, both as a transposition flap and as a free-tissue transfer. Although the
most direct pathway to the paraumbilical perforators that supply the large skin island of
the flap is from the deep inferior epigastric artery, numerous collateral pathways exist
from above that recruit blood from the intercostal vessels and the internal mammary
artery, even if it has been ligated or used for myocardial revascularization. Awareness of
these collateral pathways and care to preserve them whenever possible, combined with
the willingness to supplement blood flow with a microvascular anastomosis of the deep
inferior epigastric vessels, allows the surgeon to use the rectus abdominis flap and its
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variations in almost any major chest-wall reconstruction [654]. So, the pedicled TRAM
flap is the most common method of autologous breast reconstruction. Common risk
factors for complications from pedicled TRAM flap reconstruction include smoking,
obesity, and postoperative radiotherapy. Patients with these risk factors are often
candidates for a vascular delay procedure whose purpose is to enhance the blood flow
within the TRAM flap. Despite advances in free flap breast reconstruction, pedicled
TRAM flap breast reconstruction remains an excellent option for unilateral breast
reconstructions. Unlike microsurgical breast reconstruction, the pedicled TRAM flap
does not require sophisticated postoperative monitoring and can be performed efficiently
in any hospital setting. Furthermore, with the addition of a vascular delay procedure,
pedicled TRAM reconstructions can be safely performed even in traditionally “highrisk” patients [655]. Modern trends in breast reconstruction using the TRAM flap have
promoted adequate blood supply to the flap while minimizing donor-site defects in the
anterior abdominal wall. The pedicled TRAM flap remains one of the most frequently
used flaps, but the indirect blood supply in this flap has required many modifications and
refinements. Such modifications have included the bipedicled TRAM flap, the free
TRAM flap, and the supercharged TRAM flap. To avoid donor-site morbidities, the
muscle-sparing free TRAM, DIEP, and superficial inferior epigastric artery (SIEA) flap
were introduced. The DIEP flap requires meticulous technique but offers proven
reliability and a low rate of complications. As surgeons become more comfortable with
harvesting DIEP flaps, the frequency of usage seems likely to increase. The latissimus
dorsi musculocutaneous flap, gluteus maximus musculocutaneous flap, and others may
be selected when these modifications of free TRAM flap are unavailable or unusable
[656]. The transverse musculocutaneous gracilis free flap is a valuable choice for
autologous tissue, unilateral or bilateral breast reconstruction. This procedure is an
excellent and customized option for immediate or delayed breast reconstruction in
patients with small to moderate size breasts. Few descriptions of flap dissection and
breast mound shaping are available [657]. Latissimus dorsi miniflaps can be used to
reconstruct central and upper quadrant resection defects, replacing the volume excised
with autogenous tissue. Partial mastectomy, axillary dissection, flap harvest, and
reconstruction of the resection defect is performed as a one-stage procedure through a
single lateral incision. This oncoplastic approach allows extensive local excision during
breast-conserving surgery without cosmetic penalties in a group of patients normally
treated by mastectomy [658]. The latissimus dorsi musculocutaneous flap provides a
readily available local source of well-vascularized muscle and fat that can be used in
conjunction with tissue expanders and implants to reconstruct the breast after
mastectomy in both an immediate and a delayed fashion. The procedure is
straightforward, consistent, and well tolerated by patients. Donor-site morbidity is
minimal and the aesthetic results can be outstanding. Use of this technique is
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recommended as a versatile and predictable method for breast reconstruction [659]. The
gluteal region is an excellent donor site for autogenous breast reconstruction, particularly
when the lower abdomen is not suitable. The superior gluteal perforator flap involves
microsurgical transfer of skin and fat from the buttock without muscle sacrifice. Gluteal
myocutaneous flaps have been described, but they have several problems, including a
short vascular pedicle, exposure of the sciatic nerve, and recipient vessel size
discrepancy needing vein grafts [660]. The substantial experience with the superior
gluteal free flap for breast reconstruction indicates that this is a more difficult but
important free flap for breast reconstruction. Compared with the standard TRAM free
flap, it is a much less forgiving operation with many specific technical details. With
careful attention to details on flap design, recipient vessel selection anastomsis, and flap
insetting, the success rate and morbidity of the gluteal flap operation are highly
acceptable. For patients unsuitable for the TRAM flap for autologous tissue
reconstruction, this is a very valuable alternative. It can achieve some spectacular results
in breast reconstruction in terms of volume, replacement, and projection – even in very
thin patients [661].
Muscle-sparing autogenous breast reconstruction has enhanced the multidisciplinary
care that is available to patients who have breast cancer. The Rubens free flap is another
choice for autogenous tissue breast reconstruction. It uses the fatty area in the region
generally described as the hip overlying or just above the iliac crest. It is based on the
deep circumflex iliac artery and is indicated as a secondary choice in the presence of a
previous abdominoplasty or TRAM flap breast reconstruction. Closure of the abdominal
wall musculature along the iliac crest is the most exacting portion of this operation and is
a key to its ultimate success [662]. The DIEP flap has proven reliability, a low
complication rate, and is applicable to many clinical scenarios. Avoidance of muscle
sacrifice in the abdomen ultimately translates into greater patient satisfaction. The
increased demands, in terms of surgical expertise, are more than offset by decreased
postoperative pain and decreased donor site morbidity. The methods that were used to
innovate the DIEP flap have been applied to other donor sites and the available options
for patients have been expanded [663]. The DIEP flap is becoming a widely practiced
method of autologous breast reconstruction. Although it has been shown to be a safe and
reliable technique with acceptable morbidity, disadvantages include a comparatively
higher incidence of venous congestion and total flap loss compared with autologous
reconstruction with a pedicled or free TRAM flap. Venous congestion is reported in up
to one third of cases of breast reconstruction with a DIEP flap. If venous congestion is
detected and addressed intraoperatively compared with postoperatively, outcomes are
significantly improved. A wide variety of techniques have been introduced to augment
venous drainage to treat congestion and prevent flap failure [664].
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Perforator-based microsurgical reconstruction of the breast has steadily increased
since the introduction of the technique in the 1990s. The use of perforator flaps has
allowed for the transfer of large amounts of soft tissue with decreased morbidity. For
breast reconstruction, the DIEP flap, the superior and inferior GAP flaps, and the
transverse upper gracilis flap are all options. An alternative source uses posterior thigh
soft tissue based on profunda artery perforators, termed the profunda artery perforator
flap. Preoperative imaging helps identify posterior thigh perforators from the profunda
femoris artery. These are marked, and an elliptical skin paddle, approximately 27 × 7 cm,
is designed 1 cm inferior to the gluteal crease. Dissection proceeds in a suprafascial
plane until nearing the perforator, at which point subfascial dissection is performed. The
flap has a long pedicle (approximately 7 to 13 cm), which allows more options when
performing anastomosis at the recipient site. The long elliptical shape of the flap allows
coning of the tissue to form a more natural breast shape. The donor site is well tolerated
and scars have been hidden within the gluteal crease. Long-term follow-up is needed to
evaluate for possible fat necrosis of the transferred tissue. This is an excellent option
when the abdomen is not available because of the long pedicle, muscle preservation,
ability to cone the tissue, and hidden scar [665]. The procedure appears to offer less
postoperative pain, lower abdominal morbidity, and better preservation of the rectus
muscles than the more conventional flaps. However, the major disadvantage of these
flaps is that they can be difficult to harvest, resulting in longer operative times. The
challenges in flap dissection are a result of the variability in the vascular anatomy of the
deep inferior epigastric artery and its perforating branches through the rectus muscle.
The location, number, and caliber of the perforators and the intramuscular trajectory of
the deep inferior epigastric artery branches vary greatly not only from individual to
individual, but from one hemiabdomen to the other. The establishment of a presurgical
map of the vessels on the abdomen facilitates surgical planning and may decrease
operating room time, reduce intraoperative complications, and possibly improve
outcomes. The available techniques for preoperative planning are the currently available
imaging modalities of hand-held Doppler, color Doppler (duplex) ultrasound, CT
angiography, and MRI angiography [666]. The vessel selected depends on multiple
anatomical and surgical considerations, and the decision-making process can be
exceptionally time-consuming, in part because of the wide variation that occurs in
vascular anatomy. Preoperative imaging can greatly improve the efficiency of the
selection process. Doppler ultrasonography is the most frequently used modality for
vascular mapping, but the results are mixed because most perforating arteries have a
diameter of less than 15 mm, the threshold for reliable visualization with
ultrasonography. A CT angiographic evaluation performed with the use of specific
postprocessing and display techniques may be more accurate for identifying the most
suitable vessel. CT angiography provides valuable information that can help optimize
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surgical planning, decrease time spent in the operating room, and improve the outcome
of breast reconstruction surgery [667]. The use of preoperative CT angiography reduces
the operative time, postoperative flap-related complications, and donor-site morbidity
compared with Doppler ultrasonography. Preoperative CT angiography has the potential
to reduce operative cost and increase efficiency in the operating room. Thus,
preoperative mapping by CT angiography should be strongly considered for
abdominally-based free flap breast reconstruction [668, 669].
In summary, microsurgical tissue transfer involves the use of excess skin and fat
(flaps) from a remote location to reconstruct the breast. Most often, tissues are
transferred from the abdomen and buttocks. Less commonly, thigh flaps are used. These
operations can provide durable, aesthetic reconstructions. In addition, advances in
microsurgical techniques have improved operative success rates to the range of 99%. The
selection of an appropriate flap for microsurgical breast reconstruction is multifactorial
and is based on patient and oncological factors. These factors include patient
comorbidities, body habitus/availability of donor tissues, cancer stage, and the need for
postoperative adjuvant radiation therapy, as well as the risk of cancer in the contralateral
breast. Appropriate choice of flap and surgical technique can minimize the risk of
operative complications. Additionally, several large series have established that
microsurgical breast reconstruction has no impact on survival, or loco-regional/distant
recurrence rates [670, 671]. There is no longer any doubt that free flaps can achieve the
best breast reconstruction. Proof has been the rapidly increasing popularity of the method
[672]. In breast reconstruction with a free flap, the selection of suitable recipient vessels
remains one of the most critical decisions for the surgeon. Most surgeons use one of the
branches of the axillary vascular system, the thoracodorsal vessels. In recent years, free
autogenous tissue transfer for breast reconstruction has become increasingly common.
The free TRAM flap and the more recently described DIEP flap are currently the
methods of choice for postmastectomy breast reconstruction. For patients who cannot
have a TRAM flap, free flaps from other donor sites (superior gluteal flap, inferior
gluteal flap, Rubens flap, and lateral transverse thigh flap) also have become important
options [673, 674]. Current recipient vessels for microvascular breast reconstruction
include the internal mammary and the thoracodorsal systems [675, 676]. The number one
cause of death in American women is heart disease. Studies have clearly shown the
superiority of internal mammary artery grafts for coronary revascularization over other
conduits or intracoronary techniques. As we operate on older patient populations, the
need for internal mammary artery use for coronary artery bypass grafting (CABG) after
autologous breast reconstruction may arise more frequently. As the number of patients
we operate on who may later require their internal mammary artery for CABG increases,
so must our understanding of the implications of our selection of recipient vessels for
free autologous breast reconstruction too [677].
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New techniques for postsurgical breast reconstruction have been recently introduced.
Over the last decade, autologous fat from subcutaneous tissue has been used by plastic
surgeons for face volumization. It has also been used with growing frequency for
aesthetic breast enhancement. Currently, experts in this field are becoming increasingly
aware of the potential of fat for breast reconstruction. These new procedures include
autologous fat grafting with or without the enrichment with autologous stromal vascular
fraction (SVF), platelet-derived growth factors (PDGF), and insulin. Fat grafting is
increasingly popular and is becoming a common practice in plastic surgery for
postmastectomy breast reconstruction and aesthetic breast augmentation. However, the
safety of fat transfers to postmastectomy defects has been called into question in recent
debates due to the, albeit rare, observations of their possible influence on local cancer
recurrence. The majority of concerned opinions are based on the safety of fat
supplementation with additional amounts of adipose mesenchymal and stem cells. In
experimental conditions, these cells were shown to create pathophysiological
microenvironments and promote neoplastic transitions. This raises the question as to
whether breast reconstruction with enriched fat is sufficiently safe to be performed
without scientific justification and whether the present legal regulations are sufficient to
guarantee patient safety in small facilities. In a number of circumstances, patients who
have undergone treatment in profit-oriented offices, outside the system of oncological or
surgical centers, might have been left without any long-term cancer surveillance. Valid
opinions have also been expressed on the grounds of the ethical doubts concerning the
advertising used by cosmetic practitioners who, on occasion, tend to overemphasize the
putative benefits of stem cell applications despite the scant support in evidence-based
medicine (EBM). Real progress in this field is possible only in scientific research that
relies on bioethical evaluation, properly planned clinical trials, and the judgment of peers
[678]. The reported improvement of fat graft viability with these techniques likely
depends on the presence in the SVF of multipotent resident adipose-derived stem cells
(ASC). The clinical advantage derives from the plasticity of ASC and their ability to
generate new functional adipose tissue and vessels. However, there is an ongoing debate
regarding the possible interplay between breast tumor cells and resident or transplanted
ASC for their capacity to locally secrete growth factors. Thus, concerns over the
oncological safety remains a controversial and hot topic among scientists and surgeons.
Basic science and laboratory research repeatedly show a potentially dangerous effect of
ASC on breast cancer cells. Clinical research, although limited, continually fails to show
an increase in breast cancer recurrence after breast fat grafting, with the exception of one
small study on a subset patient population with intraepithelial neoplasm of the breast
[679]. Most of the data in the literature concerning ASC is derived from in-vitro models,
whereas the knowledge of ASC behavior in-vivo remains scarce. Recent reports
concerning SVF/ASC enrichment of fat graft did not describe any significant worsening
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of prognosis for patients undergoing those procedures. However, further studies and
longer follow-ups are needed to specifically define technical procedures and to confirm
the safety of procedures of SVF/ASC enrichment during postsurgical breast
reconstruction [680-689].
As the demand for postmastectomy breast reconstruction has continued to rise,
options for the implantable soft-tissue replacement products which enhance the aesthetic
and reconstructive outcome of these procedures has grown as well. While the most
common product used in an alloplastic breast reconstruction is an ADM derived from
human sources, many other options are currently available, each offering their own
unique properties and benefits [690]. The use of ADM in many plastic surgery
procedures, including breast reconstruction, has increased dramatically in recent years.
While expander/implant reconstruction can be performed successfully with standard
techniques, the introduction of ADM has added a new tool with which to achieve lasting,
predictable results [691]. ADM have generated interest for their possible applications in
secondary revisions following prosthetic breast reconstruction. These materials can be
effective in a variety of situations, including implant displacement, synmastia, capsular
contracture, incisional support, and pocket conversion. ADM can also be placed in the
setting of delayed breast reconstruction and to augment nipple projection. These
biomaterials have demonstrated feasibility and success for many complex deformities.
However, there is an associated learning curve that includes an understanding of proper
technique and patient selection [692]. The use of ADM has allowed for single-stage
immediate breast reconstruction after mastectomy at a significantly decreased cost
compared with two-stage expander/implant reconstruction. The use of a pedicled
autologous dermal flap in the same fashion as ADM in women with larger, ptotic breasts
has also allowed for single-stage immediate breast reconstruction with similarly low
complication rates and without the added procedural cost of using ADM. There have
been no prior studies evaluating whether the added procedural cost for ADM is costeffective relative to using an autologous dermal flap in single-stage immediate breast
reconstruction following mastectomy. Sensitivity analysis showed that ADM was not
cost-effective when the complication rate for autologous dermal flaps was below 20%.
ADM is not a cost-effective technology in patients who can have an autologous dermal
flap in single-stage immediate breast reconstruction [693-697].
Breast reconstruction is a multi-stage process, leaving many patients overwhelmed
by the surgeries they have had to endure by the time they reach the final stages. Patients,
however, are encouraged to complete their new breast by undergoing NAC
reconstruction. These last two procedures improve the aesthetic result by transforming
the surgically created breast mount into a more natural-appearing breast. This final touch
enhances body image, restoring the patient’s feeling of wholeness. These procedures are
mostly done in the office under local or no anesthesia, depending on the sensation
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present in the reconstructed breast. Creation of the NAC is the final and important
component of the breast reconstruction process [698]. Along with continuing progress in
reconstructive surgery of the breast, numerous techniques of NAC reconstruction have
been developed. Although many technical descriptions of NAC reconstruction exist in
the medical literature, insufficient evidence-based data are present about the outcome.
The impact of NAC reconstruction is well described in the literature. However, it is
astonishing that the plastic surgical literature lacks evidence-based trials addressing this
issue. Clearly, more evidence-based trials are necessary to ensure that recommendations
for a particular technique are based on solid scientific data [699]. With time and
experience, some methods have been discredited to historical significance only while
others have evolved to widely accepted concepts used by surgeons all over the world,
which in turn contributed new ideas and modifications. In addition to those favorite
techniques, others are reserved as second-line alternatives in specific situations. The
principle criterion for a pleasing NAC is symmetry regarding several parameters: color,
texture, size, and projection [700]. The ideal reconstructed NAC provides sustained
projection, the fewest complications, and high levels of patient satisfaction. A variety of
materials are available for projection augmentation, including autologous, allogeneic,
and synthetic materials. To date, there has been no systematic review to study the
efficacy, projection, and complication rates of different materials used in NAC
reconstruction. The results revealed heterogeneity in the type of material used within
each category and inconsistent methodology used in outcomes assessment in NAC
reconstruction. Overall, the quality of evidence is low. Synthetic materials have higher
complication rates and allogeneic grafts have nipple projection comparable to that of
autologous grafts. Further investigation with high-level evidence is necessary to
determine the optimal material for NAC reconstruction [701-703].
Breast reconstruction procedures were not recommended in the past for those who
planned for subsequent childbearing because of the transposition of portions of the
abdominal wall during the procedure into the anatomical position of the breast, implying
possible adverse effects over the contour of these manipulated areas during pregnancy
and delivery. Uneventful pregnancy and delivery can be anticipated in breast cancer
survivors who had undergone breast reconstruction via TRAM or its derivatives with
minor negative effects on either the breast or the abdomen [704]. There are reports of
patients having normal full-term pregnancies following pedicled TRAM flap breast
reconstruction. These are individual cases and there is only limited published evidence to
support the safety of pregnancy following surgery of this nature. Little is known about
the effects of pregnancy after free tissue transfer, therefore it has been difficult to advise
patients, in this situation, what the recommended course of action should be. We can
conclude that TRAM flap breast reconstruction is not an obstacle to normal pregnancy
and delivery. Patients need to be guided through the potential risks to their health if they
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should become pregnant, before reconstruction takes place. Obstetric and oncological
specialists, as part of the multidisciplinary setting, need to be involved early in
pregnancy to further inform and counsel these patients [705].
Breast reconstruction has been shown to have a positive effect on the psychological
well being of women with breast cancer. Numerous studies have demonstrated that
reconstruction performed concurrently with mastectomy is oncologically safe. Recent
refinements in surgical techniques and prosthetic technologies, development of novel
tissue substitutes, and increasing use of adjuvant radiotherapy have led to changes in the
practice of breast reconstruction following mastectomy. Nevertheless, although
increasing numbers of women are choosing to undergo postmastectomy reconstruction,
this trend is inconsistent across demographic subgroups. In addition, the paradigm of
performing immediate reconstruction on allcomers is being challenged by increasing use
of postoperative radiotherapy. It is now appreciated that the implications of performing
reconstruction in the setting of radiotherapy are both profound and controversial. Finally,
questions are being raised about the factors that influence the ultimate surgical goal,
namely patient satisfaction. Mastectomy is often associated with significant
psychological sequelae including distorted body image and sexual dysfunction. Breast
restoration is assumed to allow a full emotional and physical recovery from a breast
cancer crisis [706, 707]. The goal of postmastectomy breast reconstruction is to restore a
woman’s body image and to satisfy her personal expectations regarding the results of
surgery. Studies in other surgical areas have shown that unrecognized or unfulfilled
expectations may predict dissatisfaction more strongly than even the technical success of
the surgery. Patient expectations play an especially critical role in elective procedures,
such as cancer reconstruction, where the patient’s primary motivation is improved
health-related quality of life. In breast reconstruction, assessment of patient expectations
is therefore vital to optimal patient care. Systematic measurement and management of
patient expectations may improve patient education, shared medical decision-making,
and patient perception of outcomes [708].
It is anticipated that investigations using newly developed, patient-reported outcome
measures provide important information about outcomes following reconstruction, which
in turn will facilitate the decision-making process for both patients and surgeons [709].
Achieving an aesthetic outcome following postmastectomy breast reconstruction is both
an important goal for the patient and plastic surgeon. However, there is currently an
absence of a widely accepted, standardized, and validated professional aesthetic
assessment scale following postmastectomy breast reconstruction. Of the 12 different
professional aesthetic assessment scales that exist in the literature, the most commonly
used scale was the four-point professional aesthetic assessment scale. The highest score
on the modified Scientific Advisory Committee’s (SAC) Medical Outcomes Trust
(MOT) criteria was assigned to the ten-point professional aesthetic assessment scale.
