Oncologic Breast Surgery (2014) Veronesi Italia 290 Str.

Updates in Surgery
Carlo Mariotti
Editor
Oncologic Breast Surgery
Forewords by
Giorgio De Toma
Umberto Veronesi
123
Editor
Carlo Mariotti
Department of Surgery
Breast Surgery Unit
Ospedali Riuniti University Hospital
Ancona, Italy
The publication and the distribution of this volume have been supported by the Italian
Society of Surgery
ISSN 2280-9848
ISBN 978-88-470-5437-0
ISBN 978-88-470-5438-7 (eBook)
DOI 10.1007/978-88-470-5438-7
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Foreword
It is our belief that oncologic breast surgery is a very complex specialty, which
involves the surgeon in both phases of demolition and reconstruction. As the discipline is constantly evolving, surgeons often feel overwhelmed by the wealth of different data and the variety of information related to this specialty.
Breast cancer is no more considered a disease of an organ, but rather affecting
health at a systemic level. In addition, it is now possible to rely on advanced methods to determine the spread of cancer, and on more technically sophisticated surgical procedures for radical treatment.
Hence the purpose, fully achieved by the Editors and the board of Authors invited, to provide the surgeon with an easy-to-read text, but nevertheless modern and
complete, so as to override the contrast between the vanguard of scientific acquisitions and the practicality of surgery.
The search for radical therapy associated with conservative surgery still represents the dilemma of those who get involved in the treatment of malignant breast
tumors; the Authors seek answers to this question, highlighting, with admirable scientific rigor, how results are influenced by the consideration of the evaluation criteria of individual cases, and from these it is possible to deduce and apply increasingly radical curative strategies.
Rome, September 2013
Giorgio De Toma
Foreword
Surgical treatment of malignant diseases of the breast represents an exemplary

model of multidisciplinary management. The combined modality approach to the
treatment of breast cancer patients, which includes primary surgical treatment, radiation therapy, endocrine therapy and chemotherapy, needs careful integration of
these modalities with the new methods of reconstructive surgery. This book provides such a practical approach to the successful management of the disease. For
this endeavor, the Editors have invited leaders in the field of breast surgery to provide a truly international flavor to the reader. The content of this monograph edited by an excellent breast surgeon, Carlo Mariotti, would therefore be relevant to
clinicians around the world.
The seventeen chapters are organized in major parts ranging from the basic
principles of surgery to the difficulties of partial breast resection, to the most
advanced field of breast repair after nipple sparing mastectomy.
The breast is the heart of femininity and remains in the mind of everyone of us
as the true symbol of womanhood with the role of nurturer, nourisher and comforter. This evokes a strong sense of affection and the importance of this delicate
organ in the minds of women, who combine the seductive aspect and the maternal
role capturing in men the source of desire and giving children satisfaction and the
bond to life itself.
Part III is composed of eleven chapters dealing with specific issues, which consider the advances of science in the field of oncological senology. All these chapters are of utmost importance since they can help any breast surgeon face specific
conditions, which, even if infrequent, require great experience and wise decisions.
In conclusion, this textbook is an excellent, user-friendly guidebook for anyone
who cares for, or manages, patients with breast cancer, particularly residents, fellows, and practitioners of general surgical oncology. For this reason, it would be a
worthy addition to most surgical and oncological libraries.
Milan, September 2013
Umberto Veronesi
IEO Istituto Europeo di Oncologia
Milan, Italy
vii
Preface
At the beginning of my career I approached senology, the issue of mammary disease, and its therapy by chance: I would have never thought it could then
become the core of my professional life, reserving for me a thrilling surgical and
professional experience and, particularly, an incomparable human and relational experience.
I had the chance and the luck to witness the growth of senology as a discipline, the evolution of scientific research and of the medical and surgical treatment of breast cancer; I saw senology becoming an independent discipline, even
in its multiple professional values; I attended the birth of the first breast surgery
wards in the perspective of local diffusion of the Breast Unit.
This volume, whose purpose is to give the reader an overview of the surgical and oncologic problems of mammary disease, arises in this context.
The text is subdivided into three parts and seventeen chapters: the first part
introduces to the latest improvements in the field of instrumental and interventional diagnostics and of anatomical pathology, opening a window onto health
care organization; the second part analyzes the conservative course of the surgical treatment; in fine, the last part examines specific features of mammary disease and its treatment.
Ancona, September 2013
Carlo Mariotti
ix
Acknowledgements
Thanks to my everyday coworkers Gabriele Bianchelli, Enrico Lenti, and

Francesco Braccioni.
Thanks to my younger collaborators Pietro Coletta, Sonia Maurizi, Angela
Maurizi, Marco Gentili, Eugenia Raffaeli, and Elisa Sebastiani (to whom I owe the
illustrations in chapters 4 and 5) for the willingness and the enthusiasm that they
are able to add to my work.
Furthermore, I have to thank all the colleagues who realized the chapters of the
book: my gratitude is addressed to the willingness and the high proficiency that
they put in this work, but, above all, I thank them for the sincere friendship that
unites us.
I also thank Juliette Kleemann and Donatella Nebulone at Springer for supporting me in this effort with courtesy, competence, patience, and remarkable congeniality.
I thank and dedicate this work to my wife, my sons Eugenio and Francesco, and
to my daughter Ludovica for their presence in my daily life.
Carlo Mariotti
xi
Contents
Part I - Preliminary Remarks on Modern Surgical Treatment

1 Instrumental and Interventional Diagnostics . . . . . . . . . . . . . . . . . . .
Gian Marco Giuseppetti, Letizia Ottaviani, Enrico Lenti, Barbara Franca
Simonetti, and Silvia Baldassarre
2 The Pathology of Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Alfredo Santinelli and Tommasina Biscotti
23
3 The Breast Unit and the Organization of Health Care . . . . . . . . . . .

Riccardo Masetti, Gianluca Franceschini, Daniela Terribile,
and Alba Di Leone
47
Part II - Conservative Program

4 Conservative Surgery and Oncoplastic Surgery . . . . . . . . . . . . . . . . .
Carlo Mariotti, Pietro Coletta, Sonia Maurizi, and Elisa Sebastiani
59
5 Conservative Mastectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Carlo Mariotti, Pietro Coletta, Angela Maurizi, and Elisa Sebastiani
85
6 Sentinel Node Biopsy and Axillary Dissection . . . . . . . . . . . . . . . . . . 101

Riccardo Bussone, Ada Ala, Pietro Maria Ferrando, and Gretha Grilz
Part III - Specific Issues
7 Surgery for Ductal Carcinoma In Situ (DCIS) . . . . . . . . . . . . . . . . . . 117
Federico Buggi, Matteo Mingozzi, Camilla Rossi, Annalisa Curcio,
and Secondo Folli
xiii
Contents
xiv
8 Radioguided Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

Paolo Burelli and Christian Rizzetto
9 Pagets Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Luis J. Sanchez, Marco Bernini, and Jacopo Nori Cucchiari
10 Breast Cancer in Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
Francesca Catalano, Giusy Scandurra, Concetta Ravalli,
Filippo Fraggetta, and Giuseppe Catanuto
11
Breast Cancer in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

Guglielmo Miconi
12 Locally Advanced Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

Stefano P. Drago and Giovanni Battista Grassi
13 Prophylactic Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
Matteo Ghilli and Manuela Roncella
14 Intraoperative Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
15 Primary Surgery in Metastatic Breast Cancer . . . . . . . . . . . . . . . . . . 231
James O. Murphy and Virgilio S. Sacchini
16 Reconstructive Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
Carlo Mariotti, Gabriele Bianchelli, Michele Riccio,
Angelica Aquinati, and Elisa Sebastiani
17 Preoperative Systemic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
Massimiliano DAiuto and Giuseppe Frasci
Afterword
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
Contributors
Ada Ala Department of Surgery, Breast Surgery Unit, Citt della Salute e della
Scienza Hospital, Turin, Italy
Angelica Aquinati Department of Surgery, Breast Surgery Unit, Ospedali Riuniti
University Hospital, Ancona, Italy
Silvia Baldassarre Department of Radiological Sciences, Clinical Radiology
Unit, Ospedali Riuniti University Hospital, Ancona, Italy
Marco Bernini Department of Oncology Surgery, Breast Unit, Careggi
University Hospital, Florence, Italy
Gabriele Bianchelli Department of Surgery, Breast Surgery Unit, Ospedali
Riuniti University Hospital, Ancona, Italy
Tommasina Biscotti Department of Pathological Sciences and Public Health,
Pathological Anatomy and Histopathology, Politechnic University of Marche,
Ancona, Italy
Federico Buggi Breast Unit, Morgagni-Pierantoni Hospital, Forli, Italy
Paolo Burelli Department of General Surgery, Breast Unit, Santa Maria dei
Battuti Hospital, Conegliano (TV), Italy
Riccardo Bussone Department of Surgery, Breast Surgery Unit, Citt della Salute
e della Scienza Hospital, Turin, Italy
Francesca Catalano Breast Unit, Cannizzaro Hospital, Catania, Italy
Giuseppe Catanuto Breast Unit, Cannizzaro Hospital, Catania, Italy
Pietro Coletta Department of Surgery, Breast Surgery Unit, Ospedali Riuniti
Annalisa Curcio Breast Unit, Morgagni-Pierantoni Hospital, Forli, Italy
xv
xvi
Contributors
Massimiliano DAiuto Department of Senology, Breast Surgery Unit, Istituto

Nazionale dei Tumori, Naples, Italy
Alba Di Leone Multidisciplinary Breast Center, Catholic University of Rome,
Rome, Italy
Stefano P. Drago Department of General Surgery and Surgical Oncology, San
Filippo Neri Hospital, Rome, Italy
Pietro M. Ferrando Department of Surgery, Breast Surgery Unit, Citt della
Salute e della Scienza Hospital, Turin, Italy
Secondo Folli Breast Unit, Morgagni-Pierantoni Hospital, Forli, Italy
Filippo Fraggetta Pathology Unit, Cannizzaro Hospital, Catania, Italy
Gianluca Franceschini Multidisciplinary Breast Center, Catholic University of
Rome, Rome, Italy
Giuseppe Frasci Department of Senology, Preoperative Therapy Unit, Istituto
Nazionale dei Tumori, Naples, Italy
Matteo Ghilli Department of Oncology, Breast Surgery Unit, Pisa University
Hospital, Pisa, Italy
Gian Marco Giuseppetti Department of Radiological Sciences, Clinical
Radiology Unit, Ospedali Riuniti University Hospital, Ancona, Italy
Giovanni Battista Grassi Department of General Surgery and Surgical
Oncology, San Filippo Neri Hospital, Rome, Italy
Gretha Grilz Department of Surgery, Breast Surgery Unit, Citt della Salute e
della Scienza Hospital, Turin, Italy
Enrico Lenti Department of Surgery, Breast Surgery Unit, Ospedali Riuniti
Carlo Mariotti Department of Surgery, Breast Surgery Unit, Ospedali Riuniti
Riccardo Masetti Multidisciplinary Breast Center, Catholic University of Rome,
Rome, Italy
Angela Maurizi Department of Surgery, Breast Surgery Unit, Ospedali Riuniti
Sonia Maurizi Department of Surgery, Breast Surgery Unit, Ospedali Riuniti
Contributors
xvii
Guglielmo Miconi Department of General Surgery, Breast Unit, Fano Hospital,

Fano (PU), Italy
Matteo Mingozzi Breast Unit, Morgagni-Pierantoni Hospital, Forli, Italy
James O. Murphy Breast Service, Department of Surgery, Memorial SloanKettering Cancer Center, New York, USA
Jacopo Nori Cucchiari Department of Oncology Surgery, Breast Unit, Careggi
Letizia Ottaviani Department of Radiological Sciences, General Radiology and
Pediatrics Unit, Ospedali Riuniti University Hospital, Ancona, Italy
Concetta Ravalli Breast Unit, Cannizzaro Hospital, Catania, Italy
Michele Riccio Department of Surgery, Breast Surgery Unit, Ospedali Riuniti
Christian Rizzetto Department of General Surgery, Breast Unit, Santa Maria dei
Battuti Hospital, Conegliano (TV), Italy
Manuela Roncella Department of Oncology, Breast Surgery Unit, Pisa
University Hospital, Pisa, Italy
Camilla Rossi Department of Surgery, Breast Unit, Morgagni-Pierantoni
Hospital, Forli, Italy
Virgilio S. Sacchini Breast Service, Department of Surgery, Memorial SloanKettering Cancer Center, New York, USA
Luis J. Sanchez Department of Oncology Surgery, Breast Unit, Careggi
Alfredo Santinelli Department of Pathological Sciences and Public Health,
Pathological Anatomy and Histopathology, Politechnic University of Marche,
Ancona, Italy
Giusy Scandurra Breast Unit, Cannizzaro Hospital, Catania, Italy
Elisa Sebastiani Department of Surgery, Breast Surgery Unit, Ospedali Riuniti
Barbara Franca Simonetti Department of Radiological Sciences, Clinical
Radiology Unit, Ospedali Riuniti University Hospital, Ancona, Italy
Daniela Terribile Multidisciplinary Breast Center, Catholic University of Rome,
Rome, Italy
Part I
Preliminary Remarks
on Modern Surgical Treatment
Instrumental and Interventional

Diagnostics
Gian Marco Giuseppetti, Letizia Ottaviani, Enrico Lenti,
Barbara Franca Simonetti, and Silvia Baldassarre
1.1
Introduction
Interventional radiology is a branch of radiology that includes all invasive procedures or minimally invasive diagnostic and therapeutic performed using radiological guidance (ultrasound, fluoroscopy, computed tomography and magnetic resonance imaging). Its goal is to achieve results equal to, or better than, the corresponding surgery, with less risk, fewer complications, and lower costs. It is an emerging discipline in many fields, often indispensable in both the diagnostic and therapeutic-surgical phases.
In the field of breast imaging, it is reserved for lesions that pose a diagnostic
dilemma and remain unsolved with conventional diagnostic imaging, or for the
programming of a therapeutic intervention-surgery.
The increased experience of radiologists in breast diagnostic, technological
developments and the ability to use dedicated equipment, have led to the identification of a large number of breast lesions of small dimensions, whose type is not
always easy to define. For example, it is often necessary to differentiate malignant
disease at an early stage, or with a borderline benign pathology, or to differentiate
recurrence from a scar, using cytologic techniques (percutaneous fine needle cytology from 21 to 27G, PC; fine needle aspiration cytology, FNAC) and/or histologically by percutaneous biopsy (PB) with needles size between 820G or surgical
biopsy. The different collection methods must be properly placed and used in the
diagnostic process, so it is essential to become familiar with the information they
provide, their limitations and possible complications.
G. Giuseppetti ()
Department of Radiological Sciences, Clinical Radiology Unit,
Ospedali Riuniti University Hospital,
Ancona, Italy
C. Mariotti (ed.), Oncologic Breast Surgery,
Updates in Surgery
DOI: 10.1007/978-88-470-5438-7_1, Springer-Verlag Italia 2014
G. Giuseppetti et al.
In parallel with the increase in the detection of nonpalpable lesions, the frequent
diagnosis of tumors in the pre- or minimally invasive phase has led the surgical
field to a search for less invasive interventions that require more and more often a
precise location of the lesion and its extension; this is achieved with close cooperation between radiologists, nuclear medicine physicians, surgeons and pathologists
in the multidisciplinary management of the patient.
Recently, in senology and other sectors, minimally invasive interventional radiology procedures have been used, with curative or palliative purposes, when treating benign or malignant tumors (percutaneous treatment with radiofrequency technology, using lasers and focused ultrasound, etc.), and have delivered interesting
and promising results, although on a limited number of properly selected cases.
1.2
Percutaneous Cytology
Fine needle aspiration cytology (FNAC) was developed over a century ago and has
long been used in the diagnostic workup of breast lesions, as it is fast and minimally invasive and provides adequate sensitivity and low costs [1, 2]. However, even
when perfectly executed, cytological examination has up to 510% rate of false
negatives [3], due to the exact target localization, the pathologists experience in
correctly classifying benign cases with very different morphologies, and the heterogeneity of the neoplastic architecture, as the collection can be sampled from areas
of fibrosis, necrosis, fat or normal tissue. However, ecomammography/cytological
embedded data have been shown to possess a very low percentage of diagnostic
error that, in the case of concordance of tests, presents a percentage of false negatives around approximately 1% [47]. The positive cytology is in principle a very
specific relief and the rate of false positives is considered irrelevant: less than 1%
(FNAC specificity=99%) [4, 7] and mostly due to the poor quality or quantity of
the extracted material. However, the limits of this technique stem from the inability, when cytological sampling is positive, to differentiate forms in situ from infiltrating and the evaluation of the biological parameters of the neoplasm.
Cytology can be performed under mammographic stereotactic guidance (currently fallen into disuse) or ultrasound (US), which is generally preferred when the
lesion is sonographically visible, because it is low-cost, rapid, and offers a high precision sampling that is well tolerated by patients [8, 9]. Under stereotactic imaging,
the breast lesion can be located in a three-dimensional space (coordinates x y & z)
by means of a double exposure stereotactic mammography obtained by tilting the
arm of the tube and measuring the position of the lesion on the two mammograms
on a prone patient (alternatively she can be sitting on dedicated equipment). The
stereotactic guidance is used in the case of lesions visible only on mammography,
such as areas of distortion, small opacities or focus of microcalcifications: when
considering the high number of inconclusive samples with cytological examination,
it is preferable and it is recommended, cost and time being similar, to use larger
needles in modality core biopsy or vacuum biopsy.
Complications are extremely rare if the method is successful, and are mostly due
1 Instrumental and Interventional Diagnostics
to bleeding (hematoma and bruising), which occurs more frequently in areas where
the breast is richer with superficial venous structures; generally, these complications
are resorbed in a few days. Pneumothorax on the other hand is a serious but extremely rare complication, which affects one case per 10,000 biopsies [1, 2, 9].
Prerequisites for accurate cytological diagnosis are the close cooperation of
operators (radiologist and pathologist) for proper targeting of the lesion, the experience and expertise of the pathologist in handling the extracted material and
preparing cytologic samples representative of the lesion.
1.2.1
Collection Technique
The method of sampling for cytological examination is relatively simple although

it requires training and experience: the procedure can be carried out using only a
needle with a caliber from 2127G and variable length in relation to the depth of
the lesion, and by exploiting the lift by capillarity of the material. Alternatively, the
needle can be connected to a common disposable syringe (20mL), mounted on gun
device type CAMECO, performing manual aspiration or by connecting the needle
with suction devices with vacuum pump that allow a greater operating freedom.
Typically, 2223G needles are used that, due to their larger gauge, allow the collection of a greater quantity of material, even if some authors prefer to use lower gauge
needles (2527G), that guarantee the collection of sufficient material and are suitable for the diagnosis in a more practical, less traumatic and quicker way. As
already said, the US guidance is always preferred for the radiological stereotactic
guidance, if the lesion is visible by US, as it is faster, of simpler execution, less
expensive, in the absence of ionizing radiation, more flexible, with a smaller percentage of inadequate results and better tolerated by the patient.
As for the US examination, the patient is positioned supine, and the collection
is performed taking the taut skin of the breast between thumb and forefinger so as
to immobilize the area of interest and prevent the formation of tunnel due to loss of
contact probe-skin at the time of the introduction of the needle; this, in addition to
facilitating the introduction of the needle decreases the blood supply, which in turn
lowers the risk of inducing hemorrhage.
The sampling should be performed with the needle inside the lesion by performing rapid and multiple inward and outward movements associated with rotations,
under constant instrumental guidance, to ensure a representative sample is collected; finally, it is important to take good care of interrupting the suction before
removing the needle.
The needle is introduced by the customer by free hand, going in the direction
of the lesion with a perpendicular or oblique approach.
With the perpendicular approach, the needle is inserted at the midpoint of the
probe and placed perpendicular to the lesion, which is visualized in the center of
the scan. In relation to the depth of the lesion, the path of the needle will have a
defined angle, which can be corrected in real time; with this access only the tip of
the needle appears, in the form of a point of echogenicity, when it intersects the
field of view at the level of the lesion. The perpendicular approach is undoubtedly
fast, well-suited for superficial or deep lesions and requires no special accessories,
but it does require a solid experience.
The oblique approach, for which special adapters can be used with different
angles, is more favorable than the previous one, since the needle can be visualized
along its path in the breast toward the target. The transducer is positioned so that
the lesion appears next to the lateral margin; the needle, inserted in the vicinity of
this margin, is directed, with different obliquity in relation to the seat of the target,
to the field of view, where it is immediately identified and followed along the path
to the lesion. The most important limitation of this approach is the impossibility to
reach very superficial lesions. The oblique approach is more difficult than the perpendicular one, because the path is decidedly longer than the needle; when executed with special kits though, it is easier and less operator dependent, therefore,
preferable at the beginning for operators with limited experience and most suitable
for cytology of deep lesions near the chest wall [1, 2, 8, 9].
1.2.2
Cytological Diagnostic Conclusions
The results of cytology may be available after a few hours, with a report that must
be clear and include a diagnostic conclusion as suggested by the European
Guidelines (Table 1.1) [10].
1.2.3
Indications
Despite its inherent limitations, the cytology, when performed by a team of experts
(radiologist, pathologist), may still play a role, if properly placed in the diagnostic
workup of breast diseases, in determining the benign or malignant lesions [11]. The
choice of the lesions to be examined by biopsy is crucial, giving careful consideration to possible alternative diagnostic tools. In particular, this technique should be
preferred in lesions characterized by a liquid component and/or necrosis phenomenon
Table 1.1Reporting system for breast FNAC (C1-C5) in accordance with the European
Guidelines. (Modified from [10])
C1
Inadequate for diagnosis - the cause shall be indicated (little or no cellularity,

artifacts unsuitable equipment, etc.)
C2
Benign epithelial cells - negative finding for malignant cells, sometimes specific
diagnoses can be formulated (e.g., fibroadenoma)
C3
Atypia probably benign - uncertain findings indicate the need for further investigation
(e.g., histological biopsy)
C4
Suspicious of malignancy - the cytological features are suggestive, but not diagnostic
of malignancy (e.g., lesions borderline or low-grade ductal carcinoma)
C5
Malignant - the cytological features are diagnostic of malignancy and, where possible,
indicate the Nuclear Grade and report the presence or absence of microcalcifications
(complicated cysts, papillomatous lesions) [12], or localized in particularly difficult

areas (axillary, close proximity to the chest wall, the presence of adjacent breast
implants).
Performing a biopsy under mammography guidance, with a stereotactic device,
is reserved for lesions not visible by US and it is, at present, less frequently used
and even abandoned as, in cases of distortion of the drawing breast radial scar and
microcalcifications (typical lesions best or only evident with mammography), it is
imperative to proceed by core biopsy or vacuum biopsy. For the limits of FNAC,
related to the high percentage of inadequate results (C1 230%), the high percentage of false negatives (520%), the high number of equivocal results (C3) and the
inability to find positive cases to evaluate the biological parameters of the tumor
and to differentiate the forms in situ from those invasive, it is appropriate in most
cases to resort to percutaneous biopsy. The continuation of the diagnostic with the
use of percutaneous biopsy is also required in all cases of discrepancies between
results of cytology and conventional imaging, and in equivocal cases (C3) after
cytology, whereas the positive predictive value for carcinoma in C3 cases is 20%
(in fact, some malignant lesions are more often adjustable as C3: tubular carcinoma, well-differentiated ductal carcinoma, lobular carcinoma and ductal carcinoma;
as well as some benign lesions are more often related to C3: fibrocystic , fibroadenoma and adenosic injury) [13].
1.3
Percutaneous Biopsy
Percutaneous biopsy (PB), performed by US or stereotactic guide needle size

between 8 to 20G, is currently the most appropriate method for the characterization
of histological lesions and therefore is widely used in clinical practice to replace
surgical biopsy.
The small number of malignant lesions diagnosed in the final histopathological
examination, combined with considerable problems with surgical biopsies (high
costs and stress for the patient, sometimes need to use general anesthesia, postoperative risks such as infection, thrombosis and embolism, scars, crowded operating
rooms) have prompted the research for more cost-effective interventional techniques that are less invasive and able to get a satisfactory answer to the histological diagnosis. At the same time, the planning of treatment or therapeutic/surgical
follow-up is required.
Recently, new systems have come into use, increasingly sophisticated, easy and
rapid to apply, that allow, albeit a more complex procedure than cytology, the
extraction of frustules of tissue, sufficient for a precise and complete histologic
diagnosis of the lesion. This makes adequate planning of therapeutic treatment possible, with a consequent reduction in the number of diagnostic surgical biopsies
and, ultimately, costs. PB allows both histological and biological characterization
of the lesion, thus defining aggression and receptor appearance (ER, PgR, Ki67, Cerb B-2), useful parameters, where indicated, for a possible neoadjuvant presurgical chemotherapy [1417].
There are several types of PB depending on the type of needle that is used [2,
9, 18]:
Core Needle Biopsy or biopsy with needles shot of the semi-automatic type
(tru-cut), with a guillotine gauge between 14 and 20G that allow you to make
multiple microhistological withdrawals of the suspected area;
Vacuum Biopsy (VB) or biopsy using an aspiration technique, which, through
gauge needles between 8 and 14 G, allow large mammary withdrawals to be
made with a single access.
No method of PB is 100% accurate, even with very high sensitivity values,
which approach 95/97%, compared to 90% of percutaneous cytology [1316]. The
diagnostic capacity depends on the type of lesion (node or calcification), the diameter of the needle used (from 14G to 18G) and the amount of tissue (number of frustules) taken. Moreover, it has to be considered that 1030% of microhistologically
diagnosed carcinoma in situ, are associated with foci of invasiveness discovered
during the subsequent surgery. Additional limitations are represented by the difficulty of interpreting morphologically complex but benign diseases (atypical epithelial hyperplasia, injury scleroelastosica or radial scar), which require excisional
biopsy surgery, because of their characteristics and their possible association with
foci of atypical ductal hyperplasia (ADH) or ductal carcinoma in situ (DCIS)
[1922].
PB, according to major scientific societies, is indicated in many cases, particularly in assessing [23]:
Lesions considered highly suggestive or suspicious for malignancy (BIRADS
category 4 and 5), to confirm the diagnosis and guide the definitive treatment
Lesions with multicentric distribution to facilitate the planning of the treatment
Lesions assessed as probably benign (BIRADS category 3), only when there are
valid clinical indications, in particular in the diagnosis of fibroadenoma (greater
diagnostic confidence of benign lesions, which relieve the patients stress)
Lesions undiagnosed after FNAC (C1 and C3, the discrepancy between the
radiologist and pathologist)
Injuries characterized by the discrepancy between cytologic findings and clinical signs
Diagnosis of specific histological types (lobular carcinoma, tubular or cribriform)
When information is needed that cytology cannot provide, such as neoplastic
invasiveness and aggressiveness
When the patient prefers mastectomy despite conservative treatments being
available or she must undergo other nonsurgical therapies (older women candidates for hormonal therapy, adjuvant chemotherapy before surgery, etc.).
The use of PB is also recommended (given the paucity of material obtainable
with FNAC and the high number of inadequate results) when dealing with suspicious lesions characterized by calcification, breast and radial distortions of the drawing-scar. In particular, several authors suggest the use of VB in cases of calcification,
because of the possibility of taking greater quantity of material, and open biopsy
when dealing with the distortions of the drawing breast and the radial scar [20, 21].
Percutaneous biopsy, generally performed in an outpatient clinic or day hospital, under (optional) local anesthesia, can be performed under US guidance, stereotactic or MRI, depending on the visibility and the instrumental characteristics of the
lesion.
1.3.1
Preliminary Evaluation
Prior to performing the biopsy, the available clinical indications must be evaluated;
profiles of technical feasibility, considering the BIRADS of the target lesion and the
outcome of global imaging techniques including mammography, US and mammary magnetic resonance.
It is of particular relevance that an informed consent is obtained in writting and
that the document contains a brief description of the procedure and includes a note,
detailing the option of leaving a small nonmagnetic clip (from the stereotactic
guide) and the expected duration of the procedure. Moreover, it is important that
the expected results and available alternatives to the biopsy be clearly stated, suggesting that this procedure has been shown to deliver a high percentage of accurate
diagnoses. Finally, the risks associated with this procedure must be described, in
particular the rather rare complications, typically hemorrhagic in nature, as well as
short-lived neck and back discomfort due to the particular body position that must
be held for several minutes during the procedure.
The general evaluation of the patient is key: in particular, the pharmacological
treatment with anticoagulant and antiaggregant drugs must be suspended with standard methodology; and the ability of the patient to hold a supine position (for the
echographic guide), or prone (for the stereotactic table), for a long enough time.
It is good practice to place a cannula on the arm that is not used for the biopsy,
to keep a venous access open in case complications arise during the procedure, or
just to satisfy standard ambulatorial procedures.
1.3.2
US-guided Breast Biopsy
When the lesion can be located through US, this should be the method of choice to
guide the intervention, as it is cheaper, more practical, simpler and faster (310
min); moreover, it offers the ability to locate the needle in real time within the
lesion, as already listed for the case of the US-guided cytological biopsy [8].
The preferred types of needle for this procedure include: tru-cut, semi-automatic and snap-fit types [2, 9].
The procedure is as follows: having ensured sterile conditions, the appropriate
choice of needle gauge (1420G) and under a regime of local anesthesia, a small
skin incision is made, which facilitates the crossing of the cutaneous layer. The needle is inserted with the tip facing the lesion and its path is visualized on the US
monitor (the probe is kept at either 45 or parallel) and the needle is stopped when
it is facing (or it has penetrated) the target lesion. The guillotine is extracted (so as
10
to be able to follow the progress inside the lesion), which triggers the shirt, thus cutting the frustule of tissue, and pulling the needle with the frustule intact inside (Fig.
1.1).
This procedure is generally repeated 36 times from different orientations, so
that enough tissue might be gained, from different regions of the lesion. The
extracted samples must be fixed in formalin. At the end of the procedure, it is advisable to manually press onto the interested region for several minutes to minimize
the risk of bleeding and hematoma formation; it is not necessary to suture the skin
incision, but a steri-strip type of medication and ice treatment can suffice. The
dressing can be removed the next day.
By adopting a similar procedure, a tissue sample can be obtained with a vacuum-assisted biopsy (VAB), employing needles with larger gauge (8 and 14G),
through which multiple samples can be obtained from a single access point.
Moreover, in the case of a benign pathology, the same procedure can be adopted for
the complete vacuum-assisted percutaneous removal of the mammarian lesion.
It can be considered as a viable alternative to all surgeries for lesions smaller
than 1 cm, that did not result in atypia of the core biopsy, but that are candidates for complete removal.
This procedure can be performed in the US room and it is generally better
accepted by patients, because of the absence of scars; also since it does not require
an operating room, it is generally much cheaper. Complications similar to the open
surgery alternative are possible [24].
Once the target has been identified, a local dosage of anesthetic is delivered
between the skin and the lesion, and a ventaglio around the lesion. At that point,
a small skin incision (34mm) is performed and the VAB needle is introduced. It
is preferable to position the needle below the lesion, which is then explored in a
layer by layer fashion. Once the removal is complete, as assessed by a real-time US,
a nonmagnetic clip can be placed.
Fig. 1.1 a Nodular area, hypoechoic multilobulated contours (BIRADS 3, cytology C3). b
Extraction technique microhistology with tru-cut (histology: fibroadenoma)
1.3.3
11
Stereotactic Breast Biopsy
Stereotactic breast biopsy is an interventional radiology method for the localization, sample extraction and, in selected cases, removal of a breast lesion that is clinically nonpalpable, but has a mammographic readout. It is based on a geometrical
argument, for which a pair of two-dimensional images incident at a known angle
(typically 30) can be processed to determine the localization of a given feature,
such as a lesion, in a three-dimensional space (with coordinates x, y, z).
It is currently used mostly in digital mammography, where the radiographic film
is replaced by a detector that transduces incident x-rays into electronic signals that
can be digitized and operated upon on a computer. From these data, an image can
be reconstructed, so called digital mammography, which is then visualized on a
high definition monitor. Once the lesion is spatially localized, the sample-taking
system allows the precise positioning of needles and the extraction of histological
samples for diagnostic purposes.
1.3.3.1 Procedure
Having acquired a mammography standard image, that can be either cranial-caudal,
oblique or lateral depending on the visibility and the location of the lesion, a stereotactic pair of images can be acquired. The images should be angled at 30 to one
another (+15 and 15 compared to the standard image). The location of the lesion
is then manually identified in each image before a computational algorithm evaluates the three-dimensional coordinates of the lesion. Under local anesthesia, a needle can be inserted to extract the tissue sample. X-ray images of the extracted samples are acquired and analyzed to select the most significant ones for further pathological classification, such as those containing microcalcification or dense breast
tissue. Finally the extracted samples are fixed using formalin and sent to the pathologist along with a form that specifies the patient personal information, clinical
query, the radiological suspicion and the possibility of a biological characterization.
1.3.3.2 Extraction Systems
This method can be performed with the adaptive systems placed on normal mammograms (patient sitting in front of the machine) or with a dedicated stereotactic
table (Fig. 1.2). The latter case, against a higher cost, allows the procedure to be
carried out with the patient in a prone position, with the operational area outside the
visual field of the patient and allows 360 access to the breast. The stereotactic table
is a table consisting of an ergonomically shaped height adjustable padded surface
on which the patient lies prone. A circular opening of diameter of about 25 cm
allows the breast to protrude in the operational area, located below the table top.
Under the table, a "C" shaped angle arm supports the x-ray tube and the spherical
collimator at +15 and 15 for the acquisition of the stereotactic images. A second
arm to C provides the support to the compression plate of the breast and to the
pointing device that received the stereotactic coordinates, driving on the lesion the
operating instrumentation. The characteristics of the various tables and the possibility of positioning the patient allows, in most cases, the shortest route between the
skin and the lesion of the breast to be followed (Fig. 1.2).
12
b
Fig. 1.2 a Stereotactic table and console
work. b Positioning of the patient and
mammographic detection of the lesion.
c Tissue sample to be examined
1.3.3.3 Instruments
The stereotactic biopsy history begins with the ABBI system (Advanced Breast
Biopsy Instrument) (Fig 1.3) in the early 1990s, whose goal was the complete
removal of the mammary non palpable lesion (NPL). Trocars ranging from 5 to
20mm were utilized to perform an excisional biopsy of the lesion with local anesthesia providing very little advantages over a surgical biopsy that requires an operating room.
In the spring of 1993, four radiologists (Burbank, Parker, Brody, Zerhouni) and
a surgeon (Thomas J. Fogarty) developed the mammotome, a dedicated system for
stereotactic breast biopsy [17]. On August 5th 1994 the first stereotactic biopsy was
performed.
The mammotome was the ancestor of a series of systems built around an aspiration unit (VB) and an operating window positioned lateral to the needle tip with
a diameter ranging between 12 and 7G. Using the mammotome instead of the ABBI
system, the lesion is not removed as a monolithic unit, but rather it is divided out
and removed in pieces: this is important, as it leads to greatly reduced trauma and
much improved tolerability.
The procedure is typically performed in a day hospital. In fact, once the lesion
and the needle insertion point are located, a local anesthetic is administered by infiltration to skin and target. Then, a 34mm skin incision is made and the needle is
introduced. After centering the target, the tissue is ready to be extracted (Fig. 1.2).
13
Fig. 1.3 a ABBI cannula. b Sample with ABBI. c ABBI x-ray sample
The radiological control of the operating region and of the extracted samples permits real-time quality control over the entire procedure (Fig. 1.4). The typical duration of the procedure is about 20 minutes.
Another commonly adopted technique is the core biopsy, in which tissue
extraction is performed with snap needles, with gauges greater than 1 mm
(818G) (Fig. 1.5). In this technique, a series of repetitive extractions produce a tissue-map of the breast. This procedure, which is less invasive, better tolerated and
the more versatile of the VB types, unfortunately tends to underestimate the lesion
type. Limitations of the core biopsy include a reduced amount of material in adipose breasts; presence of fragmented tissues or noncontiguous samples; the need
for multiple reintroductions; and a general tendency to underestimate microcalcifications.
At the end of the procedure, it is important to perform a control mammography
to prove the effective removal of the target and to clinically evaluate the breast to
rule-out hemorrhages and hematoma. If those are present, perform manual compression first, followed by a mechanocompressive one after a few minutes; where
necessary, apply compression with tensoplast. A simple steril-strip is applied to the
needle point of entry.
1.3.4
MR Guided Breast Biopsy
As magnetic resonance became the imaging technique of choice in senology, due