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However, this scale has limited clinical usefulness due to its poor responsiveness to
change, lack of interpretability, and wide range of intra- and inter-rater. A “gold
standard” professional aesthetic assessment scale needs to be developed to enhance the
comparability of breast reconstruction results across techniques, surgeons, and studies to
aid with the selection of procedures that produce the best aesthetic results from both the
perspectives of the surgeon and patients [710]. Patient-reported outcomes provide an
invaluable tool in the assessment of outcomes in plastic surgery. Traditionally, patientreported outcomes have consisted of either generic or ad hoc measures. However, more
recently there has been interest in formally constructed and validated questionnaires that
are specifically designed for a particular patient population. To date, the most frequently
used measures are still generic measures. The 36-Item Short-Form Health Survey (SF36) was the most frequently used and most successfully applied showing evidence of
responsiveness in multiple settings. Other measures such as the Hospital Anxiety and
Depression Scale (HADS), the Hopwood Body Image Scale (BIS), and the Rosenberg
Self-Esteem Scale (RSE) were able to show responsiveness in certain settings but lacked
evidence as universal tools for the assessment of outcomes in reconstructive breast
surgery. Despite the recent advent of measures designed specifically to assess patientreported outcomes in the breast reconstruction population, there still appears to be a role
for the use of generic instruments. Many of these tools would benefit from undergoing
formal validation in the breast reconstruction population [711]. All studies reported good
levels of satisfaction. Methodological deficiencies (small sample sizes, context and study
designs, satisfaction assessment, and basic statistical analysis) limit the generalizability
of the findings. Overall, studies suggested that patients were satisfied with breast
reconstruction whatever the technique used, whereas age or procedure timing did not
affect general satisfaction. Breast symmetry, size, shape, and scars were reported as
influencing the patients’ score. NAC reconstruction positively influenced satisfaction;
radiation before/after reconstruction achieved satisfactory cosmesis, and complications
predicted dissatisfaction [712-716].
Follow-up of patients with breast cancer is directed to the early detection of
recurrent or metastatic disease and the detection of new primary breast cancer. The
survival benefit of early detection is limited to some patients with local failure or new
primary tumors. That imaging is not used in follow-up of patients who have had breast
cancer reconstruction is related to possible interference with this putative benefit by the
reconstructive procedure. Such follow-up is accomplished by the patient’s own
surveillance, clinical examination, and laboratory testing supplemented by imaging
studies. Clinical follow-up trials of women who have undergone breast reconstructive
surgery show no evidence that locally recurrent breast carcinoma is masked when
compared with follow-up of women who did not undergo reconstructive procedures.
Reshaping of the contralateral breast to match the reconstructed breast introduces the
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possibility of interference with palpation as well as mammographic distortion in some
women. This is an uncommon practical problem except when complicated by fat necrosis
[717]. Therefore, the data on surveillance imaging of the reconstructed breast are
extremely limited. However, by assessing the potential role for imaging in this setting
and applying the principles of screening, there is a potential theoretic advantage of
surveillance imaging in a very small subset of women: those with autologous tissue
reconstructions and moderate to high risk of recurrence. A prospective registry study of
surveillance imaging in this target population would be the appropriate way to determine
its benefit and its impact on survival outcomes [718-720].
In conclusion, remarkable advances have been made in the field of breast
reconstruction, especially since general surgeons, patients, and the community as a
whole have become more knowledgeable and accepting. This has provided an impetus
for plastic surgeons to develop better techniques. In general, less time now elapses
between ablative and reconstructive surgery, and frequently reconstruction follows
immediately. Procedures requiring fewer steps with less donor and recipient site
morbidity are favored for both the mound and NAC reconstruction. There is a definite
trend toward submuscular implantation to minimize the negative effects of capsular
contracture. With a deficiency of skin or muscle, the trend is toward using
musculocutaneous flaps primarily, latissimus dorsi, and the rectus abdominis flap.
Occasionally, microvascular flap reconstruction is indicated for extensive chest wall
defects, e.g., postirradiation injury. Postoperative closure techniques in breast
reconstruction have remained largely unchanged over the past 75 years, despite recent
use of adhesives and subcuticular staples and the advent of self-anchoring barbed sutures
[721, 722]. Reconstructed breasts are not capable of nourishment, frequently are not
erogenous, and most often are not as pleasing to the eye as the contralateral breast. Yet,
reconstruction in the majority of cases has improved the quality of life for those women
who have developed breast cancer and offered hope to those women in a high-risk
category for developing breast cancer. To those ends, the search for the perfect breast
reconstruction will continue [723]. Advances in materials and techniques, especially
those involving transposition of muscle and skin flaps, have made breast reconstruction
possible for most women who undergo mastectomy for breast cancer. The availability of
this option can alleviate the breast and chest wall deformity that results from virtually all
local treatment of breast cancer. It is essential that the reconstruction surgeon be part of
the breast cancer management team from the beginning of treatment planning and that
this surgeon work closely with the general surgeon, medical oncologist, and radiation
therapist as well as the adjunctive treatment team members. The patient’s clinical status
and the type of local treatment will be significant determinants of the reconstructive
options. For women with Stage I breast cancer, these decisions may be based largely on
the oncologist’s local and adjunctive therapy procedures and the woman’s desire to
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proceed or delay. For women with systemic disease, all members of the breast
management team may need to agree on the advisability and timing of reconstruction.
For appropriate patients, who are aware of and accept the risks involved, contralateral
prophylactic mastectomy and bilateral reconstruction can provide a good solution to an
otherwise difficult problem. Bilateral reconstruction can produce exceptionally good
aesthetic results and, because good symmetry is achieved in the initial surgery, it only
costs about 5% more than unilateral reconstruction [724]. Central to all of the numerous
decisions regarding the timing, type, and extent of breast reconstruction is the primary
goal of the entire team: the best possible management of the breast cancer itself. The
promise of attractive, symmetric, and natural appearing breasts, complete with a
symmetric NAC, has eased somewhat the diminishment of self-esteem and the threat to
femininity that can accompany the loss of a breast. By lowering fear, the widely
recognized availability of breast reconstruction may encourage more women to monitor
their breasts and seek diagnosis of changes and may influence selection of the type of
local treatment if cancer is detected. Because of the psychological and cultural
significance of the breast, the reconstructive surgeon must be particularly sensitive to the
psychological and aesthetic expectations of the patient. Even in those patients with
metastases and limited life expectancy, breast reconstruction can enhance the quality of
life [725]. Continued close cooperation between the general surgeon and the plastic
surgeon will assist the patient in her return as a functioning member of society and not
mere survival as a mastectomy cripple [726-737].
Chapter X
Aesthetic Breast Surgery
Health is multidimensional. Mortality, morbidity, and cost are traditional health
indicators, whereas outcomes research relates to quality of life and health-related quality
of life [738]. Elective aesthetic cosmetic surgery of the female breast appears not to
warrant the same attention to informed consent or authorization as other surgical
procedures. Arguments for benefits do not need to be persuasive since the prospective
patient is usually “sold on the idea.” More rather than less information is necessary
where the surgery will not achieve what is claimed for it and where there are significant
risks of harm. Augmentation mammoplasty does not provide a solution to problems of
body image, self-esteem, and sexuality: it may result in considerable pain, suffering,
financial and emotional cost, interference with life choices, and a loss of trust in health
care professionals. In view of the emerging data which points to the doubtful efficacy
and safety of the procedure and the prosthetic devices, and since elective cosmetic
surgery is said to be a growth industry, checks and balances need to be in place to ensure
women are informed participants in decision-making. They require the best possible
advice, care, and support. Changing fashions and popular demand are forcing us to adapt
higher standards in breast surgery [739].
There are many methods of measuring the breast and their clinical applications are
well described in the literature. However, there has been no attempt to compare these
various methods to allow the user to have a broad overview of the subject. All of the
methods can be classified into those that measure:
1) volume;
2) shape; and
3) surface area.
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Each category consists of several methods that work through different mechanisms
and they vary in their reliability and feasibility. Based on their mechanism, the volume
measurement methods were further grouped into the natural shape methods, the
stereological method, the geometrical methods, and the mathematical modeling method.
More objective breast evaluation can be achieved if all three dimensions (volume, shape,
and surface area) are considered. In the volume measurements, 3-D modeling and the
MRI are the most reliable tools. Linear measurement (geometry) and mathematical
modeling are less accurate but are more economical. In the shape measurements, besides
the traditional linear measurement, 3-D methods that can deliver color-coded maps and
Swanson’s 2-D photographic measurement system are capable of depicting and tracking
breast shape changes after surgery. Although the surface area metric has not been used
extensively, it has potential in clinical and research applications [740]. The first two
dimensions constitute the breast footprint. The third dimension is the shape of the breast
on the footprint. It is important for the surgeon to understand how change in each of the
parameters can be affected. The upper and lateral breast borders are relatively mobile,
but the inferior and medial breast borders are relatively fixed. All four borders can be
changed with certain surgical maneuvers. The breast is a skin structure that is held in
place by skin/fascial zones of adherence, and the breast itself is mobile over the
pectoralis fascia. Measurements before and after breast augmentation, breast reduction,
mastopexy, and mastopexy-augmentation have been obtained so that the surgeon can
better predict results. The change in suprasternal notch-to-nipple distance and the change
in suprasternal notch-to-inframammary fold distance have been measured. Being able to
explain the issues and the potential changes makes it easier for a surgeon to manage
patients’ expectations [741]. Breast symmetry, size, and shape are key components of
aesthetic outcomes of augmentation mammoplasty, reduction, and reconstruction. Many
have claimed that the 3-D scanning technique, which measures breast volumes directly
and assesses the asymmetry of the chest and breast on a 3-D model, is superior to
anthropometric measuring in accuracy, precision, and reproducibility. The documented
methods of 3-D body surface imaging include laser scanning, stereo photography, and so
on. To achieve ideal aesthetic results, individualized surgery planning based on a reliable
virtual model of the prospective surgery outcome could be of considerable value in
decision making and assisting in guidance for the surgery procedure. Additionally, the 3D scanning technique is applicable in postoperative monitoring of morphological change,
notably, in a dynamic way. Another distinguishing feature is that it enables virtual
division of breast volume, thus surgeons could virtually divide the breast volumes into
portions using 3-D scanning during the programming and evaluation of surgery plans.
However, because 3-D surface scanning cannot look through the breast substances and
reach the interspace between the chest and posterior border of the breast/dorsal limit of
the breast, the inframammary fold in larger breasts cannot be correctly imaged, leaving
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the preoperative inframammary fold reference lacking. Therefore, 3-D scanning is
thought to be inaccurate in large and/or ptotic breasts. Another fact that prevents 3-D
scanning from wide application is its high cost and lack of access [742]. Creating or
recreating an aesthetically pleasing breast shape in reconstructive and aesthetic breast
surgery is an act that most experienced “breast” surgeons will find self-evident. A simple
three-step philosophical and hands-on approach will make it easier for young and
unexperienced plastic surgeons to not only analyze the problematic breast but also come
up with an easy surgical strategy to create reproducible results [743, 744]. Knowledge on
the forces acting on a woman’s breast and on the mechanical properties of the breast
tissues is important for studying the effects of plastic surgery techniques for breast
reconstruction as well as for the design of cosmetic breast implants. Surprisingly, there
are no data in the literature regarding mechanical loads on the breast tissues during daily
or sport activities, and there are no coherent sources of data in regard to mechanical
properties of the breast tissues [745].
Approximately 500,000 cosmetic breast operations are done every year. The majority
of these are for cosmetic reasons and include breast augmentations, mastopexies, and
breast reductions. Common procedures include breast reconstruction following
mastectomy for cancer. Augmentations are most commonly performed using saline
implants in strictly cosmetic situations and occasionally silicone implants in select cases.
Complications are unusual, breast-feeding is usually possible, and mammographic cancer
detection is accurate provided that specific mammographic views are obtained. Most
cosmetic breast surgery is not covered by insurance with the exception of breast
reduction [746]. Insurance companies evaluate the medical necessity for breast reduction
surgery based on internal company medical policies, but the correlation of insurance
company criteria to the scientifically established indications for reduction mammaplasty
has never been studied. Insurance company medical policy requirements with respect to
reduction mammaplasty are, in many cases, arbitrary and without scientific basis.
Requirements for a specific volume of reduction, a minimum age, a maximum body
weight, and a trial of conservative therapy are required by the majority of managed care
medical policies, even though scientific support for any of these requirements is not
evident in the medical literature [747]. Appropriate follow-up care, including early
postoperative serial mammography, is essential for women receiving cosmetic breast
surgery. Postoperative complications include infection, poor wound healing, and pain.
Hypertrophic scar formation, which may disrupt the normal breast contour, may be
reduced by gentle and frequent massage of the scar. Avoiding sun exposure and using
sun screens may prevent hyperpigmentation of the scar. Reduction mammoplasty is
associated with sensory loss, which is occasionally permanent. Special complications
associated with augmentation mammoplasty include diffusion of silicone through the
implant and unfavorable breast appearance secondary to capsular contracture. Capsular
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contracture may be prevented by regular implant exercises. Preoperative and early
postoperative serial mammograms are essential to differentiate surgical from malignant
changes [748]. Women seek reduction mammoplasty for alleviation of their symptoms of
mammary hypertrophy, which may include upper back and neck pain, strain, or muscle
spasm. Brassiere strap grooves develop mostly on the shoulders of women with
hypertrophied breasts. Varying degrees of the deformity are observed in such cases. To
date, there is no universally accepted definition and classification for brassiere strap
groove deformity [749]. Many of these women also desire an improvement in their
appearance. Augmentation mammoplasty is sought by women for enlargement of the
breasts and to attain a well-proportioned figure. Women who have experienced
postpartum involution of the breasts request augmentation mammoplasty to regain the
size and shape of their breasts prior to pregnancy [750]. In the last decade, entirely new
techniques in breast reduction and reconstruction have evolved. What remains unclear is
whether or not these new procedures, some of which carry additional surgical risk and
cost, are superior from a patient perspective. Thus, plastic surgeons are ever more reliant
on clinical research to provide high-level evidence to facilitate clinical decision-making,
as well as policy negotiations and advocacy [751].
Breast deformities and mastopexy continue to challenge plastic surgeons.
Deformities such as Poland syndrome, tuberous breast, gynecomastia, and other
congenital conditions are uncommon, therefore, management experience is often limited.
Various techniques have been described, with no general consensus regarding optimal
management. Mastopexy has become more common and is performed both with and
without augmentation mammaplasty. However, a variety of techniques are available, and
a thorough understanding of the indications, patient selection criteria, and techniques is
important to optimize outcomes [752]. Degrees I and II ptosis and atrophy of the female
breast can definitively be corrected by the modified periwinkle shell operation. More
problematic are the long-term results after correction of a degree III condition, especially
when silastic prostheses for augmentation have been used. The long-term results can be
optimized by a combination of dermal and glandular mastopexy and mammary implants
[753]. Mastopexy includes multiple skin incision design and parenchymal manipulation
options. Patient evaluation includes assessment of goals, degree of ptosis, tissue volume,
skin quality, and breast position on the chest wall. There are critical technical details for
each of the incision options, the various methods of parenchymal manipulation, and
implant placement. The potential for complications is greatest for combined
augmentation and mastopexy. Although they are effective, mastopexy procedures have
the greatest incidence of litigation among aesthetic breast procedures [754]. Currently,
four techniques of short scar mastopexy have been described: the periareolar, the
vertical, the inverted-T, and the L-shaped scar. A large number of techniques have been
published for minimal ptosis, whereas for significant ptosis, the number of surgical
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options is limited. It is evident that limited scar techniques can be applied to all grades of
ptosis, but there is no one technique that can satisfactorily correct all degrees of ptosis.
Plastic surgeons should weigh the advantages and limitations of each technique to
correctly address breast ptosis [755]. Mammoplasty performed with an inverted-T skin
resection pattern is a useful technique to treat moderately or severely ptotic breasts. This
method of skin resection is conducted via three incisional components: periareolar,
vertical, and horizontal. A simple modified winch suture can be inserted with the
inverted-T technique to reduce the length of the horizontal incision [756].
The objective of breast reduction surgery is to reposition the nipple, remove excess
parenchyma, and tailor the skin to fit the new shape [757]. The four geometric
differences between the normal and enlarged breast are: vertical excess, broadened base,
horizontal excess, and a descended NAC. All breast reduction techniques use a specific
pedicle and a separate skin incision pattern, so they should be named after the scar and
pedicle used. Technique selection must consider the degree of hypertrophy and ptosis,
the skin and gland quality, the patient’s requirements, and the surgeon’s experience and
preferences. The comprehension of basic breast geometry, a universal language for
communication and a simple algorithm to approach the breast reduction patient are
valuable tools, particularly for the surgeon who is becoming acquainted with reduction
mammoplasty procedures [758]. The evidence indicates that resection volume is not
correlated directly to the degree of postoperative symptom relief. Increased breast
resection weight may increase the risks of complication. The evidence is inconclusive on
whether increased body mass index (BMI) is associated with increased risk of
complications. Perioperative antibiotics may reduce the risk of infection associated with
reduction mammoplasty, and in standard reduction mammoplasty procedures without
liposuction, the use of drains is not beneficial. Reduction mammoplasty has been shown
to improve quality of life [759]. Breast reduction is confirmed to be a very useful
operation, being a cosmetic as well as symptomatically beneficial procedure. It is seen to
be a cause of a major increase in the unit’s workload as its popularity increases [760].
Although plastic surgeons have empirically “known” of the benefits of reduction
mammoplasty for their patients, a paucity of outcome studies have been reported. A
systematic evaluation of patient-focused outcome measures demonstrated that consistent
improvement in physical symptoms was found across most studies, as was a high degree
of patient satisfaction (78-95% very or moderately satisfied), and some have shown
improvement in body image and psychological well-being. However, although consistent
improvements in patient quality of life have been identified after reduction
mammoplasty, inconsistencies among study designs do not allow formal meta-analysis
[761].
The goal in breast reduction surgery is to reduce volume but at the same time to
maintain circulation, sensation, and breast-feeding potential [762]. Any pedicle can be
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used to achieve a good breast reduction. We need to look at the skin pattern as separate
from the pedicle design. There are numerous (and good) combinations available.
Different situations will determine which combination is preferable. A standard inferior
pedicle Wise pattern technique has been performed and now variations of the vertical
technique have been used. A dermoglandular or central pedicle is the most likely to
achieve all three. This medial pedicle gives the best breast reduction results. On the other
hand, a lateral pedicle is used for mastopexies so that the inferior and lateral tissue can
be rotated up under the areola. When faced with a re-reduction of a previous inferior
pedicle, the vertical technique can still be used, and an adaptation of the inferior pedicle
can be very acceptable. The superior pedicle is reserved mainly for very small reductions
or mastopexies, but still the medial pedicle allows better lateral resection even in small
reductions, and the lateral pedicle with recruitment of tissue allows for some autoaugmentation in mastopexies [763]. The recent findings of the experience with the B
technique have been quite helpful and rewarding. Drawing a lateral angle when planning
the procedure obtains a more circular areola contour and avoids last moment
modifications. Also, upper pole undermining allows for an upper pole horizontal
plication in the cases of a simple mastopexy. These modifications have been used over
the last 30 years with no special complications and very satisfactory results [764]. In all
cases of moderate- to high-grade hypertrophy of the breast, with or without ptosis, the
reduction mammoplasty with L-shaped suture lines proves to be an effective method that
avoids unacceptable scars extending to the midline of the thorax, especially in the young
patient [765]. The use of dermoglandular flaps in reduction mastopexy was advocated by
Paul Tessier, who never published his method before his death in June 2008. Dr. Tessier
is acknowledged as the “father” of craniofacial surgery, but he had interest in aesthetic
surgery, and was quite proud of the technique he had developed using dermoglandular
flaps in reduction mammoplasty. He had literally hundreds of techniques and methods
that he had developed but which never found their way into print, both because of his
enormous surgical schedule, and perhaps his self-imposed standards for anything that he
published, which were almost impossibly high. The technique proposed by Dr. Gargano
is similar in some ways to Dr. Tessier [766].
The standard split-thickness superior pedicle vertical mammoplasty technique
sometimes suffers from tension on the NAC. A bisected full-thickness superiorly based
flap offers two vectors for transposition within the context of superior pedicle vertical
mammoplasty. The procedure increases both upper-pole fullness and projection of the
breast while decreasing tension on the NAC. The surgical procedure contributes to a
natural appearance of the breast. It should provide a useful and simple surgical option,
increasing the versatility of the superior pedicle vertical mammoplasty technique [767].
A controversy exists between vertical mammoplasty and the “traditional”
keyhole/inferior pedicle method of breast reduction. The breast can be considered a cone.
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Breast projection then is the ratio between the nipple projection and the breast base. Two
key concepts need to be considered: the orientation of the ellipses during excision of
breast tissue in breast reduction and the role of the breast base/inframammary fold.
Breast projection is not determined by the scars [768]. Vertical scar mammoplasty, first
described by Lötsch in 1923 and Dartigues in 1924 for mastopexy, was extended later to
breast reduction by Arié in 1957. It was otherwise lost to surgical history until Lassus
began experimenting with it in 1964. It then was extended by Marchac and de Olarte,
finally to be popularized by Lejour. Despite initial skepticism, vertical reduction
mammoplasty is becoming increasingly popular in recent years because it best
incorporates the two concepts of minimal scarring and a satisfactory breast shape. At the
moment, vertical scar techniques seem to be more popular in Europe than in the USA. A
recent survey, however, has demonstrated that even in the USA, it has surpassed the rate
of inverted T-scar breast reductions. The technique, however, is not without major
drawbacks, such as long vertical scars extending below the inframammary crease and
excessive skin gathering and “dog-ear” at the lower end of the scar that may require long
periods for resolution, causing extreme distress to patients and surgeons alike. Efforts are
being made to minimize these complications and make the procedure more user-friendly
either by modifying it or by replacing it with an alternative that retains the same
advantages. Although conceptually opposed to the standard vertical design, the
circumvertical modification probably is the most important maneuver for shortening
vertical scars. Residual dog-ears often are excised, resulting in a short transverse scar
(inverted T- or L-scar) [769]. The main indication of the circumvertical technique is the
removal of 400-1000 mg of breast tissue. It is also an intermediate method and an
alternative between the periareolar and the vertical techniques. The advantages of the
circumvertical technique is that it is simple and fast to accomplish, only the inferior half
of the gland is operated, there is no transection of the lactiferous ducts, at the end of the
surgery there is a harmonious redistribution of the pleats, the vertical scar never crosses
the submammary fold, and at the end of the surgery an acceptable result is almost always
observed. The posterior skin retraction will improve this initial result even more. The
Marcaine infiltration allows some hours of postoperative pain relief. In brief, this
technique is ideal for young women because it neither distorts the remnant anatomy nor
alters the future lactation, being a good alternative to moderate and large hypertrophies
[770]. The patients seeking our help for breast reduction are very often young and
probably planning to have children later in their lives. Therefore, it is most important to
offer them a method of reduction mammoplasty that leaves as little scars and as much
physiological function as possible. The vertical reduction mammoplasty is a method that
leaves normal sensibility in almost all cases, the possibility of lactation, little scarring,
and a pleasant form. The method can be used in all cases, ranging from mastopexy to
reduction weights of over 2 kg of each breast. The vertical technique developed by
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Claude Lassus and Madeleine Lejour is a contemporary method of reduction that leaves
few scars and conserves a maximum of physiological function. The method needs
surgical skill and therefore it is not suitable for beginners in breast surgery. It is difficult
to teach because it uses no patterns such as those of Strömbeck or McKissock but it gives
the breasts a new form based on the anatomical circumstances and wishes of the patients
[771]. The vertical reduction mammoplasty can be challenging to learn. In addition, first
attempts to perform the vertical reduction mammoplasty based on a technique described
by Elizabeth Hall-Findlay can lead to inconsistent aesthetic results. These problems
include a persistent vertical dog-ear deformity at the nadir of the incision, a teardrop
deformity of the NAC, lateral deviation of the nipple, and lateral axillary fullness [772].
For the last 20 years, D.H. Lalonde has added the No Vertical Scar breast reduction
to his armamentarium of reduction techniques. This operation is almost the same as the
inferior pedicle T-scar reduction. However, a small modification of the Wise pattern
permits the deletion of the vertical portion of the T-scar. The first 14 years of the Dr.
Lalonde’s practice consisted almost exclusively of the T-scar reduction. He currently
uses the Vertical reduction, the T-reduction, and in over 150 cases, the No Vertical Scar
reduction [773]. The short scar periareolar inferior pedicle reduction (SPAIR)
mammoplasty is a technically straight-forward and reliable technique for managing the
excessively large or ptotic breast that gives consistent and stable results over time.
Advantages related to improved shapes with limited postoperative shape change should
encourage the serious student of breast surgery to be familiar with the technique and
concepts involved. It is recommended as an excellent option for women seeking
reduction or mastopexy [774]. Procedures that minimize the resultant scars while
achieving comparable results are preferred by patients and greatly enhance their overall
satisfaction. Suction mammoplasty – and indeed all short-scar procedures that are
performed on the breast, face, and body – rely to variable degrees on harnessing the
under-appreciated capability of the skin to shrink or retract. Patients with breast
hypertrophy represent a wide spectrum of deformities based on NAC size, shape, and
location, skin quality and tone, and breast volume. No one breast reduction technique is
ideal for reducing all breasts. Suction mammoplasty represents one of a number of
methods of reduction mammoplasty that can be selected according to variations in
anatomy, patient desires, and surgeon preference [775]. Breast reduction by liposuction
alone is an appealing technique that has failed to gain widespread acceptance. Despite
numerous studies on liposuction, the majority of surgeons remain skeptical. Two groups
of patients that qualify for this procedure can be defined. However, the aesthetic result
will be pleasing only for young patients. For elderly patients, liposuction breast reduction
will simply achieve a weight reduction of the breast without improving the shape.
Universally good liposuction results for breast weight reduction and elevation of the
NAC are reported. Improvement in breast shape and correction of ptosis cannot be
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achieved for elderly patients. Young patients with a preoperatively pleasing breast shape
can expect a preservation of the shape with the benefit of minimal scarring. Liposuction
breast reduction is appealing due to selective removal of fat, ease of the procedure, and
minimal scarring. The main disadvantage is that a correction of shape and ptosis is not
possible with liposuction, and only young patients can expect an aesthetically pleasing
result. Elderly patients may benefit from faster recovery times, a less invasive procedure,
and low costs. The application of a new technique to a cancer-prone organ represents a
potentially serious medical-legal issue because follow-up imaging may be impaired and a
possible spread of cancer cells cannot be ruled out. Despite its technical appeal, breast
reduction by liposuction alone mandates a cautious approach [776].
Therapeutic mammoplasty, the use of reduction mammoplasty and radiotherapy to
surgically treat breast cancer, is an established technique for selected breast cancers and
can extend the role of breast-conserving surgery. Most frequently described is the use of
a wise pattern reduction for tumors that lie within the expected mammoplasty excision.
However, mammoplasty techniques can be safely adapted to treat patients with cancers
in all areas of the breast. Technique will vary depending upon the tumor position. Breast
cancers may lie within the normal excision site of a recognized mammoplasty method
(scenario A) or outside of the expected excision sites (scenario B). In scenario A, a range
of recognized techniques can be performed without adaptation to widely excise the
tumor and reshape the breasts. In scenario B, the techniques need to be adapted. Three
decisions are needed for planning in scenario B: the skin incision, the NAC pedicle
orientation, and finally the method of filling the cancer defect. The latter can be achieved
by either extending the nipple pedicle or by creating a secondary pedicle within the
breast dissection. Either method will move tissue that is normally excised into the cancer
defect. For central tumors an inferior pedicle is usually used to both fill the defect and
recreate the nipple [777-797].
Female glandular hypomastia is a frequently encountered entity that occurs either
developmentally or by postpartum involution. Historically, women have long sought
breast enlargement to improve physical proportions, to foster a more feminine
appearance, or to enhance self-image [798]. Breast augmentation remains one of the top
surgical procedures performed by plastic surgeons, probably the most commonly
performed aesthetic surgical procedure. Current literature supports the concept that
breast augmentation outcomes are optimized using a concept of “the process of breast
augmentation.” Breast augmentation is often thought of as a surgical procedure:
however, the non-surgical aspects of the procedure are more important for optimizing
outcomes and minimizing reoperation and complications. The process of breast
augmentation includes patient education, tissue-based preoperative planning, refined
surgical technique, and defined postoperative management [799]. Choices of incisions,
pocket plane, and myriad implant characteristics constitute the basis for surgical
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planning. Analysis of physical characteristics and inclusion of the patient in implant
selection contribute to overall satisfaction and reduce requests for secondary surgery.
Technical expertise in implant positioning and aseptic handling helps to prevent capsular
contracture, implant malposition, and other shape problems. Despite the need for
secondary surgery in some, patient satisfaction is high [800]. Driving forces behind the
choice to have augmentation surgery appear to be related to feelings of low self-esteem
and self-confidence. Although there is a large literature related to breast augmentation,
little of it is research-based. The research that there is focuses on complications and their
treatment, with an emphasis on capsular contracture. Few of the studies are long-term,
although complications have been noted as long as 25 years after initial implantation.
There is a need for research into the experience of women undergoing augmentation
mammoplasty but, perhaps more importantly, there is also a need to examine ways in
which women can be helped to accept themselves as they are. The increasing demand for
reduced scars has led to the development of numerous minimal incision procedures,
which constitute the most recent and exciting advances in breast surgery. Numerous
different periareolar techniques are described in an attempt to eliminate scars on the
breast surface by restricting them to the interface between the areola and the skin. The
circumareolar mastopexy with augmentation is an excellent procedure for the right
patient. Correct preoperative assessment of the patient’s skin, as well as their desires and
expectations, are as critical as the surgeon’s experience and acquaintance with his own
circumareolar technique. If all these factors can be brought together, however, successful
operations can be performed, happy patients will ensue, and less scars will be placed
[801]. These conclusions show a clear evolution of the technique as well as an
improvement in the obtained aesthetic results. New techniques for periareolar
mammoplasty based on repositioning the breast parenchyma and maintaining this new
architecture with a stronger and more durable supporting system have been developed.
The development of new materials, technical refinements in the technique, and increased
experience will undoubtedly lead to even better results in the future [802].
Cosmetic breast augmentation and postmastectomy breast reconstruction surgery
using synthetic implants have become established in surgical practice over more than 40
years. The operative technique for implant placement have changed somewhat during
this time, as many different implant presentations have become available, but the same
basic materials (polydimethylsiloxane and polyurethane) have remained in use [803].
Augmentation mammoplasty, so far, seems to be an operation with an indefinite endpoint
regarding the longevity of results. It is also a procedure that has wide monetary
implications and would often seem to be inappropriately used. With the advent of the
latest polyurethane-covered prostheses, marketed under various trade names such as
Meme, Replicon, and Optimam (Polytech, Dieburg, Germany), a more predictable result
can be obtained, at least for the first six years. Much controversy still exists [804].
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Polyurethane breast implants were first introduced by Ashley in 1970, with the intention
of trying to reduce the high incidence of capsular contracture associated with smooth
shelled, high gel bleed, silicone breast implants. The sterilization of the polyurethane
foam in the early days was questionable. More recently, ethylene oxide (ETO)-sterilized
polyurethane has been used in the manufacturing process and this has been shown to
reduce the incidence of biofilm. The improved method of attachment of polyurethane
onto the underlying high cohesive gel, barrier shell layered, silicone breast implants also
encourages biointegration. Polyurethane-covered, cohesive gel, silicone implants have
also been shown to reduce the incidence of other problems commonly associated with
smooth or textured silicone implants, especially with reference to displacement, capsular
contracture, seroma, reoperation, and biofilm and implant rupture. These findings
contribute to our understanding of polyurethane implant safety, and give reasoning for a
significant reduction in clinical capsular contracture rate, up to ten years after
implantation, compared to contemporary silicone implants. A more permanent matrix
equivalent to polyurethane may be the solution for reducing long-term capsular
contracture [805]. Even if the safety of the polyurethane prosthesis has been the subject
of many studies and professional and public controversies, nowadays, polyurethanecovered implants are very popular in plastic surgery for the treatment of capsular
contracture. The polyurethanic capsule is a well defined foreign body reaction
characterized by synovial metaplasia, a thin layer of disarranged collagen fibers, and a
high vascularization. These features make possible a “young” capsule and a low
occurrence of capsular contracture even over a long period (ten years). The polyurethane
implants may be difficult to remove but there is no evidence that they cause an increase
in the other complications: there is no evidence of polyurethane-related cancer in longterm studies (after five years). Polyurethane foam-covered breast implants remain a valid
choice for the treatment of capsular contracture even if it would be very useful to verify
the ease of removal of the prosthesis and to continue investigations on biodegradation
products [806].
Three companies currently offer FDA-approved breast implants (Allergan, Mentor,
and Sientra), but their product offerings – including permanent breast implants, breast
tissue expanders, sizers, and postoperative warranty – can be difficult to compare
because of brand names and company-specific jargon. The ability to have a brandagnostic understanding of all available options is important for both the surgical trainee
as well as the surgeon in clinical practice [807]. In the USA, women seeking breast
implants for augmentation, revision, or reconstruction can choose between saline-filled
devices and round, silicone gel-filled devices. The USA has seen significant shifts in the
breast implant market over the past five decades. From the moratorium on silicone gel
breast implants in 1992 to their approval in 2006, there have been many developments in
their manufacturing and usage. Meanwhile, saline breast implants have remained
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somewhat unchanged, still offering a few distinct advantages but none of the
technological innovation of the silicone gel models [808]. Form-stable, highly cohesive
silicone gel-filled breast implants are marketed in other countries and are currently under
review by the FDA. Allergan has conducted clinical studies to investigate the safety and
effectiveness of its round and anatomical (Style 410) devices for USA marketing
approval. The most frequently reported complications were reoperation, implant removal
with replacement, implant malposition, and capsular contracture. The FDA approved the
round devices in 2006. The weight of the scientific literature suggests that silicone gelfilled breast implants do not increase a patient’s risk of cancer, autoimmune disease,
reproductive effects, or suicide. As differently shaped, cohesive breast implants continue
to be introduced, breast implant surgery will become more customized to the patient’s
biological conditions and desires [809]. Choosing between round and anatomical formstable implants is a key decision in the process of breast augmentation. Anatomical
devices have been subject to a number of misconceptions that have limited their use.
However, in optimal clinical practice, the benefits and risks of both anatomical and
round implants should be considered for any given patient. Patient and surgeon education
is fundamental in ensuring that misunderstandings are addressed. The choice between
anatomical and round devices should be based on a combination of patient desires,
anatomy, and surgical history [810]. With the 2006 FDA approval of round silicone gel
breast implants in the USA, there still remained a lack of versatility in implant options.
The approval of Sientra’s shaped cohesive implants in 2012 brought with it the
innovations needed to address varying patient needs. Because access to shaped devices is
still fairly recent in the USA, some surgeons remain uncomfortable with implementing
shaped cohesive gel implants into their practice. Important factors for shaped-implant
selection include chest base diameter, implant height, implant volume, and implant
projection for the patient’s desired outcome. With experience, surgeons will find new
utility with shaped implants for a variety of patients in their practices [811]. The recent
approval of MemoryShape implant by the FDA introduces a novel implant available to
the surgeon for cosmetic and reconstructive breast surgery. These implants are unique
due to the texture of the shell, the anatomical shape and dimensions, the degree of crosslinking of the gel, and relative form stability. The cross-linking, form stability, and
cohesiveness of these implants provide surgeons with an innovative tool to more closely
create a natural breast in both shape and youthful firmness [812]. Macrolane (Q-Med,
Uppsala, Sweden), a compound composed of hyaluronic acid, is the newest product to be
marketed for breast augmentation. Like many previous breast augmentation products,
Macrolane has been authorized for use with very little published scientific data on its
safety and efficacy in breast augmentation. It is strongly recommended that clinicians
review the lack of data on Macrolane before offering it as a treatment option to patients
[813, 814].
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Breast implants are medical devices used for augmentation of the breast, to
reconstruct the breast after mastectomy, and to correct breast asymmetry. The breast
prostheses are likely the most frequently used medical implants. The evolution of
modern silicone breast implants was not straightforward and is characterized with a lot
of medical, forensic, and public attention. Currently, it is sufficiently established that
implants are safe and can be used for breast reconstruction and aesthetic augmentation.
Prosthesis can rupture and produce local symptoms but there is no evidence that silicone
breast implants can be of any health hazards for the patients [815]. Breast implants have
been used for about four decades for both reconstructive and aesthetic purposes. In 1963,
the quality of the artificial implants was revolutionized by the introduction of the silicone
gel-filled implant. Since, this modern prosthesis has gone through an evolution of change
and improvement with several types of devices with many variations and styles within
each class. Actually, for the last three decades, approximately one million women have
received silicone breast implants in the USA. But, in 1992, the American FDA banned
silicone from the market, leaving saline implants as the only product generally available
as an alternative until now. Other filler materials were introduced in the USA and in
Europe [816]. So, the silicone breast implants have recently come under scrutiny by the
FDA and received much unfavorable media coverage. The gel-filled breast implants
which in 1976 were “grandfathered” by the FDA have now been required to provide
scientific evidence of safety and effectiveness by July 9th, 1991. The possible risks of
silicone breast implants include capsular contracture, interference with early tumor
detection by routine mammography, development of sarcomas in laboratory animals (no
human cases are reported), silicone gel leakage, and connective tissue disease. In the less
frequently used polyurethane-covered implants, the degradation of the polyurethane to
diaminotoluene (TDA) has caused liver cancer in laboratory animals, yet at present, this
type of implant has been voluntarily removed from the market by the manufacturer. After
reviewing the available evidence, the American Society of Plastic Surgery (ASPS) still
considers silicone breast implants reliable and safe [817]. Evolution of silicone breast
implant design has focused primarily on advances in implant fill, surface texture, and
shape. Fifth-generation, shaped, form-stable, silicone breast implants from all three
major implant manufacturers are now approved for use by the FDA in the USA. As part
of this approval, the FDA mandated Core Study follow-up of silicone implants for ten
years after premarket approval [818]. Modern implant design has aimed to optimize
aesthetic outcomes while minimizing implant-related complications, such as capsular
contracture and device rupture. One of the most significant advances has been the use of
highly cohesive silicone which, through extensive cross-linking, maintains its shape
within the body in the presence of physiologic forces. Overall, silicone breast implants
are associated with a high degree of patient satisfaction and low rates of complications.
Further independent research is necessary to better establish long-term outcomes [819].
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Despite the ban on silicone gel breast implants in 1992, the last decades witnessed a
dramatic increase in the number of cosmetic breast augmentation procedures performed
in the USA. According to the ASPS, over 132,000 women in this country underwent the
procedure every year. It is estimated that they have been implanted in over two million
women in the USA. This is an underestimate of the actual number of breast
augmentations performed annually, as increasing numbers of non-surgeon physicians are
now performing cosmetic surgery. Given the rising number of women who now seek
cosmetic breast augmentation surgery, it is likely that women’s healthcare providers will
be asked by their patients about breast augmentation [820]. Yet, augmentation
mammoplasty is a surgical procedure with known risks and complications. Despite this,
millions of women have opted to undergo the procedure. With the recent publicity
surrounding this procedure, and the current concern about long-term side effects, the
rationale behind women’s choice has been questioned. Often, health care professionals
are less than empathetic when a woman complains about experiencing complications.
This attitude seems to “blame the victim” [821]. Despite five decades of rapidly
expanding application of polydimethylsiloxane as a relatively safe implantable
biomaterial, the American public is being told by a vocal minority that its use in the
breast implant may be dangerous. Most of the furor has been generated by consumer
advocates with support of a handful of scientists who have expressed opinions, not well
supported by facts, about the risks of these devices. These anxieties have been fueled in
the public’s mind by a media more interested in sensationalism than disciplined
reporting. The controversy has complicated the regulatory process and has become
politicized in the halls of State Legislatures and Congress. Remarkably, this controversy
has not involved the many other biomedical applications of silicone [822]. The FDA has
required manufacturers of the implants to submit evidence of their safety and
effectiveness. The implants have been shown to benefit women in psychological studies.
Physical risks include capsular contracture (affecting up to half of wearers), impaired
mammographic results, implant rupture, and possibly connective tissue disease. Human
studies would benefit from improved research design, including controls and long-term
follow-up. Professional societies of plastic surgeons, whose members benefit
commercially from breast augmentation and reconstruction, have campaigned forcefully
for the continued and increased use of breast implants by women [823].
Standard techniques have been used for the successful placement of mammary
prostheses to enhance or replace breast tissue. All breast implants are surrounded by a
capsule. The most common complication of breast implant surgery is hardening and
contracture of the capsule. Explanation of implants is indicated for implant rupture,
infection, extrusion, siliconoma, breast pain, painful capsular contracture, malposition,
significant patient fear, and systemic symptoms thought secondary to implants. A
number of alternatives are available for postexplant reconstruction, including
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myocutaneous flaps and free tissue transfers [824]. Several alterations to both elastomer
shell and filler gel have been made over the years to improve silicone gel implants ability
to replicate the natural breast and to decrease the incidence of capsular contracture. The
latter is a pathological process involving the periprosthetic tissues formed in response to
the presence of the implant. When severe, capsular contracture may cause firmness,
distortion, and pain [825]. In the past 30 years, there have been multiple published
reports associating silicone breast implants with scleroderma, morphea, systemic lupus
erythematosus (SLE), rheumatoid arthritis, calcinosis, Raynaud phenomenon, esophageal
dysmotility, sclerodactyly, and telangiectasia (CREST) syndrome, and the socalled
“human adjuvant disease.” The alleged offending material, silicone, is a synthetic
polymer containing a silicon-oxygen backbone. Beginning with the heating of silicon
dioxide (SiO2) in the presence of carbon, elemental silicon is produced. Methylchloride
is added and the resulting product is hydrolyzed to form low molecular weight
prepolymers which are linked to form linear silicone polymers and cross-linked to yield
silicone rubbers or elastomers. The polymeric and hydrophobic characteristics of silicone
and the presence of electrostatic charges and organic sidegroups make silicone a
potentially ideal immunogen, leading to cross-reactivity with autoantigens. Silicon is an
essential constituent of proteoglycans which theoretically could result in immunological
cross-reactions between silicone and connective tissues. Although the literature contains
numerous examples of silicone-associated autoimmune disease, there is no consistent
pattern of immunological abnormalities observed. There are, however, some intriguing
and interesting observations [826]. Understanding the immunology of silicone breast
implants, at present, consists of reconciling an increasingly large body of data with an
older, established, but otherwise unsubstantiated theory. Despite the variety of silicone
breast implants, there are nevertheless certain phenomena that occur with all silicone gelfilled devices. Recent clinical findings suggest that in some patients, silicone will act as
an adjuvant on native macromolecules and render them immunogenic. Further largescale studies are needed to determine if a link between silicone exposure and
autoimmunity exists. Also, since the inducing events of autoimmune diseases are
unknown, studies on silicone could provide a model for autoimmune diseases associated
with toxicological factors [827].