to unparalleled diagnostic sensitivity (9599%), lesions have been noticed that can
be detected with MR but not with echography or mammography [2, 25].
Interpreting a novel breast lesion, characterized using either morphological or
dynamical criteria during a MR session, is difficult due to the high rate of false positive detections that may occur even when the procedure is perfectly executed.
14
b
Fig. 1.4 a Breast at the end of the procedure;
the small incision on the skin locates the needle point of entry. b Positioning of the frustules of tissue taken for x-ray control. c In the
x-ray control, frustules show the presence of
microcalcifications
When a lesion is first detected with MR, and presents itself with concerning characteristics, it is necessary to confirm it in a second-look traditional imaging session and then proceed to extract a sample using either the US or mammographic
guided biopsy techniques discussed earlier. If a lesion cannot be confirmed with
traditional imaging, than the biopsy must be performed under magnetic resonance
guidance despite increased difficulties, execution times and costs [2629].
This technique requires ad-hoc instrumentations, including a dedicated support,
or open coil, that permit the positioning of a compression and localization system
such as Universal Grid or Post & Pillar through which the biopsy needle can
be introduced. Notably the needle needs to be made of a material that is compatible with strong magnetic fields. Nonmagnetic coaxial needles are inserted and
under MR guidance, either manually or through CAD (Computer Assisted
Detection), localized to a lesion that was previously detected with basic exam or
after intravenous contrast medium (icm) administration. Through the coaxial needles, cutting needles are introduced (1416G) or greater caliber VAB needles
15
Fig. 1.5 a Different types
of breast needle biopsy
(core biopsy and VAB)
and breast gauges (818G). b Needle core
biopsy: details of
sampling window
(811G). After the extraction, it is good practice to leave a radiopaque clip or USreflector in the place of the lesion, that can be later recognized via traditional imaging techniques [25, 27].
The patient needs to be adequately informed of the possible MR contraindications, including paramagnetic contrast agent and possible complications, such as
bleeding, or the presence of a needle close to the chest wall; moreover, the patient
must be able and willing to remain prone for the duration of the exam (approx.
45min).
1.3.5
Sample Handling for the Pathologist
Typically, four frustules must be extracted for a diagnosis of neoplasia to be treated with primary systemic therapy PST (number of frustules correlates with diameter of neoplasia). The samples must then be immediately fixed with neutral buffered
16
formalin 4% (pH 6.87.2) for 648 h. The request for histological examination
must be accompanied with full clinical information (including the intention of treating with PST when the neoplasia is locally advanced) and a copy of the mammography (or US) report containing the time of the exam, the characteristics of the
detected lesion, its location and dimensions, the BIRADS category and the number
of extracted samples. If microcalcifications are detected, the frustules containing
them must be identified on the postextraction radiograph and sent in separate
marked containers. The quality of the material must be described along with the
length of the biggest frustule. Each container holds 23 frustules at most. For each
inclusion, four sections are obtained at two different levels (approx. 50m each)
and stained with hematoxylin-eosin.
The pathologist can require further sectioning of the samples if there is an
inconsistency between the clinical inquiry and the report of the pathologist (particularly for microcalfications). Moreover, the presence of microcalcifications can be
confirmed through additional x-ray scanning of the samples.
1.3.6
Medical Reporting
The pathologist report must contain a full diagnosis of the detected lesions and their
eventual relationship with the microcalcifications (distinguishable in intraluminal
and stromal) and the specification of the category B (B1-B5 in accordance with the
European Guidelines) (Table 1.2) [10]. It must also contain, in a dedicated session,
Table 1.2 Final diagnostic histological type (B1-B5) in accordance with the European Guidelines.
(Modified from [10])
B1
Unsatisfactory/normal breast tissue (normal tissue, it may indicate that the lesion was
not sampled properly or that there is a benign lesion such as lipoma or hamartoma characterized by normal breast ducts and lobules or mature adipose/fibrous tissue).
B2
Benign (benign lesions including fibroadenomas, fibrocystic changes, sclerosing adenosis and duct ectasia and extends to include other non-parenchymal lesions such as
abscesses and fat necrosis).
B3
Benign but of uncertain malignant potential (lesions with uncertain malignant potential which may provide benign histology on further surgical biopsy, but either are known
to show heterogeneity or to have an increased risk, albeit low, of associated malignancy.
Pathological conditions such as ductal epithelial hyperplasia and/or atypical lobular, papillary lesions, radial scar and phyllodes tumor. The majority of B3 lesions require surgical excision).
B4
Suspicious of malignancy (suspected lesions, in which the definitive histologic diagnosis of carcinoma in situ or invasive cannot be made with certainty are included; or mainly necrotic problems or, for example, when there are apparently neoplastic cells in the
context of a blood clot).
B5
Malignant (cases of unequivocal malignancy; further categorization into in situ and invasive malignancy should be undertaken whenever possible. Other forms of malignancy
such as malignant lymphoma may also be classified as B5).
17
the clinical information that was given in the request for the histological exam.
When a carcinoma is diagnosed, the following must be specified: cancer invasion,
histological type and degree (optional) (e.g., Elston Ellis Grade), and if vascular
invasion is present.
Biomarkers (ER, PgR, Ki67, HER2) are not routinely evaluated. An exception
is made prior to PST or, later, upon request of a clinician. Their evaluation is performed on all available frustules that contain the lesion.
1.4
Lesion Localization
In the case of excision, during the presurgical phase, nonpalpable small lesions
need to be located precisely to ensure complete excision, with a good cosmetic
result and without excessive or inaccurate resections.
This localization can be done with dermographic pencil (skin centering), with
metal markers (metal centering) or with the ROLL technique (radioisotopic centering). The choice of the centering method depends on the characteristics of the
lesion, its topography in the breast, the availability of equipment and the confidence
the operative unit has in the method.
Skin centering. In particular situations, such as superficial or deep lesions, or
ones near the pectoral muscle or breast implants, or periareolar or retroareolar
lesions, we can limit ourselves to a simple localization with US guidance on the
skin of the lesion (skin marker) with dermographic pencil, specifying the size of the
lesion and its distance/depth to the skin surface.
Centering with wire. It came into use in the 1970s, after progressive technological developments and currently it is the most used method of localization in
clinical practice. It uses the latest devices which feature repositionable markers and
needle with curved wire (Homer needle).
When the site of the lesion is identified, the spindle-metal marker system, having a suitable length for the depth of the lesion and the thickness of the mammary
gland, is inserted and is advanced with US guidance (if the lesion is visible to US)
or stereotactic guide (according to Cartesian coordinates x, y, z). Once the lesion is
reached (the exact position is verified in real-time US or with x-rays in the case of
stereotactic guide), the spindle is extracted by slightly advancing the metal marker,
its extremity being bent like an hook, opens and anchors into the breast tissue.
A unilateral biprojective mammogram (cranial-caudal, medial-lateral projection) is carried out to document the location of the tip of the marker (Fig. 1.6); the
medical report must be clear, complete and exhaustive with reference to the performed maneuver and particularly to the location and distance of the tip of the
marker from the lesion. This information is necessary both to the surgeon, in view
of the operation, and for forensic reasons.
The inaccurate placement of the metal marker, namely the migration of its position, which is a possibility in adipose breasts, must always be documented mammographically and written up in the report.
18
a
Fig. 1.6 Metal landmarks placed on a nodular
lesion, partially irregular, rounded contours,
in QIE (excess upper quadrant of the right
breast). Cranio-caudal projecton (a); mediolateral projection (b); the landmark appears
regularly localized within the lesion (Histology: DCI)
Complications like hematoma, vagal crisis and sporadic pneumothorax may

occur, although rarely, for deep lesions located near the pectoral muscle and chest
wall.
Centering postVB. This method of lesion localization consists of releasing a
clip in the lesion site after the biopsy procedure and before withdrawing the needle-cannula. During decompression, a dislocation of the clip may occur, but this
can be avoided by slowly releasing the mammary compression.
When the lesions are small or have been removed almost completely by the
withdrawal, it is necessary to position the clips because they are essential both to
the surgeon, in the case of resection as a preoperative marker, and to the radiologist, in the case of follow-up in order to locate and identify exactly the area subjected to biopsy.
Clips are metallic, nonmagnetic, and may also be US visible, like Gel Mark
(BARD Seno RX). The latter is made of a titanium clip, wrapped in a cylinder of
biodegradable collagen gel, that allows the marking and then the localizing of guidance lesions with US, which otherwise are only visible mammographically (such as
small clusters of microcalcifications or areas of mammography distortion).
Radioisotopic centering (ROLL: Radioguided Occult Lesion Localization).
It is an advanced technique that permits the precise localization and removal of the
breast lesion by injecting a small amount of human serum colloidal albumin labeled
with 99mTc in the center of the lesion with stereotactic or US guidance.
After the injection of the marker the correct centering of the lesion is made by
performing a scintigraphic check.
19
During surgery a gamma radiation absorbing probe (gammaprobe) is used,

which is able to detect the signals emitted by the trace radioisotope in the lesion,
and thus locating the hot spots, which will guide the surgical removal.
This procedure, which requires close collaboration among the surgeon, radiologist, nuclear medicine physician and pathologist, has some advantages over the
traditional procedure with metal markers such as:
Greater precision in centering the lesion, with exact detection of the corresponding cutaneous projection, which allows the surgeon to plan the location and the
type of incision to be performed
Accurate excision of the lesion during surgery with better cosmetic results and
less excision of healthy tissue
Elimination of problems related to the risk of dislocation of the metal marker
before or during surgery with residues of the marker in the postsurgical phase
Ease and speed of execution.
Certainly the ROLL technique exposes staff to an inevitable radioactivity connected to the radioactive drug used and it is burdened by significant costs related to
the equipment (gammaprobe), which is the same as that used for the sentinel lymph
node.
It also requires precise planning, a surgical room and anatomical pathology,
which need to be readily available, since the operation must be carried out within
24 hours of the injection of the radioactive drug.
1.5
Percutaneous Treatment
In recent years, the widespread use of conservative surgery in the treatment of initial breast cancer has offered good cosmetic results, while ensuring complete
removal of the tumor with sufficient safety margins and similar survival rates as
those of the most demolitive treatments.
The growing demand for these treatments has brought about the search for percutaneous minimally invasive techniques that would allow the eradication of the
breast tumor without the need for surgery [30].
Although for several years, some percutaneous techniques (PLA: percutaneous
laser ablation; RFTA: radiofrequency thermal ablation) have existed and are widely used in clinical practice for the treatment of benign nodules of the thyroid or
hepatic tumoral lesions, they have only recently been applied in senology.
In these methods heat, which causes irreversible alterations and then cell death
by hyperthermia, is used as a physical agent for inducing tumor necrosis.
Various instances of treatment of breast lesions with percutaneous techniques
exist in the literature, which provide promising results. However, all these studies
respect strict inclusion criteria, which are essential for the success of the procedure
with the positive outcome for the patient [3143].
In particular, treatment with PLA or with RFTA is possible solely for individual
invasive breast lesions with a maximum diameter of less than 23cm, diagnosed
by core needle biopsy. They must be clearly identifiable and definable with US
20
examination and must be at least 1cm away from the overlying skin or from the
chest wall; lesions should be excluded that have an intraductal component, the lobular form or multifocal-multicentric and bilateral.
Both percutaneous procedures (PLA and RFTA) are performed with US guidance where monitoring in real time permits, the correct positioning of the needles
and the effect of therapy during and after treatment to be assessed. MRI can also be
useful to show the effects of necrosis on the lesion and on the surrounding tissue.
Percutaneous laser ablation (PLA). Optical fibers are inserted through thin
needles (2122G), placed percutaneously at the level of the target region to be
ablated, and, by carrying laser energy, they induce heat (temperatures between
50100C) with consequent irreversible destruction of proteins and tissue by coagulation necrosis [31, 32, 37, 43].
Radiofrequency thermal ablation (RFTA). A needle-electrode is inserted in
the neoplastic nodule by percutaneous access and allows the application of
radiofrequency energy for a time varying from 15 to 18 minutes.
As an effect of the radiofrequency, heat is generated by friction from the movement of the ions present in the tissue with consequent destruction of the tissue and
cell necrosis [33-35, 38-43].
In addition there are other recent techniques of minimally invasive treatment in
benign breast disease with US-therapy. In order to induce cellular necrosis, they use
the heat produced by US beams with a high intensity signal focused on confined
nodules like fibroadenomas. Here they appear to induce a thermal ablation with a
consequent reduction in the dimension and consistency of the nodule.
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The Pathology of Breast Cancer

Alfredo Santinelli and Tommasina Biscotti
2.1
Introduction
Infiltrating breast carcinoma is the most common cancer in women, accounting for
23% of all cancers in women. Its incidence increases rapidly with age and varies
10-fold worldwide, being high in Europe, North America and Australia, and low in
sub-Saharan Africa and in southern and eastern Asia (including Japan).
The etiology of breast cancer is multifactorial, involving reproductive factors,
diet, lifestyle, and hormones. This disease occurs more frequently among women
who have an early menarche and/or a late age at menopause, remain nulliparous or
have few children with the first pregnancy at a late age. A high body mass, also
linked to a high total caloric intake, or intake not counterbalanced by caloric consumption, is a risk factor for postmenopausal breast cancer, as well as a high intake
of fat, particularly saturated animal fat, and of meat, particularly red or
fried/browned meat. Also the consumption of alcohol has been consistently associated with a moderate increase in the risk of breast cancer [1]. A recent review
conducted by a Canadian task force concluded that active smoking is related to
both pre- and postmenopausal breast cancer, and added that also passive smoking is casually related to premenopausal breast cancer, but the data are insufficient
to allow a conclusion in postmenopausal breast cancer [2]. High levels of physical
activity are associated with a reduction in risk of breast cancer, both in premenopausal, and in postmenopausal women; moreover, this benefit is independent
of race and ethnicity. Many data show a strong and consistent link between blood
concentrations of estrogens, progesterone, androgens, and prolactin in post- and
premenopausal women and the risk of developing breast carcinoma [3]. A recent
national study in USA demonstrated no increase in risk of developing breast can-
A. Santinelli ()
Department of Pathological Sciences and Public Health, Pathological Anatomy
and Histopathology, Politechnic University of Marche, Ancona, Italy
e-mail: a.santinelli@univpm.it
Updates in Surgery
23
A. Santinelli, T. Biscotti
24
cer among current users of the new oral contraceptives with very low dose of estrogen [4]. On the contrary, the postmenopausal hormone-replacement therapy seems
to increase the risk of developing breast cancer (relative risk ranging from 1.3 to
1.6, according to the duration of use) using both unopposed estrogen, and estrogen
plus progestin. This risk is greatest among lean women, i.e., women with low levels of circulating estrogen due to their low body mass [5].
2.2
Proliferative Epithelial Lesions of the Breast:

Relationship with Breast Cancer
The main proliferative epithelial breast lesions can be schematically subdivided in

the following groups:
1. Fibrocystic changes
2. Ductal hyperplasia (usual and atypical) and columnar cell lesions (typical and
atypical)
3. Sclerosing lesions (sclerosing adenosis, radial scar, and microglandular adenosis)
4. Intraductal papilloma
5. Atypical lobular hyperplasia and classic lobular carcinoma in situ.
2.2.1
Fibrocystic Changes
The term fibrocystic changes refers to a multitude of benign breast changes that
are considered to represent normal, but exaggerated, hormonally mediated breast
tissue responses. It is present in more than 35% of females 20 to 45 years of age.
The characteristic histological changes include stromal fibrosis, dilated ducts with
cyst formation, apocrine metaplasia, and mild usual epithelial hyperplasia without
atypia. Fibrocystic changes do not increase the risk for subsequent carcinoma
development [6].
2.2.2
Ductal Hyperplasia (Usual and Atypical) and Columnar Cell

Lesions
Moderate and florid examples of usual epithelial hyperplasia (UDH) occur in the
latter premenopausal years and are seen in 2030% of women undergoing breast
biopsy. On histological examination moderate and florid hyperplasia are characterized by a ductal proliferation with the presence of five or more cell layers above the
basement membrane; there is a variable cell composition, a variable architecture,
and a variable morphology of the nuclei, which do not show any atypia. In women
affected by UDH, it is demonstrated a slight increased relative risk (1.5 to 2 times)
of subsequent invasive breast carcinoma in the ensuing 5 to 15 years from the diagnosis, compared to women matched for age, who had no breast biopsy.
The average age of women with atypical ductal hyperplasia (ADH) is similar to
2 The Pathology of Breast Cancer
25
that of usual hyperplasia and approximately 10% of biopsy samples taken as part
of mammographic screening program contain this type of lesion. ADH is an intraductal cell proliferation, having the same cytological and architectural features as
low-grade intraductal carcinoma, which involves from a minimum of a part of one
duct, to a maximum of two to three ducts or to a maximum of 2mm in major diameter [7]. ADH is associated with a 45 times relative risk of developing breast cancer in the ensuing 10 to 15 years after the diagnosis [8].
Columnar cell lesions comprehend columnar cell change (CCC), columnar cell
hyperplasia (CCH) and flat epithelial atypia (FEA). CCC and CCH are identified in
up to 40% of core biopsy specimens performed for microcalcifications; FEA comprises about 1% to 2% of these cases. These lesions are more frequent in premenopausal and perimenopausal women, 44 to 51 years old. The CCC and CCH are
histologically characterized by enlarged terminal-duct lobular units (TDLU) with dilated acini lined by one/two layers (CCC) or more than two layers (CCH) of nonatypical columnar epithelial cells. FEA has the same microscopic appearances of CCC
and CCH with low-grade cytological atypia and absence of architectural complexity as is found in ADH. From recent follow-up studies, it is evident that CCC and CCH
are associated with a very low risk for the subsequent development of carcinoma [9].
Results from retrospective studies have indicated that up to 30% of patients with FEA
on needle-core biopsy have a worse lesion on excision; nevertheless, limited data from
other retrospective studies suggest that for FEA the risk to develop a subsequent breast
cancer is not so high and generally lower than the risk evidenced for ADH.
2.2.3
Sclerosing Lesions
Sclerosing adenosis (SA) occurs at any age, but it is most frequent in premenopausal and perimenopausal women; its incidence is not well known. It derives
from TDLU and it is formed by distorted, elongated and/or obliterated glands surrounded by myoepithelial cells, dispersed within a sclerotic stroma. It is a benign
lesion and does not increase the risk to develop breast carcinoma.
A radial scar (RS) may occur at any age; its incidence ranges from 4% to 28%
depending on series (e.g., autopsy versus surgical excision) and it is frequently multiple (up to 67%) and bilateral (up to 43%). It derives from TDLU and it is constituted by a central zone of fibroelastosis from which ducts and acini radiate, exhibiting various benign alterations such as UDH. The ducts and acini entrapped in fibroelastosis are lined by epithelial and myoepithelial cells. A RS is considered a generalized risk factor for subsequent breast cancer with a relative risk equal to 2.0
[10]. The risk increases with multiple and/or large radial scars.
Microglandular adenosis (MGA) is a very rare benign incidental lesion that
occurs more frequently between 45 and 55 years. It is microscopically characterized by small, round tubules lined by a single layer of flat or cuboidal benignappearing epithelial cells, without a myoepithelial cell layer but with the presence
of a basement membrane. It is a benign lesion but it is frequently associated with
invasive carcinoma [11]. For this reason, if it is diagnosed on needle-core biopsy, a
complete excision is warranted.
26
2.2.4
Intraductal Papilloma
Intraductal papillomas (IPs) can be solitary (SIPs), with a frequent subareolar location, or multiple (MIPs), and more frequently located at the periphery of the mammary gland. SIPs most commonly occur in the fifth and sixth decades, whereas
MIPs occur in a younger age group. Microscopically, IPs are constituted by multiple branching papillae lined by epithelium and myoepithelium within one or more
dilated ducts; they may be associated with usual or atypical hyperplasia, apocrine
metaplasia, and squamous metaplasia [12]. SIPs and MIPs are associated with a relative risk to develop breast cancer equal to 2.0 and to 3.0, respectively.
2.2.5
Atypical Lobular Hyperplasia and Classic Lobular

Carcinoma in Situ
Atypical lobular hyperplasia (ALH) and classic lobular carcinoma in situ (cLCIS) have
been diagnosed in women of all ages, but they are more common in premenopausal
women. ALH and cLCIS are incidentally found in 0.54% of otherwise benign breast
biopsies. They are multicentric in as many as 85% of patients and bilateral in 3067%
of the cases. ALH and cLCIS arise in the TDLU and are characterized by an intra-acinar proliferation of small, uniform, non-cohesive cells with or without pagetoid spreading in the adjacent terminal duct. In ALH, this cell proliferation does not obliterate all
the acinar lumina of a mammary lobule, whereas in cLCIS all the acinar lumina of a
mammary lobule are obliterated and the single acini are also enlarged by the cell proliferation [13]. Both ALH and cLCIS are immunohistochemically negative to E-cadherin in about 85% of the cases [14]. ALH and cLCIS are generalized risk factors for
subsequent breast cancer and non-obligate precursors. The relative risk to develop a
breast cancer ranges from 4.0 to 5.0 for ALH and from 8.0 to 10.0 for cLCIS [13].
2.3
In Situ Ductal and Lobular Carcinoma of the Breast
According to the 4th Edition of WHO classification of Tumors of the Breast [15],
ductal carcinoma in situ (DCIS) is classified as follows:
DCIS of low nuclear grade
DCIS of intermediate nuclear grade
DCIS of high nuclear grade.
According to the same classification, lobular carcinoma in situ (LCIS) is
subdivided in:
Classic LCIS (cLCIS)
Pleomorphic LCIS (pLCIS).
2.3.1
Ductal Carcinoma in Situ
DCIS is a neoplastic, malignant proliferation of epithelial cells confined to the
27
ductal-lobular system, without evidence of stromal invasion. It accounts for

2025% of newly diagnosed breast cancers in the western countries. In the last
3035 years, the incidence of DCIS increased from 1.9 per 100000 in 19731975
to 33 per 100000 in 2005.
Typically, on gross examination of a surgical excision specimen, DCIS is lacking of any characteristic aspect. If DCIS comedo-type is present, we can see, on the
cut surface, small specks representing comedo necrosis within the cut ends of the
ducts. The lack of gross findings may make specimen handling difficult and a sliced
specimen radiograph may be very useful to localize the microcalcifications.
DCIS most predominantly involves the ducts, although the high-grade DCIS
may extend into the lobules as so-called lobular cancerization. Historically, DCIS
was classified on the basis of the architectural pattern of epithelial proliferation and
was subdivided in comedo-type, cribriform, solid, micropapillary, papillary, or
mixed type. Nevertheless, this system of classification had some problems in terms
of low reproducibility among pathologists principally caused by the high frequency of multiple architectural patterns in each lesion. The new WHO classification
system cited above is principally based on the level of nuclear atypia, and the architectural pattern and the presence or absence of comedo necrosis are recorded separately [15].
DCIS of low nuclear grade is microscopically characterized by a proliferation
of small, monomorphic cells growing in micropapillary, solid, cribriform, or papillary patterns. The nuclei are small, uniform, with dispersed chromatin, and without
evident nucleoli. Mitoses are rare and the necrosis, particularly comedo necrosis, is
usually absent. Intraluminal microcalcifications may be present. DCIS with purely
micropapillary pattern may be associated with a more extensive distribution,
involving more than one breast quadrant, than the other morphological variants.
DCIS of intermediate nuclear grade is composed of cells with mild to moderate
variability in size, shape, and placement. These cells have completely lost any kind
of polarization and grow more frequently as solid or cribriform patterns. The nuclei
have a variably coarse chromatin, and variably prominent nucleoli. Mitoses may be
present as well as punctuate and/or comedo necrosis. Microcalcifications are frequently present and may show patterns of distribution similar to both low-grade and
high-grade DCIS.
DCIS of high nuclear grade is composed of highly atypical cells most often
growing in solid, cribriform or micropapillary patterns. Nuclei are large, pleomorphic, with irregular contours, clumped chromatin and very prominent nucleoli.
Mitotic figures are usually very common. This lesion shows very frequently a
comedo necrosis with abundant necrotic debris in duct lumina surrounded by a typical solid proliferation of large pleomorphic neoplastic cells. Microcalcifications
are very common and are associated with necrotic intraluminal debris.
DCIS of low nuclear grade typically shows a homogeneous and very strong
immunohistochemical staining for estrogen (ER) and progesterone (PR) receptors,
whereas it does not show HER2 overexpression. On the contrary, DCIS of high
nuclear grade is frequently negative for ER and PR and shows HER2 overexpression [16].
28
Some prognostic and predictive factors seem to be important to help to guide

the choice of therapy. Features such as young age, larger size, high nuclear grade,
presence of comedo necrosis, and positive margin status have been associated with
an increased risk of local recurrence and/or progression to invasive cancer [17]. ER
status was predictive to benefit from tamoxifen in the patients who underwent
lumpectomy and radiation therapy [18]. In the near future, other targeted drugs
against, for example, HER2 could be useful to reduce the risk of relapse and progression to infiltrating carcinoma.
Breast cancer-specific mortality among women affected by DCIS is extremely
low ranging from 1% to 2.6%. From a theoretical point of view, DCIS could not
cause the death of the affected patient. This phenomenon is due to the presence of
invasive cancer not recognized at the time of the diagnosis, or invasive recurrence
after treatment; in fact, DCIS recurs as invasive cancer in about 50% of the cases.
Studies correlating the morphologic and genetic features of breast cancer precursors have been performed using loss of heterozygosity (LOH), chromosomal
and microarray-based comparative genomic hybridization (CGH), fluorescent and
chromogenic in situ hybridization (FISH and CISH), and microarray-based geneexpression profiling.
Genomic and transcriptomic analyses have helped to unravel the complexity of
ductal carcinoma in situ (DCIS). DCIS has been shown to be a complex and heterogeneous disease, and the different molecular subtypes found in invasive breast
cancer (e.g., luminal, basal-like and HER2) are also found in DCIS.
In the early 2000s, it was suggested that low- and high-grade DCIS, and their
respective invasive counter-parts, would be fundamentally different. This concept
primarily stemmed from the observation that low-grade DCIS and low-grade invasive ductal carcinoma of no special type (NST) are often diploid/near-diploid and
harbor recurrent deletions of the long arm of chromosome 16 (16q), which are present in more than 70% of cases. On the other hand, high-grade DCIS and high-grade
invasive ductal carcinoma NST have more complex karyotypes, are usually aneuploid, and harbor multiple amplifications. Despite the higher degree of genetic
complexity observed in high-grade DCIS and high-grade invasive breast cancers,
deletions of 16q are found in less than 30% of cases.
Histologic grade is undeniably associated with type, pattern, and number of
genetic aberrations found in DCIS and invasive cancer and with their transcriptomic profiles. Many studies on the molecular aberrations found in subtypes of DCIS
suggest that ER-positive low-grade DCIS is characterized by expression of hormone receptors, lack of HER2 overexpression, and lack of expression of basal
markers. At the genetic level, these lesions have rather simple, diploid/near-diploid
karyotypes and they show, as hallmark recurrent changes, the concurrent presence
of deletion of 16q (> 70%) and gains of 1q (> 70%) and 16p (> 40%). Not uncommonly, these three genetic aberrations are the product of the der(16)t(1;16)/
der(1;16) unbalanced chromosomal translocation.
High-grade DCIS/high-grade invasive ductal carcinoma NST are more heterogeneous and can be subdivided by microarray expression profiling as luminal B,
HER2, basal-like, and molecular apocrine. They would often lack hormone recep-
29
tors, over-express HER2 and harbor HER2 gene amplification, occasionally

express basal markers, and show higher prevalence of aneuploidy, complex karyotypes, and harbor multiple amplifications.
When taken as a group, less than 30% of high-grade DCIS harbor entire deletions of 16q. However, the prevalence of loss of 16q and gain of 1q is significantly more prevalent in ER-positive high-grade DCIS (50%) than in HER2-positive
and basal-like high-grade DCIS.
These observations suggest that up to 50% of ER-positive high-grade DCIS and
invasive ductal carcinomas NST may stem from ER-positive low-grade lesions;
however, a substantial proportion of ER-positive luminal high-grade cancer may
originate de novo.
Intermediate-grade DCIS shows genetic similarities to both low- and highgrade DCIS, including gain of 1q and loss of 8p, 11q, 16q and 17p. The lines of evidence currently available suggest that the majority of these lesions may be the product of progression of ER-positive low-grade DCIS, whereas a smaller subgroup
may represent the lower end of the spectrum of DCIS with molecular aberrations
characteristic of high-grade lesions [19].
2.3.2
Lobular Carcinoma in Situ
cLCIS is discussed in Section 2.2.5. Pleomorphic lobular carcinoma in situ (pLCIS)