Many implants may need in-vivo evaluation by imaging, particularly if they lead to
complications and/or clinical symptoms. They can also pose problems in the assessment
of surrounding breast tissue by conventional mammography. In this respect, imaging
modalities such as ultrasound, CT, and MRI offer greater possibilities to assess a failing
implant, as well as surrounding breast tissue [828]. All radiologists need to be able to
recognize the normal appearances of the more commonly used implants on various
imaging modalities, and breast radiologists in particular are facing new challenges when
imaging the women involved [829]. There are some reports suggesting that implants can
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interfere with mammography and may lead to delayed breast cancer diagnosis, even
when implant-displaced mammography (Eklund technique) is performed. The augmented
breast is a challenge to the mammographer. Many of the palpable and mammographically
detected abnormalities in these patients are related to the implant itself. Since, however,
there is breast tissue present with cosmetic augmentation, the full range of fibrocystic
and neoplastic conditions that can affect the breast may be seen. The presence of the
implant makes imaging the breast more difficult because the implant obscures the nearby
breast tissue [830]. Recent reports suggest that screening mammography may not be
appropriate in augmented women, but breast self-examination may be effective in these
women. Ultrasonography may be useful in screening augmented women without risk of
rupturing the implant. In appropriate cases, MRI should be considered as an adjunct to
mammography and ultrasonography. The question of whether augmented women should
not undergo CNB because of the possibility of damage to the implant should be
considered. The challenge of the screening and diagnosis of breast cancer in augmented
women is important in order to detect more of their cancer at a preclinical stage, because
we can expect to see breast cancer in augmented women with increasing frequency over
the next decades [831]. MRI has proved to be an excellent imaging modality in locating
free silicone and evaluating an implant for rupture, with a sensitivity of approximately
94% and specificity of 97%. Silicone has a unique MRI frequency and long T1 and T2
relaxation times, which allows several MRI sequences to provide excellent diagnostic
images. The most commonly used sequences include T2-weighted, short-TI inversion
recovery (STIR), and chemical shift imaging. The T2-weighted and STIR sequences are
often used in conjunction with chemical water suppression. The most reliable findings on
MRI for detection of implant rupture include identification of the collapsed implant shell
(linguine sign) and free silicone within the breast parenchyma [832]. The MRI
appearances of various complications of polyacrylamide gel injection mammoplasty
include breast asymmetry, intramammary or extramammary gel displacement, including
intrathoracic extension, and glandular atrophy, inflammation, and infection resulting in
mastectomy. Because polyacrylamide gel has a high water content, it has been found that
sagittal and axial T2-weighted are the best sequences to use to detect complications
[833]. MRI is the primary modality for assessing the integrity of silicone implants and
has excellent sensitivity and specificity, and the FDA currently recommends periodic
MRI screening for silent silicone breast implant rupture. Familiarity with the types of
silicone implants and potential complications is essential for the radiologist. Signs of
intracapsular rupture include the noose, droplet, subcapsular line, and linguine signs.
Signs of extracapsular rupture include herniation of silicone with a capsular defect and
extruded silicone material. Specific sequences including water and silicone suppression
are essential for distinguishing rupture from other pathologies and artifacts. MRI
provides valuable information about the integrity of silicone implants and associated
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complications [834]. Although there are many 3-D imaging systems currently available
on the market, all of them require a high degree of interaction on the part of the user,
making them clinically impractical. Moreover, though claims have been made regarding
the validity of these systems for imaging the breast form, there have been no previous
reports validating any commercially-available implant simulation models in the plastic
surgery literature. A novel 4-D (automated 3-D) breast imaging system has been
validated as an evidence-based simulation tool for patient consultation, surgical
planning, and outcomes analysis in cosmetic breast augmentation. Based on a series of
longitudinal correlation studies with several patient cohorts, a highly statistically
significant degree of correlation and reliability between the automated measurements
obtained with the 4-D system and manual measurements has been found [835-837]. No
association has been found between the presence of breast implants in a breast and an
increased risk of breast cancer. However, as the population of women with breast
implants ages, an increasing number of them will develop breast cancer: a reflection of
the fact that the incidence of the disease increases with increasing age. Debate continues
on the effect of breast implants on the efficacy of mammography in diagnosing breast
cancer, and the role of other imaging techniques for this purpose, as well as the
limitations that the presence of implants place on percutaneous biopsy techniques [838].
The majority of women receiving breast augmentation surgery do so at a time in their
lives when both reproduction and lactation are common. It does not occur to most
women to consider the possible effects breast augmentation surgery may have on their
future ability to exclusively breast-feed their baby. Most women raise concerns about
their inability to exclusively breast-feed years after surgery when they have a child. It is
therefore important that women considering breast augmentation surgery be fully
informed of the possible effects surgery may have on their future ability to lactate.
Women who undergo breast augmentation surgery have a greater incidence of lactation
insufficiency. Factors directly related to the surgical procedure as well as short- and
long-term complications of surgery compromise future ability to exclusively breast-feed
a baby. Factors directly related to surgery include severing of the lateral and medial
branches of the fourth intercostal nerve or the nerve endings of the NAC, which lead to
reduced sensation and loss of the suckling reflex resulting in decreased milk production.
Hematoma formation increases the risk of developing capsular contracture therefore
necessitating the need for further surgical intervention. Infection also requires further
intervention and, as a result, further risk to the breast tissue. Long-term breast pain,
capsular contracture, and pressure effects on the breast from the implant are all possible
long-term complications that compromise a woman’s future ability to lactate and
exclusively breast-feed her baby. With good surgical technique and proper postoperative
management, most of the complications associated with surgery that may result in
insufficient milk production can be minimized but not always avoided. Compared with
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non-augmented women, women who have had augmentation surgery have a higher
incidence of lactation insufficiency [839]. Far more information is available about the
relationship of breast reduction surgery and lactation than about breast augmentation
surgery and lactation. Women are often able to breast-feed after breast augmentation
surgery. Depending upon the type of breast reduction surgery, estimates of the number of
women who can lactate after reduction surgery range from 0-70% [840]. Women who
have had breast surgery are likely to have many questions and misgivings about their
ability to breast-feed. In order to answer the woman’s questions and provide her with
supportive and guiding care, the lactation consultant must understand the nature of the
surgery, the reasons for it, and the likely outcome with respect to the ability to lactate
[841].
Although breast prosthesis implantation is the most common technique of cosmetic
breast augmentation, other unusual techniques such as autologous fat implantation as
well as direct liquid silicone and paraffin injections have also been used [842]. Since the
1980s, there has been an increased interest in autogenous fat grafting for breast
augmentation. However, concerns over graft survival and interference with breast cancer
screening have limited its application. Autologous fat grafting is an increasingly popular
procedure used for facial rejuvenation and body contouring. A review of the literature
demonstrated that there is no standard test for determining fat viability or volume
augmentation after grafting. Furthermore, there is no difference in cell viability seen
between syringe aspiration and liposuction pump aspiration harvest techniques. The
decision to wash or centrifuge the fat plays very little role in fat graft survival. There is
no difference between cell viability as a function of harvest location. Nearly all studies
show no significant effect of local anesthesia on adipocyte cells. There are excellent data
that support the fact that low-shear devices maintain fat structural integrity. There is
quality evidence that supports longevity of fat grafted to the breast. Two studies support
large-volume fat grafting longevity but fail to prove their results using objective
measures or with sufficiently large sample sizes. External pre-expansion devices improve
total graft survival rate. There is quality evidence to support that fat should be injected
soon after harvesting, as properties of fat begin to change after processing.
Microneedling (preconditioning) before fat grafting has been demonstrated to improve
fat survival. Currently, the highest levels of evidence derive from human studies of
clinical trials and animal studies using human fat. The evidence helps to address the need
for accurate and quantitative viability assays. These assays would facilitate a systematic
evaluation of each procedural step during fat graft harvest, processing, and grafting to
improve the overall viability and predictability of fat grafts [843]. As the technique of
autologous fat grafting is being refined and perfected, its clinical applications are
expanding. The use of autologous fat grafting for primary breast augmentation is
controversial due to a lack of clarity regarding its safety and efficacy. Most notably,
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concerns about interference with the detection of breast cancer have been raised, but
these have not been clearly addressed in the literature [844]. Recent technical advances
in fat grafting and the development of surgical devices such as liposuction cannulae have
made fat grafting a relatively safe and effective procedure. However, new guidelines
issued by the ASPS in 2009 announced that fat grafting to the breast is not a strongly
recommended procedure, as there are limited scientific data on the safety and efficacy of
this particular type of fat transfer. Recent progress by several groups has revealed that
multipotent adult stem cells are present in human adipose tissue. This cell population,
termed ASC, represents a promising approach to future cell-based therapies, such as
tissue engineering and regeneration. In fact, several reports have shown that ASC play a
pivotal role in graft survival through both adipogenesis and angiogenesis [845]. Since its
introduction, refinements in harvesting and grafting techniques have improved results.
The available literature consists primarily of case reports and series. There are no RCT,
and outcomes thus far have not been measured in a standardized way. The limited data
relating to breast cancer screening did not note a significant interference. Concerns have
been raised that the placement of mature adipocytes and ASC into the hormonally-active
environment of the breast may potentiate breast cancer, but there are no RCT that
investigate this possibility and a consensus regarding the basic science is still
developing. Large multicenter, prospective RCT are necessary to further investigate the
many issues relating to the application of autogenous fat grafting for augmentation of the
breast [846]. So, the use of autologous fat transfer for breast augmentation is still
controversial due to ongoing concerns regarding its efficacy and safety, most notably,
concerns about breast cancer risk and detection. Autologous fat transfer for breast
augmentation is not yet standardized. Therefore, outcomes vary widely depending on the
surgeon’s expertise. The majority of reported complications are of low morbidity, and
based on available data, the procedure has a good long-term safety profile. Although
there is no evidence that fat grafting increases breast malignancy risk, long-term followup is required [847-852].
Revisionary breast surgery in previously augmented patients is complex, with many
variables that have to be considered. Obtaining durable repairs is challenging because
these patients often present with thinned breast tissue, inadequate local tissue, and/or
scarred breast envelope from multiple procedures. Capsular contracture, ptosis, tissue
atrophy, and wrinkling/rippling are some of the most frequent reasons for reoperation.
Conventional repair techniques generally involve a combination of capsule modification
(capsular flaps), site change, mastopexy, and implant exchange. Recently, ADM have
been introduced into revision surgery to reinforce soft tissue, reinforce the implant
pocket, and potentially mitigate capsular contracture [853, 854]. Simple application of
negative suction drains through the umbilicus during transaxillary breast augmentation
obtained a more natural drainage and an easier positioning of the drain at the dependant
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portions than placement of the drains at the transaxillary incision site. Moreover, the
patient was more satisfied due to increased comfort while wearing clothes, which
resulted in a quicker recovery to everyday activities. In addition, the scar of the drain site
was hidden on the inner side of the umbilicus [855-857]. Many of these patients present
with secondary problems or complications following their primary breast augmentation.
Two of the most common complications are capsular contracture and implant
malposition. Familiarity and comfort with the assessment and management of these
complications is necessary for all plastic surgeons. An up-to-date understanding of
current devices and techniques may decrease the need to manage future complications
from the current cohort of breast augmentation patients [858, 859]. Abdominoplasty and
breast surgery are frequently appealing to patients as combined procedures. The practice
of combining abdominoplasty with other procedures originates from abdominoplasty
performed in conjunction with intra-abdominal or gynecological surgery. Initially, the
focus of combined surgery was on ensuring safety and minimizing local (e.g., wound
healing) complications. As surgeons began combining abdominoplasty with distant
procedures such as breast surgery, because the individual procedures have little adverse
impact on one another and are not altered because of the combination, concerns with
systemic morbidity surpassed the initial focus on avoiding local complications.
Prevention of venous thromboembolism became a paramount concern. Some surgeons
perform abdominoplasty in conjunction with other procedures more frequently than in
isolation, reflecting broader societal demand. Indeed, because of the effects of pregnancy
and aging, abdominoplasty is being performed in conjunction with breast surgery with
frequency sufficient to have driven the term “mommy makeover” into mainstream
parlance. Consideration regarding length of surgery and the other recommendations
allows for the safe and successful execution of this common combination [860].
Deformities caused by partial mastectomy can often be helped by plastic surgical
techniques. Immediate repair of partial mastectomy defects is especially useful when
skin, as well as breast tissue, has been resected. Distant tissue can be used, but most
partial mastectomy defects are best repaired with local flaps. Shifting the defect into the
axilla, where it is less noticeable, is often helpful. Alternatively, the breast can be
reshaped using techniques similar to those used in reduction mammoplasty. In that
situation, reduction of the opposite breast often is indicated for symmetry [861].
Fundamental principles of management of breast burns begin with recognition and
preservation of any viable breast bud tissue. Reconstruction begins when the burned
breast envelope is insufficient to allow unrestricted breast development. Complete
contracture release is obtained by incision or excision of the restricting burn scar and
thick split-thickness grafting. Occasionally, breast mound reconstruction with regional
musculocutaneous flaps or tissue expanders is necessary. Balancing procedures, such as
reduction or mastopexy of an opposite unburned breast, are often helpful. After a period
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of six to 12 months of compression garments, scar management, and settling, NAC
reconstruction is undertaken and consists of a combination of local flaps, full-thickness
grafting, or composite grafts tailored to each patient’s needs. Long-term follow-up is
necessary to ensure that breast development continues satisfactorily and that contractures
do not recur [862].
One positive consequence of the challenge to silicone breast implants has been
renewed interest in the psychological dimensions of plastic surgery. When asked
questions about the psychological outcomes of women with breast implants, plastic
surgery responded with work that is changing the very framework on which concepts
such as body image and quality of life are founded. In the course of exploring the
psychological impact of breast augmentation, traditional ways of thinking about patient
characteristics and motivations have been called into question. There is a new focus on
evidence-based outcomes research and an active search for methods that are valid,
reliable, and sensitive enough to recognize and measure the emotional impact of
changing physical appearance. With more information about psychiatric comorbidities
and the identification of variables that influence patients’ attitudes, augmentation
mammoplasty with implants is better understood. Meanwhile, a new generation of
investigators has been stimulated to study and reinterpret the psychodynamics of the
aesthetic surgery experience [863]. The psychological aspects of cosmetic breast
augmentation have been the focus of a great deal of empiric study over the past 50 years.
Methodological limitations of the studies investigating the preoperative psychosocial
status of breast augmentation candidates make it difficult to draw firm conclusions about
the potential psychological differences between these women and those not interested in
breast augmentation. Postoperative satisfaction rates are high, and several studies suggest
that patients experience improvements in body image following surgery. The effects of
breast augmentation on other areas of psychological functioning are less clear. Based on
the epidemiological studies published to date, the suicide rate among women with
cosmetic breast implants is two to three times the expected rate. The literature in this
area should be used to guide the psychosocial assessment and management of cosmetic
breast augmentation patients. There currently is little evidence to support a
recommendation that all women who present for cosmetic breast augmentation be
required to undergo a psychiatric evaluation before surgery. Given the relationship
between breast implants and suicide, however, it is recommended that women with a
history of psychopathology who present for breast augmentation, or those who are
suspected by the plastic surgeon of having some form of psychopathological
abnormality, should undergo a mental health consultation before surgery [864].
In conclusion, when silicone gel breast implants became the subject of a public
health controversy in the early 1990s, the most pressing concern was safety. Another,
less publicized issue is the need for implants. Stakeholders in this history constructed
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need as legitimized individual desire, the form of which shifted with changes in the
technological and social context [865]. Breast augmentation remains a popular aesthetic
procedure. Even with the current negative publicity, breast augmentation continues to be
a widely accepted procedure. The materials that make up the breast implants have been
in use for over 40 years with only minimal complications. Scar contractures continue to
be the major complication with this surgery. A causal relationship between silicone
breast implants, neoplasms of the breasts, or autoimmune diseases have not been
demonstrated in experimental studies on humans. Scientific data presented to the FDA
will determine if silicone-containing products will continue to be used for implantation.
There is enough concern among some physicians and patients that many are now turning
to saline implants. Some of the patients do not entertain the idea of saline implants
because of the incidence of deflation and reoperation [866].
The silicone breast implant controversy has amassed a great deal of media coverage
in the past years. Unfortunately, separating fact from fiction has been extremely
frustrating and difficult, not only for physicians but for women who have either had or
are considering cosmetic or reconstructive surgery of the breast. Breast implants are
placed not only by plastic and reconstructive surgeons, but by otolaryngologists, “facial
plastic surgeons,” obstetricians/gynecologists, general surgeons, dermatologists, and
family practitioners. It is the ethical and legal responsibility of the physicians who elect
to perform these procedures to provide adequate care and follow-up for these patients
when either real or perceived problems arise. Accurate information, reassurance, and
occasionally reoperations are required for many of these patients [867]. There are
informational gaps, but not all of these can be laid at the door of imperfect studies or
failed scientific methods. Certain properties of the implants are still unmeasurable,
immunological investigation is still evolving, the cause of wound contraction is
inexplicable here or in the burnscar contracture, and the indications for and results of this
surgery necessarily are subjective. Still, there are a number of investigative avenues open
to us, and our cumulative experience shows no reluctance on the part of plastic surgeons
to initiate further studies [868].
Breast enhancement through augmentation improves not only the woman’s physical
appearance but also contributes to her psychological well-being. With the current
emphasis placed on women’s breasts in the media, it is not surprising that small-breasted
women feel inadequate. Recent FDA approval of saline implants has given them a new
image, and more women are seeking breast augmentation. As long as the woman
understands that this operation has associated risks, a physician-patient relationship may
be developed resulting in many years of happiness and increased self-esteem. The shape,
contour, and size of a woman’s breasts are permanently altered by augmentation
mammoplasty and breast reduction. Although each case is unique, the outcome of each
procedure should result in a satisfied patient [869]. Mankind remains infatuated with
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finding the “fountain of youth,” and plastic surgery has become a very important
component in the search for eternal youth. Invasive procedures such as face-lifts, body
contouring, and implantation of silicone mammary implants as well as less invasive
procedures such as wrinkle decreasing protocols using filler substances or botulinum
toxin, effectively reshape and rejuvenate the aging face or body. However, despite the
improved cosmetic appearance of the individual, these treatments disrupt normal aging
processes on cellular and molecular level. For example, silicone degradation products
promote protein denaturation and activate cells of both the innate and adaptive immune
system, thus perpetuating a chronic proinflammatory response of the local tissue [870].
Nevertheless, breast augmentation remains one of the most common aesthetic procedures
performed in the USA. Silicone implants have undergone an evolution with the
availability of both fourth- and fifth-generation devices from the three leading
manufacturers in the USA. Clinicians should strive to provide ongoing data and sound
science to continue to improve clinical outcomes in the future [871].
The future may hold promise for the introduction of new implants for the
augmentation of the breast and for reconstruction. The constant demand and pressure
placed on the manufacturers to keep developing new fillers are proof that satisfaction
with saline implants is lacking. Today, however, the saline implant may be believed to be
the safest breast implant available for clinical application. The demand necessitates that
implants be used for enhancement of a woman’s self-image and for reconstruction. The
smooth-surface implants are considered more popular and safer for patients, perhaps
because it has been well documented that the shell may have been the cause of the
problem. However, the constancy in holding on using and reapplying the same principles
of a faulty shell may not be as scientific an endeavor as we have done in the past, and to
keep placing different fillers in the faulty shell. Perhaps the lamination process used in
manufacturing, the air in the shell, or wear and tear produce mechanical weakening of
the shell that eventually will lead to loss of integrity of the silicone-shell breast implant.
The global community is looking to plastic surgeons for a solution. The applications and
the demand for breast implants are global in nature. Meanwhile, as clinicians are waiting
for a new implantable breast device, they will continue to use what is available and
advise patients that the implantation of a breast prosthesis is not a life-long endeavor.
There is a need, however, for the implants to be maintained by the process of exchange
every eight to ten years. Breast reaugmentation is to be performed as a standard because
plastic surgeons will be waiting for further clarifications from the regulators or the
scientific community. The goal is to produce a good outcome and maintain safety for the
patients with a high standard of care [872]. The breast implant issue is a “bad news/good
news” story. For many women with implants, the controversy has caused a fair degree of
anxiety which may or may not be resolved as further information becomes available. It
has also taken its toll on Dow Corning. Whole lines of medical products have been
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eliminated or are being phase out. The development of new medical applications has
been terminated. As a consequence, employees have lost their jobs. What the effect will
be on the biomedical industry as a whole remains to be seen. While silicones have been
an important component in various medical devices, it is likely that other materials can
be used as replacements. However, suppliers of non-silicone materials are also reevaluating their role in this market. For example, Du Pont, the nation’s largest chemical
company, has determined that the unpredictable and excessive costs of doing business
with manufacturers of implantable medical devices no longer justifies the unrestricted
sale of standard raw materials into this industry. Other companies are quietly following
suit. On the up side, it is possible that the research being driven by this controversy will
result in a greater understanding of the immunological implications of xenobiotics, of the
importance of non-biased observations, of the need for ready access to valid data sets,
and of the opportunity for valid scientific information to guide legal decisions. Only time
will tell [873-875].
Chapter XI
Breast Surgery Complications
Most breast operations are categorized as low-morbidity procedures, but a variety of
complications can occur in association with diagnostic and multidisciplinary
management procedures. Some of these complications are related to the breast itself, and
others are associated with axillary staging procedures. Some of them are general, nonspecific complications (wound infections, seroma formation, and hematoma). Other
complications are specific to particular breast-related procedures: lumpectomy (including
both diagnostic open biopsy and breast-conservation therapy for cancer), mastectomy,
ALN dissection, lymphatic mapping/SLNB, and reconstruction [876]. Over the past three
decades, breast-conservation therapy with lumpectomy and WBI has become a standard
option for the majority of women with newly diagnosed breast cancer. Long-term local
control is achieved in approximately 85% of patients, and the therapy is generally well
tolerated. There can, however, be long-term effects on the breast and other nearby tissues
that may range from asymptomatic findings on examination to severe, debilitating
problems. Infection, fat necrosis, and severe musculoskeletal problems such as
osteoradionecrosis or soft-tissue necrosis are uncommon, affecting less than 5% of
patients. However, changes in range of motion, mild-to-moderate musculoskeletal pain,
and arm and breast edema are much more common. As more women choose breastconservation therapy for management of their breast cancer, physicians will encounter
these problems, as well as in-breast tumor recurrence, with greater frequency [877].
Upper-extremity pain is a common and debilitating problem for patients with breast
cancer. Although there is considerable literature describing symptoms, little is available
on the specific disorders responsible for pain and debility in these patients. Cervical
radiculopathy, brachial plexopathy, neuropathy, rotator cuff tendonitis, adhesive
capsulitis, epicondylitis, postmastectomy syndrome, swelling, and bone metastases are
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among the common disorders responsible for upper-extremity pain in breast cancer
patients [878].
Needle biopsy of the breast is widely practiced. Imaging-guidance ensures a high
degree of accuracy. However, sporadic cases of disease recurrence suggest that in some
cases the procedure itself may contribute to this complication. There is histological
evidence of seeding of tumor cells from the primary neoplastic site into adjacent breast
tissue following biopsy. However, as the interval between biopsy and surgery lengthens
then the incidence of seeding declines, which suggests that displaced tumor cells are not
viable. Clinical recurrence at the site of a needle biopsy is uncommon and the
relationship between biopsy and later recurrence is difficult to confirm. There is some
evidence to suggest that cell seeding may be reduced when vacuum biopsy devices are
deployed [879, 880]. Pneumothorax is a rare but recognized complication of diagnostic
FNA of the breast. The reported incidence of pneumothorax after diagnostic aspiration of
the breast in seven series varied between three in 100 and one in 10 000, but the weight
of evidence tended towards the latter rate. Two studies reported that the complication is
more common in the hands of trainees. It is not always possible to maintain the
aspirating needle parallel or tangential to the chest wall. Pleural puncture may be more
common than is apparent, and is most common in the tail of the breast in a thin woman.
It is important that breast clinicians are aware of the risk of pneumothorax but, provided
proper care has been taken, this complication is not the result of a negligent act [881].
In animal tumor systems, all three major treatment modalities, surgery, radiotherapy,
and chemotherapy, may increase the incidence of metastases in the presence of
circulating viable tumor cells. In breast cancer patients, selected studies can be found
which report an increased incidence of metastases after surgery, radiotherapy, or
chemotherapy, but these effects appear to exert little influence on overall survival.
Caution is advised in using systemic therapy prior to effective primary tumor
cytoreductive treatment. Minimal surgery, loco-regional radiotherapy, and effective
adjuvant systemic therapy may result in the improved survival of patients with breast
cancer with minimal functional or cosmetic impairment [882]. There is great interest
among oncologists concerning what we might learn by examining the pattern of relapse
after breast cancer surgery. What you see depends upon how hard you look. Up to now,
investigators have examined the hazard ratio for relapse every 6-12 months. In a research
paper, the Milan group have looked at the hazard ratio every three months and have
found, for the first time, a distinct, very early peak of relapse in a group of
premenopausal, node-positive patients not given chemotherapy or hormone therapy
[883]. Thus, the act of surgery can provoke the outgrowth of dormant micrometastases,
which often leads to the failure of screening to deliver its promise. The therapeutic
consequence of this idea involves the use of antiangiogenic drugs before surgery [884].
Dormant breast cancer cells are a reality that cannot be overlooked. They may stay
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dormant either after a spread of cancer cells caused by surgery or after being generated
by spontaneous or induced mutations in the course of breast gland growth [885]. For
various reasons, it is believed that the short postoperative period is critical for
eliminating minimal residual disease, thus markedly impacting long-term survival.
Unfortunately, both animal and human studies have shown that surgery induces
suppression of antimetastatic cell-mediated immunity at this critical period, which is
suggested to worsen patients’ prognosis. The use of prophylactic interventions feasible in
cancer patients to avoid postoperative suppression of cell-mediated immunity has been
shown to significantly reduce postoperative metastasis in animal models, including
mammary adenocarcinoma, and initial data suggest similar efficacy in breast cancer
patients. Prophylactic interventions can easily be applied by health-care practitioners and
hold promise in reducing long-term recurrence and metastasis in cancer patients [886].
To explain bimodal relapse patterns observed in breast cancer data, it has been proposed
that metastatic breast cancer growth commonly includes periods of temporary dormancy
at both the single cell phase and the avascular micrometastasis phase. The half-lives of
these states are one and two years, respectively. It has also been suggested that surgery to
remove the primary tumor often terminates dormancy resulting in accelerated relapses.
These iatrogenic events are very common in that over half of all metastatic relapses
progress in that manner. Assuming this is true, there should be ample and clear evidence
in clinical data. Dormancy can be identified in these diverse data but most conspicuous is
the sudden escape from dormancy following primary surgery. These quantitative findings
provide linkage between experimental studies of tumor dormancy and clinical efforts to
improve patient outcome [887-889].
Loco-regional failures after primary treatment for breast cancer include a diverse
group of lesions that represent different categories of failures with various prognoses.
Although patients with chest wall recurrences and regional nodal failures after traditional
radical surgery have a poor prognosis, many patients can still achieve a significant
degree of palliation and even long-term survival or cure with carefully orchestrated
multimodal treatment. In patients who have breast failures after breast-conservation
surgery and radiation, long-term salvage and cure can be achieved for the majority with
prompt detection and appropriate treatment, which, like treatment for primary breast
cancer, includes a consideration not only of local control but also of the risk of
subsequent systemic failure and its need for treatment [890]. Despite the success of both
breast-conserving surgery and mastectomy, some women will experience a loco-regional
recurrence of their breast cancer. Predictors for loco-regional recurrence after breastconserving therapy or mastectomy have been identified, including patient, tumor, and
treatment-related factors. The role of surgery, radiation, and chemotherapy as treatment
has evolved over time and many patients now have the potential for salvage after locoregional recurrence. In those instances where evidence is lacking or not definitive, expert
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opinion may be used to recommend imaging or treatment [891]. Loco-regional relapse
after breast-conserving surgery and radiation therapy is operable and not associated with
concurrent distant metastases in most cases. Salvage mastectomy results in loco-regional
control for most patients. The extent of the surgery relates to the extent of the locoregional recurrence and does not carry an increased complication rate. The outcome of
salvage mastectomy depends on the disease-free interval from initial breast-conserving
surgery and radiation therapy to loco-regional recurrence. Additional factors, such as the
extent and histological type of the recurrence, as well as the ALN status, either at the
time of initial breast conservation or at salvage mastectomy, may influence outcome and
require further study [892]. SLNB became the standard of care before consensus on the
technique was reached and without RCT having shown a similar or decreased axillary
recurrence rate. Uni- and multivariable analyses showed that the lowest recurrence rates
were reported in studies performed in cancer centers, in studies that described the use of
99m
Tc-sulphur colloid, and also when investigators used the superficial injection
technique or evaluated the harvested SLN with H&E and IHC staining (p < 0.01). The
axillary recurrence rate in SLN-negative patients is 0.3%, which is well within the
desired range. The median sensitivity of the procedure appears to be as high as 100%.
The recurrence rate is influenced by the differences in the lymphatic mapping technique
[893, 894].
Breast-conservation therapy has gained acceptance as treatment for limited disease
due to breast cancer. Unfortunately, a minority of patients who undergo this therapy will
develop cellulitis of the breast, often recurrently, months to years later. A definitive
pathogen has not been identified in the large majority of cases reported to date. Whilst
some patients develop systemic toxicity with local skin changes of cellulitis, others
manifest no fever, chills, or leukocytosis. Local breast findings gradually clear with
antibiotic treatment: when breast changes persist, non-inflammatory causes, including
tumor recurrence, of the breast should be considered. More study is needed to define risk
factors for the development of breast cellulitis complicating breast-conservation therapy
[895]. The clinical scenario of upper extremity cellulitis after axillary dissection for
breast cancer mimics the presentation of cellulitis in the lower extremity. Until
diagnostic methods or treatment advances can eliminate the indications for axillary
lymphadenectomy, many women treated for breast cancer will be at long-term risk for
the development of cellulitis due to localized immune impairment. Patient and physician
awareness of this syndrome is the best available tool to prevent secondary exacerbation
of lymphedema. Prompt treatment with appropriate antibiotics appears universally
successful. Antistreptococcal antibiotics should not be withheld pending results of blood
or tissue cultures, since in only a few cases a pathogen will be isolated. Although there
are no studies confirming the concept, it is likely that appropriate treatment for
lymphedema may reduce the risk of infection [896].
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Seroma is a common problem following breast cancer surgery causing patient
discomfort and prolongation of hospital stay [897]. Breast seromas are tumor-like
collections of serosanguineous fluid in breast tissue that occur following excision biopsy,
lumpectomy, mastectomy, and plastic surgery procedures such as augmentation,
prosthesis explantation, breast reduction, and breast reconstruction. Mammographically
seromas are water-density masses located at the surgical site. They exhibit features
characteristic of fluid collections on sonographic evaluation [898]. Seromas are the most
frequent complications following breast surgery, resulting in significant discomfort and
morbidity with possible delays in commencing adjuvant therapies. Varied clinical
practices exist in the techniques employed to prevent and manage seromas. Although
prevention is the best strategy, seromas remain problematic. Prevention is key to the
management of seromas. Methods employed to prevent seromas include suction
drainage, shoulder immobilization, quilting sutures, fibrin sealants, and innovative
measures of managing the axilla, among others. The evidence demonstrated that a
combination of quilting and drains significantly reduces the incidence and volumes of
seromas. These effects are sustained by minimizing use of electrocautery, alongside
increasing frequencies of ASLNB and node sampling. The efficacy data on fibrin
sealants is inconclusive and consequently should not be routinely used alone or
accompanied by quilting sutures. Clinically significant seromas deemed “symptomatic”
by patients and complicating infected seromas should be aspirated. There are limited
data on the recommended treatment of established seromas with a paucity of high-quality
studies and further research involving RCT are indicated [899]. Seroma, as a
complication of prosthetic breast reconstruction, results in patient distress, increased
office visits, undesirable aesthetic outcomes, and – importantly – may escalate to
infection and frank prosthesis loss. Seromas following prosthetic breast reconstruction
are complicated by the hypovascular, proinflammatory milieu of the mastectomy skin
flap, the geometrically complex dead space, and the presence of a foreign body with
potential contamination and biofilm. There is reasonable evidence to suggest that these
factors contribute to a progression of seroma to infection and prosthesis loss [900].
Postoperative swelling following prosthetic implant breast augmentation and
reconstruction is not uncommon. Prompt diagnosis and targeted treatment are critical.
Current treatment recommendations achieve a diagnosis using specialized equipment
with needle-guided imaging and/or surgical modalities. These techniques are expensive
and delay diagnosis and treatment. Some surgeons use an in-office, non-imaging
technique to drain periprosthetic fluid after unilateral breast swelling after breast
reconstruction or augmentation. This technique is effective in diagnosing and treating
seroma fluid with minimal risk of implant damage or perforation [901, 902].
Upper extremity lymphedema is a relatively frequent complication following the
management of breast cancer [903]. About one-third of all women treated for breast
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cancer develop arm lymphedema. In addition to the worry of the cancer itself, the
swollen and heavy arm is both a physical and a psychosocial handicap for the patients.
The incidence of lymphedema does seem to be reducing with modern approaches to
breast cancer management. Axillary treatment seems to determine its development but
more studies looking specifically at this problem are needed [904]. Lymphedema is often
accepted as an inevitable and untreatable common consequence of breast cancer
management. There has been little investigation of its pathophysiology, but reasonable
hypotheses can be elaborated based on the known physiology of lymph production and
removal. Chronic edema of the arm (postmastectomy edema) often develops without
warning months or years later. Although the original cause of postmastectomy edema is
damage to axillary lymph drainage routes by surgery and radiotherapy, many
observations suggest that additional factors are involved. Recent attention has focused on
the Starling forces in the skin and subcutis in postmastectomy edema. An important
finding was that the protein concentration, and hence colloid osmotic pressure, of the
subcutaneous interstitial fluid of the postmastectomy edema arm is unexpectedly lower
than in the unaffected arm, correlating negatively with the degree of swelling. There are
several possible explanations for this, such as a rise in capillary filtration rate, or
interstitial proteolysis. A systemic component to postmastectomy edema is suggested by
the finding of a lower plasma protein concentration in affected women compared with a
matched postmastectomy group without swelling. A recent study using intravital
capillaroscopy has indicated that angiogenesis occurs in the skin in postmastectomy
edema, and an increased capillary surface area for filtration could result in an increased
fluid load on a compromised lymph drainage system. Further elucidation of the
pathophysiological processes in postmastectomy edema, in particular the adjustments to
Starling forces, will enable more effective therapy of this distressing condition [905].
Lymphedema is generally described by arm swelling and dysfunction. Both diagnosis
and treatment remain largely empirical. A large clinical experience suggests that
outcome is best with a multidisciplinary team approach that is based in an outpatient
setting and combines gradient compression garments, sequential pneumatic pumps, and
ancillary support services. Through this program, a majority of patients see greater than
50% reduction in their lymphedema [906]. Previous surgical and conservative treatments
have not always given satisfactory and permanent results, conceivably because
lymphedema causes hypertrophy of the subcutaneous adipose tissue. From this point of
view, liposuction combined with controlled compression therapy is an interesting
approach, as the hypertrophied adipose tissue is effectively removed and the outcome
sustained by wearing a compression garment. The use of a compression garment after
liposuction is necessary in order to maintain the normalized arm volume [907].
Physiotherapy contributes to its treatment, using different techniques that have been
developed over the years. Physiotherapy resources used for lymphedema treatment
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include complex decongestive therapy, pneumatic compression, high-voltage electrical
stimulation, and laser therapy. The literature shows that better results are obtained with
combined techniques. Complex decongestive therapy is the most used protocol, and its
association with pneumatic compression has demonstrated efficacy. The new techniques
high-voltage electrical stimulation and laser present satisfactory results [908]. Clinical
recommendations guide survivors to avoid the use of the affected arm. This may lead to
deconditioning and, ironically, the very outcome women seek to avoid. Recently
published studies run counter to these guidelines [909].
The four principles of the Casley-Smith method for the treatment of lymphedema of
the arm are skin care, manual lymphatic drainage, compression in the form of bandaging
and/or garments, and exercise. Both benzopyrones and exercise will produce a continued
reduction after the treatment course. They are particularly useful in a less compliant
patient. It is stressed that the effect of patient compliance, particularly after treatment,
makes a great difference to the ongoing success of the regime. A comparison between the
efficacy of various current treatments and their cost shows that this combined and
conservative method of treatment should be considered before recourse to pumps or
surgery. The latter seldom achieve the results of decongestive lymphatic drainage, and,
in the long term, they are more expensive. Certain preventive measures may be indicated
following e.g., mastectomies. Prevention of the onset of lymphedema is of extreme
importance. However, a return to as normal a lifestyle as possible by the patient is also
essential. The earlier treatment begins after the onset of lymphedema, the better the
prognosis for the patient. Lymphedema can and should be treated [910]. The Vodder
technique differs in the use of adapted pressure and its application. The constant change
in pressure optimizes results, moving fluid in the skin, increasing lymphomotoricity, and
softening fibrosis, with the positive side effects of reducing pain and relaxing tense
muscles. Another difference from other methods is the technique of stretching skin, not
sliding it. Because of the fluid content in lymphedema, which is different from all other
edemas, the combination of manual lymphatic drainage with compression treatment is
the only solution for this pathology. Depending of its severity, each case requires
individualized treatment. Phase 1 (intensive treatment) consists of daily treatment with
up to two sessions per day for up to two hours. This phase is combined with special,
individual skin care and remedial exercise. In phase 2, the goal of treatment is to
maintain the results achieved in phase 1. The frequency of treatment is changed, but
there is still the need for permanent, continued therapy. In phase 1, an average reduction
of more than 40% of edema volume is achieved. In phase 2, the results are maintained
and, with repetitions of phase 1, further improvement is possible. Thus, long-term results
with permanent improvement are possible. Because of the complexity of the technique,
no one can learn manual lymphatic drainage in one week. Students require a great deal of
correction, and the technique must be checked constantly. To become a certified Vodder
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therapy, a four-week education program must be completed, and reviews must be
attended every two years to maintain certification. The best education produces the best
results for patients as long as patients are compliant. Therefore, the Vodder School also
includes a patient education program as part of its curriculum [911]. Recent research has
investigated the use of fibrin sealant in ALND performed for staging breast cancer. The
majority of complications of axillary dissections in breast surgery stem from the two
factors that influence the formation of seromas, hematomas, and lymphedema: the oozing
of small transected vessels and the creation of a reservoir due to the removal of tissue.
An effective surgical adhesive could improve hemostasis and tissue adherence, thereby
decreasing the frequency of these postoperative problems [912].
Axillary reverse lymphatic mapping (ARLM) is a surgical technique that was first
described in 2007 as a method to prevent lymphedema by mapping and preserving the
lymphatic drainage of the arm during SLNB or ALND procedures for breast cancer. The
ARLM procedure was feasible during ALND. Nevertheless, it was restricted by low
identification rate of arm lymph nodes during SLNB. ARLM was beneficial for
preventing lymphedema. However, this technique should be performed with caution
given the possibility of crossover SLN-arm nodes and metastatic arm nodes. ARLM
appeared to be unsuitable for patients with clinically positive breast cancer due to
oncological safety concern [913]. Thus, several problems remain to be resolved in the
practical application of this technique.The ARLM technique had several limitations that
include a poor success rate for identification of arm lymph nodes and lymphatics. The
occurrence of common lymphatic drainage pathways of the arm and the breast in a subset
of patients also raises concerns regarding its oncological soundness [914]. Identification
rates of arm nodes were insufficient using blue dye. Although this was improved using
radioisotopes, radioisotopes alone do not permit visual mapping of arm lymphatics.
Fluorescence imaging may be useful to improve the identification rate of arm nodes and
lymphatics. On the other hand, the arm nodes may be involved with metastatic foci in
patients with extensive ALN metastases. Moreover, the SLN draining the breast may be
the same as the arm node draining the upper extremity in a minority of patients. These
issues represent important drawbacks of the ARLM procedure. The success of ARLM in
reducing lymphedema has not yet been determined. Further studies are needed before
this can be accepted as a standard procedure in surgical management of breast cancer
[915-919].
Mastectomy will continue to play a substantial role in the treatment of breast cancer,
because many women either are not candidates for or do not desire to have breast
conservation. Many patients treated with mastectomy will desire reconstruction, and
many of these will be advised to receive adjuvant radiotherapy, which has been shown to
increase overall survival in certain high-risk patients. There continues to be considerable
controversy regarding the compatibility of radiation therapy and breast reconstruction
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due to increased complications and decreased cosmetic outcome. These can be
minimized by careful modern surgical and radiation techniques, and in most cases the
result is acceptable, including for reconstructions with prosthetic implants as well as
autogenous myocutaneous flaps [920]. Burns occur rarely after breast reconstruction, and
results from loss of sensory and thermoregulatory skin functions. The ineffectiveness of
skin thermoregulatory reflexes, caused by different surgical procedures, plays an
essential role in the pathogenesis of burns to reconstructed breasts. Tissue expansion and
radiotherapy are also essential etiological factors [921]. Although several studies have
found obesity to increase the risk of postoperative morbidity in autologous breast
reconstruction, there remains some controversy over the influence of obesity for muscleconserving abdominal flaps, including muscle-sparing TRAM, DIEP, and SIEA flaps. In
comparison to free TRAM flaps, muscle-conserving abdominal flaps showed a lower
pooled incidence of flap loss, fat necrosis, and abdominal bulge or hernia in obese
patients. Obesity increases the risk of both flap-related and donor-site complications in
breast reconstruction using muscle-sparing TRAM, DIEP, and SIEA flaps. In comparison
to conventional TRAM flaps, however, muscle-conserving abdominal flaps may have an
advantage in reducing the morbidity in obese patients [922]. The TRAM procedure has
gained popularity over the last decades as an autogenous technique for breast
reconstruction. Several outcome studies have demonstrated complications from this
procedure. Women should be informed about the possible complications prior to surgery.
Physical therapists can play an important role in rehabilitation and education for patients
who are planning to undergo or who have undergone the TRAM procedure. It is
important that physical therapists become well acquainted with the surgical procedure
and treatment guidelines to effectively treat patients who have undergone the TRAM
procedure, especially as this procedure increases in popularity. In addition, it is
important that further research be conducted to substantiate the valuable clinical
contribution that physical therapy has on successful recovery following the TRAM
operation [923]. There is scant literature regarding a recently identified clinical entity
termed “red breast syndrome.” Its clinical presentation has been described as a noninfectious, self-limited erythema of a postmastectomy breast reconstructed using ADM.
Its incidence, risk factors, pathophysiology, clinical course, management, and long-term
sequelae are largely unknown [924]. ADM have been used in breast surgery for a decade.
They are widely used in implant-based breast reconstruction to provide coverage of the
inferolateral aspects of the prosthesis. Numerous benefits have been reported with this
approach including improved fold control, better support and control of the implant
pocket with concomitant reduced risk of malposition, and improved lower pole
expansion. Seroma, infection, mastectomy skin necrosis, and expander/implant loss are
the most commonly reported complications with this approach, and the incidences vary
widely among studies. Patient selection and adherence to established intraoperative
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technique principles related to ADM use are both critical to minimizing the risk of
complications. ADM are also being used in aesthetic breast surgery, revision breast
surgery, and NAC reconstruction, but clinical experience is limited [925]. In the studies
evaluated, ADM-assisted breast reconstructions exhibited a higher likelihood of seroma,
infection, and reconstructive failure than prosthetic-based breast reconstructions using
traditional musculofascial flaps. ADM is associated with a lower rate of capsular
contracture. A careful risk/benefit analysis should be performed when choosing to use
ADM in implant-based breast reconstruction [926].