is the most widely recognized variant of LCIS. Its incidence is lower than the incidence of ALH and cLCIS, as well as it being common in women older than those
affected by ALH and cLCIS. On gross examination, it is impossible to see both
pLCIS and cLCIS. Microscopically, pLCIS is constituted of cells with large nucleolated nuclei (34 times the size of a lymphocyte) and with marked pleomorphism.
The nuclear features are similar to those seen in DCIS of high nuclear grade.
Mitoses may be numerous and a central comedo necrosis in the involved space is
often present. Unlike cLCIS, pLCIS may contain microcalcifications, in particular
if there is necrosis. Also pLCIS is usually negative to E-cadherin by immunohistochemistry [13].
Cases of cLCIS are uniformly positive for ER and PgR and negative for HER2
by immunohistochemistry. On the contrary, pLCIS shows negativity for ER and PR
in 34% and 38% of cases, respectively. Moreover, cases of pLCIS are highly positive for HER2 in about 15% of the cases. Finally, cases of pLCIS show higher proliferation rate (measured by Ki-67 immunostaining) and more frequent positivity to
p53 with respect to cLCIS [13].
The low incidence of pLCIS and the frequent misdiagnosis as DCIS, do not
allow us to have sufficient information on the natural history of this lesion.
Nevertheless some morphological features, such as a high degree of pleomorphism,
presence of comedo necrosis, high proliferation rate, the bulk of disease, seem to
indicate a potentially aggressive behavior of pLCIS; moreover, also the genomic
profile of pLCIS seems to suggest a more aggressive biological potential. Thus, in
the absence of large clinical outcome studies with long follow-up, it is regarded as
30
prudent to manage the cases of pLCIS as for the cases of DCIS of high nuclear
grade [13].
Genetic analyses have revealed that cLCIS harbors recurrent deletions of 16q
and gains of 1q and the der(16)t(1;16)/der(1;16) unbalanced chromosomal translocation. The chromosomal aberrations found in cLCIS are a prevalence of losses of
16q, 16p and 17p and gains of 6q.
The target gene of 16q loss in cLCIS is CDH1, which maps to 16q22.1 and
encodes E-cadherin, a protein involved in cell-cell adhesion and in cell cycle regulation through -catenin/Wnt pathway. This gene was first reported as an invasion/metastasis-associated gene and several lines of evidence suggest that it may
also have tumor suppressor properties. CDH1 germ-line mutations have recently
been linked to some forms of familial lobular carcinoma [20].
E-cadherin is reduced or absent in the vast majority of cLCIS, whereas it is
reported to be expressed in normal or only slightly reduced levels in DCIS and
other types of invasive breast carcinomas.
The mechanisms of CDH1 gene inactivation in cLCIS are not restricted to physical loss of 16q; truncating and missense mutations and gene promoter methylation
have also been described in these lesions. Understanding the molecular aberrations
of the E-cadherin-catenin axis has provided additional ancillary markers for the differentiation of LCIS and solid low-grade DCIS, including -catenin and catenin
p120 [21].
Concurrent identical truncating CDH1 mutations in cLCIS and adjacent ILC
have been demonstrated, providing strong evidence for the role of CDH1 gene
inactivation in the pathogenesis of lobular lesions, as well as positioning cLCIS as
precursor of ILC. Therefore, ALH and cLCIS should not only be considered risk
indicators but also non-obligate precursors of invasive carcinoma.
pLCIS is a precursor of ILC, given the evidence that demonstrates that pLCIS
and pleomorphic ILC harbor remarkably similar genetic aberrations and that both
have the characteristics of lobular carcinomas, including 16q loss, 17p loss, 1q
gain, and loss of E-cadherin expression.
pLCIS does harbor deletions of 16q and gain of 1q; however, these lesions show
additional genetic aberrations, including amplification of key oncogenes, deletion
of 8p and 13q, and gain of 8q, which may account for their higher nuclear grade
and reported more aggressive clinical behavior. A recent CGH analysis of a series
of pLCIS and cLCIS confirmed the similarities between these lesions at the genomic level and suggested that nonapocrine and apocrine pLCIS may be distinct levels
of genetic complexity. While nonapocrine pLCIS shows levels of genetic instability similar to those observed in cLCIS, apocrine pLCIS display more and specific
genomic changes, including amplification of 17p11.217q12 and 11q.13.3, gain of
16p, and loss of 11q and 13q [22].
The molecular evidence available to date suggests that pLCIS is a genetically
advanced lesion and is likely to not be a comparable precursor of pleomorphic ILC.
Further studies are required to define the diagnostic criteria for apocrine and nonapocrine pLCIS and the actual risk of progression conferred by the different types
of pLCIS.
2.4
31
Invasive Breast Carcinoma: Histological Classification
The WHO classification of invasive breast carcinoma is reported in Table 2.1 [15].
The invasive breast carcinoma NST, also known as ductal carcinoma NST, is the
most common type, comprising between the 40% and 75% of cases in the various
published series [23]. The remaining invasive breast cancers are classified as special type breast carcinomas; the most frequent histological types are lobular carcinoma (5% to 15% of cases), tubular carcinoma (1% to 2.5% of cases), mucinous
carcinoma (1% to 5% of cases), cribriform carcinoma (0.5% to 3% of cases),
medullary carcinoma (about 1% of cases), invasive micropapillary carcinoma
(1.2% to 2.3% of cases), metaplastic carcinoma (about 1% of cases), and apocrine
carcinoma (0.5% to 3% of cases). The rare types comprehend invasive papillary
carcinoma, secretory carcinoma, carcinoma with neuroendocrine features, lipid and
glycogen-rich carcinomas, oncocytic carcinoma, salivary gland-like tumors, and
skin adnexal type tumors [15].
An invasive breast carcinoma is classified as special type when more than 90%
of the neoplasia shows the typical morphological features of that special type. When
a breast cancer shows two different morphological aspects and none of these histological aspects is represented by more than 90%, the tumor is classified as mixed.
The most frequent mixed types of invasive breast cancers are represented by a combination of an NST carcinoma and lobular carcinoma, an NST carcinoma and
tubular/cribriform carcinoma, or an NST carcinoma and mucinous carcinoma [15].
2.4.1
NST Carcinoma (Ductal Carcinoma NST)
It is a malignant epithelial neoplasia that derives from the TDLU. Its frequency
increases with the increase of patient age and it is very rare before the age of thirty in patients without a family history of breast cancer. Male breast carcinoma may
be seen, even if the female/male ratio for this tumor is about equal to 100/1. On
gross examination, NST carcinoma looks like as a firm, well to poorly defined,
sometimes stellate nodule. The size at presentation may range from a few millimeters to many centimeters. Microscopically it is composed of malignant epithelial
cells with different grades of atypia arranged in tubules, trabeculae or sheets. The
nuclear atypia, the extension of tubular pattern, and the frequency of mitoses vary
with the degree of differentiation. The prognosis of a patient affected by invasive
NST carcinoma depends on traditional prognostic factors such as histologic grade,
lymph node stage, tumor size, lymphovascular invasion, as well as the effectiveness of therapy [15].
2.4.2
Lobular Carcinoma
The mean patients age at presentation is 63years. In these last years there is some
evidence to suggest that the incidence of this invasive carcinoma subtype is
32
Table 2.1 Histological classification of invasive breast carcinoma
Invasive carcinoma of no special type (NST)
Pleomorphic carcinoma
Carcinoma with osteoclast-like stromal giant
cells
Carcinoma with choriocarcinomatous features
Carcinoma with melanotic features
Invasive lobular carcinoma
Classic lobular carcinoma

Solid lobular carcinoma
Alveolar lobular carcinoma
Pleomorphic lobular carcinoma
Tubulolobular carcinoma
Mixed lobular carcinoma
Tubular carcinoma
Cribriform carcinoma
Mucinous carcinoma
Carcinoma with medullary features
Medullary carcinoma
Atypical medullary carcinoma
Carcinoma with aprocrine differentiation

Carcinoma with signet-ring-cell differentiation
Invasive micropapillary carcinoma
Metaplastic carcinoma of no special type
Rare types
Carcinoma with neuroendocrine features
Low-grade adenosquamous carcinoma

Fibromatosis-like metaplastic carcinoma
Squamous cell carcinoma
Spindle cell carcinoma
Metaplastic carcinoma with mesenchynal
differentiation
Chondroid differentiation
Osseous differentiation
Other types of mesenchymal differentiation
Mixed metaplastic carcinoma
Myoepithelial carcinoma
Neuroendocrine tumor, well differentiated
Neuroendocrine carcinoma, poorly differentiated (small cell carcinoma)
Carcinoma with neuroendocrine differentiation
Secretory carcinoma
Invasive papillary carcinoma
Acinic cell carcinoma
Mucoepidermois carcinoma
Polymorphous carcinoma
Oncocytic carcinoma
Lipid-rich carcinoma
Glycogen-rich clear cell carcinoma
Sebaceous carcinoma
Salivary gland/skin adnexal type tumors
Cylindroma
Clear cell hidradenoma
33
increasing at a faster rate than other types of breast cancer. Macroscopically, the
appearance of this tumor is variable, from a gray or white, firm, well circumscribed
mass to a not well-defined area of thickening. The average tumor size at presentation is 2.4cm. Histologically, lobular carcinoma may be subdivided in the following variants: classical, alveolar, solid, tubulo-lobular, pleomorphic, and mixed. The
neoplastic cells are typically uniform, non-cohesive, with regular, round or oval,
eccentrically placed nuclei with small nucleoli. Only in the pleomorphic variant,
there is a great pleomorphism of the cells that, anyway, show single files and targetoid periductal arrangement, as in the classical subtype. The majority (75%) of lobular carcinoma are classified as grade 2, 15% as grade 1, and only 10% as grade 3
[24]. LCIS is associated with invasive lobular carcinoma (ILC) in about 70% of
cases. ILC is immunohistochemically negative to E-cadherin in more than 85% of
cases [21, 25]. The histologic variant of lobular carcinoma seems to be important
for the prognosis; the tubule-lobular variant has a very low risk of local and distant
recurrences, whereas the solid variant has high risk of regionally and distant sites
recurrences (82 and 54%, respectively). Metastatic pattern of ILC differs from that
of invasive carcinoma NST. ILC frequently metastasizes to bone, serosal cavity,
gastrointestinal tract, uterus, ovary, and meninges, while invasive carcinoma NST
shows a preferential tumor extension to the lung. ILC does not have a different
prognosis with respect to invasive NST carcinoma; also in this type of invasive
breast tumor, the prognosis depends on traditional prognostic factors.
2.4.3
Tubular Carcinoma
The mean age of the patients ranges from 58 to 64 years. On gross examination,
tubular carcinoma is a hard nodule with a stellate appearance, the size usually ranging from 1.0 to 2.0 centimeters. Microscopically, it is entirely composed by angulated tubules with a single layer of epithelial cells often showing apical snouts.
More than 90% of the tumor must be composed by these tubules to classify it as
tubular carcinoma. By definition, tubular carcinoma is of histological grade 1 as it
scores 1 for tubule formation, 1 or rarely 2 for nuclear atypia, and 1 for number of
mitoses [26]. Even if nodal metastases can be detected in 1219% of the cases
(related with tumor size and generally involving only one or two nodes), the prognosis of this neoplasia is extremely good with 5-year and overall survival rates for
patients with this tumor equal to 94% and 88%, respectively [27].
2.4.4
Mucinous Carcinoma
Mucinous carcinoma is more frequent in postmenopausal women, with a mean age

of 59 to 71 years. On macroscopic examination it appears as a soft, well circumscribed
mass with a gelatinous aspect on a cut surface. The characteristic histological features are nests, trabeculae, acini, or sheets of neoplastic cells dispersed in a pool of
extracellular mucin. Intracellular mucin may also be present with the presence of some
34
signet-ring cells. Mucinous carcinoma may have nodal metastases in 14% of cases
and it principally depends on the size; for example, tumors less than 1cm in maximum size have a very low risk (less than 4%) to have lymph node metastases. The
prognosis is very good with an overall 5-year survival of 8086% [27].
2.4.5
Cribriform Carcinoma
This tumor arises in peri-postmenopausal women (average age ranges from 53 to

58 years). At presentation cribriform carcinoma generally has a mean size greater
than 2.0cm and, on gross examination, it is a moderately well-defined mass with a
stellate/gray cut surface. Microscopically, the neoplastic cells are organized in a
cribriform pattern and have a low or, rarely, an intermediate cytonuclear grade. As
with tubular carcinoma, these invasive tumors are of histologic grade 1 [28].
Lymph node metastases may be present in a percentage of cases similar to that
reported for tubular carcinoma with only one or two metastatic nodes. The prognosis of the patients affected by invasive cribriform carcinoma is excellent with a 5year survival rate of 100% [28].
2.4.6
Medullary Carcinoma
The average age of the patients affected by this cancer is 52 years, but 49% of them
are less than 50 years old. Macroscopically, medullary carcinoma is a well-defined
and circumscribed mass with a gray/tan cut surface; its average size is greater than
2.0cm. This tumor is characteristically composed by pleomorphic nuclear grade 3
cells, arranged in a syncytial growth pattern for more than 75% of the nodule, without glandular structures, and with a diffuse, moderate to marked lymphoplasmacytic infiltrate which is present into and all around the tumor. To classify an invasive
breast cancer as a medullary carcinoma, all the histologic features cited above must
be present. Medullary carcinomas are of histologic grade 3 [29]. There is no consensus regarding the prognosis of medullary carcinoma; this is probably caused by
the problematic reproducibility in the diagnosis of this lesion. Nevertheless, it has
been recorded that node-negative patients with medullary carcinoma have a better
prognosis than node-negative patients with an NST tumor of histologic grade 3 (10years survival rate of 84% versus 63%).
2.4.7
Invasive Micropapillary Carcinoma
This tumor can arise in all ages (from 28 to 92 years), with an average age of 53 to
59 years. Macroscopically, it is a gray/white, stellate nodule with a mean size generally greater than 2.0 cm. Histologically, invasive micropapillary carcinoma is
composed of nests of eosinophilic cuboidal/columnar cells surrounded by an arti-
35
factual clear space. Characteristically, the neoplastic cells display a reverse polarity, with the apical pole of neoplastic cells in contact with the artifactual empty stromal spaces that surround the clusters of neoplastic cells. This lesion is typically of
histologic grade 3 (58% to 82%) or grade 2 (18% to 33%) and shows lymphovascular invasion in the majority of cases (from 63% to 76% in different series) [30].
Lymph node metastases have been recorded in 69% to 95% of cases. Despite some
discordant data, the prognosis of patients affected by invasive micropapillary carcinoma seems to be similar to prognosis of patients affected by NST cancer when
matched for other prognostic features [31]. However, skin involvement seems to be
correlated with a worse prognosis in this type of invasive breast cancer.
2.4.8
Metaplastic Carcinoma
This neoplasia usually arises in the sixth and seventh decades of life as a palpable
breast mass or, sometimes, as inflammatory carcinoma. On gross examination, metaplastic carcinoma is a solid mass greater than 3.0cm, which typically has a tan/white
cut surface; cystic areas may be present. Microscopically, metaplastic carcinoma is
composed of spindle cells in about 70% of cases; the cells show moderate/severe nuclear atypia, with a conspicuous number of mitoses, and are arranged in fascicles,
possibly with a storiform pattern [32]. Many times, a squamous differentiation and/or
an association with intraductal carcinoma or NST invasive carcinoma are present. Other mesenchymal components, including chondroid, osseous, rhabdomyoid and even
neuroglial differentiation, may be seen. Metaplastic carcinomas are generally of histologic grade 3, but the prognostic value of grading in metaplastic carcinoma is uncertain. This type of tumor is typically negative for ER, PR, and HER2 [33]. Lymphnode metastases are less frequent in metaplastic cancers than in invasive carcinoma
NST of similar size and grade. However, as in other triple-negative breast cancers,
distant metastases, preferentially brain and/or lung metastases, can be found at the
time of diagnosis. Metaplastic breast cancers have lower response rates to conventional adjuvant chemotherapy and a worse clinical outcome than those of other types
of triple-negative breast cancers.
2.4.9
Apocrine Carcinoma
This tumor has clinical characteristics similar to those of NST invasive carcinoma.
Also on gross examination, apocrine carcinoma lacks specific features. Microscopically, the neoplastic cells show typical apocrine differentiation with abundant
eosinophilic granular cytoplasm and large nuclei with prominent nucleoli. Many studies have shown no difference in outcome, including survival, between apocrine carcinomas and NST invasive cancers, when matched for standard prognostic parameters [34]. The importance of diagnosing an apocrine carcinoma may be in the potential for the development of therapeutic strategies directed against the increased androgen signaling that seems to be common in this type of cancer.
36
2.5
Prognostic and Predictive Factors of Early Invasive

Breast Carcinoma
2.5.1
Grading
All invasive carcinomas (NST and special types) are morphologically subdivided
according to their degree of differentiation which reflects how closely they resemble normal breast epithelium. To objectively assess the histological grade, the original methods by Patey & Scarff [35] and Bloom & Richardson [36], have been
modified by Elston & Ellis [37]. According to this method, the following three
tumor features are evaluated to assess the histological grade: tubule formation, as
expression of glandular differentiation; nuclear pleomorphism; and mitotic counts.
A numerical scoring system of 1 to 3 is used to separately evaluate each feature.
Table 2.2 shows how to assign each score to each feature in order to determine the
final grading by summing all the scores. Moreover, Table 2.3 shows some score
thresholds for mitotic counts with the corresponding diameters of the high power
field (HPF) of the microscope. It is necessary to determine the diameter of a HPF,
because it varies with the different oculars of the microscope. The three values
obtained with the evaluation of each feature are added together to produce scores
of 3 to 9, to which the histological grade is assigned as follows: 35 points, well
differentiated (grade 1); 67 points, moderately differentiated (grade 2); 89 points,
poorly differentiated (grade 3). To obtain an optimal evaluation of histological
grade, a high quality of tissue preservation and of histological section, in terms of
cutting and staining, is required. Histological grade is a powerful prognostic factor.
In unselected breast cancer series, the overall survival is significantly better in
patients with grade 1 tumors (about 75% of patients alive after more than 20 years
from the diagnosis), than in those with grade 2 or grade 3 tumors (about 55% and
45% of patients alive after more than 20 years from the diagnosis, respectively).
For these reasons, histological grade should be included as a component of the minimum dataset for histological reporting of early invasive breast cancer.
2.5.2
Tumor Size
Tumor size is indispensable to determine the pathological T in TNM system published by American Joint Committee on Cancer (AJCC)/Union for International
Cancer Control (UICC), which is the most widely used system for staging breast
cancer [15]. For this purpose, the evaluation of tumor size is performed on the gross
and microscopic examination. T classification depends on the maximum size of
invasive carcinoma; concomitant DCIS should not be considered. If multiple areas
of invasion are present, T classification is based on the largest focus. A small cancer and some special types of breast carcinomas, such as the classical variant of
ILC, are often best evaluated by measuring size on glass slides. Increasing tumor
size is independently associated with a worsening survival, with a 10-years cumulative survival of 0.9 in tumors less than 1cm in maximum diameter, against a 10-
37
years cumulative survival of 0.5 in tumors more than 2.5cm in maximum diameter [38]. For these reasons, the size of invasive carcinoma should always be specified in the histological report of early invasive breast cancer.
2.5.3
Lymph Node Status
Lymph node status is the most important single prognostic factor for all except a
small group of breast cancers that appear to metastasize hematogenously without
the involvement of nodes. For example, basal-like carcinomas, a molecular subtype
with a poor prognosis, is rarely associated with an extensive nodal involvement; for
the patients affected by this cancer, other prognostic markers are more important
than nodal staging. Nodal metastases are strongly correlated with tumor size and
the number of invasive carcinomas [38]. According to the TNM system, a lymph
node can be macrometastatic (presence of a metastatic deposit > 0.2 cm in size:
N1), micrometastatic (> 0.02 cm, up to 0.2 cm; or > 200 cells in a single nodal
cross-section: N1(mi)), or can show isolated tumor cell clusters (ITCs, no larger
than 0.02cm, or < 200 cells in a single nodal cross sections: N0(i+)) [15]. While
Table 2.2 Histological grade in invasive breast tumors: method for assessment
Feature
Score
Tubule and gland formation

Majority of tumor (> 75%)
Moderate degree (1075%)
Little or none (< 10%)
Nuclear pleomorphism
Small, uniform nuclei
Moderate increase in size and polymorphian
Marked variation
Mitotic counts
Dependent on microscope field area
13 (see Table 2.3)
Table 2.3 Histological grade in invasive breast tumors: score thresholds for mitotic counts
Field diameter
(mm)
Mitotic count (score)

1
0.40
59
10
0.45
611
12
0.50
814
15
0.55
917
18
0.60
10
1120
21
0.65
12
1324
25
38
the presence of macrometastatic lymph nodes and the number of positive nodes are
strongly related to prognosis, the presence of micrometastases or ITCs seem to
have actually a limited impact on prognosis, estimable in less than 3% at 5 and 10
years when compared with node-negative women [39]. Moreover, positive nodes
are a marker of distant dissemination and surgical removal of lymph nodes does not
appear to have a major effect on survival [40]. Finally, even if negative nodes are a
favorable prognostic factor, 1030% of patients will eventually develop distant
metastases.
2.5.4
Lymphovascular Invasion
Lymphovascular invasion (LVI) can be present in up to 50% of invasive breast carcinomas, even if in medical literature, the percentages of breast cancer with LVI are
different, principally due to differences in stringency of diagnosis. With this argument, it is necessary to underline that the application of strict criteria for determination of the presence of LVI is advisable. The assessment of LVI should be concentrated on breast parenchyma around the tumor and not within it. LVI is microscopically seen as small groups of neoplastic cells within clear spaces lined by
endothelium. Sometimes fixation shrinkage artifact may mimic LVI, especially
when spaces arise around nests of neoplastic cells; moreover, DCIS extending outside the infiltrating tumor could be mistaken for LVI. In all these cases, the
immunohistochemistry may be helpful by staining endothelial (CD31 and D240)
and myoepithelial (calponin, p63, etc.) cells. LVI is generally correlated to locoregional lymph node involvement, and it is also an important independent prognostic
factor, very useful especially in node-negative patients [41]. Moreover, LVI can
also predict local recurrence following breast conservation surgery, as well as flap
recurrence after mastectomy. Finally, LVI in the dermis is a particularly poor prognostic factor, being strongly associated with local recurrence and distant metastases. The presence/absence of LVI should be included as a component of the minimum dataset for histological reporting of early invasive breast cancer.
2.5.5
ER and PR Expression
ER is a nuclear transcription factor that, when activated by the hormone estrogen,

stimulates the growth of normal breast epithelial cells [42]. PR is regulated by ER,
so its presence indicates that the estrogen-ER pathway is intact and functional. If
expressed, PR is activated by the hormone progesterone, which also stimulates the
cellular growth. Invasive breast carcinomas frequently (6580%) express ER and
PR, especially if they are grade 1 or 2 [43]; in women affected by these carcinomas,
the hormone estrogen, which binds ER present in the nuclei of neoplastic cells, can
stimulate their proliferation; this phenomenon, of course, is detrimental. ER and PR
tests are performed by immunohistochemistry which is a sensitive, specific, and
inexpensive method that can be performed on formalin-fixed paraffin embedded
39
tissue sections [43]. The nuclear immunohistochemical staining of ER and PR is

evaluated and expressed as a proportion of positive invasive neoplastic cells with
respect to all the invasive neoplastic cells, the result ranging from < 1% to 100%
positive cells. The evaluations of ER and PR should be performed on the entire
invasive breast carcinoma present in the glass slide. Many clinical studies and randomized trials have shown that ER, in combination with PR, is a strong predictive
factor of response to hormonal therapies such as tamoxifen and aromatase
inhibitors. The former binds ER and blocks estrogen-stimulated growth, while the
latter suppresses the production of estrogen. There is a direct correlation between
the likelihood of response to hormonal therapies and the level of ER and PR expressions [43]. Nevertheless, also tumors with very low levels of ER and PR may
respond well to the hormonal therapies [44]. ER-positive and PR-positive tumors
are associated with the best rate of response (about 60%). ER-negative and PR-negative tumors are essentially unresponsive [43]. The remaining two discordant phenotypes of tumor are associated with intermediate response rates, although there is
debate as to whether ER-negative and PR-positive tumors actually exist. All the
pathological reports with the diagnosis of early invasive breast carcinomas should
contain the percentage of neoplastic cells positive for ER and PR.
2.5.6
Ki67 Expression
Ki67 is a nuclear antigen expressed in all phases of the cell cycle other than the G0
phase. This antigen can be reliably assessed by using immunohistochemistry; for
this purpose, MIB1 is the most widely used antibody. The nuclear immunohistochemical staining of Ki67 is evaluated and expressed as the percentage of positively staining neoplastic cells among the total number of invasive neoplastic cells, the
result ranging from < 1% to 100% positive cells; staining intensity is not relevant.
The evaluation of Ki67 should be performed on the invasive edge of the tumor (i.e.,
the neoplastic areas in which there is a highest positivity); if clear hot spots (i.e.,
foci with maximum positivity) are present, they should be considered in the count
[45]. Many retrospective studies have demonstrated the prognostic value of Ki67,
but the cut-off values to designate low and high Ki67 neoplastic populations
differ widely [46]. Some data suggest that Ki67 predicts neoadjuvant and adjuvant
chemotherapy response in ER-negative tumors; in these cases a straightforward
hypothesis is that the higher rate of response to chemotherapy observed in patients
with ER-negative tumors could be due to the consistently higher values of Ki67 in
these tumors. If so, Ki67 levels may be very helpful to select those patients most
likely to benefit from chemotherapy [47]. Moreover, a randomized trial by PenaultLlorca et al. has demonstrated that a high level of Ki67 may be predictive of benefit from adding docetaxel to fluorouracil and epirubicin chemotherapy as adjuvant
treatment for patients with ER-positive tumors. According to the 2009 St. Gallen
Consensus Conference, invasive breast cancer can be subdivided in the following
three groups of Ki67 positivity: low (Ki67 value 15%), intermediate (Ki67
value > 15% and 30%), and high (Ki67 value > 30%) [48]. At the 2011
40
St. Gallen Consensus Conference, Ki67 value was considered important, together
with ER, PR, and HER2, to subdivide a luminal A tumor phenotype from a luminal
B one, and 14% was established as the suitable cut-off value [49]. Nevertheless, all
these data suggest that the percentage of invasive neoplastic cells positive for Ki67
should be indicated in the histological report of early invasive breast cancer.
2.5.7
HER2 Status
The HER2 proto-oncogene is located on chromosome 17 and encodes the epithelial growth factor receptor of type 2; this receptor is positioned on the cytoplasmic
membrane of normal breast epithelial cells and consists of an extracellular domain,
an intramembranous part, and an intracellular domain. HER2 is very important in
the growth and differentiation of the normal epithelial cells. Many studies demonstrate that the HER2 gene is amplified in about 15% of tumors in patients with primary breast cancer and that amplification is strictly correlated with a very high
expression of the receptor. In the clinical practice, HER2 status is determined by
immunohistochemistry and/or in situ hybridization (ISH) techniques, such as fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH),
and silver in situ hybridization (SISH). These methods provide results that are
essentially equivalent in terms of clinical efficacy [50]. Generally, immunohistochemical and ISH determinations are used in a complementary manner: first of all
the less expensive immunohistochemistry is applied, then, if the result is equivocal
(i.e., positive 2+), one of the above mentioned ISH methods are utilized in order to
demonstrate an eventual gene amplification. Both the immunohistochemical and
ISH determinations are performed by using standardized tests, FDA approved, that
assure an optimal reproducibility of the results. The evaluation of HER2 immunohistochemical staining can furnish the following results: negative (0), no staining;
negative (1+), partial, faint/moderate membrane staining in more than 10% of neoplastic cells; positive (2+), complete, faint/moderate membrane staining in more
than 10% of neoplastic cells; positive (3+), complete, strong membrane staining in
more than 10% of neoplastic cells. The evaluation of ISH glass slides, performed if
a result positive (2+) is obtained by immunohistochemistry, furnishes a dichotomous result: presence of gene amplification or absence of gene amplification. This
result is principally determined by the ratio between the number of signals of HER2
gene and the number of signals of chromosome 17 centromere; if this ratio is
greater than 2, there is gene amplification. If the result of the ratio ranges from 1.8
to 2.2, it is advisable to repeat the evaluation more than once to classify the case as
amplified or not amplified. HER2 status is a prognostic and a predictive factor.
Patients affected by HER2 positive breast cancers (i.e., positive 3+ by immunostaining or positive 2+ by immunostaining with gene amplification by ISH) have a
worse prognosis with respect to patients with HER2 negative breast cancers. This
is true also for patients with small size breast carcinomas [51]. Nevertheless,
numerous studies, in the last 1015 years, have demonstrated that HER2 positive
invasive breast cancers respond favorably to therapies that specifically target the
41
HER2 receptor (e.g., trastuzumab, lapatinib, pertuzumab). The main reason for
assessing the HER2 status today is to select patients for this type of targeted therapy. The HER2 status should be included as a component of the minimum dataset
for histological reporting of early invasive breast cancer.
Since biomarkers (i.e., ER, PR, Ki67, and HER2) are targets and/or indicators
of highly effective therapies against invasive breast cancer, accurate assessment is
essential and mandatory. Every pathology laboratory should provide accurate and
reproducible results, either having dedicated staff (i.e., technicians, biologists,
pathologists) for these assessments, and performing intralaboratory quality controls, and participating in interlaboratory ones [44, 45, 50].
2.6
Breast Cancer Genomics and Expression Profiling
It is known that altered gene expression is fundamental to the neoplastic process. A

few years ago, genomic and expression microarray technology, which enables us to
simultaneously examine changes in thousands of gene, was used to subclassify
breast cancer and establish signatures for the prediction of good versus bad and
responsive versus non-responsive cancer [52].
Proposals for identifying and substratifying patients using more clinically useful
grading systems (i.e., stratifying intermediate grade into low risk/grade 1 and high
risk/grade 3) and those with tumors that are likely to recur (recurrence scores) [53]
has been suggested.
There is still much to do in terms of standardization of platforms, use of appropriate quality controls, statistical methods for analysis and cut-offs used to separate
cancers into different groups but, nevertheless, the technology holds much promise
for adding to and extending the current classification of breast cancer to help to
optimize patient management.
Comparative genomic hybridization (CGH) and microarray-based comparative
genomic hybridization have demonstrated that breast cancers are decidedly heterogeneous at the genomic level, and there is a correlation between the pattern of gene
copy-number aberrations and histological grade and estrogen receptor (ER) expression in both ductal carcinomas in situ (DCIS) and invasive carcinomas NST. Grade
1 invasive carcinomas NST are usually diploid or near-diploid, and have been
shown to harbor recurrent deletions of 16q (> 85%), gain of 1q (60%) and gains of
16p (40%), which may result from an unbalanced chromosomal translocation
involving chromosomes 1 and 16 in up of 40% of cases [54]. Grade 3 cancers, however, are remarkably heterogeneous, often aneuploid, but deletions of 16q are found
in only approximately 30% of cases, and are almost restricted to ER-negative
lesions. In fact, approximately 50% of grade 3 ER-positive cancers harbor the typical pattern of gene copy-number aberrations found in grade 1 tumors [55]. This has
led to the hypothesis that the progression from low- to high-grade breast cancer is
an uncommon biological phenomenon, which may be restricted to tumors of ERpositive phenotype. Intermediate-grade DCIS and grade 2 invasive carcinoma NST
harbor more complex genomes than grade 1 lesions; however, deletions of 16q and
42
gain of 1q are found in a substantial number of cases.