Because so many women have had breast augmentation mammoplasty, it is
inevitable patients in the primary care settings will have complications related to the
procedure or the type of implant. The most common complications include:
1)
2)
3)
4)
5)
6)
7)
changes in breast sensation;
capsular contracture;
calcifications;
mammography distortion or inaccuracies;
gel-bleed;
implant rupture or leakage; and
possible systemic reactions involving the immune system.
The double-bubble deformity is a widely recognized complication of breast
augmentation, but there have been very few articles in the peer-reviewed literature
devoted exclusively to this topic. The key to understanding the causes and correction of
the double bubble lies in an appreciation of the anatomy of the inframammary fold.
Correction of the deformity varies depending on whether or not patients had preexisting
anatomical features predisposing them to development of a double bubble. A variety of
surgical strategies, including use of a dual-plane pocket, form-stable shaped implants,
capsulorrhaphy, pocket plane conversion, and use of ADM can play a role in prevention
and treatment of the double-bubble deformity [927].
Recent worldwide media speculation that silicone gel-filled breast implants may be
linked to an increased incidence of breast and other cancers, and connective tissue
disease (particularly systemic sclerosis) has caused concern to the medical profession
and public alike. Until carefully controlled studies have been performed to prove the
safety of these implants, the FDA has restricted their use to research and breast
reconstruction. Research has so far failed to prove a causative relationship between
silicone implants and cancer or connective tissue disorders [928]. The silicone gel breast
implant controversy has generated much confusion, making informed decision making
for physicians and patients increasingly difficult [929]. The FDA’s decision to limit the
use of silicone gel breast implants was surrounded by a great deal of misleading
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191
information in the popular press [930]. Review of the literature suggests that silicone, a
man-made polymer containing the element silicon, does not appear to fulfill the
characteristics of an ideal synthetic soft-tissue substitute, although it may be the best
substitute available. Silicone breast implants are associated with local inflammation and
tissue fibrosis, with breast fibrous capsule contracture developing in 10-40% of the
patients. There are no epidemiological data that establish a direct link between silicone
and cancer or rheumatic disease. However, scleroderma appears to be over-represented
among the published articles on patients with silicone breast implants and rheumatic
disease. Autoantibodies of unclear significance may be found in 5-30% of women with
silicone breast implants [931]. In 1992, the FDA announced that breast implants filled
with silicone gel would be available only through controlled clinical studies despite the
fact that they had been used for mammoplasty in millions of women around the world for
more than 30 years. The safety of silicone gel breast implants had come into question
after several reports on a possible association between the implants and subsequent
development of connective tissue diseases. Risk assessment refers to the systematic,
scientific characterization of potential adverse effects of human exposures to hazardous
agents or activities. There now appears ample evidence from the scientific literature for
the safety of these prostheses [932]. So, they were reintroduced in 2006, with a call for
improved surveillance of clinical outcomes. There were possible associations with
decreased risk for primary breast and endometrial cancers and increased risks for lung
cancer, rheumatoid arthritis, Sjögren syndrome, and Raynaud syndrome. Evidence on
breast implants and other outcomes either was limited or did not exist. The evidence was
most frequently not specific to silicone gel implants, and studies were rarely adequately
adjusted for potential confounders. The evidence remains inconclusive about any
association between silicone gel implants and long-term health outcomes. Better
evidence is needed from existing large studies, which can be reanalyzed to clarify the
strength of associations between silicone gel implants and health outcomes [933].
In recent years, requests for breast implant surgery have occurred for several reasons.
First, the number of diagnosed breast cancer cases has increased, and the number of
reconstructive surgeries consequently has multiplied. Second, the number of patients
who constantly try to achieve a better physical shape, corresponding in Western
countries to the common image of prosperous and tonic breasts, has proliferated. These
circumstances have led to an increasingly frequent need for more accurate and
sophisticated imaging methods to study prosthetic breast implants and their integrity.
Rupture of a breast implant is a recognized complication of augmentation mammoplasty
and reconstructive breast surgery. Diagnostic imaging for the study of patients with
suspected breast implant ruptures uses different techniques of radiological investigation
such as mammography and ultrasonography, even if the current gold standard is MRI. In
fact, proper cooperation and coordination between radiologists and dedicated plastic
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surgeons are fundamental for the proper management of patients and the complications
they may experience [934]. Due to concerns over the extravasation of silicone gel within
adjacent tissue and distant body sites, considerable attention has been given to the
radiographic detection of mammary implant rupture. Mammography supplemented with
ultrasonography constitutes the most cost-effective initial study, followed by MRI if
these are equivocal. MRI is the most sensitive and specific study to evaluate breast
implant rupture [935]. Despite numerous studies advocating ultrasonography and MRI in
the evaluation of women with possible silicone breast implant rupture, an appropriate
algorithm has not been published for the optimal use of these tests. In asymptomatic
patients, the pretest rupture prevalence is 6.5%. If a screening ultrasonography shows no
rupture, the probability of rupture drops to 2.2%. If ultrasonography shows rupture, the
probability of true rupture increases to 37.8%. Removal of implants in this setting will
result in a high probability of extracting normal implants. However, if MRI after the
ultrasonography shows rupture, the probability of true rupture increases to 86%, which
gives better assurance of removing true-ruptured implants. In “symptomatic” patients
(i.e., breast asymmetry, capsular contracture) with implants ≤ ten years old, the
prevalence of rupture is estimated at 31%. If ultrasonography shows no rupture, the
probability of rupture drops to 16%. If ultrasonography shows rupture, the probability of
true rupture is 79.7%, and this probability increases to 97.5% if a follow-up MRI also
shows rupture. In symptomatic patients with implants more than ten years old, the
prevalence of rupture is estimated at 64%. If ultrasonography shows rupture, the
probability of true rupture increases to 94%, and no further diagnostic work-up is
necessary. In an asymptomatic patient who is worried about the integrity of her implants,
ultrasonography should be used as an initial diagnostic test because of its lower cost. If
ultrasonography shows no rupture, no further work-up is necessary. If ultrasonography
shows rupture, the low probability (37.8%) of true rupture requires a confirmatory test
using MRI. In “symptomatic” patients, the high prevalence of rupture markedly raises the
post-test probability of rupture for positive ultrasonography findings. Particularly in
“symptomatic” patients with implants more than ten years old, the high post-test
probability of rupture (94%) with a positive ultrasonography obviates the need for any
further diagnostic testing. This diagnostic algorithm will assist plastic surgeons in
counseling women who are worried about the integrity of their silicone breast implants
[936].
Fibrous capsular contracture is by far the most common cause of unsatisfactory
results following augmentation mammoplasty [937]. Capsular contracture is a common
complication associated with the use of breast implants. Numerous RCT addressing the
efficacy of textured surface breast implants in reducing capsular contracture have yielded
non-uniform results. Only three of these studies found significantly lower rates of
capsular contracture with the use of textured implants. However, when all seven studies
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193
were pooled, the OR was found to be 0.19 [95% confidence interval (CI), 0.07-0.52],
indicating a protective effect for surface texturing on the rate of capsular contracture.
Submuscular placement was the only subgroup in which significance was not achieved.
However, this subgroup consisted of a single study, which was dramatically
underpowered. The results demonstrate the superiority of textured over smooth breast
implants in decreasing the rate of capsular contracture [938]. The silicone granuloma
was first described in the literature in 1964. During the course of clinical practice, the
plastic surgeon will encounter a silicone granuloma in a breast augmentation or
reconstruction patient. Although case series have been reported, there is no consensus
regarding the treatment of silicone granulomas. This important clinical entity warrants
investigative attention to better understand its clinical implications and prevention [939].
Capsular contracture frequently requires revision surgery. “Capsulectomy, site change,
and implant exchange” has been referred to as the gold standard treatment of clinically
significant contractures. However, the actual clinical evidence behind this algorithm
remains elusive at best. There is limited clinical evidence behind the surgical
management of capsular contracture. Site change and implant exchange are associated
with reduced contracture recurrence rates and likely play a beneficial role in treating
capsular contracture. The data on capsulectomy are less conclusive. ADM may be a
useful adjunct but still requires long-term data [940-942].
Infection after breast implant surgery occurs in 1.1-2.5% of procedures performed
for augmentation and up to 35% of procedures performed for reconstruction after
mastectomy. Infection following breast implants is an uncommon event. This is
somewhat surprising, since the human breast is not a sterile anatomical structure. The
flora found in the breast are derived from the nipple ducts and closely resemble those of
normal skin. Most infections result from skin organisms and occur in the immediate
postoperative period, although infections can occasionally present after many years.
These organisms, predominantly Staphylococcus epidermidis, may in some cases be
responsible for firmness secondary to capsular contracture. Diagnosis of breast implant
infection relies on the clinical presentation of breast pain, swelling, erythema, and
drainage in conjunction with ultrasound-guided cultures of periprosthetic fluid.
Treatment of the periprosthetic infection usually involves implant removal, but salvage
by systemic antibiotics is sometimes possible. Atypical mycobacteria are very rarely the
cause of infection, but can be extremely difficult to eradicate when involved. Toxic
shock syndrome has been reported to occur following breast implants and is a lifethreatening problem requiring immediate removal of the implant. It may be significant
that in some cases with effusion and infection occurring many months or years after
implant placement, there has been a preceding event such as a laryngitis or flu-like
illness. This suggests the possibility of a bacteremia being involved in the causation of
the infection. If this were the case, then these patients should be handled in a fashion
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similar to those with prosthetic heart valves. Accordingly, it is advised that penicillin
“V” be given beforehand when a patient with breast implants is to have any dental
procedure. It must be stressed that there is no statistical or scientific proof at the present
time that this is of any value. In conclusion, when dealing with these large foreign
bodies, absolute sterility is essential, and excellent surgical technique to obviate
hematoma and the occurrence of tissue ischemia is mandatory. Evidence of severe
infection necessitates implant removal, but in less severe cases a trial of i.v. antibiotics is
permissible. Having removed an implant, further insertion should be deferred, preferably
for six months. If the new implant can be placed in a different plane, that is,
submuscular, this is desirable. Exposed implants can be salvaged but this requires
considerable judgment and one should be prepared for re-exposure or frank infection
[943-946].
Silicone gel implants for breast augmentation and reconstruction have been in use
since 1962. Significant local complications include capsular contracture, rupture, gel
“bleed,” and spread of the implant material to RLN as well as histological findings of
foreign body granulomas in the capsular tissue and in lymph nodes. Through MRI
spectroscopy and atomic emission spectroscopy, silicon compounds were found in the
blood of some women with silicone breast implants. Silicone and silica have also been
found in liver. Well-publicized case reports have raised significant concerns regarding an
association between implants and systemic disease. However, despite the availability of
silicone implants for over 30 years, controlled epidemiological studies were not carried
out until 1992. Currently available epidemiological data are extremely limited. In part,
because the majority of implants were used after 1981, the incidence of long-term
problems is not yet known [947]. Connective tissue disease occurring after cosmetic
surgery with crystalline silica (silicone) injections or implants have been described in
patients who have had silicone augmentation mammoplasty. This disorder which consists
of autoimmunity-related complications, collectively known as autoimmune/inflammatory
syndrome induced by adjuvant (ASIA), has been called “human adjuvant disease.”
Previous data suggest that while some patients tend to develop postexposure autoimmune
phenomena such as ASIA, other do not. However, thus far, no criteria for risk
stratification were suggested. Therefore, a recommendation was made to avoid silicone
implantation, e.g., individuals with previously diagnosed autoimmune disorders or with
genetic preponderance for hyperactive immune system should not be considered as
candidates for silicone implantation [948]. Although otherwise indistinguishable from
other connective tissue disease, these patients may experience improvement or remission
following implant removal. Current data suggest that the risk of disease after silicone
breast augmentation is less than 1% [949, 950]. Silicone was originally regarded as inert
in the human body. Silicone medical devices have been associated with various
complications that may involve an immune reaction to silicone or a silicone organic
Breast Surgery Complications
195
complex which can provoke a varied systemic autoimmune illness in patients who have
had various foreign materials placed in the breast. Controversy exists as to which
complications have a cause and effect relationship, and which represent coincidental
findings. It is difficult to distinguish between non-specific local reactions and reactions
that have an immunological basis. More than 2,000,000 women in the USA have had
silicone breast implants inserted for reconstruction or augmentation mammoplasty: Since
first reported in 1982, published anecdotal reports have appeared with increasing
frequency of patients in whom autoimmune connective tissue diseases developed after
mammary augmentation with silicone gel-filled elastomer envelope-type prostheses.
Although scleroderma has been reported most often, other diagnoses have included SLE,
rheumatoid arthritis, Sjögren’s syndrome, and mixed connective tissue disease. Other
patients have ill-defined connective tissue-like illnesses. The occurrence of
dermatomyositis and polymyositis after silicone breast implants appears to be infrequent
[951]. Data on the reported cases do not in any way prove a causal relationship between
breast implants and immune disease. Given the natural incidence of autoimmune
diseases, we would expect a coincidental occurrence in the USA of more than 2,000
cases of autoimmune disease in women who had undergone breast implant surgery.
Additional information must be obtained to resolve the question. The true incidence of
autoimmune disease in patients with implants needs to be determined. A prospective
registry of implant patients should be established and comprehensive retrospective
information obtained on the implant patient population. Further experimental work is
necessary on the bioreactivity of silicone. Patients with implants and autoimmune
disease, once identified, must be carefully evaluated by physicians who are experienced
in the treatment of autoimmune disease [952, 953].
Although silicone breast implants have been linked to various short-term
complications, less is known about their long-range effects. Most attention has focused
on connective tissue disorders, but the range of immunological disturbances observed in
women with implants suggests that consideration also be given to other chronic diseases,
including cancer. Recent controversy has arisen regarding the potential carcinogenesis of
medical silicone-gel as used in breast implants. The greatest attention has focused on
breast cancer, given clinical reports suggesting an association and observations that
mammographic visualization is deterred by implants. Findings from epidemiological
studies, however, actually suggest that breast cancer risk might be reduced among
women with implants, although the biological mechanism remains undefined. In
addition, most studies do not suggest that women with breast implants have more
advanced breast cancer at diagnosis or a worse prognosis than those without implants.
The majority of studies have focused on women who received implants for cosmetic
reasons, with little previous investigation of women who received implants for breast
reconstruction following cancer surgery. In terms of other cancers, animal as well as
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clinical data suggest potential risks of sarcomas and hematological cancers, including
multiple myeloma. A review of the pertinent literature shows that although rodents do
demonstrate the development of sarcomas to any inert material, including silicone-gel,
the phenomenon is species specific. The risk of these cancers has not yet been
adequately addressed by epidemiological studies, although several ongoing studies
should provide insights. It will be important for studies to consider effects of other
lifestyle factors as well as to analyze relationships according to duration of implantation,
a demonstrated determinant of implant deterioration. In addition, consideration should be
given to type of implant, including implants with polyurethane foam covers, which can
leak toluene diamine, a demonstrated carcinogen in animals [954, 955]. So, although
surgical implantation of breast prostheses has become increasingly popular while the
incidence of breast cancer is increasing each year, there has been no definitive consensus
regarding the casual relationship between augmentation mammoplasty and breast cancer
incidence, detection, treatment, mortality, and survival. The published evidence,
including epidemiological studies and case reports, states that there is no breast cancer
risk in prior augmented women. Moreover, there is also no significant difference in
frequency, stage, or mean tumor size between augmented and non-augmented women
[956]. The challenges of managing breast cancer in women with augmented breasts
include screening, diagnosis, oncological and revisional surgery, and surveillance. In
addition, women with augmented breasts frequently have greater expectations of
cosmetic outcomes. More breast clinicians will be affected by these challenges as
augmentation grows in popularity and women with implants reach the age range in which
they are at higher risk of developing breast cancer. In the USA, more than two million
women have undergone augmentation, making this the second most commonly
performed cosmetic procedure. With a lifetime risk of developing breast cancer of one in
eight, it is projected that more than 50,000 women who undergo augmentation each year
in the USA will develop breast cancer at some point in their lives. Management of breast
cancer in previously augmented breasts presents a unique range of challenges. Patients
can be reassured that the presence of an implant does not increase the risk of breast
cancer developing or affect the prognosis if breast cancer does develop. Clinical
judgement is made balancing surgical and oncological principles to provide the best
cosmetic outcome [957].
There are increasing concerns about a possible association, without evidence of
causation, between kinase-negative anaplastic large cell lymphoma (ALCL), a rare nonHodgkin’s T-cell lymphoma, and breast implants:
1) there is a positive association between breast implants and ALCL development,
but likely under-recognition of the true number of cases;
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197
2) a recurrent, clinically evident seroma occurring six months or more after breast
implantation should be aspirated and sent for cytologic analysis;
3) kinase-negative ALCL that develops around breast implants is a clinically
indolent disease with a favorable prognosis that is distinct from systemic kinasenegative ALCL;
4) management should consist of removal of the involved implant and capsule,
which is likely to prevent recurrence, and evaluation for other sites of disease;
and
5) adjuvant radiation or chemotherapy should not be offered to women with
capsule-confined disease.
Little agreement, however, was found regarding etiologic risk factors for implantassociated ALCL. Breast-associated ALCL occurred in women with and without
implants. No prospective epidemiological study has linked implants and ALCL.
However, a single case-control study in Dutch women reported increased odds of
association between ALCL and implants, and an estimated frequency of one in one
million women with and without breast implants. An association, without evidence of
causation, was reported between breast implants and ALCL. Breast-associated ALCL
occurred rarely in women with and without breast implants and had a primarily indolent
clinical course, which may provoke a revision of the WHO nomenclature for lymphoma:
however, aggressive clinical behavior was also reported. The cases of ALCL were not
confined to a specific type of implant. Public awareness has increased following a safety
communication warning of the association of breast implant-associated ALCL by the
FDA in 2011. Difficulty with determining an accurate assessment of risk, including
diagnosis, or standardized treatment regimen has led surgeons to commonly omit
preoperative discussion of this rare and frequently misunderstood cancer. Risk disclosure
is a form of respect for patient autonomy, and informed consent has positive practical
and moral consequences for the practice of plastic surgery. Breast implant-associated
ALCL should be included during preoperative counseling on the risks of breast
implantation when obtaining informed consent. Pertinent aspects of decision-making
include disease awareness, presenting symptoms, and resources for concerned patients.
Education of health care professionals and provision of patient-focused materials ensures
effectiveness of the informed consent process. Substantial further research is needed to
improve our understanding of the epidemiology, clinical aspects, and biology of this
disease [958-964].
Although many patients who undergo reduction mammoplasty are obese, reports on
whether obesity is a risk factor for postoperative complications have been conflicting. A
meta-analysis indicated that the risk of surgical complications and tissue necrosis after
reduction mammoplasty is higher in obese patients than in non-obese patients and that
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the risk gradually increases with an increase in the severity of obesity. The findings of
this study could form a basis for preoperative patient education, surgical method
selection, and determination of the extent of postoperative care [965]. Owing to the
relatively short time endoscopic-assisted plastic surgery procedures have been done,
there are few published reports of complications. The complications associated with
endoscopic techniques are similar to those with open techniques. It is clear, however,
that a subset of complications specific to endoscopic procedures exists. As endoscopic
techniques and instrumentation are further developed, and as surgeons move higher up
on the “learning curve,” these complications should be reduced [966, 967].
Over the last few decades, the psychosocial problems following mastectomy have
become well recognized and surgical treatment for breast cancer has become less
mutilating. For women with small cancers, a number of equally effective treatments are
available and involving the patient in the choice of treatment appears to reduce morbidity
[968]. Therefore, in recent years, doubt has been shed on the necessity of mastectomy for
women with early-stage breast cancer. Apart from purely medical studies comparing
radical mastectomy to less intruding surgical treatment, a number of studies have been
published investigating the impact of breast-conserving treatment versus mastectomy on
quality of life. With respect to medical issues (treatment modality, stage of disease),
methodological issues (design, measurement moment, and sample size), and results
(psychological discomfort, changes in life patterns, and fears and concerns), there is no
solid proof of a better psychological adjustment after breast-conserving treatment and
there are no substantial differences between the different treatment modalities in changes
of life patterns and fears and concerns. However, the results with respect to body image
and sexual functioning favor the use of breast-conserving treatment [969]. Breast cancer
has been widely studied with respect to its psychological impact because it is a disease
which threatens an organ that is intimately associated with self-image, self-esteem,
sexuality, femininity, and reproductive and nurturing capacity. Breast cancer is a
significant stress for any woman: however, women vary widely in their response to
diagnosis and treatment. The following issues: social, psychological, and medical
variables contribute to the psychological response of women in the pre- and postsurgical
treatment period [970]. From the available evidence, it is clear that mastectomy is
associated with a substantial psychological and psychiatric morbidity. To date, there is
no convincing evidence that counseling can prevent this morbidity, but monitoring of
women’s psychological adjustment can lead to early detection and effective treatment of
their problem. The use of immediate or delayed implantation or reconstruction appears to
reduce the psychiatric morbidity in those women who are particularly concerned about
their appearance at the time of surgery. Psychiatric morbidity is further increased when
adjuvant chemotherapy is used and when treatment results in persistent arm pain and
swelling. A shorter course of adjuvant chemotherapy and reduction of surgery within the
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199
axilla could reduce psychiatric morbidity. The role of radiotherapy is still unclear, but in
some studies a link has been found between the amount of radiotherapy given, adverse
effects, and psychiatric morbidity. In women undergoing breast conservation, the
reduction in body image problems is offset by greater anxiety about recurrence and
depression caused by radiotherapy. Exploring and allowing choice when a patient has a
strong preference for breast conservation or mastectomy appears to reduce morbidity.