Similarly to the low-grade DCIS and invasive carcinomas NST, lobular carcinomas also harbor deletions of 16q, gains of 1q and 16p. There is evidence to suggest that the differences between low-grade ductal and lobular proliferations is the
target gene of 16q deletions; unlike the low-grade ductal proliferations for which
the target gene of 16q deletions has not been yet identified, lobular lesions have
CDH1 as the target gene [56]. This gene encodes E-cadherin and the loss of this
adhesion molecule expression has been shown to lead to the characteristic discohesiveness and patterns of invasion and metastasis of lobular carcinoma [57].
In addition to the CDH1 loss of function and lobular phenotype, additional
genotypic-phenotypic correlations have been recorded in the various types of breast
cancer. For example, secretory carcinomas and adenoid cystic carcinomas [58]
have been shown to harbor recurrent chromosomal translocations, namely t(12;15)
and t(6;9), respectively. These translocations lead to the formation of the chimeric
fusion gene ETV6-NTRK3 and MYB-NFIB [58]. Moreover, micropapillary [59]
and mucinous [60] carcinomas have been shown to have distinct patterns of gene
copy-number aberrations when compared to grade- and ER-matched invasive carcinoma NST.
Complete genomic sequencing studies of breast cancer have demonstrated that
they are heterogeneous in terms of the mutations, structural variations and copynumber aberrations they show. In fact, few mutations have been shown to be highly recurrent (e.g., TP53, PIK3CA and PTEN) in invasive carcinoma NST. With the
clinically defined subgroup of breast cancers (i.e., ER-positive/HER2-negative,
HER2-positive and ER-negative/HER2-negative), a great degree of heterogeneity
in terms of the patterns and types of gene copy-number aberrations, mutations and
somatic rearrangements has been documented.
The association of gene alterations with prognosis and response to therapy in
breast cancer is known in the literature. Many genes already correlate with known
biomarkers (ER; HER2; Ki67), and the behavior of cells or tumors is determined
by coordinated expression of many genes; it is impossible that the analysis of one
or a few genes can accurately predict the clinical behavior beyond what is already
known.
The analysis of gene expression using DNA microarrays is used to identify
novel prognostic and predictive factors, and a number of diagnostic tests based on
the assessment of patterns of gene expression in tumors are commercially available.
The use of microarray analysis makes it possible to assess the level of expression
of all genes in the human genome. The analysis of global gene-expression patterns
may facilitate the prediction of tumor behavior, including the risk of developing
distant metastases and response to specific therapies.
An important advantage of microarray analysis is that specific properties of
cells can be recognized by the expression level of a large set of genes. This has been
defined as expression signatures or multigene predictor. A gene-expression signature can be defined by the cell type in which its component genes are expressed
or by the biological process in which its component genes are known to function.
Currently, gene-expression profiles based on microarrays or multigene reverse
43
transcription-polymerase chain reaction (RT-PCR) represent the most advanced

genomic technology, with respect to the application to clinical practice.
Through the gene-expression profile, it has been possible to subdivide breast
carcinomas in two categories: ER-positive and ER-negative [61].
The ER-positive group is characterized by the expression of many genes specific to breast luminal cells, whereas most of the ER-negative tumors express genes
characteristic of myoepithelial cells.
From these two categories, it is possible to characterize with distinct clinical
outcomes further subgroups of breast carcinomas: basal-like type tumors (ER-negative tumors expressing myoepithelial/basal gene such as keratin 5, 14 and 17);
HER2-like tumors (ER-negative tumors that over-express the HER2 gene); luminal
A and luminal B (both ER-positive tumors clustering together) [61].
Gene-expression profiling has been applied to breast carcinoma prognosis and
has identified a 70-gene and 76-gene prognosis signature [52, 61]. The genomic
high-grade and genomic low-grade groups of tumor can be acknowledged on
the basis of a histological grade-related signature. In addition, a RT-PCR 21-geneexpression profile for prognosis in patients with tamoxifen-treated node-negative
breast cancer has been identified [62]. Probably the most promising and clinically
useful area for the application of microarray analysis is the prediction of response
to treatment, including chemotherapy [63], radiation and hormonal therapy. The
prognostic gene-expression profiles that can be used in clinical practice are: 70gene signature, genomic grade index (GGI), and 21-gene recurrence score.
70-gene prognosis signature (e.g., MammaPrint) has been developed as a
microarray-based test that can be used to determine the prognosis of patients
with stage 1 or 2, node-negative invasive breast cancer of tumor size < 5.0cm.
This test classifies tumors into good and poor prognosis, which is an independent predictor of distant metastasis [52].
GGI is a gene expression signature developed to better define histologic grade
assessment and a strong prognostic factor in ER-positive disease. This signature
seems to accurately classify not only histological grade 1 and 3 tumors into GGI
grade I and III, respectively, but can also stratify cancers with histological grade
2 into grade 1-like, which have a low frequency of distant relapses, and grade
3-like, which have a clinical behavior similar to that of tumors with histological grade 3.
The 21-gene recurrence score is a qRT-PCR-based signature based on the
expression of 21 genes that can be applied to RNA extracted (e.g., Oncotype
DX). The 21-gene recurrence score is a mathematical function developed to
predict the risk of distant relapse at 10 years for patients with ER-positive,
lymph node-negative breast cancers [62]. It is a continuous variable and an
independent prognostic factor for patients with ER-positive, node-negative
breast cancer and treated with adjuvant endocrine therapy [62]. On the basis of
this, patients can be classified into three categories, including low risk, intermediate risk and high risk, which equate with 10-year relapse rates of 7%, 14% and
30%, respectively. The 21-gene recurrence score also correlates with benefit
from chemotherapy in ER-positive breast cancers.
44
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The Breast Unit and the Organization

of Health Care
Riccardo Masetti, Gianluca Franceschini, Daniela Terribile,
and Alba Di Leone
3.1
Introduction
Breast cancer is acknowledged as an international priority in health care. It is

currently the most common cancer in women worldwide, with demographic
trends indicating a continuous increase in incidence. Only in the European
Union, it is estimated that by 2020 there will be approximately 372,000 new
cases of breast cancer per year and 103,000 deaths [1].
The enormous burden placed by this disease both on the population and on
health care systems explains the 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.
The observation, confirmed in many studies, that being treated by coordinated teams of specialists from various fields of oncology, specifically trained
in breast diseases may improve survival rates and patients quality of life, has
progressively opened the way to a multidisciplinary approach in breast care
[29]. 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.
The present chapter reviews the lines of development of this multidisciplinary model of breast cancer care and analyzes the requirements of a highquality breast unit, its potential advantages and the many open issues that still
require proper definition and implementation.
R. Masetti ()
Multidisciplinary Breast Center, Catholic University of Rome,
Rome, Italy
e-mail: riccardo.masetti@rm.unicatt.it
Updates in Surgery
47
R. Masetti et al.
48
3.2
The History of Breast Unit Development
The concept of streamlining the evaluation and management of patients with

diseases of the breast through a comprehensive program is not new. In the
USA, as early as 1931, Dr. Cusham D. Hagensen developed a clinical subspecialty in breast disease, and in Europe, Charles-Marie Gros organized a medical clinic dedicated to breast diseases in Strasbourg in 1960 [10, 11]. But it
was not until 1979 that the first free-standing multidisciplinary facility The
Van Nuys Breast Center was founded in California by Melvin J. Silverstein,
opening the way to a cultural change in the management of breast diseases
and initiating a worldwide debate on the importance of a collaborative
approach in breast care [12].
At the First European Breast Cancer Conference in Florence in October
1998, a Statement was issued declaring that all women across Europe should
have access to fully equipped, dedicated Breast Units [13]. Shortly after, a
position paper was published by the European Society of Mastology (EUSOMA) on the standards required for the creation of high-quality breast units
across Europe [14, 15].
The European Parliament (EP) issued two resolutions on breast cancer in
the European Union (EU) in 2003 and 2006 respectively, calling on the EU
member states for the establishment of a network of certified multidisciplinary
breast centers essentially meeting the core criteria set by EUSOMA [15, 16].
Similar efforts were initiated also in the United States by the American
College of Surgeons who in 2006 developed the National Accreditation
Program for Breast Centers (NAPBC) [17], and by the Senologic International
Society (SIS) who also approved a voluntary accreditation program for its
worldwide affiliated Societies [18].
In 2010, the EP adopted a further Written Declaration on the Fight
Against Breast Cancer in the European Union, calling for measures to ensure
the provision of multidisciplinary specialist breast units and the development
of a certification protocol in accordance with the EUSOMA guidelines by
2016 [19].
In Italy, as a response to the call of the EP, a Senate Health Commission in
2010 recommended to activate and certify a proper network of breast units
and consequently, in 2012, the Italian Ministry of Health created a Working
Group that is currently developing uniform guidelines to assist regional
governments in the implementation of this task [20, 21].
3.3
The Requirements of a Breast Unit
The EP has indicated that the creation of breast units in all countries of
Europe, including Italy, should refer to the EUSOMA guidelines [22].
Such guidelines indicate that a specialist multidisciplinary breast unit
should serve a population of at least 250300,000 citizens and recruit at least
3 The Breast Unit and the Organization of Health Care
49
150 newly diagnosed cases of primary breast cancer (at all ages and stages)
each year. This is considered the minimum caseload sufficient to maintain
expertise for each team member and to ensure costeffectiveness.
The core team of the breast unit must be guided by a clinical director and
include two or more breast surgeons, each personally performing primary surgery on at least 50 newly diagnosed cancers per year and regularly attending a
weekly multidisciplinary meeting (MDM). These breast surgeons should be
able to undertake basic reconstruction and there should be standard arrangements with one or two nominated plastic surgeons (noncore team members)
with special expertise in breast reconstructive techniques.
The core team should also include two or more fully trained radiologists,
with continuing experience in all aspects of breast imaging, tissue sampling
and image-guided localization procedures. They should read a minimum of
1000 mammograms per year (5000 for those involved in screening programs)
and participate in a national or regional quality assurance program.
Other core team members must include a lead pathologist, a medical oncologist, a radiation oncologist, a breast diagnostic radiographer, a data manager
and at least two breast care nurses.
The unit must possess suitable and up-to-date imaging equipment and offer
access to all services, which even when provided in different locations, must
be supervised by the breast units core multidisciplinary team.
All core team members have the obligation to attend a MDM held at least
weekly to discuss diagnosis, pathological findings and treatment options for
every case treated in the breast unit. The units must have written protocols for
diagnosis and for management of cancers at all stages, agreed upon by all core
team members. Units must record data on diagnosis, pathology, primary treatment and clinical outcomes. Regular audit meetings should take place, with
annual production of performance and audit figures.
3.4
Advantages of the Breast Unit Model
Breast units can provide a facilitated access, in one place and at one time, to
high-quality diagnosis and treatment. Patients greatly appreciate the opportunity to receive high-quality health and psychosocial care by a broad-based
interdisciplinary team of specialists of all areas and of all necessary expertise,
in a technically competent manner, with good communication, shared decision-making and cultural sensitivity that can significantly improve the quality
and continuum of care [23, 24].
Patients are also starting to acknowledge that being treated in a specialized
breast unit can offer improved oncologic outcomes. A significant number of
studies support the evidence that multidisciplinarity, specialization and higher
caseload can be associated with better survival.
Kesson et al. have documented an 18% lower breast cancer mortality rate
and an 11% lower all-cause mortality rate at five years in women receiving
R. Masetti et al.
50
multidisciplinary breast cancer care as compared to similar patients treated in

neighboring hospitals over the same time period [2].
Sainsbury et al. examined differences in survival in 12,861 women with
breast cancer in Yorkshire as a function of consultant caseload and showed that
the 5-year breast cancer survival was significantly better for surgical caseloads
> 30cases/year in conjunction with availability of full range treatment options
[3]. Similar evidence was provided by Stefoski Mikeljevic and associates who
documented a 4% lower survival at 5years and a 10% increase in the relative
risk of death in patients managed by surgeons with workloads of < 30 new
cases per year as compared to surgeons with a workload >50 new cases year
[4]. Skinner et al. studied the effect of surgeon and hospital specialization on
survival after breast cancer treatment in 29,666 patients from the Los Angeles
County Cancer Surveillance Program database. Surgeon specialization
appeared as an independent predictor of survival on multivariate analysis, with
a 33% reduction in the risk of death at 5 years when treatment was provided
by a surgical oncologist accredited by the Society for Surgical Oncology [5].
Chen et al. in a study that examined outcomes in 13,360 breast cancer
patients treated with surgery in various hospitals in Taiwan showed that 5-year
survival rates by hospital volume in their setting were 77.3% for high-volume
(>585 cases), 74.5% for medium-volume (259585) and 72.1% for low-volume hospitals (<258) [9].
Guller and colleagues, in a review of 233,247 patients who received either
breast-conserving surgery or mastectomy for localized breast cancer, showed
that patients operated on at low-volume hospitals were significantly more likely to die or develop postoperative complications and were less likely to undergo breast-conserving surgery when compared to patients treated in high-volume hospitals [25].
3.5
Barriers to Breast Unit Development
Even though significant efforts have been devoted throughout the world to the
creation of multidisciplinary breast units, the process is still challenged by
many controversies [26].
In Italy, as in most European countries, there are at least three major barriers that limit the proper development of the Breast Unit model and these are
discussed in the Sections 3.5.13.5.3.
3.5.1
Financial Barriers
The establishment of specialized breast units has an economic impact due to

the high level of specialization of the personnel and the use of expensive technologies. This can be a quite relevant problem if one considers the continuous
reduction in resources that the health care system has to face. To justify the
51
economic investment a minimum caseload of 150200 newly diagnosed cases

per year is required [2729].
At present, reimbursements for breast cancer-specific surgical interventions in almost all European countries are regulated by the diagnosis-related
group (DRG) system, that does not take into account disease severity, the type
of technology used, quality outcomes and the complexity of the treatment. As
a result, average DRG-reimbursements for breast cancer patients appear largely inappropriate for the quality of care provided by a breast unit.
Wagner et al. investigated the expenditure and income structures of an
EUSOMA certified breast center in Germany, separating costs into fixed and
variable components. After stepwise deduction of all relevant costs, and taking into account income for the individual remuneration areas, it was calculated that to cover real costs additional revenue of 1,288 per calculated case
would have been needed [30]. The validity of these data was confirmed by
Kckemann et al. who calculated that an additional sum of 1,646 per patient
with a first diagnosis of breast carcinoma would be needed to cover costs [31].
Moreover, European DRG systems vary from country to country. The reimbursements for an index case treated with partial mastectomy may range from
577 in Poland to 5,780 in the Netherlands [32]. In Italy, there are major
inconsistencies in the DRG system. At present, no additional reimbursement is
provided for breast reconstruction after mastectomy or for the concurrent
treatment of bilateral cancers. With the current DRG system, reimbursement is
the same for a patient with unilateral cancer that undergoes a unilateral mastectomy with no reconstruction, as well as for a patient with bilateral cancer
that undergoes a bilateral mastectomy with immediate bilateral reconstruction.
In other words, same reimbursement for a simple operation that lasts one hour
as for a highly-complex operation that can last many hours and that carries
considerable additional costs for the implants [33].
Therefore, it is evident that a thorough review of the DRG system to
ensure fair and appropriate reimbursement for breast cancer treatments is a
mandatory condition for the effective development of a network of breast
units.
3.5.2
Lack of a Core Curriculum in Breast Surgery
Even though specialist training in breast cancer is one of the key mandatory
requirements of the EUSOMA guidelines, to date there is no residency program in breast disease in any country of the world. Training in breast oncology has been guided more by common sense than by specifically structured programs [3440].
For surgeons, in United Kingdom only, general surgery residents have the
choice to specialize in breast surgery, after 3 years of general training, by
attending breast units at designated university centers [35]. In Italy, starting
from 2012, some postgraduate schools in general surgery have established an
R. Masetti et al.
52
elective course in breast surgery that residents may choose to attend during the
last year of their training program.
The Italian Association of Hospital Surgeons (ACOI) has organized a
Special School of Breast Surgery, structured as a collaborative teaching
effort of multiple specialized hospitals [41]. ACOI offers two annual courses
(basic and advanced) that provide opportunities of multidisciplinary learning
and professional development in the field of breast surgery through hands on
interactive programs and direct participation in clinics and surgical activities.
The Italian School of Senology has offered more traditional training activities (residential courses, seminars, masters, consensus conferences, workshops, etc) dedicated also to nurses, radiographers, psychologists and volunteers [42].
Similar or even greater challenges exist with regard to the training of breast
care nurses (BCNs) [43, 47]. EUSOMA acknowledges the key role of BCNs in
assisting the patient and providing psychosocial support from the moment of
diagnosis throughout the entire process of oncologic treatment.
Even though the European Oncology Nursing Society has recently taken on
board a project to build an international curriculum for training of BCNs [47],
at present, specialist education is licensed only in the United Kingdom with a
university masters degree, while in Germany the requirements for oncologyspecialized nurses are integrated into the certification guidelines of the
German Society of Senology [43].
In Italy, as in many European countries, even if the need of nursing staff
with specialized training has become clearly evident, measures for creating a
well-defined and uniform BCNs curriculum are still in their infancy.
3.5.3
Controversies in the Accreditation Process
Significant efforts have been devoted to the development of a well-structured

certification process for breast units.
In the United States, the NAPBC process grants Full Accreditation to
those centers that comply with 90% or more of its accreditation standards,
Contingency Accreditation to centers that meet less than 90% but more than
75% of the standards and Accreditation Deferred to centers that meet less
than 75% of the standards at the time of survey. To maintain accreditation,
centers must undergo an on-site review every three years [48, 49].
In Europe, the EUSOMA process grants two levels of accreditation:
Initial and Full accreditation. Initial accreditation can be requested by
units that declare to comply with the standards indicated in the guidelines [50].
Full accreditation may be applied for when a unit has 5 years of audit data,
which may include cases treated prior to initial accreditation.
Even though the EP has invited member states to comply with the EUSOMA process, to date the accreditation landscape in Europe remains quite heterogeneous. In some countries, breast units are not requested to undergo any
53
certification or auditing process, and in the others, there are no common policies with regard to who should do the certifying and how.
Taran and associates collected data on the certification process in nine
European countries, confirming consistent variations in the planning and performance of the certification process (carried out by public organizations in
five countries and by private companies in the others), as well as in the auditing modalities and frequencies of different European countries [51].
Uniformly accepted global accreditation standards for breast units are
much needed in order to avoid hospitals without the proper specialization, or
that do not provide the high-quality services requested by accreditation standards, claiming to have breast units [52, 53].
3.6
Conclusions
The breast unit model, centered on a team of specialists from various fields of
oncology, specifically trained in breast diseases and working together in a collaborative fashion, is unanimously viewed as the gold standard to offer optimized care to all women with breast cancer.
Thirteen years after the EUSOMA position paper and 10 years after the
first call to action on breast cancer by the EP, huge disparities in breast cancer
treatment still exist across the EU and the landscape of European breast units
remains quite heterogeneous.
Consistent action is needed toward the goal of establishing an adequate
network of certified breast centers in all European countries by 2016. This
action should be focused on the approval of proper modalities for a standard
certification process, definition of specific training curricula for all core team
members and a global improvement of reimbursement policies for breast units.
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Part II
Conservative Program
Conservative Surgery
and Oncoplastic Surgery
Carlo Mariotti, Pietro Coletta, Sonia Maurizi, and Elisa Sebastiani
4.1
The Evolution of Breast Surgery
Breast cancer (BC) is a nosological entity of high social interest due to its
high rate of occurrence, as well as to the devastating consequences that
patients may suffer, both esthetically and psychologically, and also in terms of
the economic and organizational commitment to research and public health
that it entails.
It is needless to say that the importance of the breast for women goes
beyond its mere biological function, since it is among the most significant
symbols of femininity and sexuality.
The total or partial removal of the breast alters the patients body image,
with serious consequences for her daily/working life and relationships, often
triggering psychological disorders, that vary in type and severity. Therefore,
the surgical approach, besides pursuing oncologic radicality, needs to encompass an adequate cosmetic solution for the patient. These considerations,
which nowadays seem to be obvious, are the outcome of a great conceptual
evolution that has marked an epochal change in BC surgery, a revolution,
which has lasted for more than a century and based on various elements:
Scientific research, which, over the years, has gained a more and more
refined knowledge of the biological factors that influence biological
behaviour and natural history of the disease
Improvement of diagnostic tools
Increased treatment options
Growth of cultural awareness of the problem for women
Role of the mass media.
C. Mariotti ()
Department of Surgery, Breast Surgery Unit, Ospedali Riuniti University Hospital,
Ancona, Italy
e-mail: mariotticarlo@alice.it
Updates in Surgery
59
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C. Mariotti et al.
In fact, we have gone through the knowledge and the observation of an

already locally advanced disease, due to a late diagnosis deserving a very
destructive and invasive treatment for the patient, both physically and psychologically, to an early diagnosis of a small tumor, often not even palpable. This
has allowed a more conservative treatment, which favors excellent cosmetic
and functional outcomes, while rigorously respecting the principles of oncologic radicality.
William Halsted (18521922) considered to be the father of breast surgery,
delineated radical mastectomy in 1894, which still bears his name, and has
represented the surgical therapy of BC for about 100 years [1].
The revision of Halsteds concepts represented the first step towards modern breast surgery. The following aspects were questioned:
(a) The belief that BC first spreads through the lymphatic system and then into
the blood stream
(b) The belief that BC, regardless of size, spreads cells throughout the
parenchyma and the rich lymphatic network, and explaining why the total
removal of the breast is always required
(c) The belief that all the lymphatic system, including that which penetrates
the pectoral muscles, is entirely affected through the mechanism of permeation, by the spreading of the cancer, making mandatory the removal of
the pectoral muscles during the mastectomy.
Only later instead, it became clear that the lymphatic diffusion of the tumor
almost always occurs exclusively through an embolic mechanism and not a
permeative one.
Failures regarding local recurrence (LR), disease free survival (DFS) and
overall survival (OS), has opened up new fields of surgical research. On the
one hand, there were surgeons who supported a radical extremism (extended
radical mastectomy [2, 3], and super-radical mastectomy [4]. On the other
hand, those who encouraged the hypothesis of a different course of action,
supported by the first attempts at a conservative approach, were more in line
with new scientific ideas, technology and innovative therapies (chemotherapy
and radiotherapy) and also more respectful towards women.
The first results were encouraging, although not in the long term, but they
had the outstanding role of breaking down the barrier of scepticism about the
effectiveness of therapies that were not traditional.
The role of women has been of great relevance in this evolutionary process:
knowledge and awareness of BC and of the options for treatment and cure, has
given the patient the right to be part of the decision-making process of therapy.
The conservative cycle, which throughout the years influenced BC surgery
first, then axillary surgery, and later radiotherapy and chemotherapy, emerged
slowly, with the gradual abandonment of what had represented the therapeutic
standard for a long time. The decline of radicality thought began in 1948
when the International Society of Surgery acknowledged the possibility of
safeguarding the pectoralis major muscle during radical mastectomy, which
later became known as the modified radical mastectomy of Patey [5, 6].
4 Conservative Surgery and Oncoplastic Surgery
61
Ten years later, the first true conservative surgical treatment, lumpectomy
combined with radiation, was proposed by surgeons from Guys Hospital of
London. The not brilliant outcomes, both in terms of survival and LR, held
back, although temporarily, the development of conservative surgery. Between
1963 and 1968, a multicentral randomized study was being carried out to compare radical mastectomy with and without the dissection of the internal mammary chain. Published by Lacour in 1976, it involved five centers with 1453
patients enrolled, with an equal 5 year survival rate between the two procedures [7]. This data was consolidated by a similar study carried out by the
Cancer Institute of Milan [8] with a 10-year follow-up and another study by
Lacour in 1983 [9].
4.2
The Achievement of Conserving Surgery
The failures of aggressive surgery made way for the Milan I trial (Milan I
19731980), which marked the history of breast-conserving surgery (BCS). It
was presented to the international scientific community by Veronesi in 1969
[10], with the proposal of a new surgical operation, the quadrantectomy, which
employs the removal of the breast quadrant along with the tumor, the overlying skin, as well as the pectoralis muscle fascia, with a radial incision from the
areola to the periphery of the breast. This treatment, which soon became
known by the acronym QUART, was combined with an axillary lymphadenectomy and locoregional radiotherapy.
In this study, a clinical trial was carried out on 701 enrolled patients, comparing quadrantectomy with radical mastectomy, and no significant differences
resulted in terms of DFS and OS in the long term . The results of this multicentral study had great impact and resonance on the scientific world and beyond. It
was published for the first time in the New England Journal of Medicine, but it
also appeared in nonscientific newspapers (The New York Times, 2nd June
1981) and represents a milestone in the history of breast surgery [11, 12].
At the same time, as support, a randomized French study appeared in scientific journals. It compared mastectomy and lumpectomy with the sampling of
axillary lymph nodes, followed by radiotherapy on the mammary glands, obtaining the same results in terms of DFS, OS and LR after 10 and 15 years [13, 14].
Another fundamental study was the randomized American study NSABP
B-06 of 1976 carried out on 1851 patients, which compared radical mastectomy, lumpectomy and lumpectomy with radiotherapy, obtaining the same
results in terms of DFS and OS. This study has proved the role of radiotherapy in reducing LR after lumpectomy [15-17]; this data was confirmed later in
2000 by the study EORTC 10801 [18].
The above mentioned literature has radically changed traditional convictions, reinforcing the concept that the prognosis of BC is not closely linked to
the extension of the locoregional treatment, but more to the characteristics of
the disease (scientific research continued to clarify this aspect throughout the
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years). A less aggressive local treatment does not affect the natural history of
the disease.
At that point, the new challenge was:
Extension of breast excision needed
Adequate free margin
Treatment to be combined with surgery
Timing and modality of treatment.
In the Milan II trial, the Cancer Institute of Milan randomized 705 patients
with T1 tumors and compared QUART with tumorectomy with axillary dissection and radiotherapy (TART). 10 years later, the real significant difference
was in the percentage of locoregional recurrences of the TART group [19]. The
role of radiotherapy was given importance by many subsequent studies, such
as the Milan III trial, which was carried out on 567 patients with tumors up to
2.5cm, where QUART was compared to quadrantectomy without radiotherapy (QUAD) [20].
In addition to these results were those obtained from equivalent studies,
which evaluated, as an endpoint, qualitative parameters on the improvement in
the quality of life linked to every single surgical procedure, rather than the survival.
The 1980s were a historical breakthrough for the surgical treatment of BC;
thanks also to the Italian School the entire way of treating breast cancer has
been revolutionized; from the maximum tolerable treatment to the minimum
effective treatment, conservative surgery as a treatment for breast cancer
went beyond the purely surgical facts and became a new philosophy and a new
way of handling and approaching patients [21].
The following years brought about scientific confirmation and the consolidation of ideas. A conservative cycle started, initially focused on glandular
surgery (breast-conservation therapy, BCT) and later able to influence another
oncologic dogma, the axillary lymphadenectomy, by introducing the lymph
node sentinel technique, and successively radiotherapy, which became increasingly PBI (partial breast irradiation), intra or postoperative . Finally, oncoplastic surgery and conservative mastectomy moved a step closer to less aggressive surgery, customized to the individual case, based on the instrumental,
pathological or clinical data and discussed and agreed on with the patient.
Actual key points of the surgical treatment are:
A detailed study of the disease (imaging, histological and biological assessment) and of the patient
Choice of surgical treatment discussed and agreed on with the patient
Local tumor control
- Centering of lesion
- Complete removal with free margin
- Correct sending of the surgical specimen to the pathologist (patients
details, orientation of piece, specimen fixation)
Esthetic, functional result.
4.2.1
63
Indications and Contraindications for BCT
The indications for BCT are, as follows:

T < 3cm, N01a
No multifocality and multicentricity
Good esthetic results expected
Easy access to radiotherapy
Availability of follow-up.
The contraindications for BCT are, as follows:
I and II trimesters of pregnancy
Multicentricity
Previous radiotherapy
Persistent positive margins after surgical treatments.
These are the historical indications of conservative surgery; the experience throughout these years, and the confirmations obtained through results,
have led to the revisiting of clinical cases in which conservative surgery could
be used by adding innovative oncoplastic surgical techniques: large tumors
(T2 lesions), tumors with an extensive intraductal component, lobular histology, risk of margin close, unfavorable ratio between the volume of the breast
and the size of the tumor (Fig. 4.1).
Fig. 4.1 Veronesi quadrantectomy
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64
However, BCS diffusion, success and oncologic safety have, over the
years, shown some limitations and raised new questions:
How much of the parenchyma is to be removed?
Is it possible to operate conservatively on larger tumors?
Is it possible to operate conservatively on tumors localized in small breasts
or in quadrants at esthetic risk?
To what extent does research on the cosmetic result respect oncologic safety?
Which radiotherapy?
The need to obtain an adequate balance between oncologic radicality,
extension of indications for conservative treatment and achievement of excellent cosmetic outcome, has established the oncoplastic surgical approach. This
approach represents a further development in the surgical treatment of BC,
respecting oncologic principles but, at the same time, preserving the esthetic
integrity of the female body.
4.3
The Oncoplastic Surgery
This term was coined by Audretsch, in 1998, to indicate the necessity of combining and integrating plastic surgery techniques with oncologic surgery techniques for BC surgical treatment [22]; it was later used by Silverstein (2010):
oncoplastic breast surgery combines oncologic principles with plastic surgical techniques [23].
Oncoplastic surgery (OPS) is the most advanced expression of BCS, since
it aims at conserving the breast parenchyma while realizing an excellent cosmetic outcome for the patient, respecting the principles of oncologic radicality. This technical approach guarantees the pursuit of radical conserving surgery at its greatest extent and also guarantees demolitive surgery, conservation
and cosmesis. It is a philosophy that requires a good knowledge of anatomy
and surgical techniques, technical skills, adequate training, ability to grasp the
cosmetic aspect and to foresee the achievable outcome, as well as a good ability to communicate with the patient.
How can I remove this cancer with large margins of normal tissue while
at the same time making the patient look as good or better than she looks
now? (Silverstein MJ) [23].
OPS involves:
Removal of the ideal volume of breast parenchyma, to reduce the risk of
LR
Avoidance of breast deformity, especially for tumors situated in quadrants
at risk (upper-inner and lower)
Enlargement of indications for BCS and, therefore reduction of indications
for mastectomy
Ability to render BCS safer and better cosmetically.
Indications for oncoplastic surgery can be divided into:
65
1. Oncologic indications
(a) Necessity of extensive breast resection (more than 2040%) (average
weight of the tissue resected with traditional technique, 40g; oncoplastic, 220 g [24]; average volume with traditional technique, 117 cm3,
oncoplastic, 200cm3 [25])
(b) Necessity of margin free (the risk of residual tumor is inversely proportional to the quantity of tissue removed around the tumor: the probability of residual tumor is 59% with 1 cm healthy tissue, 17% with
3cm [26])
(c) Large tumors (T2)
(d) Tumors with extensive intraductal components or lobular histology
(e) Patients not eligible for radiotherapy or mastectomy with reconstruction, because of age, comorbidities, size and characteristics of the breast
(f) Patients who ask for breast conservation.
2. Cosmetic indications
(a) Tumor size/breast size ratio (<20%)
(b) Location of tumor (central, lower or medial quadrants)
(c) Request to reduce breast size
(d) Significant ptosis and/or breast asymmetry.
The oncoplastic approach requires meticulous planning before the procedure:
Tumor localization
Size of the tumor
Careful instrumental study (Mx, US, RM) of the spread of the tumor within the breast (localized, 55%; segmentally extended, 35%; irregularly
extended, 10%) [27]
Tumor size/breast size ratio
Age of patient
Comorbidity
Probability of re-operation
Contralateral reshaping
Presence of donor sites for flaps
Patients choices and expectations
Informed consent.
4.3.1
Oncoplastic Surgery: the Techniques
There are many surgical techniques that a breast surgeon needs to be aware of
when planning an operation and for the optimization of the outcome: the cosmetic outcome depends on technique, volume that needs resecting and localization of the tumor; the various proposed classifications of surgical operations reflect the opinions and the experience available in literature and have
for the most part a didactic purpose.
Yangs group, in Korea, proposes a classification based on the size of the
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Table 4.1 OPS techniques. (Modified from [28, 29])
Volume replacement
Volume displacement
Glandular reshaping
Lateral thoracodorsal flap
Parallelogram mastopexy lumpectomy
Thoracoepigastric flap
Purse-string suture
ICAP flap
Round-block technique
TDAP flap
Batwing mastopexy
LD myocutaneous flap
Tennis racket method

Rotation flap
Reduction mammoplasty
Wise pattern (inverted T)
Vertical pattern
Table 4.2 OPS techniques. (Modified from [32])

Central tumors, occupying
1020% of breast volume
Peripheral tumors, occupying

1020% of breast volume
Excision of > 2040% of

breast volume, techniques
of tissue transfer
Inferior pedicle (Grisotti)

Inferior to NAC: inverted T
mammoplasty (central
(WISE) mammoplasty, vertical
tumors involving the NAC) scar mammoplasty
Latissimus dorsi mini flap
Benellis round-block
technique (central tumors
not involving the NAC)
Inferior-outer/inner:
J or L-mammoplasty
Thoracodorsal artery
perforator lipodermal flap
Lateral or medial to NAC:

lateral and medial mammoplasty
Intercostal artery perforator

flap
Inframammary fold: IMF-plasty

Superior to NAC: inferior
pedicle (Grisotti) mammoplasty;
periareolar (Benelli) mammoplasty
NAC, nipple-areolar complex
excised breast tissue, which defines the possibility of reconstructing the breast
defect with breast reshaping or with transposition of the remaining breast tissue, (volume-displacement techniques), or the necessity of undergoing an
immediate resection-reconstruction with autologous tissue transfer (volume
replacement techniques) (Table 4.1) [2831].
White, from the British school, introduced two important elements: localization of the tumor with respect to the nipple-areolar complex (NAC) and the
percentage of breast parenchyma to be resected (Table 4.2) [32].
When choosing a surgical technique other authors also take into consideration the density of the glandular tissue (almost entirely fatty, scattered fibrogranular densities, heterogeneously dense, extremely dense) [33]. An
67
Table 4.3 OPS techniques. (Modified from [34])