However, attention still needs to be paid to the early recognition and treatment of
psychological problems in patients with breast cancer [971]. Young women undergoing
treatment for breast cancer remain understudied despite unique needs. Psychoeducational
interventions help to relieve symptoms and emotional distress during treatment, but
effects do not appear to persist over the longer term. In the clinical context, the
performance of prognostic risk prediction models in this population is poor. Surgical
decision-making is often driven by fear of recurrence and body image rather than
prognosis, and decision aids may help young women to synthesize information to
preserve their role in the treatment process. First, shared decision-making, second,
balancing body image, fear of recurrence, and recommended treatment, and third,
palliative care for metastasis are essential research priorities for the clinical setting. In
the larger social context, unique family/partner dynamics as well as financial and
insurance concerns warrant particular attention in this population [972].
Cancer is a family affair. Clinical work and research studies have shown that cancer
does indeed invade the entire family, and that family members, especially spouses, are
often highly distressed individuals. The family in general and the spouse in particular
cannot, therefore, be looked on as natural supporters for cancer patients, but rather as a
system that is itself in need of help and support [973]. Breast cancer affects a woman’s
body image and feelings of sexuality. Little is known about the perceptions of spouses to
the sensitive topics of sexuality and body image. A qualitative inquiry was undertaken
using in-depth interviews. A diagnosis of breast cancer brought some relationships
closer. Mastectomy by disturbing body image did obliterate sexual relationships for a
significant period of time. Women often felt (wrongly) that their partner would be
repulsed by changes. More support in relation to sexuality and body image could
improve relationships by identifying and clarifying perceptions, and therefore the quality
of life [974]. A growing body of evidence suggests that sexual dysfunction may be
among the more common and distressing symptoms experienced by breast cancer
survivors. A review of the literature suggests a wide range of rates for the prevalence of
sexual problems in breast cancer survivors. Factors that may affect prevalence rates
include the methods used to determine prevalence and the demographic and medical
characteristics of the patients studied. With regard to treatment effects, evidence suggests
that breast cancer patients who undergo chemotherapy are at high risk for sexual
dysfunction after treatment. In contrast, there is little evidence of a link between type of
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surgical treatment (e.g., lumpectomy vs mastectomy) or treatment with TMX and sexual
functioning outcomes. A growing body of evidence suggests that sexual problems can be
a long-term side effect of breast cancer treatment. Oncology professionals should initiate
communication about sexual difficulties, perform comprehensive assessments, and
educate and counsel patients about the management of these difficulties [975, 976].
An unexpected statistically significant relationship between cosmetic breast implants
and suicide has been found in some epidemiological investigations completed in the last
several years. Across the studies, the suicide rate of women who received cosmetic
breast implants is approximately two- to three-fold the expected rate based on estimates
of the general population. Although the first study of this issue suggested that the rate of
suicide among women with breast implants was greater than that of women who
underwent other forms of cosmetic surgery, the largest and most recent investigation in
this area found no difference in the rate of suicide between these two groups of women.
Over the last decades, of the large number of epidemiological studies on various longterm adverse health outcomes among implant recipients, this excess of suicide is the only
serious adverse effect supported by credible research. But an association of suicide with
cosmetic breast implants based on comparisons with the general population does not by
itself support a cause-and-effect relationship regarding the role of implants. The higherthan-expected suicide rate among women with cosmetic breast implants warrants further
research. Etiological-epidemiological research is urgently needed to evaluate whether the
association between breast implants and suicide is spurious (e.g., reflecting increased
prevalence of underlying psychopathology and other risk factors for suicide in women
seeking implants) or reflects an actual role for implants in suicide. As a first step, sound
epidemiological nested case-control studies are required to characterize the preimplant
psychiatric history of women with implants who commit suicide compared with women
with implants from the same cohort who do not commit suicide. Second, large-scale
retrospective cohort studies are needed to compare suicide rates among women with
implants versus those among women without implants matched on preimplant diagnoses
of psychiatric disorders, year of diagnosis, year of birth, family history of psychiatric
admissions, and other relevant factors that influence suicide risk. This type of large-scale
complex epidemiological research may be difficult to complete in countries with
restrictive privacy laws and widespread litigation, but only after such appropriate
etiological research is completed can any credible cause-effect inference be made
regarding the role, if any, of cosmetic breast implants in suicide. In the absence of
additional information on the relationship, women interested in breast augmentation who
present with a history of psychopathology or those who are suspected by the plastic
surgeon of having some form of psychopathology should undergo a mental health
consultation before surgery [977-979].
Chapter XII
Anesthesiological Issues
Pain is the most distressing symptom in patients with breast cancer and can occur at
all stages of the disease due to the cancer per se as well as due to various diagnostic and
treatment modalities. Although the genesis of the pain is multifactorial, sectioning of the
intercostobrachial nerve and related injury of the intercostal nerves and other nerves in
the region are the nerve lesions diagnosed more often. Persistent pain after breast cancer
surgery is increasingly recognized as a potential problem facing a sizeable subset of the
millions of women who undergo surgery as part of their treatment of breast cancer.
Importantly, an increasing number of studies suggest that individual variation in
psychosocial factors such as catastrophizing, anxiety, depression, somatization, and sleep
quality play an important role in shaping an individual’s risk of developing persistent
pain after breast cancer surgery [980]. A proper pain assessment helps in identification
of pain syndromes and guides in formulating analgesic strategies. Primary therapies of
breast cancer like surgery, chemotherapy, and radiotherapy for bony metastases can
cause substantial pain relief. However, multimodal analgesic approaches incorporating
pharmacological, interventional, as well as non-conventional techniques should be
employed prior to, in conjunction with, and after primary therapies of breast cancer.
Patients post mastectomy and breast reconstruction can suffer from acute nociceptive
pain and chronic neuropathic pain syndromes. The prevalence of chronic neuropathic
pain following breast cancer surgery may exceed 50% by current estimates, and with the
increase in life expectancy of these patients, providing adequate pain relief is of
paramount importance to improve their quality of life [981]. Several preventative
measures to control acute postoperative pain and chronic pain states such as
postmastectomy pain and phantom pain have been tried [982]. The approach to patients
undergoing surgery for breast cancer requires pre- and postoperative follow-up by a
multidisciplinary team. This approach can provide a rational choice of surgical
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technique, identify patients with risk factors, minimize or eliminate risk factors whenever
possible, diagnose beforehand the postmastectomy pain syndrome, and provide adequate
treatment to improve the quality of life for this specific patient population [983].
Postoperative pain management following breast surgery has traditionally involved i.v.
and oral narcotics. However, pain control is not always adequately achieved through
these means and may cause unwanted side effects, including headache, nausea, vomiting,
constipation, altered mental status, sleep disturbance, and respiratory depression [984].
Regional analgesia, opioids, and several oral analgesics are commonly used for the
treatment of acute pain after breast cancer surgery. While all of these treatments can
suppress the acute postsurgical pain, there is growing evidence that suggests that the
postsurgical comorbidity will differ in accordance with the type of analgesic used during
the surgery. A considerable number of clinical studies have been performed to
investigate the relationship between the acute analgesic regimen and common
comorbidities, including inadequate quality of recovery after the surgery, persistent
postsurgical pain, and cancer recurrence. Previous studies have shown that the choice of
the analgesic modality does affect the postsurgical comorbidity. In general, the use of
regional analgesics has a beneficial effect on the occurrence of comorbidity. In order to
determine the best analgesic choice after breast cancer surgery, prospective studies that
are based on a clear definition of the comorbidity state will need to be undertaken in the
future. Alternative forms of pain control have been used successfully in other surgical
fields but have been utilized only recently in breast surgery [985]. Neural blockade can
be useful for the identification of nerves involved in neuropathic pain syndromes or to be
used as a treatment in its own right [986, 987].
Paravertebral blocks are becoming increasingly popular, especially as an anesthetic
adjunct for breast procedures. New reports suggest additional reasons for adding this
block to the anesthetic armamentarium. Recent studies demonstrate a benefit from
preoperative placement of a paravertebral block, not only in reducing acute postoperative
pain, but also statistically significant reductions in the percentage of patients that
develop chronic postsurgical pain one year after surgery. Another study found that the
breast-cancer recurrence rate at 36 months after surgery was lower in the paravertebral
group compared with the general anesthesia-only group of patients. Paravertebral blocks
are a well-established option to provide anesthesia and postoperative analgesia during
breast surgery. Recent studies suggest additional benefits to this procedure. Not only is
acute pain better controlled, but the development of chronic mastectomy pain syndrome
and recurrence of cancer may be reduced by preoperative placement of paravertebral
block. These studies provide additional reasons why this block should be considered as
part of the anesthetic for breast surgery [988]. It is well established that thoracic
paravertebral block with or without general anesthesia provides better postoperative
analgesia and reduces the risk of nausea and vomiting after breast surgery as well as the
Anesthesiological Issues
203
incidence of chronic pain. Paravertebral block improves the quality of recovery after
breast cancer surgery and provides the patient with the option of ambulatory discharge
[989]. Propofol-paravertebral anesthesia is a unique combination of paravertebral nerve
blocks and propofol that regulates the cellular microenvironment during surgical period.
Growing evidence points to its ability to attenuate perioperative immune-suppression of
cancers. Abundant studies show that cancer patients who undergo perioperative
propofol-paravertebral anesthesia exhibit less recurrence as well as metastasis. Over the
last decades, increasing concerns have been put on the promotional role of propofolparavertebral anesthesia in the prognosis of breast cancer patients. Among them,
propofol-paravertebral anesthesia participates in several bioprocesses in the development
of breast cancer, including inhibiting hypoxia-inducible factor (HIF) activity, elevating
serum concentration of nitric oxide index (NOx), depression of the neuroepithelial cell
transforming gene 1 (NET1) signal pathway, blocking the nuclear factor kappa B (NFκB) pathway following a decreased expression of matrix metalloproteinase (MMP),
increasing natural killer (NK) cytotoxicity, and affecting transforming growth factor
(TGF)-β-targeted ras and HER2/neu gene pathways. This will provide an alteration
pattern of surgical anesthesia technique in breast cancer patients with poor prognosis
[990-992].
Short-term postsurgical recovery is complicated by many factors, including
imbalanced inflammatory and immune response, acute pain associated with functional
impairment, and chronic postmastectomy pain. Opioids, most common drugs used for
treatment of cancer pain, are immune-suppressive, and therefore, they might directly
and/or indirectly influence long-term cancer recurrence. Moreover, they also produce
endocrinopathy, which consists primarily of hypothalamic-pituitary-gonadal axis or
hypothalamic-pituitary-adrenal axis dysfunction. The interindividual variability in both
chronic postmastectomy pain and opioid response is believed to be largely underlined by
genetic variability in the gene locus for μ-opioid receptor (OPRM1) that modulates
opioid pharmacodynamics. For this reason, OPRM1 genotype may play a key role both
in short-term postmastectomy outcome and in long-term follow-up, becoming a new
biomarker for breast cancer recurrence in patients suffering from chronic
postmastectomy pain managed by opioid therapy. Hence, OPRM1 might be used in near
future to customize the opioid therapy, avoiding not only opioid side-effects but also the
disease progression. Therefore, a personalized pain treatment strategy might be useful to
both manage pain and control cancer disease progression [993]. The effect of
pharmacological analgesic modalities for breast cancer surgery interventions is varied
[non-steroidal anti-inflammatory drugs (NSAIDS), opioids, anticonvulsants, ketamine,
and lidocaine]. Likewise, data from high-quality RCT on wound infiltration (including
liposome encapsulated) and infusion of local anesthetic are minimal and conflicting.
Conversely, abundant evidence demonstrates paravertebral blocks and thoracic epidural
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Ciro Comparetto and Franco Borruto
infusions provide effective analgesia and minimize opioid requirements, while
decreasing opioid-related side effects in the immediate postoperative period. Other
techniques with promising – but extremely limited – data include cervical epidural
infusion, brachial plexus, interfascial plane, and interpleural blocks. In conclusion,
procedural interventions involving regional blocks are more conclusively effective than
pharmacological modalities in providing analgesia to patients following surgery for
breast cancer [994].
Breast surgery performed under general anesthesia is associated with a high
incidence of postoperative nausea and vomiting. Between 60-80% of patients undergoing
mastectomy (with ALND) experience postoperative nausea and vomiting. First, the risk
factors related to patient characteristics, surgical procedure, anesthetic technique, and
postoperative care can be reduced. More specifically, the use of propofol-based
anesthesia can reduce the incidence of postoperative nausea and vomiting. Secondly, a
wide range of prophylactic antiemetics, including butyrophenones (droperidol),
benzamides (metoclopramide), glucocorticoids (dexamethasone), clonidine, a small dose
of propofol, and serotonin receptor (SR) antagonists (ondansetron, granisetron,
tropisetron, dolasetron, ramosetron, and palonosetron), are available for preventing
postoperative nausea and vomiting after breast surgery. Traditional antiemetics
(droperidol and metoclopramide) are frequently used for the prevention of postoperative
nausea and vomiting during the first 24 hours after anesthesia. The available nontraditional antiemetics that have been shown to be effective for prophylaxis against
postoperative nausea and vomiting are dexamethasone, clonidine, propofol, and
supplemental oxygen. Antiserotonins (ondansetron, granisetron, tropisetron, dolasetron,
and ramosetron) are highly effective for preventing postoperative nausea and vomiting
for 24 hours postoperatively, compared with traditional antiemetics. Ramosetron is
effective for the long-term (up to 48 hours) prevention of postoperative nausea and
vomiting. Better results can be obtained by combining antiemetics, because they have
different sites of action. Combination antiemetic therapy is often effective for preventing
postoperative nausea and vomiting after breast surgery. Thirdly, antiemetic therapy
combined with granisetron and droperidol or dexamethasone, and a multimodal
management strategy which includes a package consisting of dexamethasone, total i.v.
anesthesia with propofol, and ondansetron are highly effective in preventing
postoperative nausea and vomiting. Combinations of an antiserotonin (granisetron or
dolasetron) and droperidol or dexamethasone are more effective than monotherapy with
antiserotonins. Fourth, electroacupoint stimulation at the P6 point (Nei-Guwan) as a nonpharmacologic therapy is as effective as ondansetron for preventing postoperative nausea
and vomiting. Overall, these pharmacological and non-pharmacological approaches
reduce the incidence of postoperative nausea and vomiting following breast surgery.
Most of the published trials indicate improved prophylaxis of postoperative nausea and
Anesthesiological Issues
205
vomiting following breast surgery by avoiding risk factors, and by using effective
antiemetic agents in women scheduled for mastectomy (with ALND). The clinician must
weigh the benefits of using pharmacological and non-pharmacological approaches for
postoperative nausea and vomiting against the risk of occurrence of adverse events.
Knowledge of the risk factors for postoperative nausea and vomiting, antiemetics, and a
non-pharmacological approach are needed for the management of postoperative nausea
and vomiting in women undergoing breast cancer surgery [995, 996].
The introduction of enhanced recovery after surgery protocols has revolutionized
pre- and postoperative care. To date, however, the principles of enhanced recovery have
not been applied specifically to patients undergoing breast surgery. Use of the thoracic
block, from both analgesic and anesthetic viewpoints, is well supported by evidence and
should be encouraged. Trials specific to breast surgery regarding aspects such as
perioperative fasting, preanesthetic medication, prevention of hypothermia, and
postdischarge support are scarce, and evidence was extrapolated from non-breast trials.
Trials on postoperative analgesia and prevention of postoperative nausea and vomiting in
breast surgery are generally of small numbers. In addition, there is heterogeneity between
studies. The principles of enhanced recovery can be adopted in breast surgery [997].
Chapter XIII
Conclusion
The outcome of breast cancer surgery, with respect to cosmetic results, loco-regional
control, and prognostic information from nodal staging, may vary substantially. Optimal
breast cancer care starts with a proper surgical act, which can only be performed when
optimal imaging and preoperative diagnosis are available. Next, on the basis of all
perioperative findings, the right surgical procedure should be indicated after
multidisciplinary consultation and discussion, keeping the objective of the final outcome
in mind. The surgical act itself is best performed by an experienced surgeon who has
maintained his experience after sufficient training. The outcome of the different
procedures can be measured according to simple criteria and prospective registration
[998]. Many studies have demonstrated gaps in healthcare quality for all medical and
surgical specialties, including breast surgical care. How to optimally measure and
improve quality has generated debate at the local, state, and national level. Attempts to
judge medical performance by private companies using non-risk-adjusted administrative
databases may not be accurate and may unfairly penalize surgical care. Breast surgeons
and their professional organizations need to take ownership of quality measure programs
because others will surely do so if we do not. Participation in one or more of these
programs is beneficial because peer performance comparison allows identification of
potential areas for individual or institutional improvement and demonstrates the
commitment of breast surgeons to quality improvement. This commitment may gain even
greater importance if trends continue toward performance-based physician payment,
patient steerage, licensure, and board certification [999]. Quality assurance is the process
by which quality care can be assessed. The general principles include setting a standard
with the aim of achieving particular outcomes, followed by the evaluation of parameters
that allow for quality assessment. Loco-regional and survival outcomes are the major
parameters but require years to evaluate and have other limitations. Other parameters
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therefore may assist in evaluation, such as the availability of the structures and processes
required to achieve desired outcomes. Unlike chemotherapy and radiotherapy, the quality
of surgery is difficult to quantify, yet it is central to the issue of loco-regional control and
survival. In breast cancer surgery, quality control starts at the diagnostic service, from
referral by the family practitioner to the appropriate triage of patients thereby preventing
diagnostic delays. The surgical oncologist is pivotal in the multidisciplinary input
necessary with both radiologists and pathologists in achieving the correct preoperative
diagnoses of symptomatic and screen detected lesions as specified by many of the
guidelines. Quality control of the operative surgery addresses issues such as training,
volume, and life audit of the surgeon. Standardization of operative technique, pathology
reporting with emphasis on specimen orientation and margins, and management of the
axilla and how it impacts on adjuvant treatment are other important issues. More
recently, the availability of breast reconstruction services and the development of the
oncoplastic surgeon is becoming an important quality issue. Finally, the quality of the
follow-up process provides the tools to assess the outcome of both the patient and the
service [1000].