Tumor position
Procedures
Lower pole
Superior pedicle mammoplasty/inverted T or vertical scar
Lower-inner quadrant
Superior pedicle mammoplasty/V scar
Upper-inner quadrant
Batwing
Upper pole
Inferior pedicle mammoplasty/round-block mammoplasty
Upper-outer quadrant
Racquet mammoplasty/radial scar
Lower-outer quadrant
Superior pedicle mammoplasty/J scar
Central subareolar
Inverted T or vertical scar mammoplasty with NAC resection
extremely dense breast parenchyma, highly vascularized, allows the detachment of the breast from the skin as well as the muscle without risking tissue
necrosis. A different approach is necessary when treating a predominantly
fatty breast scarcely vascularized. On the basis of these assumptions, Clough
proposed a classification of OPS operations with two levels based on the
amount of tissue excised, (more or less than 20%) tumor location and breast
parenchymal density:
Level I, excision volume less than 20% of the entire gland, requiring simple glandular remodeling techniques
Level II, larger resected parenchyma, between 20 and 50%, requiring specific plastic surgery techniques (Table 4.3) [34].
Our attempt is to group all the operations that have conserving aims into
the following classification:
1. Techniques which involve or do not involve the repositioning of the NAC
2. Techniques that involve autologous tissue
3. Conserving mastectomies
4. Reconstruction techniques with fat grafting (Table 4.4).
4.4
Conserving Surgery without NAC Repositioning
4.4.1
Local Glandular Flaps
Glandular resections carried out for small tumors result in minimal substance
loss. In these cases, it is sufficient simply to suture glandular flaps to obtain a
good cosmetic outcome. In the case of greater resections (up to 10% of breast
volume), glandular suture might not be sufficient because the loss of substance
could create tension or deformation. In this case, the gland needs to be
detached, both superficially and deeply, creating local glandular flaps that
can be used to fill the resective defect, while conserving a harmonious breast
profile (Fig. 4.2).
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Table 4.4 Oncoplastic surgery techniques
1. Breast-conservation surgery without NAC recentralization
Local glandular flaps
2. Breast-conservation surgery with NAC recentralization
Inferior pedicle mammoplasty
Superior pedicle mammoplasty (inverted T scar)
V- or J-mammoplasty
Horizontal mammoplasty (batwing mastopexy)
Racqet technique
Grisotti flap (advancement and rotation)
Round-block technique (Benelli)
3. Breast-conservation surgery and reconstruction with autologous tissues
3a. Local flaps
Rhomboid flap
Lateral thoracic flaps
TDAP (thoracodorsal artery perforator)
Lateral thoracic flap/subaxillary flap
Intercostal perforator flap (ICAP)
Segmental latissimus dorsi (miniflap)
3b. Free flaps
DIEP (deep inferior epigastric perforator)
SIEA (superficial inferior epigastric artery)
SGAP (superior gluteal artery perforator)
IGAP (inferior gluteal artery perforator)
TMG (transverse myocutaneous gracilis)
Free TRAM (transverse rectus abdominis myocutaneous)
4. Conservative mastectomies
Skin sparing mastectomy
Nipple sparing mastectomy
Skin reducing mastectomy
5. Breast-conservation surgery and reconstruction with fat transposition
4.5
Conserving Surgery with NAC Repositioning
4.5.1
Inferior Pedicle Mammoplasty
This technique is suitable for tumors in the upper central quadrant, near the
NAC and, particularly, in the presence of a breast ptosis. In this case, areolar
vascularization is ensured through the inferior pedicle, according to Ribeiro
and Robbins [35, 36]. Quadrantectomy takes place at the junction of the two
69
Fig. 4.2 Local glandular flaps
Fig. 4.3 Inferior pedicle mammoplasty
upper quadrants in the upper central part. The de-epithelialization of the

extended periareolar skin takes place caudally where the nipple will be repositioned. The glandular skin is then resectioned, together with the lesion in the
upper central part, followed by subsequent glandular skin resectioning in the
lower lateral and medial columns. The lower glandular flap is cranially sutured
in the same position where the glandular resection took place and the NAC is
also placed closer, correcting any resulting deformities. Glandular suturing
takes place in the lower quadrants (Fig. 4.3).
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Fig. 4.4 Superior pedicle mammoplasty with inverted T scars
4.5.2
Superior Pedicle Mammoplasty with Inverted T Scars
This technique can be used for tumors located in the inner lower quadrant. It
begins with the de-epithelialization of the periareolar skin of the superior pedicle which is then detached together with the NAC, forming a very thin flap,
supplied with blood from the superior pedicle, according to Pitanguy and
Lejour [37, 38]. A skin incision is made in the inframammary fold along the
entire length. A skin incision is then made at the top of the breast, at the edge,
between the lower and upper quadrant, both medially and laterally. This is followed by an extensive resection of gland and skin in a caudo-cranial direction
starting from the inframammary fold. The breast will be progressively resected and detached from the pectoral muscle.
Reconstruction starts with the reapproximation of the medial and lateral
glandular columns towards the midline and ends with a skin suture made to
obtain a smaller gland with a narrow base (Fig. 4.4).
4.5.3
V- and J-Mammoplasty
The V-mammoplasty is carried out when a tumor is located in the lower quadrants, particularly in the lower-inner quadrant of medium sized breasts with no
ptosis. It is similar to mammoplasty with superior pedicle, but without incision
of inframammary fold.
71
Fig. 4.5 V-mammoplasty
The procedure involves the de-epithelialization of the periareolar region,

followed by a V-shaped skin incision with a large base at the inframammary
fold towards the inner quadrant. Once the surgical specimen is excised, a free
glandular flap is created from the lateral margin of the resection, detaching the
breast both in depth and superficially. The flap created is rotated clockwise or
anticlockwise until it can be sutured to the medial or lateral flap. The procedure ends with the repositioning of the NAC (Fig. 4.5).
The J-mammoplasty is carried out when tumors are located in the lowerouter quadrants. The NAC is repositioned cranially to allow the best possible
correction of any ptosis. Firstly, the procedure involves the de-epithelialization of the skin around the areola, followed by a skin incision that starts at the
medial edge of the de-epithelialized area and continues, as before, up to the
inframammary fold.
The second incision is contralateral to the first one starting from the lateral margin of the de-epithelialized area and, as before, continues up to the inframammary fold. The parcenchymal excision follows the skin in the form of a J.
The NAC is then repositioned centrally. The lateral and medial columns are
placed next to one another and sutured once detached from the gland (Fig. 4.6) [39].
4.5.4
Horizontal Mammoplasty or Batwing Mastopexy
The batwing mastopexy is suitable for treating lesions in the upper quadrant
and is particularly suitable for tumors in the upper-inner quadrant, at a higher
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Fig. 4.6 J-mammoplasty
Fig. 4.7 Horizontal mammoplasty (batwing mastopexy)
risk of deformity. It starts with a large omega skin incision, which includes the
upper quadrants of the breast. It continues with the resection of the skin and
the breast parenchyma in the upper quadrants (outer, central, inner) adjacent to
the NAC, including the tumor. Once an adequate surgical safety margin is
defined, the resection of the gland takes place reaching perpendicularly the
pre-pectoral plan; the surgical specimen is then detached from the deep fascia.
When the NAC and the breast parenchyma of the lower quadrants are reconstructed, they are sutured to the residual parenchyma of the upper breast hemisphere. At the end, the NAC and the breast are cranialized to correct the
breast ptosis. In some cases this procedure can end up even without the central repositioning of the NAC (Figs. 4.7 and 4.8) [40].
73
Fig. 4.8 Horizontal mammoplasty (batwing

mastopexy)
4.5.5
Lateral Mammoplasty or Racquet Technique
This technique is suitable for large tumors in the upper-outer quadrants, when
the requested glandular resection is more than 20%. With this procedure, it is
possible to remove the entire upper-outer quadrant, by sacrificing the skin
overlying a tumor, from NAC to axilla. The procedure involves the de-epithelialization of the periareolar skin, followed by a lozenge-shaped skin incision
in the location of the tumor. The sectioned area has the shape of a racket.
Glandular detachment is carried out corresponding to upper-outer quadrant,
from axilla to areola.
The mammary gland is then excised and the reconstruction is carried out to
prepare, through detachment, two local glandular flaps (medial and lateral),
which are placed next to one another and sutured together to fill the defect
(Fig. 4.9) [41].
4.5.6
Advancement and Rotation Flap (Grisotti Flap)
Technique suitable for treatment of tumors in the retroareolar area. The procedure involves a periareolar incision with a skin circumference beyond the nip-
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Fig. 4.9 Lateral mammoplasty or racquet technique
ple. It proceeds with the de-epithelialization of the skin in the medial part of
the junction between the two lower quadrants, reaching the inframammary
fold, saving a piece of skin that will replace the nipple. Extensive resection of
the breast under the areola is carried out, reaching the pectoral plane; the specimen, consisting of the gland whit the tumor, and the NAC is excised. The
reconstructive phase involves glandular suturing to fill the resected area.
The piece of skin prepared earlier is moved together with its advancement
flap and sutured proximally to build the new areola (Fig. 4.10) [42].
4.5.7
Round-block Technique by Benelli
Suitable for lesions in the upper central part, this technique is used for tumors
in small/medium breasts, situated near the NAC but not spread into it. It can
also be adapted to lesions in other breast quadrants.
75
Fig. 4.10 Advancement and rotation flap

(Grisotti flap)
The procedure begins with two concentric incisions, the inner one being at
the edge of the areola and the outer one at a distance dependent upon the location and size of the tumor, the location of the nipple and the degree of ptosis.
The larger the tumor and the further it is from the nipple, the larger the distance between the two circumferences [43].
Subsequently, de-epithelialization of the skin between the two circumferences is carried out taking the precautions necessary to ensure the conservation of the blood supply to the derm. Starting from the outer edge of the deepithelialized area, the superficial detachment of the gland from the subcutaneous layer is carried out; the gland is then dissected and detached from the
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Fig. 4.11 Round-block technique by Benelli
pectoral muscle and then excised. The reconstructive phase involves the preparation of local glandular flaps, with a superficial and deep glandular detachment, from the margins of the resection, which can be medially placed one
near the other and sutured together at glandular points. Then the circumference
of the external periareolar skin is sutured to the areola. The nipple is repositioned cranially. This operation results in a significant reduction of breast ptosis. The cosmetic outcome is satisfactory since it only leaves a surgical periareolar scar (Figs. 4.11 and 4.12).
77
Fig. 4.12 Round-block technique by Benelli
4.5.8
Conserving Surgery and Reconstruction with Autologous

Tissue
The use of volume replacement techniques in BCS, that is, the reconstruction
of the gland with the transpositioning of autologous tissue, is necessary when
the size and/or location of the glandular defect does not guarantee for a satisfactory cosmetic outcome with the sole use of residual breast tissue.
These techniques, which use autologous tissue, have the advantage of
offering the reconstruction of a natural-looking new breast and, therefore,
physical characteristics shared with contralateral one. Moreover, they allow to
have a good inframammary fold and a breast size similar to the contralateral,
thus avoiding the adjustment of the other breast. A further advantage is that no
prosthetic materials are used, with the possibility of carrying out radiotherapy
in safety. These operations are more invasive, resulting in longer hospital stay,
longer postoperative period; most of all, they require surgical skills.
These techniques can also be used to correct deformities resulting from
failed or incorrect glandular reconstruction, during BCS or after radiotherapy
(Table 4.5) [44].
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Table 4.5 Deformities post BCS. (Modified from [44])
Type I
Displacement of the nipple-areolar complex
Type II
Localized deficiency of parenchyma and/or skin
Type III
Generalized breast contracture with no localized defects
Type IV
Severe damage with heavily scarred parenchyma and skin
The aforementioned techniques, require a flap donor site and are suitable
when the tropism of the breast tissue area is altered, and when postoperative
radiotherapy is mandatory.
4.6
Local Flaps
These are useful techniques, especially to correct defects in the outer quadrants of the breast, or for obese women with a large quantity of skin and fatty
tissue on the lateral chest wall.
4.6.1
Rhomboid Flap
A flap of skin and fat, mainly on the lower lateral part of the chest wall, which
can be used as a transposition flap to cover defects in the lower-medial outer
quadrant (Fig. 4.13) [45, 46].
4.6.2
Lateral Thoracic Flap
TDAP (Thoracodorsal Artery Perforator)

This technique involves the fitting of a flap taken from the lateral and/or posterior thoracic region and transferred to fill the breast defect. The TDAP flap
consists of skin and subcutaneous tissue from the skin-beam region of the posterior surface of the chest, whose blood perfusion is guaranteed by the perforating vessels of the thoracodorsal pedicle through the intramuscular course of
the latissimus dorsi muscle; it has the advantage of conserving the functionality of this muscle. The thoracodorsal artery flows from the subscapular artery
and descends along the lateral and deep surface of the latissimus dorsi muscle
and supplies the perforating artery that feeds the skin of the lateral wall of the
chest. The flap is raised to the level of the dorsal fascia. The dissection continues through the latissimus dorsi, conserving the latter and dissecting only an
extremely confined area. Perforators are dissected up to the artery and the thoracodorsal vein. The flap is passed through a supramuscular tunnel between
the front edge of the latissimus dorsi muscle and the receiving site. The flap is
79
Fig. 4.13 Rhomboid flap
then placed to fill the breast defect; finally, the donor area is closed linearly,
resulting in a horizontal or oblique scar [47].
Lateral thoracic flap/subaxillary flap
These flaps are used in the reconstruction of the upper-outer quadrants; the
size of these flaps varies, and they might not fill the glandular defect adequately (Fig. 4.14) [48].
Intercostal perforator flap (ICAP) [49]
Segmental latissimus dorsi (miniflap)
This technique, first described from Rainsbury, is proposed in BCS, as a filler
of the glandular area, which has been removed. An axillary incision is used to
access and prepare the muscular segment; the flap has good filling capacity
and, in particular, it has good radiolucency which favors radiological followup and does not enhance scarring on the chest (Fig. 4.15) [50].
C. Mariotti et al.
80
Fig. 4.14 Subaxillary flap
4.7
Free Flaps (Remote Flaps)
Free flaps are rarely necessary after BCS, but are usually used in postmastectomy reconstruction; in fact, these are secondary free flaps, whose use is to be
reserved in the case of failure in oncoplastic reconstruction, in the case of BCS
deformity, or postradiotherapy complications. They ensure an excellent contribution of skin and adipose tissue. For further in-depth reading refer to the bibliographical referencing below:
DIEP (deep inferior epigastric perforator)
SIEA (superficial inferior epigastric artery)
SGAP (superior gluteal artery perforator)
IGAP (inferior gluteal artery perforator)
TMG (transverse myocutaneous gracilis)
Free TRAM (transverse rectus abdominis myocutaneous).
81
Fig. 4.15 Segmental latissimus dorsi flap
4.8
Conservative Mastectomies
Conservative mastectomies are discussed in more detail in Chapter 5.
4.9
Fat Grafting
Fat grafting is discussed in more detail in Chapter 16.
4.10
Conclusions
Oncoplastic surgery in its most extensive form, is a step closer to ensuring an

adequate surgical treatment of BC, complying with the strict standards of
oncologic radicality, while aiming at obtaining the best possible cosmetic out-
C. Mariotti et al.
82
come. In fact, it emphasizes the role of BCS from an oncologic (research of

local control), reconstructive and technical (the complexity of some techniques) point of view. It follows that breast surgeons have acquired new competences, including plastic surgery, making it possible to choose the most adequate surgical technique for each single case. In this surgery, more than others, a careful selection of cases is needed and exhaustive information requested from patients, since high expectations of the outcome are present.
The refinement of the techniques has allowed for more extensive BCS,
with surgical approaches unusual in traditional surgery and technical complexities overcome by adequate training. All of this is in search of rigorous and
radical local control of disease, and, most of all, with respect for women and
their bodies.
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Conservative Mastectomy
Carlo Mariotti, Pietro Coletta, Angela Maurizi,
and Elisa Sebastiani
5.1
Introduction
In the last century, breast-cancer surgery underwent a dramatic development, starting from the initial approaches of radical surgery to the more recent codification of
a series of conservative treatments that do not invalidate oncologic radicality. In 1894,
Halsted [1] delineated radical mastectomy, which remained the standard treatment
for breast cancer for many years. This operation, involving the removal of all the
breast tissue (en bloc removal of the breast and overlying skin, both the pectoralis
major and minor muscles and the axillary lymph nodes from Berg level I to III) was
a fundamental shift in the surgical treatment of this disease (local disease control),
but it was also a symbol of destruction, of a large wound, not only in surgical terms,
suffered by the patient. In 1948, Patey and Dyson [2] of Middlesex Hospital, London, proposed an alternative approach to reduce the morbidity of Halsteds operation (with the preservation of the pectoralis major muscle and the removal of the pectoralis minor muscle, the axillary lymph nodes could equally be removed). This was
perhaps the first shift toward a more local conservative surgery. Later on, Madden
[3] reinforced this course with a modified radical mastectomy that preserved both
the pectoralis major and minor muscle. The conservative surgical approach found
its assertion in quadrantectomy and radiotherapy, as described by Veronesi [4],
where oncologic radicality is combined with research into the cosmetic outcome, with
the utmost respect for the patients physical and mental integrity. Even though quadrantectomy, together with radiotherapy, is the standard treatment for breast cancer,
it is known that not all breast cancer cases can be handled safely with this type of
operation (multifocal tumors, multicentric tumors, recurrence after conservative
surgery, inability to manage radiotherapy, BRCA1-BRCA2 patients). About 2025%
C. Mariotti ()
Ancona, Italy
Updates in Surgery
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C. Mariotti et al.
86
of the cases will still need to undergo mastectomy. How can one still be conservative when the whole gland is being destroyed? How can oncologic radicality be ensured without neglecting the cosmetic and functional aspects? These are the considerations on which the course of oncoplastic surgery, a term coined by Audretsch [5],
were based and which best match the collaborative surgical aspects of breast-cancer
surgery and reconstructive plastic surgery. In 1962, Freeman [6] described his results
with subcutaneous mastectomy. In a study, published in 1984 by Hinton [7], which
compared modified radical mastectomy with subcutaneous mastectomy and immediate reconstruction with a prosthesis, no differences in survival were found. The skinsparing mastectomy (SSM) was first delineated in 1991 by Toth and Lappert [8]; this
type of mastectomy involves a periareolar incision, with the removal of the nippleareolar complex (NAC) and the skin overlying superficial tumors, an effort to maximize skin preservation and to facilitate immediate reconstruction. Simultaneously,
Kroll [9] discovered one recurrence in 100 patients during a 2-year follow-up. Since
then, the technique has been given great attention and has been subject to many studies that have shown substantial oncologic equivalence with other destructive methods. The cosmetic outcome was excellent, thanks to the preservation of the skin and
the inframammary fold, and due to a simpler immediate reconstruction, which usually does not need contralateral symmetrization. The interest in, and the success of
this surgical approach, together with the results of the clinical studies on the oncologic safety of the SSM, have increased interest in this type of operation. On the other hand, the cosmetic and emotional impact, still partly negative and linked to the
loss of the entire NAC, and the results obtained from the various techniques used for
the reconstruction of the nipple, which are not always excellent, led to the proposal
of new surgical operations: the NAC-sparing mastectomy (NSM) [10], and the skinreducing mastectomy (SRM). These three techniques belong to the new chapter of
conservative mastectomies.
5.2
Nipple-sparing Mastectomy
The NSM involves the removal of all the breast tissue while preserving the skin of
the breast, the NAC and the inframammary fold (breast-conserving mastectomy). It
might seem like another name for subcutaneous mastectomy or subcutaneous adenomammectomy. However, the NSM is a real demolitive operation that ensures
oncologic radicality but differs for the careful preparation of skin flaps, global
removal of glandula and preservation of only 35mm of the NAC.
The description given is that of the procedure that is usually carried out. However,
there is a variant of this operation that involves the preservation of a subareolar glandular tissue pad, which is irradiated during the operation using the IORT technique [11].
5.2.1
Surgical Anatomy of the Breast
The mammary gland is located in the splitting of the superficial fascia: the anterior
5 Conservative Mastectomy
87
lamina (premammary), which is not present in the areola and nipple, and the posterior lamina (retromammary). External to the anterior lamina, there is a celluloadipose layer, which varies in thickness from person to person. Below the lamina there
are large axial vessels from where vertical branches branch off toward the subdermal plexus. Fibrous projections (Coopers ligaments) pass from the anterior surface
of the mammary gland to the superficial lamina, and the retinacula are stretched
between the former and the dermis. Between the posterior lamina and the pectoral
muscle fascia there is a retromammary adipose layer, through which fibrous projections pass (suspensory ligament of the breast) keeping the mammary gland joined to
the chest wall. Anatomical studies have defined borders of the mammary gland:
large infraclavicular muscle bundles, midsternal lines, the front edge of the latissimus dorsi and the lower edge of the pectoralis major muscle on the sixth rib. The
latter border is of great importance for the presence of the inframammary fold, an
area where the superficial fascia joins to the deep pectoralis fascia.
5.2.2
The Arterial Vascularization of the Breast and Nipple-areolar Complex
The arterial vascularization of the NAC is supplied by the internal and external
mammary artery. In the NAC, these branches anastomose to form two plexus, a
massive and diffused one around the areola, and a thin and superficial one around
the nipple. Recurrent perforating arteries (inner mammary artery perforators, the
outer mammary artery perforators, anterior-medial intercostal perforators and anterior-lateral intercostal perforators) flow from this circle and reach the mammary
ducts where they anastomose with the subareolar subdermal plexus. The venous
outflow from the NAC is supplied by the tributary branches of the perforating veins
of the internal mammary, the intercostal veins and the axillary veins (Fig. 5.1).
5.2.3
The Innervation of the Breast and Nipple-areolar Complex
The innervation of the NAC is mainly supplied by the anterior-medial and anterior-lateral branches of the intercostal nerve IV. The intercostal nerves III and V,
together with the supraclavicular nerves, contribute to sensitivity. The intercostal
nerve IV enters laterally through the IV space and runs medially along the deep fascia and upwards to reach the NAC through the parenchyma. In the light of the fact
that various nerves contribute to the innervation of this area, the surgical sectioning
of some of these branches should not result in the anesthesia of the NAC. Also true
is the fact that it is practically impossible to choose preferential incisional surgical
options to conserve the nervous fiber section; such impossibility seems to be valid
also for vascularization (Fig. 5.2).
Most authors reported that the sensitivity of the nipple after NSM reduces significantly and the same is valid for its erectile function [12], with a possibility of recovery, after about 6 months, in 28% of cases.
C. Mariotti et al.
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External
mammary
artery
Anteriorlateral
intercostal
perforators
Inner
mammary
artery
perforators
Anteriormedial
intercostal
perforators
Fig. 5.1 Vascularization of the breast and nipple-areola complex
5.2.4
Planning the Surgery
1. Evaluation of the surgical indications.

2. Getting consent for the surgery. It is important to explain clearly some fundamental points: any oncologic risks, even if small, linked to the persistence of the
NAC, as well as the surgical approach chosen and the expected cosmetic outcome, any possible complications (discoloration/ischemia/ necrosis of the
NAC, the reduction-loss of nipple sensitivity and its erectile function, prosthesis infection) and problems linked to axillary lymph nodes.
3. Choosing the surgical approach: which incision to be carried out taking into
consideration any existing scars; which approach allows an easy and radical
removal of all the gland tissue; which one allows the perfect identification and
skeletonization of the retroareolar tissue and safeguards the vascular system of
the NAC.
4. Study of the axillary sentinel lymph node or the axillary lymph node dissection.
5. Planning breast reconstruction (prosthesis, type and sizes, flaps, other).
5.2.5
Indications and Contraindications
The indications and the contraindications for NSM must be carefully evaluated
before proposing and carrying out the operation. The follow-up of this new surgical approach is still too young to drive absolute criteria and the literature always
presents new elements for reflection [1215].
The criteria to select this surgery include both clinical and instrumental criteria
89
Fig. 5.2 Innervation of
the breast and nippleareola complex
Anterior-lateral
intercostal
nerves III-IV-V
Anteriorlateral
intercostal
nerves IIIIV- V-VI
(tumor size 3cm, tumor distance from the NAC > 2cm, the possibility of an MRI
of the NAC, clinically negative axillary lymph nodes, absence of Pagets disease
and the absence of an inflammatory component), and also anatomical criteria (not
big breast size, no high-grade ptosis). Oncologic and prophylactic indications are
listed in Table 5.1 together with absolute contraindications.
Literature on these indications is in sufficient agreement. Many studies have
shown that the SSM, have the same results as the modified radical mastectomy in
terms of local recurrences, both when treating infiltrating tumors and intraductal
ones [1618]. A very debated issue is the oncologic risk linked to the maintenance
of the NAC. In a literature review published in 2001, Cense [19] claimed that the
percentage of neoplastic involvement of the NAC in mastectomies varies from 5.6
to 58%, and has a significant correlation with the tumor size and its distance from
the nipple [16, 20]. In fact, in tumors larger than 4cm (T3), there are neoplastic
cells within the NAC in more than 50% of the cases. The same applies if the mass
is less than 2cm away from the NAC. In 2001, a retrospective analysis of 217 cases
by Simmons and Brennant [21] found the involvement of the NAC in 10.6% of the
cases. This percentage drops to 6.7% of peripheral tumors, with a diameter of less
than 2cm and with less than two positive lymph nodes. Analyzing the involvement
of the areola and the nipple separately, the authors sustain that the areola is implicated in only 0.9% of the cases of NAC involvement. In the rest of cases, the tumor
is restricted to the nipple. This fact favors the maintenance of the areola (areolasparing mastectomy), when the conservation of the nipple is not possible [2228].
In fact, the lymphatic drainage of the breast is not, as Sappey [29] claimed, toward
the nipple, but toward the deep lymphatic prepectoral lymphatic plexus [30]. In
addition, Welligs [31] has shown that the anatomical area of the breast where
tumors form, is the terminal duct lobular unit (TDLU), which is present only at the
C. Mariotti et al.
90
base of the nipple and not at the tip. Therefore, only the outer surface (the skin) of
the nipple remains when the core is removed together with all the glandular tissue
[3235]. The risk of the nipple involvement, therefore, seems to directly correlate
to the tumor size and the distance of the tumor from the nipple. It is necessary to
reconsider the importance of positive lymph nodes, the presence of lymphatic vascular invasion (LVI) as well as the extensive intraductal component (EIC). The risk
factors linked to local recurrence seem to be different; in the case of infiltrating
tumors one should consider the grading, the overexpression/amplification of the
HER2/neu and the molecular characteristics of the tumor (luminal B). It seems that
in situ tumors correlate with the patients age (< 45 years), absence of estrogen
receptors, grading, overexpression of HER2/neu and high value of Ki67. The preoperative histological examination might represent the best solution to define the
histological, hormonal and biological characteristics of the tumor so as to reduce
local recurrence, selecting the patients who should undergo a NSM [36]. Intraductal
mammary carcinoma and infiltrating ductal carcinoma with important in situ components, negative hormone receptors and high degree overexpression of HER2/neu,
are all associated with a high risk of local recurrence that can manifest itself as
Pagets disease of the nipple [37]. For this reason, it is absolutely necessary to
inform the patient of the existing problems and to obtain a truly informed consent.
5.2.6
The Surgical Technique
The NSM, like other conservative mastectomy techniques, involves the removal of
the entire mammary gland while sparing the cutaneous envelope. The element that
characterizes the operation is the conservation of the NAC, after an intraoperative
histological exam of the retroareolar tissue.
5.2.6.1 Skin Incisions

Several skin incisions (Fig. 5.3) have been proposed and they can be summarized
as follows:
Upper periareolar
Upper periareolar with lateral extension
Transareolar - transnipple
Inframammary /inferior lateral
Upper-outer radial
Omega (mastopexy).
An upper-outer radial incision should be given preference, due to its various advantages: excellent scar outcome; easier access to the axilla, the nipple and the complete glandular demolition; the highest possibility of conserving the areolar vascularization, and the best reconstruction time, both in small and large breasts. All the
periareolar incisions have the advantage of resulting in an almost invisible scar.
Therefore, besides allowing excellent access to the retroareolar region, they also favor the subareolar resectioning timing; they are the preferred choice for small-sized
breasts, due to the difficulties to reach the inframammary fold medially and the
91
Fig. 5.3 Skin incisions
neurovascular elements of the axilla (if lymphadenectomy is mandatory).

The periareolar incision with lateral extension certainly ensures wider access to
axilla; however, it often results in a deviation and lateralization of the NAC, requiring corrective action. The external inframammary incision has the advantage of a
hidden scar but, on the other hand, it creates a few problems as far as the demolition of the upper or middle quadrants is concerned and in reaching the axilla, especially in large breasts.
The dissection occurs along the superficial fascia, taking care to respect the skin
flap vascularization; most vessels flow deeply in the muscle band, but there might
be perforated vessels to the skin that must be coagulated (Fig. 5.4). The thickness
of the flaps must be kept constant throughout their extension. To reach this aim, the
skin must be stretched upwards by the second surgeon and the gland in the opposite direction by the surgeon.
Both these maneuvers facilitate the identification of the correct dissection
plane, which should be in the subcutaneous tissue, immediately at the surface of the
fascia, which is above the mammary gland.
From time to time, during the dissection, the skin flap must be palpated to
ensure a uniform and adequate thickness, not too thin and devascularized (necrosis!!), and not too thick as there would be a risk of glandular residue (local recurrence!!). In order to assess the vitality of the flaps and the NAC, studies have evaluated perfusion with the fluorescence emitted after an infusion with indocyanine
green dye [38].
92
C. Mariotti et al.
Fig. 5.4 Dissection of the glandular plane
The flap thickness may depend on the patients characteristics; in slim patients,
it may be only a few millimeters thick (23mm) and transparent to light, while for
obese patients, it can be up to 1cm. In all cases, the removal of glandular tissue
must be truly radical. The releasing of the gland from adipose tissue begins from
the upper quadrants getting to the pectoralis muscle up to its infraclavicular bundles of the pectoral muscle. Medially, the muscle fascia is not well-defined and the
dissection leads to the parasternal line, where the perforating vessels coming from
the internal mammary artery are present; on the lower side, the muscle is followed
up to the joint with the posterior membrane, where the skin adheres to the chest
wall at the inframammary fold. The anterior axillary pillar, the margin of the pectoralis major and the lower anterior serratus can be reached laterally. The dissection
must be carried out carefully with meticulous technique to prevent ischemia of the
skin flap. Proceeding from the top toward the bottom, the gland is mobilized from
the deep plane, incising and dissecting the pectoralis major muscle band.
5.2.6.2 Treatment of the Subareolar Tissue

The most characteristic element of this surgery is the conservation of the NAC. For
this purpose, as mentioned above, it is mandatory to carry out an intraoperative histological study of the margin of a section of the subareolar tissue. During the glandular dissection, one should proceed with meticulous care when isolating the areolar conus, which is followed and sectioned until removal from within the nipple
(avoiding the use of electrosurgery to avoid artifacts from electrocautery). This sectioning, which reaches the dermis plane, almost transforms the NAC into a sort of
dermoepidermal graft, easily revascularized from the underlying muscle tissue.
This timing is greatly facilitated by the hydrodissection technique, which consists
of infiltrating the retroareaolar tissue with an epinephrine and saline solution,
to allow the identification of an anatomical and bloodless incision plane [39]
(Fig. 5.5). This technical procedure makes the surgical procedure easier, quicker
93
Fig. 5.5 Dissection of the subareolar tissue
and probably even safer from an oncologic point of view since a subdermal plane,
which allows a better and complete removal of the retroareolar breast tissue, is
obtained. The resected retroareolar tissue is then sent for intraoperative histological
examination, subjected to the right orientation. The pathologist then prepares at
least three frozen sections at 200300 microns; a negative or positive result for
tumor presence is given. When positive, he specifies the presence of infiltrating or
in situ tumor, extension and distance from the edge of nipple (Fig. 5.6). At this
point, our choices can be: conserve the nipple, removal of the NAC or, given the
rarity of areolar accessory ducts, removal of the nipple alone; this latter variant of
the technique (areola-sparing mastectomy), which is sometimes used, involves the
closure of the circular areolar wound with a purse-string suture, creating a scar that
is almost punctiform with projection and a fairly good esthetic result. The result of
the definitive histological test must be considered with great attention, since the
possibility of false negatives from the intraoperative histological test seems to be
94
C. Mariotti et al.
Fig. 5.6 Intraoperative study
of the subareolar tissue
approximately 4.6% [4045]. In all cases in which a nipple-sparing mastectomy is

carried out for oncologic purposes, even for the treatment of noninfiltrating forms,
it is advisable to check the state of the axilla (sentinel node biopsy/axillary dissection).
5.2.6.3 Reconstruction Time

The pocket under the pectoralis major muscle is then prepared for the prosthesis
implant. It begins with the dissection of the lateral edge of the pectoralis major from
the pectoralis minor and the costal plane: in the middle sternal tract, the muscular
fibers are completely sectioned up to the subcutaneous fat and down to the inframammary fold. The muscular section, which compromises the contracture of the
pectoral muscle, is necessary to achieve good skin expansion, good inframammary
fold and also to ensure the best positioning of the prosthesis. The volumetric reintegration of the gland is obtained with the insertion of an implant made of prosthetic material. The reconstruction can be carried out in one session using an implant
with a permanent prosthesis, or in two sessions, using an expander or a prosthesisexpander, with a biological or synthetic mesh, with a flap transposition, and with
fat grafting (Fig 5.7) [46, 47].
(For further information about reconstruction, readers should refer to chapter 16).
The surgery ends with the positioning of a drain and the synthesis of the surgical
wound. The complications of the operation are listed in Table 5.4.
95
Fig. 5.7 Nipple-sparing mastectomy right (upper periareolar approach)
5.3
Skin-sparing Mastectomy
SSM was first described by Toth and Lappert in 1991 and later, still in 1991, by
Kroll, who is the father of conservative mastectomies [8, 9]. This surgery involves
the exeresis of the entire mammary gland, saving the breast skin and the removal
of the NAC and any skin overlying the tumor, including any area with previous surgical biopsy incisions. The advantages of this type of mastectomy resulting in welcoming by the surgical world are the possibilities of conserving the skin and the
inframammary fold, ensuring a better cosmetic outcome in a more natural manner,
facilitating the reconstruction time with less scars and less need for contralateral
symmetrization. In 1997, Carlson [48] proposed an SSM classification with four
types, depending on the surgical approach used and previous evaluating with the
presence of biopsy scar: Type I, only nipple-areola removed; Type II, nipple-areola, skin overlying superficial tumors and previous biopsy incision removed in continuity with nipple-areola; Type III, nipple-areola removed, skin overlying superficial tumors and previous biopsy incision removed without intervening skin; Type
IV, nipple-areola removed with an inverted or reduction pattern skin incision [18,
4953]. Nowadays, the fundamental SSM indications are the clinical conditions
themselves when an NSM cannot be carried out (refer to Tables 5.1, 5.2) (Fig. 5.8).
5.4
Skin-reducing Mastectomy
A SRM is in fact a skin-sparing mastectomy (Type IV), which involves the reduction of an excessive skin envelope. In fact, the operation is for patients with largesized breasts (jugulum-nipple distance > 25cm) and a severe degree of ptosis (areola to inframammary fold distance > 8cm). The oncologic and prophylactic indications are the same as those of an SSM and NSM. The operation must be suitably
planned, the degree of possible skin reduction must be carefully measured and,
when oncologically safe, the NAC will be conserved. This operation is often carried out combined with a breast reduction or contralateral mastopexy. The conven-
96
C. Mariotti et al.
Table 5.1 Indications (oncologic and prophylactic) and contraindications of NSM