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About the Authors
Ciro Comparetto, MD
Division of Obstetrics and Gynecology,
Azienda USL Toscana Centro, City Hospital, Prato, Italy
Email: [email protected]
Franco Borruto, MD
Consultant in Health Policy of the Government of Monaco,
Principality of Monaco
Email: [email protected]
Index
A
B
adenocarcinoma, 73, 183, 230
adenoma, 39, 40, 220
adipose tissue, 149, 175, 186, 253
adjunctive therapy, 35, 154
adolescent female, 35, 45, 218
adverse effects, 15, 37, 151, 191, 199
aesthetic, x, xii, 9, 13, 34, 36, 55, 66, 78, 117, 121,
139, 142, 145, 148, 149, 150, 152, 155, 157, 158,
160, 162, 164, 165, 169, 177, 178, 179, 185, 190,
227, 232, 246, 256, 257, 260
aesthetic surgery, xi, xii, 162, 177
amputation, 2, 6, 14
analgesic, 201, 203, 205
anastomosis, 144, 147
anatomy, 79, 99, 141, 144, 147, 163, 164, 168, 190,
218, 234
anesthetics, 10, 22
angiogenesis, 12, 64, 175, 186, 266
angiography, 147, 252
angiosarcoma, 51, 72
artery (ies), 14, 141, 144, 146, 147, 148, 251, 252
aspiration, viii, xiii, 17, 18, 19, 20, 22, 24, 26, 28,
31, 32, 40, 41, 44, 90, 92, 174, 182, 213, 215,
216, 217, 234, 238, 245, 265
asymptomatic, 25, 26, 32, 53, 62, 181, 192
axillary lymph nodes, ix, xv, 238, 239, 242
benign, x, xiv, xv, xvi, xvii, 10, 18, 19, 20, 21, 22,
26, 28, 31, 32, 33, 34, 37, 39, 41, 42, 43, 44, 45,
46, 47, 50, 51, 52, 53, 54, 58, 70, 72, 73, 85, 89,
90, 91, 92, 93, 96, 97, 100, 102, 118, 120, 130,
217, 218, 219, 221, 224, 239
benign tumors, 35, 43, 218
bilateral, 10, 34, 48, 53, 62, 66, 67, 125, 129, 131,
132, 145, 155, 247, 248, 270
biopsy, v, viii, xiii, xiv, xv, xvi, 6, 9, 17, 18, 20, 21,
22, 24, 25, 26, 27, 28, 33, 34, 37, 44, 45, 46, 47,
49, 50, 53, 54, 61, 67, 69, 75, 77, 85, 86, 87, 88,
90, 91, 92, 93, 96, 100, 102, 104, 105, 119, 120,
130, 173, 181, 182, 185, 213, 214, 215, 216,
217,222, 234, 235, 236, 237, 238, 239, 240, 241,
242, 243, 244, 245, 246, 265, 266
body image, 130, 150, 152, 157, 161, 177, 198, 199,
255
body mass index (BMI), 161
BRCA mutations, 126, 135
breast augmentation, xi, 15, 16, 35, 117, 149, 158,
159, 165, 166, 168, 170, 173, 174, 175, 177, 178,
185, 190, 193, 194, 200, 261, 262, 263, 264, 269,
272, 273
breast carcinoma, 9, 18, 21, 22, 40, 44, 48, 49, 53,
70, 73, 75, 76, 112, 128, 153, 215, 230, 231, 233,
239, 241, 245, 247, 272
breast lumps, 44, 52, 53, 221
breast mass, 17, 18, 19, 22, 26, 31, 34, 42, 43, 51,
90, 96, 100, 118, 214, 215, 238
278
Index
breast self-examination, xiv, 34, 67, 123, 172
breast ultrasound, 28, 90
breastfeeding, 220, 259
C
cancer care, xvi, 207
cancer cells, 165, 182
cancer screening, viii, 19, 68, 119, 175
cancer therapy, vii
carcinogenesis, 49, 120, 124, 195
carcinoma, ix, xv, 3, 4, 9, 18, 19, 21, 22, 24, 32, 39,
40, 42, 44, 45, 48, 50, 53, 60, 61, 62, 70, 72, 73,
74, 75, 76, 77, 82, 88, 89, 94, 97, 105, 107, 112,
118, 128, 130, 153, 214, 215, 221, 222, 223, 225,
226, 227, 229, 230, 231, 233, 239, 241, 242, 245,
265, 266, 272
cauterization, 6, 14
cell cycle, 12, 124
cellulitis, 184, 266, 268
centrosome, 127
chemoprevention, 27, 120, 125, 127, 132
chemotherapeutic agents, xv, 127, 128
chemotherapy, vii, xvi, 5, 6, 7, 8, 10, 12, 13, 26, 46,
52, 57, 62, 64, 65, 66, 68, 69, 71, 72, 74, 80, 81,
102, 113, 115, 128, 134, 138, 139, 182, 183, 197,
198, 199, 201, 208, 244, 249
clinical symptoms, 42, 171
clinical trials, 5, 8, 9, 11, 12, 13, 51, 59, 91, 105,
109, 115, 117, 127, 149, 174, 212, 226
complications, v, xv, 15, 22, 24, 26, 53, 77, 83, 87,
106, 135, 138, 139, 145, 147, 148, 151, 153, 159,
160, 161, 162, 163, 165, 167, 168, 169, 170, 171,
173, 175, 176, 178, 181, 185, 188, 189, 190, 192,
194, 195, 197, 224, 250, 259, 260, 262, 263, 264,
265, 268, 269, 271
compression, 20, 92, 177, 186, 187
connective tissue, 73, 169, 170, 171, 190, 194, 195,
269, 270
contour, 79, 141, 151, 159, 162, 178, 254
contraceptives, 36, 42
contracture, 15, 16, 139, 142, 150, 154, 159, 166,
167, 168, 169, 170, 173, 175, 178, 190, 191, 192,
193, 194, 269
counseling, xiv, 22, 35, 125, 126, 129, 130, 133,
192, 197, 198, 247
cure, xv, xvi, 1, 9, 44, 57, 58, 59, 73, 77, 81, 93,
101, 140, 183
cyst, 18, 26, 28, 31, 32, 44, 215
cystic duct, 45
cytokines, 76
cytology, 17, 22, 24, 25, 26, 40, 51, 95, 104, 105,
109, 120, 215, 217, 241, 245
D
diagnostic criteria, 50
diagnostic markers, 119
differential diagnosis, 35, 44, 46, 51, 70
disease progression, 203
diseases, vii, xv, xvi, 1, 25, 31, 57, 92, 97, 133, 171,
191, 195
drainage, xv, 28, 41, 90, 97, 100, 102, 108, 110, 111,
115, 146, 175, 185, 186, 187, 188, 193, 239, 264
E
ectopic breast, 75, 231
edema, 83, 181, 186, 187, 267
endoscopy, 15, 26, 41, 118, 120, 121
excision, x, 10, 27, 31, 40, 41, 42, 43, 45, 47, 49, 51,
53, 59, 61, 63, 65, 70, 72, 73, 75, 77, 78, 80, 82,
86, 88, 89, 90, 92, 94, 95, 96, 106, 119, 120, 145,
163, 165, 176, 185, 216, 232, 258
F
family history, 35, 37, 44, 49, 66, 123, 124, 126,
127, 130, 131, 132, 200, 248
FDA approval, 168, 178
fibroadenoma, 32, 33, 34, 43, 51, 73, 88, 220
fibrocystic disease, 16, 32, 221
Food and Drug Administration (FDA), 15, 106, 167,
169, 170, 172, 178, 190, 197
G
genes, 123, 124, 126, 127, 129, 130, 133, 247
genetic alteration, 125, 126
genetic code, 133
genetic factors, 9
Index
genetic information, 127
genetic marker, 113
genetic predisposition, 49, 129, 133
genetic testing, xv, 46, 124, 125, 126, 129, 133, 246,
247, 248, 249
genetics, 125, 133, 247
genomics, 247
genotype, 203
gonadotropin-releasing hormone (GnRH), 11
granulomas, 42, 193, 194, 269
gynecomastia, 160
H
health care, xiv, xv, xvi, 24, 33, 64, 96, 127, 157,
170, 197, 210, 224
heterogeneity, 8, 12, 55, 56, 76, 88, 107, 128, 139,
151, 205, 247
high-risk women, 26, 119, 125, 132, 215
histological examination, x, xiv, 20, 51, 99
histology, 17, 22, 43, 45, 51, 62, 67, 92, 104, 108,
112
hormonal therapy, xvi, 6, 12, 66
hormones, viii, 7, 8, 10, 11, 21, 27, 35, 36, 74, 76,
93, 182
hyperplasia, 8, 23, 32, 44, 46, 47, 48, 51, 61, 89, 96,
222, 223
hypertrophy, xi, 33, 35, 160, 161, 162, 164, 186,
219, 257
hypoplasia, xi, 38, 40
I
iliac crest, 146
imaging, v, xv, 6, 10, 17, 19, 20, 26, 28, 31, 32, 33,
34, 41, 43, 45, 46, 52, 55, 63, 64, 69, 73, 75, 78,
79, 82, 83, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,
95, 96, 101, 102, 104, 105, 108, 111, 120, 129,
147, 153, 158, 165, 171, 182, 184, 185, 188, 191,
207, 217, 218, 221, 222, 223, 234, 235, 236, 237,
238, 240, 241, 242, 251, 252, 255, 256, 262, 263,
266, 269
imaging modalities, 26, 63, 96, 104, 147, 171
immune system, 76, 179, 190, 194
immune-therapy, viii
implant placement, 15, 160, 166, 193
279
implants, xi, 15, 20, 77, 83, 118, 138, 140, 142, 144,
159, 160, 166, 167, 169, 170, 171, 177, 178, 179,
189, 190, 191, 192, 193, 194, 195, 196, 197, 200,
214, 250, 260, 261, 262, 264, 265, 269, 270, 271,
272
infection, 26, 83, 88, 142, 159, 161, 170, 172, 184,
185, 189, 193
inflammation, 25, 28, 39, 42, 53, 172, 191, 219, 271
informed consent, xii, 80, 126, 157, 197
invasive adenocarcinoma, 23
invasive cancer, 44, 59, 61, 62
ipsilateral, 8, 53, 56, 59, 65, 111, 129, 134, 227, 268
irradiation, xiv, xvi, 6, 10, 57, 59, 61, 63, 65, 67, 69,
72, 78, 80, 81, 82, 94, 101, 102, 140, 233
K
keratin, 56
kinetics, 8, 108
L
lactation, xi, 4, 32, 35, 163, 173, 263
latissimus dorsi, 14, 38, 78, 137, 145, 154, 251
lesions, xiv, xv, 11, 18, 20, 22, 24, 25, 26, 27, 28,
32, 33, 34, 42, 43, 44, 45, 46, 47, 48, 50, 51, 52,
53, 54, 58, 60, 61, 65, 66, 70, 72, 73, 85, 86, 87,
88, 90, 91, 92, 93, 95, 96, 99, 101, 118, 120, 130,
183, 201, 208, 214, 215, 216, 217, 218, 221, 222,
223, 230, 234, 235, 236, 237, 238
leukocytosis, 184
life expectancy, 126, 155, 201
lifestyle changes, 36
liposuction, 92, 161, 164, 174, 186, 259
lymph node, vii, xv, xvi, 20, 56, 74, 77, 78, 90, 97,
99, 100, 101, 102, 104, 105, 107, 112, 113, 115,
188, 194, 238, 239, 240, 241, 242, 243, 244, 245,
266
lymphadenectomy, v, 97, 106, 184, 244
lymphatic system, 97, 98, 99, 103, 141
lymphedema, 83, 184, 185, 187, 188, 267, 268
lymphocytes, 76
lymphoma, 53, 75, 97, 196, 197, 271
280
Index
M
macromastia, 33, 35, 218, 219, 260
malignancy, ix, 4, 17, 18, 20, 26, 28, 34, 37, 41, 43,
44, 47, 50, 53, 59, 82, 85, 87, 91, 93, 119, 130,
175
malignant cells, 71, 119
malignant melanoma, 75, 104, 241
malignant tumors, 72, 118
mammogram, 19, 83, 90, 94, 97
mammography, 4, 6, 7, 8, 17, 18, 20, 22, 25, 26, 28,
34, 35, 42, 44, 53, 54, 60, 62, 63, 64, 67, 69, 73,
79, 82, 85, 87, 90, 91, 93, 96, 97, 103, 118, 123,
125, 129, 131, 159, 169, 171, 190, 191, 262, 263
mammoplasty, 16, 36, 38, 43, 83, 133, 157, 158,
159, 161, 162, 164, 165, 166, 170, 172, 176, 177,
178, 190, 191, 192, 194, 196, 197, 257, 259, 262,
263, 270
mammotome, viii, 24, 88
mastalgia, 32, 33, 34, 36, 42, 44, 219
mastectomy, vii, xiv, xv, xvi, 1, 2, 3, 4, 5, 6, 7, 9, 14,
16, 19, 26, 36, 43, 47, 49, 52, 56, 58, 59, 60, 61,
62, 63, 64, 65, 66, 67, 68, 69, 71, 77, 79, 80, 82,
83, 109, 113, 114, 115, 123, 125, 126, 127, 129,
130, 131, 132, 134, 137, 138, 139, 141, 142, 143,
145,150, 152, 154, 159, 169, 172, 176, 181, 183,
185, 188, 193, 198, 199, 201, 202, 204, 211, 212,
213, 224, 225, 231, 232, 246, 247, 248, 249, 250,
251, 253, 254, 255, 256, 264, 265, 266, 268, 271,
272, 273
mastitis, 4, 33, 39, 42, 220
mastopexy, xi, 16, 158, 160, 162, 163, 164, 166,
175, 245, 246, 257, 258, 260, 264
metastases, vii, 12, 52, 58, 64, 69, 74, 75, 81, 97, 98,
99, 100, 101, 102, 103, 104, 105, 107, 109, 112,
114, 117, 138, 155, 181, 182, 184, 188, 201, 213,
231, 240, 242, 243, 244, 266
morbidity, 6, 10, 14, 18, 37, 44, 55, 56, 68, 69, 72,
80, 88, 96, 97, 103, 104, 105, 108, 110, 113, 117,
121, 142, 144, 146, 147, 154, 157, 175, 176, 181,
185, 189, 198
MRI, 6, 7, 26, 28, 41, 53, 62, 63, 64, 69, 79, 91, 92,
93, 96, 104, 105, 118, 125, 129, 147, 158, 171,
191, 194, 236, 262
N
necrosis, 53, 82, 139, 141, 142, 147, 154, 181, 189,
197, 224
nipple-areola complex, xi, 16, 229, 254, 260
nodes, ix, xiv, 12, 77, 98, 99, 100, 101, 102, 105,
108, 110, 111, 115, 188, 239, 240, 241
nodules, 42, 70, 75
non-steroidal anti-inflammatory drugs, 203
normal aging, 179
normal development, 32, 33
O
obesity, viii, 145, 189, 197
oophorectomy, 12, 134
opioids, 202, 203
ovarian cancer, 124, 125, 126, 127, 128, 129, 132,
246, 247, 249
P
p53, 23, 52, 74, 111, 124, 128
pain, 14, 15, 31, 32, 36, 146, 147, 157, 159, 163,
170, 173, 181, 187, 193, 198, 201, 202, 203, 219,
265, 272, 273
pain management, 202
pathology, xiv, xv, 27, 28, 29, 45, 47, 75, 90, 92, 94,
96, 110, 112, 114, 119, 187, 208, 209, 217, 221,
222, 223, 237, 262
pectoralis major, 38, 58, 143
pharmacological agents, 37
physical therapy, 189
plastic surgery, xii, 78, 117, 138, 139, 149, 150, 153,
159, 167, 169, 173, 177, 179, 185, 197, 198, 258,
271
polymastia, 33, 38
polythelia, 33, 37, 38
prevention, xviii, 8, 11, 14, 27, 40, 46, 67, 123, 126,
130, 131, 132, 134, 176, 185, 187, 190, 193, 204,
205, 212, 246, 248, 267, 268, 269, 270, 273
primary tumor, 56, 65, 68, 75, 95, 98, 111, 113, 153,
182, 228
prophylactic, 27, 47, 49, 67, 77, 113, 123, 125, 127,
130, 131, 132, 134, 155, 183, 204, 246, 247, 248,
266
Index
prophylactic surgery, 125, 127, 248
prostheses, 15, 132, 137, 160, 166, 169, 170, 191,
195, 196, 262
prosthesis, xii, 14, 15, 16, 137, 138, 140, 142, 167,
169, 174, 179, 185, 189, 214, 250, 261
ptosis, xi, 160, 161, 162, 164, 175, 257, 258
281
resection, 2, 26, 57, 69, 71, 79, 80, 93, 94, 95, 101,
103, 112, 117, 139, 140, 145, 161, 162, 228, 232,
253
risk factors, viii, xiii, 35, 46, 49, 123, 124, 129, 134,
145, 184, 189, 197, 200, 202, 204, 273
S
Q
quadrantectomy, x, 6, 9, 66, 79, 139, 212
quality of life, xvii, 57, 63, 68, 69, 76, 78, 126, 131,
132, 133, 152, 154, 157, 161, 177, 198, 199, 201,
255, 258, 271
R
radiation, xvi, xvii, 5, 6, 7, 8, 10, 13, 46, 47, 56, 57,
60, 63, 64, 65, 67, 69, 72, 71, 73, 74, 80, 82, 83,
86, 87, 89, 110, 111, 138, 139, 142, 143, 148,
153, 154, 183, 188, 197, 229, 230, 233, 249
radiation therapy, xvi, xviii, 6, 7, 8, 10, 56, 57, 60,
63, 64, 68, 69, 73, 80, 138, 140, 148, 184, 188,
229, 230, 233, 249
radical mastectomy, vii, xiv, 2, 3, 4, 5, 6, 7, 9, 56,
58, 64, 66, 77, 130, 143, 198, 211, 212, 225
radiotherapy, viii, 1, 6, 9, 10, 11, 50, 52, 56, 59, 60,
63, 64, 65, 66, 72, 74, 75, 76, 77, 78, 80, 81, 102,
103, 135, 137, 138, 139, 142, 145, 152, 165, 182,
186, 188, 199, 201, 208, 213, 229, 233, 249
reconstruction, v, xi, xvi, 6, 13, 14, 34, 38, 43, 49,
56, 59, 62, 64, 77, 78, 83, 117, 132, 135, 137,
138, 139, 140, 141, 142, 143, 144, 146, 147, 148,
149, 150, 151, 152, 153, 154, 158, 159, 166, 167,
169, 170, 176, 179, 181, 185, 188, 190, 193, 194,
195, 198, 201, 208, 213, 230, 245, 249, 250, 251,
252, 253, 254, 255, 256, 257, 262, 264, 267, 268,
272, 273
recovery, 15, 152, 165, 176, 189, 202, 203, 205, 273
rectus abdominis, 14, 143, 144, 154, 251
recurrence, xv, xvi, 3, 5, 12, 14, 21, 34, 36, 42, 43,
50, 51, 56, 58, 59, 60, 62, 65, 69, 71, 73, 75, 77,
79, 80, 81, 82, 83, 102, 113, 115, 117, 134, 138,
140, 142, 148, 149, 154, 181, 182, 183, 184, 193,
197, 199, 202, 203, 212, 266, 273
reduction mammaplasty, 159, 248, 258, 259
sarcoma, 71, 73, 75, 124, 229
screening, viii, xiii, xiv, 6, 17, 18, 21, 24, 25, 26, 29,
31, 34, 46, 49, 50, 53, 54, 55, 60, 62, 63, 64, 67,
68, 82, 87, 90, 96, 102, 108, 118, 120, 123, 126,
127, 130, 154, 172, 174, 182, 192, 196, 215, 217,
224, 238, 246, 248, 255, 259, 262
sentinel lymph node, xvi, 239, 240, 241, 242, 243,
244, 245
shape, xi, 3, 15, 78, 138, 144, 147, 153, 157, 158,
160, 161, 163, 164, 166, 168, 169, 178, 191, 257
silicone, xi, 15, 16, 83, 138, 140, 142, 159, 167, 169,
170, 171, 172, 174, 177, 178, 179, 190, 192, 193,
194, 195, 214, 261, 262, 264, 265, 269, 270, 271
stem cells, 56, 149, 175, 253, 263
surgical intervention, ix, 35, 41, 55, 60, 76, 173, 221
surgical resection, 9, 10, 12, 56, 71, 79, 119, 120
surgical technique, xi, xvi, 9, 10, 11, 51, 55, 66, 77,
79, 83, 114, 117, 132, 137, 139, 140, 148, 152,
165, 173, 176, 188, 194, 202, 232, 256
survival rate, ix, xvii, 22, 69, 82, 174
survivors, 151, 187, 199, 254, 267, 272
symptoms, viii, xiv, xv, 11, 17, 31, 33, 36, 42, 93,
160, 161, 169, 170, 181, 197, 199
syndrome, 37, 38, 43, 124, 132, 160, 171, 181, 184,
189, 191, 193, 194, 202, 219, 249, 268, 270, 272
T
tamoxifen, 8
techniques, x, xv, xvi, xviii, 2, 5, 9, 14, 15, 16, 17,
21, 23, 24, 26, 28, 29, 34, 35, 38, 40, 43, 50, 52,
54, 56, 57, 59, 63, 64, 65, 75, 78, 80, 81, 86, 87,
88, 90, 91, 93, 94, 95, 96, 100, 101, 102, 105,
106, 108, 114, 117, 118, 120, 121, 138, 139, 140,
143, 146, 147, 148, 149, 150, 151, 153, 154, 159,
160, 161, 162, 163, 164, 165, 166, 170, 173, 174,
175, 185, 186, 189, 191, 198, 201, 204, 215, 216,
282
Index
233, 235, 236, 238, 246, 249, 251, 252, 254, 256,
258, 261, 265, 269
therapy, vii, xv, xvi, xviii, 1, 5, 6, 8, 9, 10, 11, 12,
13, 24, 25, 36, 42, 56, 57, 58, 59, 60, 64, 65, 66,
67, 69, 71, 72, 74, 75, 77, 78, 80, 81, 82, 91, 93,
97, 101, 102, 109, 111, 113, 114, 115, 119, 137,
138, 140, 143, 159, 181, 182, 183, 184, 186, 187,
203, 204, 213, 226, 228, 231, 234, 237, 246, 249,
265, 266, 267, 268
treatment, vii, xiii, xiv, xv, xvi, xviii, 2, 3, 5, 6, 7, 8,
9, 10, 11, 12, 13, 14, 16, 17, 19, 21, 24, 27, 29,
31, 32, 34, 35, 36, 37, 39, 40, 41, 42, 44, 45, 46,
49, 50, 51, 52, 55, 57, 59, 60, 61, 62, 63, 64, 65,
66, 67, 68, 70, 71, 72, 73, 74, 75, 76, 77, 78, 80,
82, 83, 85, 91, 92, 93, 94, 96, 101, 102, 103, 104,
108, 109, 112, 118, 129, 131, 134, 139, 140, 142,
149, 154, 166, 167, 168, 182, 183, 184, 185, 186,
187, 188, 190, 193, 195, 196, 197, 198, 199, 201,
203, 208, 211, 212, 214, 218, 219, 220, 224, 225,
226, 227, 230, 231, 233, 236, 237, 238, 242, 244,
245, 248, 256, 257, 264, 265, 266, 267, 268, 271,
272, 273
tumor, vii, xiv, xv, 7, 8, 11, 14, 21, 23, 25, 26, 27,
28, 33, 40, 44, 47, 51, 52, 56, 64, 65, 66, 68, 70,
71, 72, 73, 74, 75, 77, 78, 79, 80, 81, 82, 88, 89,
91, 93, 94, 95, 97, 99, 100, 101, 102, 104, 107,
108, 111, 112, 113, 114, 119, 124, 129, 139, 140,
143, 149, 165, 169, 181, 182, 183, 184, 185, 196,
212, 223, 228, 229, 230, 239, 253, 256
tumor cells, xiv, 23, 27, 56, 93, 98, 99, 107, 114,
149, 182, 239
U
ultrasonography, 28, 35, 43, 62, 64, 69, 79, 83, 90,
103, 105, 147, 172, 191
ultrasound, viii, 20, 24, 28, 32, 41, 44, 53, 75, 86,
87, 89, 91, 93, 94, 95, 105, 118, 125, 147, 171,
193, 235, 241
V
vascular endothelial growth factor (VEGF), 111
vascular system, 148
W
World Health Organization (WHO), 41
wound healing, 142, 159, 176
wound infection, 2, 181
Y
young women, 74, 118, 126, 163, 199, 218, 272