Oncologic
Multifocal DCIS
Multifocal and multicentric T1, T2
T1 with extensive intraductal component (EIC)
Margins involvement after conservative surgery
High tumor/breast ratio
Relapse post QUART
Patient refuses BCT
Patients refusal or impossibility to radiotherapy
Difficulty for follow-up after conservative surgery
Prophylactic
BRCA1/BRCA2 (risk reduction 8196%)
Opposite breast
LCIS
ADH?
Papillomatosis?
Phyllodes tumor?
Contraindications
Tumor distance < 2 from NAC in mammography or RM studies
Nipple retraction
Subareolar microcalcifications
Bleeding from the nipple
Skin involvement
T3, T4
Inflammatory disease
Pagets disease
N+ ?
Distance from the nipple to the inframammary fold > 8cm
Large breast ( > 400cm3)
Intraoperative histological involvement of retroareolar tissues
tional method of reducing the epidermal tissue involves the removal of an ellipse
of skin around the NAC. This technique combines the skin incision used for reductive mammoplasty based on the lower pedicle with the conservation of a dermal
flap, whose final role is to be part of the lower cover of the prosthetic implant.
Mastectomy is then carried out. Reconstruction starts with the sectioning of the
lower medial fibers of the pectoralis major muscle which are successively sutured
to the upper edge of the lower skin flap. The implant is then inserted in the pocket,
which will be closed laterally with the fascia of anterior serratus muscle. In some
circumstances, it may be oncologically safe to conserve the nipple, which can be
shifted towards the position of the new nipple conserving the epidermal bridge
[5456]. In addition, other authors have proposed interventional procedures with
two to three stages, for large-sized breasts with ptosis [57, 58].
97
Table 5.2 NSM complications

Minor
Cyanosis/hypopigmentation of the NAC
Localized infection
Major
NAC ischemia (in 30%)
NAC necrosis
Flap necrosis (more frequent when risk factors such as diabetes and smoking are present (58%)
Seroma
Bleeding/hematoma
Necrosis of the skin
Implant infection (2.815%)
Late
Extended and retracted scar
Nipple or skin area retraction
Wrong positioning/displacement of the NAC
Changes in sensibility and erectile function of the nipple
Capsular retraction
Wrong positioning of the implant
Rotation of the implant
Evident breast asymmetry
Cancer recurrence (45%)
Type 1
Type 2
Type 3
Type 4
Fig. 5.8 Skin-sparing mastectomy (Carlson classification)
5.5
Conclusions
Conservative mastectomies are a further step in the conserving treatment of breast

cancer, especially the NSM, which is the most advanced surgical technique. From
C. Mariotti et al.
98
an oncologic point of view, the outcomes are reassuring, while cosmetically, they
are surely exhilarating. The conservation of the NAC definitely enhances the outcome of the reconstruction. Local recurrence compares to that of radical mastectomy or SSM. It is fundamental to carry out an intraoperative histological exam of
the subareolar tissue. The procedure has various levels of difficulty, which can be
overcome with an adequate period of training. It is of utmost importance to highlight the necessity of a good selection of cases to be treated and careful planning of
the procedure [59, 60]. The literature will surely propose further elements for a better definition of indications and also the limits of the techniques, which are already
described in part.
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Sentinel Node Biopsy

and Axillary Dissection
Riccardo Bussone, Ada Ala, Pietro Maria Ferrando,
and Gretha Grilz
6.1
Historical Background
The extent of axillary dissection has changed over time according to the evolution in understanding breast cancer characteristics. The first complete axillary lymph node dissection (ALND) was described in 1894 by Halsted in his
reports on the technique for radical mastectomy; in the Halsted hypothesis, in which breast cancer was considered a local disease, ALND was intended to be curative [1].
In the 1970s, Fisher [2] proposed that breast cancer was a systemic disease
from the outset and that survival was largely a function of tumor biology, not
surgical technique.
In the Fisher era, the primary objective of ALND was prognostication to
guide systemic therapy, a secondary objective was local control; the survival
benefit was unproved.
Nowadays we know that both the Halsted and Fisher hypothesis were
right: breast cancer is a family of diseases with a wide spectrum of behavior,
ranging from predominantly local (Halsted) to predominantly systemic
(Fisher) phenotypes.
The contemporary sentinel lymph node (SLN) concepts (first lymph node
draining the tumor, reliably mapped, and if negative, an indicator to avoiding
ALND) were first reported for breast cancer by Krag et al. [3] (using isotope
mapping) and Giuliano et al. [4] (using blue dye), respectively in 1993 and 1994.
The SLN is the first, or first few, axillary lymph node draining the tumor
site and it could predict the status of axillary nodes. The SLN hypothesis has
A. Ala ()
Department of Surgery, Breast Surgery Unit,
Citt della Salute e della Scienza Hospital,
Turin, Italy
e-mail: aala@cittadellasalute.to.it
Updates in Surgery
101
R. Bussone et al.
102
been validated by randomized studies where routine ALND has been compared
with that performed only in the case of metastatic SLN, showing that a negative SLN is highly predictive of a negative axilla [5] and that the SLN is the
node likeliest to be positive if metastatization occurs [6].
Sentinel lymph node dissection (SLND) has therefore become a routine
technique for staging breast cancer with an axillary involvement.
6.2
Axillary Lymph Node Dissection
6.2.1
Technique
The axillary contents are arbitrarily divided into three levels: level I lies lateral to, level II lies posterior to, and level III lies medial to the pectoralis
minor muscle.
The question of what constitutes an adequate ALND in breast cancer has
not been answered yet.
It has been long accepted that ALND should proceed from level I to III step by
step, and that at least ten lymph nodes should be obtained from the axillary space.
Nowadays many authors recommend a level I to II ALND as the standard
operation (the skip metastases hypothesis proved to be simply a level II or
III SLN, receiving drainage directly from the breast) and a level III further dissection only in the case of palpably suspicious nodes in levels II to III or other
high-risk features such as T3 or T4 cancers.
The possible incisions for ALND are either separate from or contiguous
with the incision used for the breast surgery. Separate axillary and breast incisions are almost always cosmetically superior to contiguous ones.
A separate incision is best done transversely, extending from the lateral
border of the pectoralis major muscle up to the anterior border of the latissimus dorsi.
After skin incision, the lateral axillary margin, up to the anterior border of
the latissimus dorsi, is dissected. The tendinous portion of this muscle crosses
the axillary vein in the superolateral operative field.
Then clavipectoral fascia (extending from the coracobrachialis to the pectoralis minor muscle, encompassing it) is then incised superiorly along the
axillary vein; the axillary contents are mobilized inferiorly, and the axillary
vein is exposed in full view. To incise the clavipectoral fascia as far as possible, the retractor should be placed deep to the pectoral minus. With this
manoeuvre, level II of the axilla is also exposed.
When the axillary vein crosses the minor and major pectoralis, the medial
pectoral nerve can be found; it lies lateral to the lateral border of the two pectoral muscles and innervates the lower third of the pectoralis major. It should be
preserved whenever possible, because if it is injured it causes muscle atrophy,
which is visible after mastectomy, especially with implant breast reconstruction.
The entire accompanying medial pectoral vessel is ligated and divided.
6 Sentinel Node Biopsy and Axillary Dissection
103
Fig. 6.1 Intercostobrachial nerve (preservation is not mandatory)
Fig. 6.2 Long thoracic

nerve and thoracodorsal
neurovascular bundle
(their preservation is
mandatory)
The intercostobrachial nerve can be sacrificed (Fig. 6.1), but the long thoracic nerve (which runs on the lateral chest wall, near the axilla floor, beneath
the thin fascia of the serratus anterior muscle) and the thoracodorsal nerve
(which runs medial to the thoracodorsal artery and vein) must be preserved
(Fig. 6.2). The thoracodorsal neurovascular bundle lies posteriorly, on the axillary floor, and is better identified after the ligation and dissection of the thoracoepigastric vein (the largest side branch of the axillary vein) and by retracting the axillary contents inferiorly. The entire axillary contents are then
removed.
A drain (21 gauge or 10 mm Jackson-Pratt) is put in place, the incision is
closed with a multi-layer suture and a compressive dressing is applied (Fig. 6.3).
R. Bussone et al.
104
Fig. 6.3 Surgery field

after ALND
6.2.2
Primary Axillary Lymph Node Dissection
The main goals of axillary surgery are:

1. Local control
2. Survival
3. Staging.
6.2.2.1 Local Control

Axillary recurrence after primary ALND is very low (< 2%) [79]. The prognostical meaning of axillary recurrence is different if it is combined with distant metastasis (about 50% of the patients) [10].
If recurrent axillary node metastasis show up after primary ALND and it is
the only recurrent site, prognosis is similar to that of a new diagnosed cancer
with positive lymph node and salvage redo ALND (technically more difficult
because of the scar tissue from the previous surgery) is usually curative [11].
6.2.2.2 Survival
In the past, most studies showed that patients who underwent ALND at the
time of lymph node metastasis diagnosis had a lower overall survival (OS).
This might had been because primary ALND was not performed at the time of
breast cancer diagnosis and, most likely, because of the disease understaging,
which involved avoiding adjuvant therapy.
On the other hand, recent studies show that ALND does not confer a survival benefit in the setting of early-stage clinically lymph node-negative breast
cancer. In a 2009 meta-analysis, even though the axillary local recurrence rate
is higher in patients that do not undergo ALND, the OS is not statistically different [12].
105
A 2011 meta-analysis, enrolling 8560 patients in eight randomized clinical

trials, does not show statistically significant differences in disease free survival (DFS), OS and axillary recurrence for patients treated with ALND or
(only) SLND, with axillary lymph node-positive or negative. Also SLND,
compared to ALND, shows less postoperative complication and a better quality of life in the long term [13].
The neo and/or adjuvant therapy, hormone therapy and radiotherapy play a
major role nowadays in the OS after axillary recurrence [14].
The primary ALND can improve DFS and OS in cN0 patients with lymph
node metastasis that still have not a systemic hematic diffusion of the disease.
6.2.2.3 Staging
Some years ago a positive axillary lymph node result was considered the main
risk factor for distant metastasis. The more lymph nodes that were involved,
the higher was the risk. Systemic adjuvant therapy was strongly influenced by
the number of axillary lymph nodes involved.
At the 2011 St. Gallen consensus conference, it was stated that the biological characteristics of the tumor play a major role in determining whether systemic therapies have to be used and that ALND is not needed anymore for
staging [15].
Even though ALND has lost its former main staging role, the number of
lymph nodes involved and the evidence of extra-capsular invasion of the nodes
still influence the adjuvant therapy and radiotherapy.
Indications for primary ALND are:
Clinically positive axilla
Axillary node metastasis on fine needle aspiration (FNA) or core biopsy
(CB)
Failed SLND
Positive SLN on intraoperative examination
Axillary local recurrence (ipsilateral or contralateral).
6.3
Sentinel Lymph Node
The sentinel lymph node/s is/are the first lymph node/s that drain the primary
tumor. Anatomical studies showed that the lymphatic drainage of the breast
starts from the deep part of the mammary gland (above the muscular fascia),
moves to the cutaneous lymphatic system of the skin, especially around the
nipple areola complex, and ends in the SLN.
6.3.1
Mapping
There are two validated techniques for SLN identification: blue dye (Patent
blue dye, PBD) and/or a radioisotope (technetium, Tc99m). The latter is bound
106
R. Bussone et al.
Fig. 6.4 Patent blue dye
tracer allows lymphatic
vessel identification
to a carrier, most commonly sulfur colloid in United States and colloidal albumin in Europe.
The identification success rate with blue dye alone varies from 65% to
90%, depending on the surgeons experience, and reaches 97% in combination
with the radioisotope [1618]. Using the radioisotope is definitely more
demanding, both from the spending and organization point of view.
The cost of technetium is very high (with an exponential increasing trend);
a nuclear medicine service and a nuclear doctor are required; surgery must follow radioisotope infiltration between 1 and 36 hours and a sensitive hand-held
gamma probe must be available in the operating room [19].
On the other hand, the blue dye technique is cheaper (Fig. 6.4). The dye is
injected in the subdermal plane, directly above the tumor, by the surgeon in the
operating room, some time before the surgery. The volume of dye injected
varies from 0.2 to 0.4 mL. All lymph nodes that show blue coloration are dissected (Fig. 6.5).
Patients who undergo this technique show a transient bluish color of the
skin and urine. A faint blue stain may persist at the breast injection site for as
long as 1 year postoperatively. About 0.5% of patients have an anaphylactic
reaction to the blue dye [20].
Fluorescent SLN mapping using green indocyanine (ICG) is currently
being tested. When the vital fluorescent dye is injected around the areola, subcutaneous lymphatic channels draining from the breast to the axilla are visible
by fluorescence; by tracking the fluorescence, it is possible to choose a better
location for skin incision and find the SLN, which is the first lymph node that
gets fluorescent (Fig. 6.6) [21].
The cost of this technique is inferior to that using radionuclide and just a
bit more expensive than using blue dye alone. A infrared probe is needed to
visualize the fluorescence on the surgery site.
107
Fig. 6.5 The SLN is
blue colored and hypercaptating (note handheld probe on the right)
Fig. 6.6 Green indocyanine allows SLN identification by fluorescence

(infrared probe visualization)
6.3.2
Site of Injection
The tracer (PBD, Tc99m or ICG) injection site can influence the SLN identification rate. Intratumoral injection has been abandoned because of the low
identification rate related to the paucity of lymphatic vessels around the tumor,
which causes a slow and sporadic migration to the SLN.
Many studies showed that independently from the subdermal site of injection, in the quadrant of the tumor or in the retroareolar area, or the peritumoral
one the SLN identified by the tracer turned out to be the same [2224].
R. Bussone et al.
108
6.3.3
False Negative Scenario
The effect of the SLND false negative rate on the prognosis is unknown. An
overview of 69 papers showed a 7% false negative rate for SLND followed by
ALND [17]. However the axillary recurrence rate after negative SLND is less
than 1% [25, 26], because other factors influence axillary recurrence (adjuvant
therapy/radiotherapy of the axilla in the breast conserving technique, tumor
biology and rapidly growing distant metastasis).
6.4
Sentinel Lymph Node Dissection
6.4.1
Technique
SLND can be performed under general anesthesia and under local anesthetic
with intravenous sedation. Before starting surgery, blue dye is injected subdermally at a single site over the tumor. Using a hand-held gamma probe, the isotope injection site in the breast (radioisotope injected beforehand) is identified.
The axilla is usually explored for SLN through a separate transverse skin line
incision prior to the planned mastectomy or breast conservation procedure. As
dissection is deepened through the axillary fascia, any blue lymphatics are left
intact and traced proximally into the axilla, blue nodes are identified, and the
gamma probe is used to identify any hypercaptating nodes. SLN are usually
found low in level I, but in about 25% of cases they are found at other locations
(along the latissimus dorsi muscle, near the axillary vein, beneath the pectoralis
minor in levels II to III, as interpectoral or intramammary SLN).
The gamma probe is very useful throughout this dissection and is indispensable in patients with a very large or fatty axilla, when blue lymphatics or
nodes are not found.
All blue SLN and hypercaptating SLN are removed; a median of 23 SLN
per patient is submitted; when multiple hypercaptating SLN (or a diffusely
hypercaptating axilla) are found, every effort must be made to remove the SLN
with the highest count. All nodes with a count 10% of the highest count are
submitted together with the SLN. The axillary incision after SLN biopsy is
closed without drainage.
The morbidity from SLN biopsy is less than that of ALND but is not zero;
patients may experience pain, seroma, hematoma, or infection.
6.4.2
When to Perform Sentinel Lymph Node Dissection
SLND must be performed in patients with diagnosis of invasive breast cancer

obtained through: core biopsy (B5b), fine needle aspiration (C5), radiological
finding (U5, R5) and definitive anatomopathological finding on the surgical
specimen.
109
SLND can be avoided and ALND can be performed directly in U5 radiological patients with suspected metastasis [27]. If no metastasis are described
SLND must be performed.
The SLND contraindications that still hold true are inflammatory carcinoma (T4) and a C5 diagnosis on any axillary lymph nodes FNA, the others
(node diameter > 3 cm, multicentrical lesions, prior surgery and male breast
carcinoma) have been removed.
Some contraindications, neoadjuvant therapy, pregnancy, in situ lesions
and prophylactic mastectomy, are still under discussion.
In patients who undergo neoadjuvant therapy, the SLN identification rate is
comparable to that of other patients, with a false negative value of 8% [28];
nevertheless the false negative value goes up to 25% if the SLND is performed
in patients with proved metastasis at the diagnosis [29].
The biological meaning of a possible understaging related to a SLN negativization after neoadjuvant therapy is currently under discussion. The present
indication is performing SLND before starting neoadjuvant therapy. However,
SLND after neoadjuvant therapy is reasonable in cN0 patients.
The SLN identification rate during pregnancy and breast-feeding is just
slightly inferior to the standard and the technique does not cause teratogenic
effects. The onset of lactation must be pharmacologically blocked.
In the in situ carcinomas SLND must be performed only when the risk of
a diagnosis of invasive carcinoma at the definitive pathology test is high
(patients with a mass on clinical examination, G3 high-grade disease, distinctive radiological pattern and node diameter > 2.5 cm) and SLND should be
performed in patients undergoing mastectomy (because mastectomy precludes
it), in case invasive disease is subsequently discovered [30].
Performing SLND in patients undergoing prophylactic mastectomy is still
controversial. The incidence of occult disease is low but patients with locally
advanced or inflammatory primary breast cancer are at high risk for contralateral disease. This selected group of patients may benefit from SLND at the
time of surgery but further studies are needed to prove it [31, 32].
6.5
Axillary Lymph Node Dissection after Positive

Sentinel Lymph Node Dissection
When the SLN is negative, SLND alone with no further ALND is an appropriate, safe, and effective therapy in cN0 patients with breast cancer because OS,
DFS and local control are statistically equivalent [33].
Although ALND is indicated when there is clinical evidence of disease in
the axilla, it is still under discussion whether ALND should be performed in
clinically silent or SLND diagnosed metastatic lymph nodes, and if this could
positively influence the OS.
The classification of metastatic lymph node is based upon metastasis
dimension:
110
R. Bussone et al.
1. Isolated tumor cell clusters (ITC, small clusters of cells not greater than
0.2mm, or single tumor cells, or a cluster of fewer than 200 cells in a single histological cross-section. ITC may be detected by routine histology or
by immunohistochemical methods
2. Micrometastasis (greater than 0.2mm and/or more than 200 cells, but not
greater than 2.0mm)
3. Macrometastasis (greater than 2.0mm)
In the current TNM classification, ITC are defined as pN0(i+), they are not
considered metastasis and therefore they should not be treated with ALND
[3436].
The clinical meaning of micrometastasis, classified as pN1mi, is currently
unknown. Micrometastases are thought to have a smaller influence on OS and
DFS among patients with early breast cancer.
In some studies, no statistically significant differences were observed in OS
and DFS between patients diagnosed pN0 and pN1mi with SLND only [3739],
or between pN1mi treated with SLND only or with SLND plus ALND [40, 41].
On the other hand, the MIRROR study, a retrospective analysis recruiting
2707 patients with early breast cancer, found that: 1) micrometastasis and ITC
were associated in the absolute reduction in the 5-year rate of DFS of nearly
10 percentage points; 2) patients who received systemic adjuvant therapy (systemic chemotherapy and hormonal therapy), the 5-year rate of DFS was significantly improved [36]; 3) not performing axillary treatment in a patient with
SLN micrometastasis is associated with an increased 5-year regional recurrence rate (2.3% in pT0 and 5.6% in pT1mi); 4) tumor size, grade 3 and negative hormone receptor status are significantly associated with recurrence and
ALND is recommended in patients with SLN micrometastasis and unfavorable
tumor characteristics [38, 42].
So ALND is not always necessary in patients pN1mi, nevertheless it seems
important to be able to reliably identify the patient at high risk of axillary
recurrence. When the SLN is macrometastatic ALND should be routinely performed.
However, data from the American College of Surgeons Oncology Group
(ACOSOG) ZOO11 trial suggest that ALND may be omitted in select patients
with one or two macrometastatic positive SLN/s. In this trial, 891 patients with
HE positive SLN were randomized to ALND (446) compared to no further
axillary treatment (445). The patients all had cT1-2 N0 tumors, breast conserving surgery, whole-breast RT, no axillary RT, and no more than two SLN-positive; there were no differences between groups in the exposure to adjuvant
chemo or hormonal therapy and follow-up was 6.3 years. Additional positive
axillary nodes were found in 27% of ALND patients but there was no difference in the rates of axillary recurrence (0.5% in ALND group and 0.9% in
SLN-only group). OS and DFS did not show a statistically significant difference between the two groups [43, 44].
Considering the evidences from the Z0011 study ALND could be omitted
in selected patients with macrometastasis detected in one or two SLN/s, nev-
111
ertheless a cautious attitude should prevail since the study is characterized by

some methodological and statistical imprecision.
Furthermore, omitting ALND in pN1 patients should be proposed only in
clinical trials with backup adjuvant therapy. The importance of ALND for the
local control of locally advanced diseases is not under discussion. ALND is
also indicated for axillary local recurrence after negative SLND and for those
patients who relapse in the controlateral axilla and do not have other distant
sites of metastasis.
Further questions are whether ALND (with positive SLN) for detecting the
number of positive lymph nodes involved is still necessary to recommend
adjuvant therapy and for the planning of the right therapeutic strategy.
A recent study showed that axillary staging does little in addressing adjuvant therapy [45]. Furthermore the gene expression profiling seems to have a
more accurate capacity to predict the response to therapy when compared to
conventional histopathology alone. In the future, the concept of surgical nodal
status staging as a prognostic factor should be replaced by an integrative biological approach, in early breast cancer patients management.
6.6
Morbidity and Complications
A systemic review of studies concerning the morbidity of patients who had

undergone axillary surgery (SLND or SLND followed by ALND) reports great
variation in the prevalence of pain (7.536%), impairment of range of motion
(031%), edema (014%), decreased strength (1119%) and sensory disorders
(166%) [46].
Most of the studies show that women who underwent SLND alone have a
better quality of life (physical, emotional and social well-being, together with
cognitive function) compared to women who underwent complete ALND
[4749].
Likewise, patients who undergo SLND are significantly less likely to suffer postoperative complications typical of ALND [4951], such as lymphedema (7 to 82% incidence rate, directly correlated with patient age, body mass
index and infection or injury) [52], paresthesia (22.6%, caused by the inadvertent division of the intercostobrachial nerve) [49], restricted arm motion (6.6%
after 3 months, with a resolution rate over one year time of 85%) [49] and
infection/seroma (21%/16% incidence rate respectively, with a 42% lower risk
for wound infection with SLND alone compared to ALND) [50, 53].
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Part III
Specific Issues
Surgery for Ductal Carcinoma

In Situ (DCIS)
Federico Buggi, Matteo Mingozzi, Camilla Rossi,
Annalisa Curcio, and Secondo Folli
7.1
Definition
Ductal carcinoma in situ (DCIS) of the breast is a noninvasive breast cancer

that encompasses a wide spectrum of diseases, ranging from low-grade lesions
that are not life threatening to high-grade lesions that may harbor foci of invasive breast cancer; its histological characteristic is the proliferation of malignant epithelial cells that are bound by the basement membrane of the breast
ducts [1], which implies no stromal invasion.
Although DCIS does not fully express the malignant phenotype, women
with DCIS have an increased propensity to develop invasive disease, thus
therapy for DCIS is ultimately aimed at the prevention of invasive cancer [2].
7.2
Epidemiology
For most of the 20th century, DCIS represented less than 1% of all newly
diagnosed cases of breast cancer, and it was mostly a symptomatic disease
characterized by patients presenting with a palpable mass or a bloody or
serous nipple discharge. In terms of treatment, so far as the 1960s, DCIS was
usually thought of as a single malignant lesion and just one option was
offered to patients, that is, mastectomy [3]. From 19752008, according to the
Surveillance Epidemiology and End Results (SEER) program, in situ breast
cancers represented approximately 15% of all new breast cancer diagnoses in
the United States, with DCIS accounting for approximately 84% of all in situ
disease and lobular carcinoma in situ forming the bulk of the remainder. DCIS
S. Folli ()
Breast Unit, Morgagni-Pierantoni Hospital,
Forl, Italy
e-mail: s.folli@ausl.fo.it
Updates in Surgery
117
F. Buggi et al.
118
was estimated to account for approximately 27% of all newly diagnosed breast
cancers or 77,795 new cases in 2011; the age-adjusted DCIS incidence has
increased an average of 3.9% annually from 1973 to 1983 and approximately
15% annually from 1983 to 2008 [4]. The introduction of screening is considered largely responsible for the apparent increased incidence of DCIS in recent
times [5].
7.3
Natural History
Comparative histologic examination, and the finding of similarities in biology

and the molecular marker profile of DCIS and infiltrative lesions, supplied
evidence that DCIS can progress to invasive cancer.
A model depicting a spectrum of disease ranging from benign entities to invasive carcinoma may apply to breast cancer, with hyperplasia and atypical hyperplasia preceding DCIS, which may in turn be the final step in the pathway prior
to the development of invasive disease [6, 7]. In summary, DCIS is presently considered to behave as a nonobligate precursor of invasive carcinoma.
Because excisional biopsy (and, to a lesser extent, core needle biopsy)
removes a substantial portion of the targeted lesion, the natural history of
untreated DCIS is unknown [1]; however, it would seem that patients who
receive no treatment beyond a diagnostic biopsy remain at significant risk of
progression to invasive disease [5].
7.4
Biology and Classification
Nowadays, there is full awareness that the old concept of DCIS as a single disease entity is no longer valid and DCIS is considered a heterogeneous group
of lesions with diverse malignant potential [8].
An average estimate of risk of progression for untreated DCIS obtained
combining several studies is 43%, (1475%) [2]; in fact, the likelihood that
DCIS will progress to invasive disease is unclear. Several classification systems aiming at consistently providing prognostic information have been developed over time with the purpose to tackle the elusive biology of DCIS and to
rationalize its management.
The earliest classifications categorized DCIS by architectural description
into five groups: comedo (layer of neoplastic cells surrounding a central area of
necrosis), cribriform (radially oriented neoplastic cells forming glandular lumina), papillary (large papillations with fibrovascular stalks), solid (ductal filling
with neoplastic cells), and micropapillary (fingerlike papillary projections into
dilated ductal spaces) [2]. More recently it became common to summarize the
classification by grouping the latter four together as noncomedo DCIS and to
compare them with the remaining comedo lesions because it was noted, in general, that the latter is often associated with high nuclear grade, aneuploidy, a
7 Surgery for Ductal Carcinoma In Situ (DCIS)
119
higher proliferation rate, HER2 gene amplification or protein overexpression

and clinically more aggressive behavior [8]. Nevertheless, it is presently
accepted that architecture alone is a poor way to classify DCIS, while other factors that reflect the biological potential of each individual lesion [9] should be
the basis for a classification system that has prognostic cababilities.
Many systems were proposed [911] without any one being universally
accepted. Nuclear grade [12], the comedo subtype, presence or absence of
necrosis, tumor size and the presence or absence of inflammatory changes
have been found to be statistically associated with the risk of local recurrence
[13]; the most benign members of the DCIS family being small, low-grade,
and without comedo-type necrosis [14]. The natural history of DCIS displaying such favorable features and treated by biopsy alone has been evaluated
with long-term follow-up and, after a median of thirty-one years, 39% of
patients developed invasive breast cancer, all of which occurred in the index
quadrant; 45% of these patients died of metastatic disease [15].
7.5
Clinical Presentation
DCIS is mostly a screening mammography-detected form of highly curable,

noninvasive, early breast cancer [16]. As early as the 1990s, DCIS was radiographically evident as microcalcifications alone in 68% and as microcalcifications within a mass in 30% [17]. Nowadays, less than 10% of disease is palpable, with an abnormality found radiographically as the most common presentation; DCIS may also present as pathological nipple discharge with or without a mass or may be identified incidentally in a breast biopsy performed to
treat or diagnose another abnormality [4]. DCIS is rarely multicentric with
radiologic and pathologic correlative studies of mastectomy specimens in
patients with DCIS indicating only one multicentric lesion out of 82 mastectomy specimens [18].
Calcifications are typically pleomorphic, varying in size, form, and density, and are grouped in segmental or linear arrangements reflecting their presence in the duct.
Patients who present with a palpable mass have a significantly higher
potential for occult invasion, multicentricity and local recurrence than those
who present with nonpalpable lesions [19].
7.6
Treatment
Mortality is an extremely rare outcome for DCIS and local recurrence has been
reported to range from 1131%, with the lowest rates in mammographically
detected lesions [20]. Because DCIS itself is nonlethal, the goal of treatment is
to reduce the likelihood of developing invasive breast cancer while respecting
patient preferences for treatment options (breast-conserving surgery alone,
F. Buggi et al.
120
breast-conserving surgery followed by radiation and mastectomy) [21] or, in

other words, to maximize local control with the least-aggressive treatment [16].
7.6.1
Conservative Treatment
As studies conducted in the 1980s proved that breast-conserving surgery plus

radiation was equivalent to total mastectomy for invasive cancer, such results
were assimilated and it was assumed that the same findings would hold for
DCIS [17].
As far as survival is concerned, available data rely mostly on retrospective
studies comparing mastectomy, breast conservation with radiation (breast-conserving treatment, BCT) and breast conservation without radiation (breastconserving surgery, BCS) that showed similar survival rates, ranging from
98100% [4]; in fact, prospective trials are not feasible owing to the need for
an enormous sample size to detect a potential difference [16]. Therefore, it is
presently accepted that treating DCIS is not about survival but about limiting
the rate of local recurrence [4]. A meta-analysis of four randomized trials comparing adjuvant radiotherapy vs no radiotherapy following local excision for
DCIS reported a 10-year cumulative risk of any ipsilateral breast event (either
DCIS or invasive cancer) of 28.1% for BCS and 12.9% for BCS + RT; radiotherapy resulted in approximately halve the rate of ipsilateral breast events in
all four trials, with no evidence of heterogeneity between the trials in the proportional reduction [22]. Remarkably, approximately half of the recurrences
after BCT are invasive cancers and up to one-fifth ultimately metastatic [23].
Even in women identified, a priori, as a group expected to be at low absolute
risk of ipsilateral breast events, for whom radiotherapy might therefore provide little absolute gain (negative margins and small, low-grade tumors), the
10-year risk of an ipsilateral event in those allocated not to receive radiotherapy was substantial at 30.1% with a 10-year absolute gain of 18.0% [22].
Overall, the yield of presently available trials is that BCT is the standard of
care for treating DCIS in patients without contraindications to this approach [2];
it is proposed to roughly two-thirds of DCIS patients. BCT is presently used in
DCIS for similar indications as for invasive carcinoma and involves the wide
excision of tumor to negative margins followed by whole breast irradiation [16].
Since DCIS is most commonly a nonpalpable lesion, several issues concerning pre- and intraoperative assessment of the extent of the disease as well
as the definition of what constitutes a negative margin need to be addressed in
order to tailor a patient-specific treatment.
7.6.2
Extent of the Disease
Despite any efforts, precise preoperative assessment of DCIS extension

remains elusive because traditional clinical evaluation proved unreliable [24]
121
and recent diagnostic tools showed some limitations as well.

Breast magnetic resonance imaging (MRI) is currently being evaluated in
DCIS and has showed that it is capable of detecting DCIS (in particular highor intermediate-grade lesions), even though it does not accurately predict the
size of the tumor [25]. Albeit MRI has shown to be highly sensitive in the
detection of invasive disease, the sensitivity for DCIS is much lower, ranging
from 4080% [26]. Additionally, MRI can both under- and overestimate
involvement, from 1125% and 1128%, respectively [27, 28]. However, the
increased sensitivity in the detection of occult multifocality and/or extensive
residual disease may help to guide local management decisions. MRI can help
in demonstrating or excluding underlying invasive cancer, which can be
accomplished with high confidence because of the high negative predictive
value for invasive cancer, and/or in demonstrating the extent of (possible)
DCIS. Mammography and MRI imaging are complementary for diagnosis of
DCIS: while MRI does not depict all DCIS cases that manifest as calcifications on mammogram, mammography does not depict all DCIS that manifest
as contrast material enhancement on breast MRI images. On the basis of current research, it appears that indeed the overall sensitivity of MRI for highgrade DCIS is sustantially higher than that of mammography.
If there is any difference at all regarding the biologic potential of cancers
detected with MR versus those detected with mammography, then cancer
detected with MR tends to exhibit features that are associated with higher biologic aggressiveness [29].
However, unfortunately, MRI does not improve the surgeons ability to
achieve clear margins following breast-conservative surgery [25].
7.6.3
Intraoperative Localization
As DCIS are being detected as radiographic lesions only, the need for imageguided localization of nonpalpable breast lesions prior to surgical excision
emerged. The most common methods for localization in the perioperative
phase are the injection dyes into the lesion, the placement of a hooked wire
and the radioguided localization (ROLL, see below).
The techniques that use dyes rely mostly on methylene blue or vegetal carbon. In the former, diffusion of the dye throughout the breast occurs in a few
hours and, after that time, the lesion cannot be seen, so the interval between
localization of the lesion and surgery must be necessarily short [30]. The technique that uses carbon involves the injection of an inert carbon mark, which
stains the tissue black in color, does not diffuse into the surrounding tissue and
therefore can be used to localize the lesion by the surgeon days or weeks later.
The main advantages of carbon localization are logistics, patient comfort and
little expense but, moreover, in terms of missed lesions and histological margins, carbon localization proved to be accurate; in fact, as the carbon mark is
immobile in breast tissue, it cannot dislodge while, in contrast, hookwires can
F. Buggi et al.
122
migrate when the patient changes position or when traction is applied during
surgery. On the other hand, for extensive or multifocal lesions several carbon
marks are difficult to follow and the localization with multiple hooked wires
remains the method of choice [31].
The wire localization involves the insertion of a hooked wire into the breast
lesion under radiologic guidance. It is an effective technique but it has several disadvantages, the most clinically significant being a relatively high positive microscopic margin rate following excision; in addition, the localization
wire has the potential to migrate at many stages prior to and during surgery
and, in cases of small lesions, precise localization of the target lesion may be
difficult due to the thickness of the tip of the wire. Besides, there have been
reports of wire transection occurring during the time of surgery and it should
be noted that the insertion site of the wire on the skin may be remote from the
ideal surgical incision in many cases, resulting in an undesirable incision and
more extensive dissection to locate the lesion and wire tip [32].
In the late 1990s, a method for localization of nonpalpable lesions called
radioguided occult lesion localization (ROLL) was described, that is based on
intratumoral injection of a nonabsorbable technetium radiotracer, preoperative
scintigraphy to display the injection site, and surgical excision of the lesion
with the aid of an intraoperative gamma detector probe. In a prospective investigation [30], the greatest advantage of ROLL in comparison with wire localization technique resulted the feasibility of performing both nonpalpable
lesion localization and sentinel node biopsy with a single intratumoral radiotracer injection. In addition, ROLL is somewhat simpler and faster to perform
for both radiologist and surgeon and can result in less discomfort to the
patient. One of the main disadvantages of ROLL is that the radiotracer is not
visible on mammograms, thus it is more difficult to assess the limits of the
lesion; to overcome this limit, some authors inject non-ionic iodinated watersoluble contrast material concomitantly with the radiotracer to verify the distribution in the lesion and surrounding tissue. However, it is possible that joint
use of ROLL and hooked wire may be advantageous to some patients, namely
those with extensive areas to be bracketed [30].
7.6.4
Margin Assessment and Re-excision
DCIS is primarily a unifocal disease, with only 8% of DCIS patients having a

multifocal growth pattern with gaps more than 10mm between foci of DCIS
[33].
Against this background, the assessment of surgical margins comes to the
fore as the most important detail in the pathologic evaluation of DCIS in
patients under consideration for breast conservation and its results are
extremely interesting because it is one of the few clinical variables that can be
controlled at least in part by physicians with the use of a wider surgical excision or with a re-excision [34].
123
The National Surgical Adjuvant Breast and Bowel Project definition of a

negative margin is no tumor cells on ink from the lumpectomy specimen [35]
and, actually, consensus exists that microscopic extension to the surgical margin warrants further surgery [36], even though the definitions of positive and
negative margins are variable in the literature; in fact, beyond the definition of
tumor touching an inked surface as a positive margin, there is little consensus
on the precise margin width necessary to maintain local control [33].
Consensus about the treatment of positive margins is based on the risk estimate for ipsilateral breast tumor recurrence for DCIS patients with a positive
margin, that is 2.25-fold higher compared with patients with negative margins
[37].
As far as margin width is concerned, studies have shown that margins less
than 1mm imply significant risk of recurrence [38]. A panel of experts recommended a 2-mm margin for DCIS [39], while there may not be additional benefit with a margin greater than 2mm [40].
A multiple-treatment meta-analysis [41] conducted in order to assess the
effectiveness of different margin widths found consistent evidence that the
larger the margin the lower the ipsilateral breast tumor recurrence (IBTR). In
particular, the risk of IBTR was lower with a negative margin larger than
10mm than with a negative margin larger than 2mm, regardless of RT status
and this finding led the authors to state that wider margins minimize the risk
of IBTR and should be a priority for clinicians making surgical plans.
In facts, what constitutes an adequate surgical margin in partial mastectomy is still an open question and in surveys of surgeons and radiation oncologists, none of the margin definitions provided (tumor not on ink, > 12mm,
> 5mm, > 1cm) were endorsed by more than half the respondents when treatment with BCS included radiotherapy [42].
Lack of consensus is also implied by the fact that a failure to achieve
appropriate margins at the initial operation leads to re-excision in a proportion
of cases that ranges between 30% to 60% of cases [43]; approximately half of
these procedures are performed in women with negative margins to obtain a
wider clear margin in the belief that a wider margin will further decrease the
risk of local recurrence [44]. Unfortunately, re-excision may have multiple
adverse consequences, including worsened cosmetic outcome, delay in adjuvant therapy and higher cost of care [45]; when indicated, re-excision should
not be carried out before inflammatory response and induration has subsided.
BCS has not always produced good cosmetic results in all patients because
achieving both complete removal of the cancer with adequate surgical margins
while preserving the natural shape and appearance of the breast together in the
same operation can be challenging; one of the limiting factors is the amount of
tissue removed, not only in terms of absolute volume but also in relation to
tumor location and relative size of breast [46]. Another limiting factor may be
a DCIS located close to Coopers ligament, requiring the removal of a skin
area that may hamper the ideal incision (see Fig. 7.1 and Fig. 7.2). The failure
of classical BCS techniques to offer solutions for challenging scenarios has
124
F. Buggi et al.
Fig. 7.1 Digital mammogram showing two clusters of microcalcifications (DCIS), extending to Coopers ligaments
Fig. 7.2 Low-power conventional histologic image (H&E) taken from the specimen of the case depicted in Fig. 7.1; DCIS with microcalcifications and necrosis projecting into a Coopers ligament
stimulated the growth of oncoplastic surgery, which has emerged as a new

approach to allow wide excision for BCS without compromising the natural
shape of the breast. It is based upon integration of plastic surgery techniques
125
for immediate breast reshaping after wide excision for breast cancer and its
oncologic efficacy in terms of margin status and recurrence compare favorably
with traditional BCS.
In patients undergoing localization lumpectomy for nonpalpable breast
cancer, it was suggested that a reliable perioperative predictor of margin
involvement could guide the extent of excision and consequently reduce the
drawbacks that come along with reoperation [47]. Therefore many methods of
intraoperative margin assessment have been proposed in the attempt to reduce
rates of positive margins, that is, serial sectioning and intraoperative radiography, intraoperative sonography, imprint cytology and frozen section margin
analysis; recently, an innovative intraoperative margin assessment device that
uses radiofrequency spectroscopy to detect differences in dielectric properties
between normal and malignant breast tissue was designed [48].
The practicality of each method remains dependent on institutional breast
surgery volume and resources, and not one has gained widespread acceptance
as a result [49], but the value of specimen radiography and comparison of
specimen radiographs with the preoperative mammograms in verifying complete excision of nonpalpable lesions has been well demonstrated [50].
However, radiologic assessment alone is insufficient for accurate evaluation of
margin status and some studies have demonstrated that margins that appear
negative on specimen radiography may be histologically positive in up to 44%
of cases [51]. Again, no consensus exists on what constitutes an adequate margin on an intraoperative radiogram and, in particular, so far no study has
addressed the correlation between such margin and the actual margin at final
pathology.
7.6.5
Mastectomy
The relative rate of mastectomy for DCIS has been decreasing over the last
three decades and the procedure is now undertaken in approximately one-third
of patients; it is particularly suited to immediate breast reconstruction with an
implant and/or autologous flap, as adjuvant RT and lymph node involvement
are unlikely [23].
Although no prospective randomized trial has compared outcomes after
mastectomy with those after breast-conserving surgery [2], a meta-analysis of
studies published up to 1998 reported local recurrence rates of 22.5%, 8.9%,
and 1.4% for lumpectomy alone, lumpectomy with radiation, and mastectomy,
respectively [51]; the latter actually affords excellent local control, approximately 98% at 7 years [52].
In terms of mortality, not one of the available observational studies has
showed a mortality reduction associated with mastectomy over BCS, with or
without radiation [1].
Thus, mastectomy remains an option for women who are not interested in
or who have contraindications to breast-conservation therapy, which includes
F. Buggi et al.
126
women in whom complete surgical clearance of tumor would result in unacceptable cosmesis, diffuse microcalcifications throughout the breast, and the
presence of a contraindication to radiation therapy [4]. In other words, mastectomy may be indicated for large tumors (above 4cm, but depending on breast
size), multicentric lesions, inadequate margins after BCS, local recurrence
after BCS (particularly with prior RT), and patient preference [5].
As stated above, regardless of the intervention, complete excision of DCIS
with clear margins is the most important factor in reducing the risk of IBTR;
however, treatment by mastectomy differs from breast conserving therapy in
important ways that may result in a lower risk of a chest wall recurrence
despite a positive or close margin.
In one of the largest series of patients with pure DCIS and positive mastectomy margins, after a median follow-up time of about 7 years, the crude rates
of chest wall recurrence were 1.4% for all patients and 4.5% for patients with
close or positive margins [53].
In fact, all forms of mastectomy leave residual breast tissue but even
among mastectomies differences exist between conventional and conservative
mastectomies in terms of the microscopic breast tissue left behind in the skin
and the inframammary fold, which is largely preserved in the latter [54]; however, skin sparing mastectomy did not prove to be a risk factor for locoregional recurrence on either univariate or multivariate analysis [54].
Even the most conservative of mastectomies, namely the nipple-sparing
mastectomy (NSM), has proved to be oncologically safe in patients with
defined clinical and pathologic criteria, mostly regarding the tumor-to-breast
size ratio, the absence of pathological nipple discharge and the distance
between the tumor and the nipple-areola complex; therefore, provided that
such criteria are met, DCIS can be treated also with NSM [55].
7.6.6
Sentinel Lymph Node Biopsy
As its very definition would suggest, DCIS is incapable of breaking through

the ductal basement membrane, of accessing breast lymphatic channels, and of
spreading locally, regionally, or distantly; it is by definition incapable of
metastatic spread and therefore, theoretically, searching for metastatic spread
of DCIS would be useless and might otherwise yield potential problems causing morbidity.
On the practical side, the strongest argument for sentinel lymph node
(SLN) biopsy in DCIS is the diagnostic uncertainty [56], and inherent sampling error of conventional pathologic techniques; therefore, despite nomenclature, SLN biopsy is presently indicated in patients diagnosed with DCIS, if
concern exists that an invasive component would be identified in the specimen
during the definitive surgery. In fact, at subsequent surgical biopsy, DCIS was
proved to be invasive carcinoma in 20.4% of lesions diagnosed at large-core
biopsy, and in 11.2% of lesions diagnosed at vacuum-assisted biopsy [57].
127
Others reported that after minimally invasive biopsy, 844% of all breast
lesions preoperatively diagnosed as DCIS are misclassified and result in harboring microinvasive or invasive foci in the histology of the resected specimen
[58]. High-risk patients are those having a palpable or mammographic mass,
histology suspicious but not diagnostic for microinvasion, multicentric disease
requiring total mastectomy, or high nuclear grade or non-high nuclear grade
with necrosis; DCIS with microinvasion is in itself high-risk [59].
Similar conclusions were drawn more recently in a review of the experience of memorial sloan-Kettering cancer center with DCIS [17], which took
into account the upstaging rate: it was reported that only about 2% of all
women with high-risk DCIS or DCIS with microinfiltration are upstaged due
to SLN findings solely and so the authors concluded that while SLN biopsy
should not be routinely used for DCIS, it is appropriate in women undergoing
total mastectomy or in women in whom the suspicion of invasive carcinoma is
high.
Overall, such an attitude is reflected in presently existing guidelines. The
Italian National Operative Force on Breast Cancer (FONCaM) [60] reports
that there is no absolute indication to SLN biopsy in DCIS cases, but it is also
specified that in cases of high suspicion for microinvasion (namely high grading, high-risk mammographic pattern and extension above 5 cm), the procedure is advised; the 2012 edition of NCCN Guidelines suggest that a sentinel
lymph node biopsy procedure should be carefully considered while treating
DCIS (albeit clinically pure) if the patient is undergoing mastectomy or local
excision in an anatomic location that could compromise the performance of a
future sentinel lymph node procedure because a small proportion of patients
with apparently pure DCIS will be found to have invasive cancer at the time
of their definitive surgical procedure.
7.7
Closing Remarks
The presently validated gold standard for treatment of DCIS is BCT (including oncoplastic techniques), while mastectomy is indicated for patients who
have contraindications to breast conservation and this situation accounts for
roughly 30% of cases. SLN biopsy is indicated when high suspicion for invasive disease is present despite the existing diagnosis of DCIS; unfortunately,
consistent risk stratification for underlying infiltrating disease is still elusive.
While our current treatment approach to DCIS is based on morphology
rather than etiology and on phenotype rather than genotype [8], future treatment will probably not be based only on further fine-tuning of already known
prognostic factors; in addition to these refinements, hopefully genetic changes
preceding the acquision of invasive phenotype will be fully recognized. A
thorough understanding of malignant transformation from genetic changes to
cell behavioral features could ultimately lead to their prevention, therefore
defusing the malignant potential embedded in DCIS.
F. Buggi et al.
128
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Radioguided Surgery
Paolo Burelli and Christian Rizzetto
8.1
Background
Wide-spread national breast screening programs, new diagnostic technologies for

imaging and growing media awareness have undoubtedly led to a greater increase
in the early diagnosis of breast cancer (BC) [12].
Incidence of nonpalpable lesions ranges between 17 and 58% in worldwide literature [3, 4]. Currently, more than 30% of breast lesions visualized by mammography and/or ultrasonography (US) are clinically nonpalpable and this percentage
is even more significant considering that it referred only to neoplastic disease [5].
Consequently, early detection of BC has brought a decrease in morbidity and mortality [6].
This subset of patients presents with a disease in which guidance to two structures is often necessary because in addition to having the tumor localized itself,
patients with nonpalpable lesions also need to identify the sentinel node. Sentinel
lymph node identification is known to be another factor in favor of a conservative
treatment in surgical management of BC.
Moreover, accurate localization of a nonpalpable lesion allows a more correct
excision in favor of cosmetic and conservative surgery [7], and also the identification of the sentinel node can permit avoidance of axillary dissection [8]. Therefore,
the issues for breast surgeons in the surgical treatment of nonpalpable lesions are
the precise localization and excision.
The gold standard is certainly the excellent centering of the lesion within the
specimen with a limited resection of parenchyma and in the case of cancer, the
complete removal of the tumor itself with macroscopically adequate surgical margins (Table 8.1).
P. Burelli ()
Department of General Surgery, Breast Unit, Santa Maria dei Battuti Hospital,
Conegliano (TV), Italy
e-mail: paolo.burelli@ulss7.it
Updates in Surgery
131
P. Burelli, C. Rizzetto
132
Table 8.1 Nonpalpable breast lesions
Type of lesions
Method of localization
Microcalcification
33.5
STEREOTACTIC
Radial scare
21.7
STEREOTACTIC/MRI
Opacity
32.8
ULTRASOUND/MRI
Spiculate mass
12.0
ULTRASOUND/MRI
The routine use of radioactive tracer techniques to guide identification and excision of breast lesions such as nonpalpable nodules, radial scare or microcalcifications, both as a diagnostic and therapeutic tool, as well as the biopsy of sentinel
lymph node, both favor the increase of radioguided breast surgery [9].
Radioguided surgery (RS) is currently the safer and better performing method
of detection and excision of nonpalpable lesions and sentinel lymph node for the
breast surgeon. This method is based on the injection of an isotope, with known
biological behavior, releasing radiation that is detected by a probe and involves
intense collaboration between surgeon, nuclear physician and radiologist.
RS contemplates the radio-occult lesion localization (ROLL), the identification
and the biopsy of sentinel lymph node and the sentinel node occult lesion localization (SNOLL) that combines both techniques at the same time [10].
Currently, in agreement with nuclear physicians, RS is also defined as innovative Guided intraOperative Scintigraphic Tumour Targeting (GOSTT) [11].
8.2
ROLL Technique
8.2.1
Introduction
The ROLL technique was developed at the European Oncologic Institute in Milan
in the first half of the 1990s [12] and then refined according to different modalities,
supplanting the wire guide localization (WGL) in terms of precision, accuracy and
efficacy [4].
This method derives its advantage from the accuracy in locating nonpalpable
lesions through an intralesional injection of a small amount of a radioactive tracer,
which is injected more frequently during US, but also by stereotactic guide,
depending on whether nodes are sonographically visible, microcalcifications present or clips (metal gell-mark, hydromark) left in place after mammotome study or
core biopsy (Fig. 8.1). The radioactive tracer is subsequently identified intraoperatively by a gamma probe [13].
The dose involves the injection of 99mTc-MAA 4MBq in 0.1cc followed by
0.1cc of air and by 1cc of iodium contrast if the injection was done under stereotactic guide. The size of albumin aggregates are 100150nm in dimension in order
to prevent the migration of radioactive tracer guaranteeing its permanence at the
injection site. The use of a proper probe for the detection of gamma radiations in
the form of digital (strokes per second-sps) or acoustic signal allows the intraoper-
8 Radioguided Surgery
133
Fig. 8.1 ROLL: injection of the
radioactive tracer in the breast
node by ultrasound guide
ative localization of the inoculated lesion and its precise surgical radioguided resection [14].
8.2.2
Indications
ROLL is indicated in the presence of nonpalpable lesions detected in US, mammographically or after magnetic resonance of the breast.
Nonpalpable breast lesions can be detected as sonographically visible nodes or
as clusters of microcalcifications, parenchymal alteration such as radial scar or a
clip left after previous minimally invasive diagnostic procedures for histological
typing, such as tru-cut and core biopsy by US or stereotactic guide with mammotome or magnetic resonance (MR).
8.2.3
Technical Execution
ROLL is a composite multidisciplinary procedure based on multiple connected

steps and is carefully performed in order to obtain the highest effectiveness. The
execution steps are summarized as follows:
Intralesional injection of the radioactive tracer under ultrasound guide and
direct verification of the centering
In case of stereotactic centering, a minimal amount of water-soluble radioopaque contrast with mammographic verification of occurred centering
Capturing of the scintigraphic image
Radioguided surgical excision
Intraoperative radiography of the removed surgical specimen (Fig. 8.2)
Histological exam.
Therefore, there are specialized skills involved in the implementation and in
the performance of the procedure: radiologist, nuclear physician, surgeon and
134
Fig. 8.2 ROLL: x-ray of the
surgical specimen with clip after mammotome
pathologist. Multidisciplinarity, combined with a proper organization that respects

given procedures, are the key requirements for a proper execution of ROLL [14].
Injection of the radioactive tracer is performed by the nuclear physician in collaboration with the radiologist. The radioactive tracer consists of about 0.05 mg
human albumin macroaggregates with diameter ranging from 10 to 150 microns
linked with 4 MBq of 99m-Technetium (99mTc) diluted in 0.10.2 cc of saline
solution. The injection is performed inside the lesion or in of the area corresponding to the microcalcifications or clip, under US or stereotactic guide, either in the
morning or afternoon, or even only a few hours before the operation according to
organizational needs. In case of US centering, verification of the proper centering
is directly and immediately revealed by the structural modifications of the lesion
consequent to the injection of 0.10.2cc of air following the radioactive tracer. For
lesions stereotactically centered, 0.10.2ml of water-soluble radio-opaque solution
is also injected in order to be able to subsequently verify the proper centering with
mammography [13].
Human albumin aggregates that are contained in the tracer used for ROLL are
of a dimension that prevent its migration through the lymphatic vessels and keep it
permanently trapped at the site of injection for at least 2436 hours.
Breast scintigraphy in anteroposterior and lateral positions performed after
injection is mandatory to verify the proper and punctiform centering of the lesion
with reference, for example, to the nipple, the breast fold or to the axilla. Also any
possible spills with skin contamination must be highlighted, any possible intraductal or intravascular spread with the presence of other or multiple areas of radioactivity that would make difficult or impossible the identification and then the excision of the centered lesion [13].
8.2.4
135
Surgery
The equipment used in the localization of the radioactive tracer in the RS involves
the use of a radioactivity detector in the form of a probe made by a metallic cylinder containing inside a crystal scintillator or a detector solidon (Ca, Zn, tellurium),
capable of detecting gamma radiations released by 99m-Tc and transforming them
into an electrical signal. The probe is connected by wire or a bluetooth wire fire system to an external processor converting the recorded radioactivity either into a digital signal (sps) readable on a display or into an acoustic signal with intensity and
frequency proportional to the radioactivity captured over the investigated area [12]
(Fig. 8.3).
In the operative room, initially the probe can be used by slowly passing over the
surface of the breast in a perpendicular fashion to identify the orthogonal projection on the skin of the lesion itself and to highlight it with a dermographic pencil.
In this way, the surgeon can choose the more appropriate incisional site and type,
according to the position of the lesion.
Radial incisions are preferred in the case of intraductal calcifications, highly
suspicious lesions, and localized lesions in the lower quadrants. While arcuate incisions are mostly preferred for lesions localized in the upper quadrants. Incisions
around the nipple, with an excellent esthetic result, are preferred, if possible, for all
benign lesions.
Once the incision has been carried out, the probe, inserted in a sterile sheath, is
from time to time moved and positioned on the surgical field in order to verify that
the higher intensity of the signal is always at the center of the part being excised.
The surgeon, reading the LED-display or listening to the intensity of the
acoustic signal, is able to precisely identify the area with the highest intensity of
radioactive signal and then guide the surgical resection around it.
Once the specimen is removed, the probe can immediately verify whether the
capitation is highest in the center. Reintroducing the probe into the surgical field of
the performed resection the surgeon will be able to verify the absence of residual
signal as proof of the complete removal of the previously centered lesion (Fig. 8.4).
Fig. 8.3 Device for detecting acoustic and digital signal
136
Fig. 8.4 ROLL: uptake occurs

on the node removed
The specimen is then x-rayed preferably on a grid or either oriented defining the
surgical margins with clips or stitches to make the pathologists task easier.
The adequate centering and excision procedure in RS of nonpalpable lesions
allows a greater than 98% retrieval rate, making ROLL the ideal surgical procedure
for nonpalpable breast lesions [12].
8.3
Sentinel Lymph Node Biopsy (SLNB)
8.3.1
Introduction
In the early 1990s, Krag, by using an intraparenchymal injection of technetium99m sulfur colloid, was the first to investigate radioguided sentinel lymph node
technique in breast surgery [15]. The procedure has since been refined at the
European Oncologic Institute in Milan [16, 17].
This method of locating the sentinel lymph node using a radioactive tracer has
been rapidly adopted by breast surgeons, thus reducing morbidity, operative time
and hospital stay [16, 17]. Several randomized trials in the late 1990s have established the efficacy of information resulting from the SLNB as important data
among prognostic factors of BC [17]. This is based on the proven assumption that
the metastatic involvement of the axillary nodes proceeds in a progressive fashion
from the first to the third level of Berg and that the skip of a level can only occur
only in exceptional cases [18]. The sentinel lymph node is, as a matter of fact, the
first lymph node to which the primary tumor relays lymphatic drainage.
Radioguided SLNB is currently considered the method of choice in staging BC
in order to avoid useless axillary dissection, which is potentially harmful due to the
related side effects [15, 17].
Indications for SLNB have been gradually extending to almost all cases of BC
[1924] for which the current absolute contraindications are limited to carcinomatous mastitis and clinically evident metastatic lymphadenopathy [25].
8.3.2
137
Technical Execution
The SLNB involves the use of a radioactive tracer that is injected in the breast the
day before surgery. It is made of colloidal particles of human albumin, approximately 80nm (Nanocoll ) in diameter, labeled with technetium-99m. The injection consists of 4050MBq of 99m-Tc-nanocol in 0.1cc of solution. The injection
can be performed perilesionally or at the subdermal level on the skin with an
orthogonal projection of the nodes or alternatively at the subdermal in the periareolar area [16, 17].
The periareolar subdermal injection site guaranteed a better propagation
through the lymphatic drainage, the peritumoral route may have a slower propagation and delayed highlighting of the sentinel lymph node, but it has the advantage
of detecting any other extra-axillary drainage pathways such as those of the internal mammary chain; while the one on the skin projection may interfere with possible association of albumin macroaggregate used in the localization of the lesion
itself if a radioguided surgical procedure is done at the same time [26].
After administration of the radioactive tracer, it is preferable to perform a quick
and gentle massage over the injection site to facilitate migration of the tracer itself.
A couple of hours after the administration, a lymphoscintigraphy must be performed to obtain planar images through a gamma camera equipped with high resolution collimator. Images are obtained in anterior and oblique-anterior projection.
After identifying the sentinel lymph node location, its position is marked on the
orthogonal skin projection with a dermographic pencil. The ideal interval between
the administration of the radiocolloid and the surgical biopsy of sentinel lymph
node, ranges between 3 and 20 hours [26].
In specific cases (poor display of sentinel lymph node or localization in anomalous areas), it can be useful to obtain images with a SPECT-CT technique [27].
Lymphoscintigraphy can also highlight multiple sentinel lymph nodes (even up
to four), all enhanced and highlighted during the surgical biopsy. If the lymphoscintigraphy does not clearly show the sentinel lymph node, one more injection
can be performed preferentially at a subdermal periareolar site. Further failure in
displaying a sentinel lymph node can suggest a massive lymphangitic metastatic
invasion so it will be necessary to opt for a complete axillary dissection.
Hence, some parameters need to be considered in the administration of radiocolloid: the site of injection, the volume of the radioactive tracer and the interval
between the injection and the surgical procedure.
8.3.3
Surgical Technique
With the support of lymphoscintigraphy, radioguided SLNB is a rather simple technique. It can be performed either under local anesthesia or general anesthesia.
SLNB can be performed before, after or at the same time as tumor surgical treatment. The organizational aspects and modalities of pathologic evaluation of the
sentinel lymph node obviously affect the choice [17] (Fig. 8.5).
138
Fig. 8.5 Sentinel node: intraoperative biopsy
When pathological evaluation of the sentinel lymph node is performed as a

definitive examination, it may be preferable to perform SLNB under local anesthesia in outpatient surgery before the operation.
When performing an intraoperative examination of the sentinel node at the
same time as the surgical excision of the breast tumor, it is obviously preferable to
do it under general anesthesia.
In the latter case, SLNB should be carried out as the first step of the surgical
procedure and while waiting for the response of the pathologist, while the surgical
excision of the tumor should be proceeded with. Intraoperative examination of the
sentinel lymph node can be carried out by the pathologist with traditional histological technique at the cryostat also associated with immunohistochemical staining or,
finally, with the biomolecular method (called OSNA: one-step nucleic acid amplification) and therefore requires, accordingly, a timing between 30 and 90min [28].
The localization procedure using the gamma probe can highlight more than one
sentinel lymph node that will be identified as first, second, and third accordingly to the greater degree of uptake (strokes per second).
The type of surgical incision depends on the location of the primary tumor. If
BC is located in the upper external quadrant, then SLNB is carried out by the same
incision used for performing the upper outer quadrantectomy. If the tumor is located in one of the other quadrants (internal or lower), a second skin incision has to be
performed in the axillary area. In this case, a 35cm skin incision should be carried out as much as possible along the anterior fold of the axilla and on the presumed incision for axillary dissection.
If the SLNB is performed during a skin- or nipple-sparing mastectomy, the
same surgical incision can certainly be used. A separate incision is also obviously
recommended in the case of different procedures or if the SLNB is performed under
local anesthesia before breast surgery.
After skin incision, a blunt dissection of the subcutaneous tissue is performed
in order to reach the axillary fascia, this will be opened along the margin of the pec-
139
toralis major muscle, thus allowing access to the axillary cavity. At this point,
remaining orthogonal to the pectoral muscle in order to avoid injury to the underlying nerve fibers and vascular vessels, it is possible to deepen into the triangular
space limited medially by the pectoralis major muscle, laterally by the neurovascular dorsal-thoracic bundle and cranially by the axillary vein in order to begin the
search for the sentinel lymph node by using the gamma probe previously wrapped
in a sterile sheath.
It is necessary to dwell on the point of maximum radioactivity by slow and
accurate movements that, combined with the high spatial resolution and the high
sensitivity of the latest probes, allows for a precise identification of the sentinel
lymph node. Radioactivity will be revealed either by the emission of an acoustic
signal or by a digital signal visible on a display. Once the lymph node is identified,
it is possible to proceed to the isolation of its vascular pedicle and then remove it.
Outside the surgical field, a final re-evaluation of the radioactivity of the removed
lymph node that will be compared with that of any other sentinel lymph nodes.
Finally, it is recommended when using the probe, to check for any residual uptake
on the surgical field.
With regards to SLNB highlighted not at the axillary level but at the internal
mammary chain, it is necessary to perform a transverse incision at the level of the
2nd or 3rd intercostal space of 23cm in length. After mobilizing the breast glands
from the underlying fascia of the pectoralis major muscle, it is possible to spread
out the fibers of the muscle itself in order to expose the upper and lower ribs, the
intercostal muscles and the sternum. Removing the portion of the intercostal muscle adjacent to the sternum, a window will be created allowing access to the intercostal space, and thus allowing the removal of the tissue surrounding the internal
mammary vessels above the pleura that contains the sentinel lymph node [29, 30].
8.3.4
Conclusions
Radioguided identification of the sentinel lymph node is currently the safest, fastest
and most effective method in the armamentarium of the breast surgeon for BC staging. Therefore, the possibility to avoid axillary dissection and thus reduce morbidity in surgical treatment of BC has become a fundamental and essential surgical
strategy for the breast surgeon [25].
Normally, the search for the sentinel lymph node leads to highlight one or two
axillary lymph nodes in the first level. However, in some, rare cases the sentinel
lymph node can be highlighted behind the pectoralis major muscle in the second
level or in the sub-clavicle site in the third level. From 5 to 8% of BCs may involve
a lymph node of the internal mammary chain with evidence of a sentinel node at
this site [29, 30].
Usually, the morbidity rate of SLNB is very low especially compared to the
morbidity rate of axillary dissection, however possible complications could be
postoperative pain, development of lymphocele or hematoma and mild paresthesia
of the medial surface of the arm [31].
140
8.4
SNOLL Technique
The acronym SNOLL identifies the combined use of both radioguided excision of
nonpalpable lesions and radioguided SLNB.
In 2001, Feggi and coworkers [9] proposed a single nanocolloidal tracer injected into the tumor for simultaneous performance of ROLL and sentinel node identification and, in 2007, this technique became known as SNOLL in a publication
from the European Institute of Oncology [32]. As a consequence, for nonpalpable
malignant lesions all types of quadrantectomies and tumorectomies can be performed in combination with the radioguided SLNB [3335].
8.4.1
Execution Technique
Theoretically, it could be useful to use two different radioactive tracers and two different sites of injection: one for the localization of nonpalpable lesions according
to the already described ROLL technique (intralesionally/macroaggregates) and
another for the identification of the sentinel lymph node (nanocolloid microaggregates/subdermal perilesional area).
Several studies have looked at these important technical aspects regarding the
types of tracers to use, if one or two, and which location to prefer for the injection.
It is possible to use a single isotope (nanocolloid) with one or more injections in the
perilesional area [9, 10, 36], because most of the isotope remains in the area of the
lesion highlighting it for the excision and only a minimal portion of the tracer diffuses along the lymphatic vessels allowing the identification of the sentinel lymph
node [16, 17].
The day before surgery, 40MBq of nanocolloid labeled with 99m-Tc are diluted in a volume of 0.1cc and injected perilesionally, preferably on the front surface
under the guidance of US (also on clips at gell-mark or hydromark) or stereotactic
in case of microcalcifications or non-US visible clips (Fig. 8.6). Preoperative lymphoscintigraphy is performed at least 2 hours after the radiotracer injection in order
to highlight the sentinel lymph node [17] (Fig. 8.7).
Fig. 8.6 SNOLL: ultrasound
centering of hydromark clip after mammotome for DCIS
sentinel node
141
sentinel node
periareolar
injection
periareolar
injection
lesion
Fig. 8.7 SNOLL:

preoperative
lymphoscintigraphy
lesion
This method can result in the injection of a single radiotracer not properly highlighting the sentinel lymph node, especially in the case of adipose breast or of deep
lesions in the inner quadrants [9, 10]. In this case, it is possible to repeat the injection of nanocolloid in the periareolar area or subdermally on the orthogonal projection of the skin lesion. This particular event might create an obstacle in the radioguided excision of the breast quadrant due to the overlapping of the radioactivity of
the perilesional area and the skin over the lesion.
Instead, the most used method involves the injection of two tracers: one for
ROLL, and the other one for SLNB the day before the operation [3638].
The tracer for the tumor is based on macroaggregates of serum albumin
10150 m in size, labeled with 1015 MBq of technetium-99m and diluted in
0.2ml of sterile saline solution, and injected intralesionally by US or stereotactic
guide (in the latter case an iodine medium contrast is also injected to verify the correct radiological centering).
The radiotracer for SLNB is a nanocolloid labeled with technetium-99m. The
injection is performed in the subcutaneous periareolar site and subsequently, after
2 hours, a lymphoscintigraphy is obtained in anteroposterior and laterolateral projections in order to highlight the sentinel lymph node [39].
The orthogonal projection of the tumor on the skin is marked with a dermographic pencil as well as the projection of sentinel lymph node at the axillary area
(Fig. 8.8).
8.4.2
Surgical Technique
First stage surgery and SLNB is performed usually by an oblique incision at the
level of the anterior margin of the pectoralis major muscle or by an arched or cross
142
Fig. 8.8 SNOLL: preoperative
marking of skin for cancer and
sentinel node
Fig. 8.9 SNOLL:

centering of the tumor occurs
on the quadrantectomy
incision in the axillary site. The incision can be limited to a few cm and by using
the probe the sentinel lymph node can be isolated and easily removed. If an intraoperative pathologic examination is needed, it can be immediately sent to the
pathologist. While waiting for the response, the excision of the BC can be performed. In the case of metastatic involvement of the sentinel lymph node, lymphadenectomy will be accomplished by extending the axillary incision.
The surgical incision for the radioguided quadrantectomy or lumpectomy is modulated depending on the topographic location of the lesion within the breast [40].
Therefore, if the lesion is located on the superior external quadrant, the same
incision can be used for isolation and contextual excision of the tumor and the sentinel node. In the case of mastectomy, it is possible to perform SLNB by the same
skin incision used for the ablating surgical procedure.
The probe for RS allows the exact location of the tumor in the surgical specimen to be known at any time, in order to define, at least macroscopically, the margins to draw and follow for an oncologically adequate excision [33] (Fig. 8.9).
143
Fig. 8.10 SNOLL: preparation
of the quadrantectomy
for x-ray
Successively, the specimen must be anatomically oriented using clips or stitches. In the case of microcalcifications or clip left by mammotome examination, it is
necessary to take an x-ray of the specimen to highlight the correct centering of the
piece and the adequacy of the gross margins (Fig. 8.10).
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Pagets Disease
Luis J. Sanchez, Marco Bernini, and Jacopo Nori Cucchiari
9.1
Epidemiology and Pathology
Pagets disease (PD) of the breast was first described by James Paget in 1874
[1]. He described 15 women with a chronic eczematous lesion of the nippleareola skin with an associated intraductal carcinoma of the mammary gland.
This entity accounts for 14.3% of all breast cancers [2] and it is almost
exclusively seen in women, male reports are anecdotal. It is usually seen in
postmenopausal women and in the vast majority of cases a ductal carcinoma
in situ (DCIS) or an invasive breast cancer (BC) is found within the breast
gland in the following diagnostic work-up or in the pathology specimen [3],
this is confirmed in almost 100% of the hundreds of cases reported in the literature. The associated breast carcinoma is of ductal histotype, lobular carcinomas can extend into ducts and create a pagetoid spread but very rarely
reach a lactiferous duct and extend to the epidermis to give a proper PD.
Ductal carcinomas causing a PD can be in situ or invasive in their nature; they
are mostly of comedo or solid histotype, although foci of papillary, cribriform
and medullary forms can be found. Paget cells are usually quite big with clear
cytoplasm containing mucin, recalling their glandular origin, and sometimes
melanin, which is taken up from adjacent keratinocytes. These neoplastic cells
tend to stay on the basal layer of the epidermis either in a single level or in
clusters. Overlying epidermal cells can erode or give rise to keratosis, while
the dermis beneath shows signs of chronic inflammation, which is the reason
for the well-known clinical appearance of PD. Immunohistochemistry studies
have led to identify a nearly 100% sensitive marker, which is cytokeratin 7
L. J. Sanchez ()
Department of Oncology Surgery, Breast Unit,
Careggi University Hospital, Florence, Italy
email: luis.sanchez@tin.it
Updates in Surgery
147
L. J. Sanchez et al.
148
(CK7), while cytokeratin 20 (CK20) is never detected [4]. Other glandular

antigens are expressed by neoplastic Pagets cells, such as epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), gross cystic disease
fluid protein 15 (GCDFP-15) and many mucins, but they do not express either
high molecular weight CKs, as the abovementioned CK20 and others like
CK10, CK12, CK14, or melanocytic antigens [57]. Besides that, Pagets cells
express also heregulin receptors like HER2/neu or co-receptors like HER3 and
HER4. Such receptors regularly bind with the motility factor heregulin-alpha,
which is normally produced by epidermal keratinocytes. This is the most reliable justification of ductal carcinoma cell chemotaxis towards the nipple-areola epithelium [8]. In PD, the hormone receptor status of Pagets cells resemble the reactivity of underlying carcinoma. PD tends to be estrogen and progesterone receptor negative because the primary carcinomas are mostly poorly
differentiated. Approximately 50% of associated BCs are identified as a palpable mass [3]; when a mass is clinically evident an invasive breast cancer is
more likely to be the primary tumor. Otherwise, when neither clinical nor radiologic findings of tumor masses are clear, a DCIS is more likely to be hidden
in the breast gland beneath. Both invasive and in situ carcinomas tend to be
central beneath the areola complex, although often multifocal [9]. Another
study showed that 45% of those primary tumors that are identified as a palpable mass are located in the upper outer quadrant [10]. Other peripheral locations are described as well.
9.2
Pathogenesis
No specific risk factors have been identified to explain PD etiopathogenesis.

The origin of PD can be traced back to the superficial extension (epidermotropism) of malignant ductal epithelial cells derived from the underlying breast
gland through the lactiferous ducts epidermotropic theory, as extensively
described by Muir from 1927 to 1934 [1113] or an intraepidermal origin (in
situ transformation theory), based upon electron microscopic findings, which
showed desmosomal attachments between Pagets cells and keratinocytes,
possibly indicating a common origin platform [14, 15]. After the first description by Paget, which was only clinical, Jacobaeus gave, in 1904, the initial
possible pathological explanation of carcinoma cell migration through lactiferous ducts, based on histologic studies of three cases. Thereafter, Muir was
the one who comprehensively theorized such a model: malignant cells extend
from luminal lactiferous ductal epithelium and infiltrate the epidermis causing
the well-known chronic rash. There is also the theory of an origin from glandular stem cells or epidermal Toker cells already present in the nipple epithelium [16]. Toker cells are present in 10% of normal nipple epithelium, they are
benign and can proliferate causing a clear cell papulosis. Another theory, the
collision theory, suggests that the epidermotropism is not always applicable.
Sometimes there might be a coincidental presence of neoplastic Pagets cells
9 Pagets Disease
149
and of an underlying breast carcinoma, based on differences in chromosomal

alterations seen between Pagets cells and the underlying breast carcinoma
cells, leading to a possible different origin [17]. However, the majority of dedicated studies have shown shared genetic changes and biomarkers between PD
cells and underlying breast adenocarcinoma cells. In fact, all the abovementioned immunohistochemistry features, as well as hormone receptor status, are
usually shared in an identical fashion by the breast gland tumor and its epidermal counterpart. The chemotaxis realized by the binding of HER2/neu receptor and heregulin-alpha [8] is, as said before, the most reliable and appropriate molecular biology explanation for such an epidermotropic model.
9.3
Clinical Features
The clinical appearance of nipple-areola chronic rash must be recognized

promptly in order to initiate the appropriate diagnosis work-up and detect an
underlying BC. A similar rash can be seen in the skin of external male and
female genitalia, but this condition, known as extramammary PD, has nothing
to do with mammary PD in terms of pathophysiology and etiology. Early clinical sig ns are predominantly inflammatory, comprising a variety of manifestations such as redness, eczema, erythema and skin thickening or crusting. An
infiltrated border is usually found. These signs can be limited to the nipple, or
can be extended to the areola or even to the surrounding skin. Initial symptoms are pain and itching. This inflammatory presentation might mimic a
benign disorder and delay cl inical suspicion of PD. An advanced lesion has a
pink/red plaque appearance with demarcated borders and can ulcerate or even
destroy the nipple-areola complex (Fig. 9.1). Rarer but not infrequent is the
pigmentation of PD lesions, since Paget cells can take up melanin from normal keratinocytes, making the differential diagnosis from melanoma difficult
without immunohistochemistry. Nipple retraction i s common as well as any
type of serous/bloody discharge from it. PD has been described in ectopic nipples too.
9.4
Diagnosis
Once any of the typical clinical signs and symptoms described above raises the
suspicion of PD, a diagnostic work-up must suddenly be started. Physical
exam, mammographic x-ray (MXR) and breast ultrasound (US) are the first
line diagnostic step in order to find any possible breast lesion or mass, which
together with the clinical suspicion of PD, can corroborate such a diagnosis.
Physical examination can reveal a mass, which might then be seen as a nodule
by MXR or US. Even if neither masses nor nodules are palpable or visible,
microcalcifications could be a possible finding seen at MXR. Any dubious
breast lesion will be biopsied independently of PD suspicion. Simultaneously
150
Fig. 9.1 Typical clinical appearance of Pagets disease with
chronic eczema and nipple erosion within the nipple-areola
complex
a cytology test by nipple-areola scraping should be performed to confirm PD

diagnosis. If all these tests end up to be negative a dermatology consultation
and a short-time follow-up, at 2 weeks, might be a sensible option. However,
even if all the tests are negative, but the epidermal lesions are very worrying,
a full thickness skin biopsy must be performed. Otherwise, if any of the aforementioned tests turns out to be positive, it is of utmost importance to rule out
which one of the following three conditions can occur:
A breast carcinoma without PD
A PD without any momentarily visible breast lesion
A PD with an associated breast lesion, biopsy confirmed to be a carcinoma.
In the case of a confirmed breast carcinoma, within the mammary gland,
but negative cytology test for the nipple-areola eczematous lesion, if the PD
suspicion remains high, a full thickness skin biopsy must be performed to rule
out PD in a reliable way. In the case of a negative skin biopsy, we are facing a
BC without PD, which will be investigated and treated consequently, while a
positive skin biopsy, as well as a positive scraping cytology, put us in front of
a mammary PD. Eventually, after the diagnostic work-up, two situations of
mammary PD can occur: 1) PD with an associated BC; or 2) a PD without any
identified underlying BC (Fig. 9.2).
In both cases a breast magnetic resonance imaging (MRI) is a recommended second line investigation, especially when an underlying DCIS or invasive
cancer has not been identified by first line investigations. MRI can also help
in detecting multifocal/multicentric lesions and in better defining lesion
9 Pagets Disease
151
PD +
DCIS
Breast lesion
identified and
cytology test
positive
Clinical
suspicion
of Pagets
Disease:
Physical
exam
MXR
Breast US
Nippleareola
scraping and
cytology test
Perform
breast
lesion
biopsy
No breast lesion
identified, cytology
test positive
Breast lesion
identified,
cytology test
negative
Breast
lesion
biopsy
positive
Condition no.
1: Pagets
disease with
associated
breast
cancer
Breast
lesion
biopsy
negative
Perform breast
MRI to exclude further breast lesions
Perform breast MRI

to confirm the
absence of breast
lesions
Perform skin
biopsy and
breast lesion
biopsy
PD +
invasive
breast
cancer
Condition no. 2:
Pagets disease
only
Both biopsies
are positive
Consider MRI and treat

as for Condition no. 1
Breast lesion biopsy

negative, skin lesion
positive
Consider MRI and treat

as for Condition no. 2
Breast lesion biopsy

positive, skin lesion
negative
Both biopsies
are negative
All tests are negative, clinical suspicion

of PD very high
Mastectomy + BCS +
RT and SLNB in case
of mastectomy or
high risk for
invasiveness
Mastectomy + BCS +
RT and SLNB or ALND
(in case of positive node
biopsy)
NAC excision + central

quadrantectomy + RT
(consider SLND in
case of suspected
invasive cancer
Treat as for any

typical breast
cancer
Consider a Dermatology
consult and program a
breast imaging follow-up
or MRI
Dermatology consult, re-evaluation at two weeks

and consider full-thickness skin biopsy
Fig. 9.2 Diagnostic and therapeutic flow-chart of mammary Pagets disease
topography with respect to the nipple-areola complex (NAC) [18, 19].

However, such advice is only a category 2A recommendation, because there
are no randomized clinical trials to demonstrate that MRI gives any advantage
in terms of survival or recurrence rate in PD.
9.5
Treatment
Mastectomy with or without axillary lymph node dissection has been the standard surgical treatment for many years [20]. Things have changed over the
years but it is still not possible today to make a category 1 recommendation for
PD surgical therapy. Some studies have shown that breast-conservative surgery (BCS) followed by radiation therapy (RT) is an adequate option to treat
PD, achieving the same survival and local recurrence rate as after mastectomy
[2125]. This is in accordance with what has already been demonstrated for
any typical in situ or invasive BC [26, 27]. A BCS treatment should always
mean an NAC excision along with the underlying breast cancer, when identified. When feasible in a conservative manner, the associated cancer could be
excised even as a different specimen not in continuity with NAC, also using
different incisions. Otherwise, when an underlying BC has not been shown by
152
the imaging work-up, an NAC excision alone, with a portion of breast gland
tissue beneath, can be done, as long as the pathologist confirms a negative
margin status. All BCS treatments must be followed by whole breast RT.
Mastectomy remains the preferred option in case of very small breast volume,
multicentricity, and in such conditions in which RT will not be possible. A
skin-sparing mastectomy might be a valid option, either with immediate or
delayed reconstruction. RT alone for PD without an underlying breast nodule
or mass has been proposed as well [2830]. However, small numbers of cases
and conflicting results, make it an option to be reserved for very selected
cases.
Axillary staging is not necessary for PD per se, being PD an in situ lesion
in its nature. Nonetheless, PD is almost always accompanied by an underlying
BC, which is why axillary staging should be considered on a case by case
basis. In the case of an underlying invasive BC a sentinel lymph node biopsy
(SLNB) or an axillary lymph node dissection (ALND) must be performed
depending on the clinical staging of the axilla and confirmed metastasis by
percutaneous US guided biopsy. Instead, when an underlying DCIS is identified by preoperative work-up, SLNB is not mandatory, unless a mastectomy is
planned, since it will preclude any axillary staging in the future, or unless the
DCIS lesion has very suspicious features, which may turn out to be invasive at
definitive pathology response. There are two retrospective studies in the literature regarding SLNB in PD [31, 32], both demonstrating the accuracy of
SLNB procedure. The more recent one [32] favors SLNB in any case of PD,
since the risk of having an underlying invasive BC is as high as 27% even
without any imaging finding at the preoperative work-up, and thus would
avoid a second intervention (Fig. 9.2). In the case of breast-conservative surgery, as already explained, RT has to be performed after any BCS for PD, considering a radiotherapic boost on the surgical site and on the NAC area.
Adjuvant systemic therapies will be chosen based on the underlying BC
parameters. For the rare cases of PD alone, as for DCIS, patients are at higher
risk of developing any BC event in the future, which is why a Tamoxifen systemic therapy could be a viable option to be discussed with the patient.
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Breast Cancer in Pregnancy
10
Francesca Catalano, Giusy Scandurra, Concetta Ravalli,

Filippo Fraggetta, and Giuseppe Catanuto
10.1
Introduction
Breast cancer during pregnancy is a dramatic event that interrupts one the most
joyful aspects of the life of a woman. The diagnostic/therapeutic setting is deeply
affected by the presence of a second individual (the fetus) during its intrauterine
development. For this reason, the most common decisional pathways need to be
modified to minimize collateral effects. Termination of pregnancy is a possible issue that has to be discussed, although currently no evidence is available regarding any benefit in terms of improved survival.
A multidisciplinary diagnostic setting is likely to reduce the chance of exposing the fetus to excessive radiation. Similarly, all the treatments need to be discussed and planned in order to be, as much as possible, in keeping with the most
advanced therapeutic strategies for nonpregnant women and be tailored to the gestational age.
10.2
Clinical and Diagnostic Work-up
Breast cancer develops in women at an average age between 32 and 38 years old,
it is the most common cancer during pregnancy and after delivery, occurring in
about 1 in 3,000 pregnant women. Delays in diagnoses are common, with an average reported delay of 5 to 15 months from the onset of symptoms [1]. A clinical diagnosis is often hustled by the typical gestational changes that makes the mammary gland tender and painful. This may cause a diagnostic delay (approximately between one and two months from clinical onset) with cancer detection at a later stage in comparison to a nonpregnant age-matched population [2].
G. Catanuto ()
Breast Unit, Cannizzaro Hospital, Catania, Italy
email: giuseppecatanuto@yahoo.it
Updates in Surgery
155
156
F. Catalano et al.
For this reason, pregnant women should undergo regular breast examination during prenatal consultations. Breast cancer during pregnancy normally arises as a discrete nonpainful lump without any other specific characteristic. Nipple discharge
is often present during pregnancy and is not only associated with breast cancer [3].
We suggest that any family history of breast cancer is investigated as this has
been reported in approximately 48% of cases while a BRCA12 mutation has
been reported in 9% of the population.
Ultrasound (US) is the most appropriate radiologic method for evaluating
breast disorders in women during pregnancy and lactation; it has a high sensitivity (nearly 98%) and specificity for the diagnosis of breast cancer. It is used as a
guide to cytology or histological confirmation and to monitor the response to
chemotherapy [4]. Therefore, US is the gold standard for the evaluation of a palpable breast mass during pregnancy [5].
The increase in size, vascularization and glandular density of the breasts in a
pregnant woman is translated to an increase in radiographic density. At mammography, the gland appears very dense, heterogeneously coarse, nodular, and confluent, with a marked decrease in adipose tissue and a prominent ductal pattern [6].
The sensitivity of mammography in detecting malignant lesions during gestation
is less than 70%. However, it is the only method for studying suspicious microcalcifications [7].
The impact of prenatal exposure to ionizing radiation depends on three factors:
radiation dose, anatomic distribution of radiation, and stage of fetal development
at the time of exposure. On the first and second month of pregnancy (organogenesis), the fetus is the most susceptible to radiation-induced malformations (congenital lesions, growth retardation, perinatal death, and postnatal neoplasias) [8]. Malformations occur with exposure to more than 0.05Gy of radiation, a dose which
is much higher than a fetal radiation exposure in a standard two view mammography (0.004Gy) [9].
The role of magnetic resonance imaging (MRI) is still controversial because lactational parenchyma, shows rapid enhancement following the intravenous administration of contrast material, followed by an early plateau. In late pregnancy, it is
difficult for the patient to assume the prone position [10].
MRI with contrast agents is possible during pregnancy, but should only be used
when other clinical decision making methods and ultrasonography are inadequate.
No well-designed studies of the efficacy and safety of MRI of the breast during pregnancy have been reported, and results of some studies have shown that gadolinium-based MRI contrast agents pass through the placental barrier and enter fetal circulation. The European Society of Radiology recently stated that use of gadolinium during pregnancy is probably safe because the quantity expected to cross the
placenta is low, and it is rapidly eliminated by the kidneys. MRI with contrast can
be used during lactation; because a small amount of gadolinium is excreted into
breast milk, it is not prudent to breastfeed for 48 hours after the examination [11].
The routine use of MRI in the evaluation and treatment of pregnant patients is not
appropriate. No results of breast MRI specificity and sensitivity in pregnant patients
have yet been reported.
10 Breast Cancer in Pregnancy
157
Fine-needle aspiration is not an adequate diagnostic procedure during pregnancy or lactation due to the high number of false positive results because of physiological epithelial hyperplasia. Therefore, this procedure is not recommended during pregnancy. The standard examination to obtain a histological diagnosis is a core
biopsy under local anaesthesia, which can be done safely during pregnancy with
a sensitivity of around 90%. Lactation should be suppressed prior to biopsy in order to reduce the risk of abscesses and milk fistulas [12]. Beyond mammography,
ultrasonography and biopsy examination, others staging examinations should be
guided by the clinical stage of the disease.
A metastatic preoperative work-up, including a chest x-ray with shielding and
liver function tests, is needed in order to determine the feasibility of surgical treatment. In a woman with symptomatic advanced bony disease a noncontrast MRI of
the thoracic and lumbar spine to exclude bone metastases could be carried out. MRI
can also be used to scan the brain and the liver. The bone scan is the only staging
examination contraindicated in pregnancy.
10.3
Pathology
From the pathological viewpoint it has been reported that breast carcinomas occurring in pregnancy share histopathological and immunohistochemical findings
similar to those occurring in nonpregnant women who are younger than 35 years
[13]. The predominant reported histology is of invasive ductal carcinomas
(71100%) [14], whereas invasive lobular carcinoma has been diagnosed infrequently [15]. Carcinomas are often associated with aggressive behavior such as high incidence of grade 3 tumors (4095%) and lymphovascular invasion [16]. Moreover,
gestational breast cancer usually involves larger tumors and shows a higher incidence of nodal involvement (5371%) than in nonpregnant patients [17].
As far as the hormone status in breast carcinomas occurring in pregnancy is concerned, it has been reported that most tumors are hormone-independent, as demonstrated in all series investigated. In a prospective series by Middleton et al. [18],
28% of the tumors occurring in pregnancy were estrogen receptor [ER]-positive
and 24% were progesterone receptor [PR]-positive compared with 45% and 36%,
respectively, of nonpregnant young women with breast carcinoma. This is in keeping with the concept that hormone-positive disease is age-related and is seen more
often in postmenopausal women. Results of HER2 expression studies are inconclusive, although data on more than 300 patients showed HER2 positivity in 42%,
which is much the same (39%) as recorded in nonpregnant patients with breast cancer who are younger than 35 years [19].
It seems that pathological features of breast cancer do not change as an effect
of pregnancy, but are determined by age. Thus, it is more likely that age at diagnosis rather than the pregnancy determines the biologic features of the tumor.
Whether increase in mammary stem cells, which are highly responsive to steroid
signaling, despite the absence of hormone receptors, may play a role in the pregnancy setting is still unknown [20].
F. Catalano et al.
158
10.4
Treatment
When a pregnant woman is diagnosed with breast cancer, the treatment options are
complex; they depend on age of gestation, on the extent of malignancy, and, on patient preferences. We would advise the acquisition of as much information as possible on the biological characteristics of the lesion before starting any treatment; this
may allow the expected prognosis of the disease to be determined and could be helpful in taking complex decisions regarding treatments and termination of the pregnancy. The pregnant woman should be assisted by an extended multidisciplinary team
that ideally should include obstetrics, pediatrics, and geneticists.
Termination of pregnancy has not been demonstrated to have any beneficial effect on breast cancer outcome and is not usually considered as a therapeutic option.
However, this can be discussed for moral or personal reasons, and once pregnancy
has been terminated, all standard treatment for non-breast cancer patients can be undertaken [21].
All treatments should conform as much as possible to standard treatment for nonbreast cancer patients. Surgery can be usually performed safely at any stage of pregnancy. Breast-conserving surgery can be performed safely as long as postoperative
radiotherapy can be performed after delivery. If mastectomy is required due to extensive multicentric carcinoma breast-reconstruction with implants can be performed
safely. Flap-based reconstructions should be delayed after delivery [22].
The axillary staging can include sentinel node biopsy although no evidence has
been provided regarding sensitivity and specificity in the setting of pregnancy. The
procedure needs to be performed with 99m-labeled technetium [23] as blue dye is
associated with a risk of anaphylaxis. The standard dose of radionuclide absorbed
by the fetus is approximately 000045Gy, which is fair amount below the thresholds
of 0.10.2Gy [24].
Administration of cytotoxic drugs or hormones during pregnancy threatens the
normal progress of the pregnancy, and generates ethical and psychological issues. We
must consider the opportunity to anticipate the childbirth and the administration of
systemic treatment after the birth of the baby. Two key factors should be taken into
account when considering chemotherapy in pregnant women: changes in maternal
physiology and the stage of fetal development.
For instance significant alterations in circulating blood volume, hepatic metabolism, renal plasmatic flow, can affect the clearance of the drugs. Furthermore decreased levels of plasmatic albumin associated with the increase of other proteins with
high circulating estrogen levels can alter drugprotein bindings [25].
The pregnancy can be divided into three periods: the period from conception to
2weeks of embryonic life (peri-implant), the period from 3 to 8weeks, and the period
from 9weeks to the delivery [26]. The peri-implant phase is characterized by a rapid
proliferation of embryonic and fetal adnexa. At this stage, the toxic effect of chemotherapy is all or nothing, and can determinate either an abortion or no apparent damage.
During the first trimester of pregnancy, chemotherapy may interfere with the organogenesis and the teratogenic risk is at a maximum: 10% for a treatment of single-agent
chemotherapy, 20% for a polychemotherapy treatment. This risk is thought to increase when chemotherapy is given in conjunction with radiotherapy [27].
159
During the second and third trimester organogenesis is complete, with the exception of the central nervous system, the heart and the genitals [28]. Even so, chemotherapy after the first trimester is not without risk: as the fetus still needs to grow and mature, and some organ systems, in particular the central nervous system and gonads develop later in fetal life.
The most obvious effects of chemotherapy include functional disorders, intrauterine growth retardation, premature birth, low birth weight. In theory, you cannot even
rule out damage to the genital system, the central nervous system and the heart [29].
Congenital malformations described in neonates whose mothers had received
chemotherapy after the first trimester when the organogenesis is complete, however,
are rare (13%) and with an incidence not different from the general population [30].
Anthracycline-based regimens are those for which the largest information is available and most of the reports demonstrate the absence of any congenital abnormalities
[31]. Combinations of anthracycline-containing chemotherapy, fluorouracil and cyclophosphamide were administered after 13 weeks of gestation to a large number of
women affected by breast cancer, either for adjuvant or neoadjuvant treatment, without harmful effects on fetuses and infants, and with high antitumor efficacy [32].
The European Institute of Oncology in Milan reported a retrospective series
about 20 women, with locally advanced or metastatic breast cancer, who were treated by surgery followed weekly epirubicin (35mg/m2) from the second trimester onward. The authors hypothesized that this regimen would allow lower peaks of plasmatic concentration of the drug lowering the risk of maternal myelotoxicity and possible placental transfer of the drug. Weekly epirubicin was well-tolerated with no grade
IIIIV toxicities reported and no congenital anomalies occurred, with the exception
of one child with polycystic kidneys. Median gestational age at delivery was 35weeks
(range 2840weeks). The development of all children was normal at a median follow up of 2years [33]. Weekly epirubicin however is not a standard regimen in the
adjuvant treatment of breast cancer.
Paclitaxel and docetaxel have been demonstrated to be toxic to the fetus in animal studies during organogenesis. Nonetheless, several case reports describe their
use in the second and third trimesters, either as single agents or in combination, with
no indication of greater risk or specific complications [34]. In a systematic review,
Mir and colleagues identified 40 series regarding taxanes used to treat breast, ovarian and lung cancer in pregnant women. There were no spontaneous abortions or intrauterine deaths, and the only malformation possibly related to taxane exposure was
pyloric stenosis in a neonate whose mother had received multi-agent chemotherapy
(doxorubicin, cyclophosphamide, paclitaxel and docetaxel) [35].
Data in the litereature on the long-term safety with respect to the health of children of patients who received anthracycline-containing chemotherapy during pregnancy are encouraging both in terms of psychomotor development and for the risk
of developing late cardiotoxicity [3638]. All evidence suggests normal neurological and neuropsychological development, without alteration of the expected growth
curve and of teeth development. Even the cardiac assessment shows no clinical cardiotoxicity in the short and long term [39]. There are, however, recent data suggesting a reduction in the thickness of the left ventricle in children whose mothers were
treated with doxorubicin during pregnancy, although this was not associated with a
F. Catalano et al.
160
clinical apparent damage [40].

A prospective register of women treated for breast cancer whilst pregnant was initiated by the German Breast Group, and this has been extended by the Breast International Group (BIG 2-03). In an abstract presented at the European Breast Cancer
Conference in 2010, Loibl and colleagues reported that of the 91 newborns exposed
to systemic therapy, three had alopecia, one was small for gestational age, one had
trisomy 18 and died 1 week after birth, one had necrotic enterocolitis and died
3weeks after birth, one had temporary apnoea, one developed sepsis, one had neutropenia and two had anemia [41].
The data regarding the administration of hormone therapy with selective modulators of estrogen receptors and with aromatase inhibitors during pregnancy are
scarce. However, congenital malformations after tamoxifen and letrozole were reported, so extreme caution is suggested. The use of tamoxifen is usually delayed until the end of pregnancy [42].
HER2 expression is high in embryonic tissues, suggesting a role in the embryonic neural and cardiac development. Placental transfer of the monoclonal antibody
trastuzumab has been observed in animal studies. Trastuzumab administration for brief
periods (i.e., one trimester or less) does not seem to endanger the pregnancy; however, prolonged exposure has been consistently associated with serious adverse
events. Many case reports described reversible oligohydramnios or anhydramnios as
a result of exposure to trastuzumab during pregnancy. It is therefore advisable to considered with extreme caution the administration of trastuzumab and lapatinib during
pregnancy, and in the case of accidental pregnancy, the drug should be stopped.
The drugs of choice for supportive antiemetic therapy are ondansetron and metoclopramide, which have been used during gestation without adverse effects on the
fetus. Data on the use of G-CSF are sporadic, although a few published case reports
are reassuring and authorize its use in the case of febrile neutropenia during chemotherapy. Steroids are usually avoided in the first trimester of pregnancy [43].
10.5
Prenatal Care
Regarding guidelines about prenatal care, we would suggest following the indications of a consensus meeting held on behalf of the European Society of Gynecological Cancer.
Pregnant women affected by breast cancer should be followed in well-equipped
specialized high risk units with a neonatal intensive care unit. The normal development of the fetus should be checked during cytotoxic treatment with ultrasound. Therefore, before starting staging examinations and treatment, an ultrasound of the fetus
should be performed to ensure that the fetus has undergone normal development and
growth to date. A cardiac assessment with a Doppler ultrasound scanner should be
planned as well, and this should include the evaluation of peak systolic velocity and
cerebral vascularization [44]. Monitoring of contractions should be performed more
frequently especially after treatment, as it has been demonstrated that this may increase contractions.
Regarding the timing of delivery, pre-term termination is not encouraged, how-
161
ever this may be requested to allow the completion of treatment in due time, however, this should be planned at least 3weeks after the last cycle of chemotherapy (delivered at 21 day intervals). Vaginal delivery when further chemotherapy has to be
administered can minimize delays and surgical complications of cesarian sections [45].
This policy minimizes the risk of neutropenia at the time of delivery. After this,
it is recommended that the placenta is examined for metastatic disease [46]. The oncologic treatment can be continued immediately after vaginal delivery, and a week
after uncomplicated cesarean section. The newborn can be breastfed, if physiologically possible (after radiotherapy), but this is however contraindicated during and after chemotherapy.
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Breast Cancer in the Elderly
11
Guglielmo Miconi
11.1
Introduction
Breast cancer is the most common cancer in women in the world [1] with 1.15
million new cases per year, of which 361,000 (27.3% of cancer in women) are
in Europe and 230,000 (31.3%) in North America [2]. Worldwide, nearly onethird of breast cancer cases occurs in patients over the age of 65 years old and
in developed countries the proportion rises over 40% [3]. Studies have shown
that around 50% of patients with breast cancer are those older than 65 years
of age and 35% are older than 70 [4]. Age in itself is a significant risk of
developing breast cancer [5] and most women who die of breast cancer are
over the age of 65 [6]. Advances in breast cancer treatment have changed
patients outcomes, particularly in developed world, and mortality rates have
been decreased by approximately 30% in the last two decades [57].
Nevertheless, the applicability of these treatment advances in women over 65,
and expecially over 70, often remains unclear. Older women are often underrepresented in clinical trials [8] and the extrapolation of data to this population can be difficult. It has been observed that elderly patients do not receive
the standard treatment compared with their younger counterparts [9] and older
patients tend to be undertreated in comparison with younger patients [10].
This undertreatment can have a strong negative effect on survival [11].
Socioeconomic differences and unequal access to healthcare contribute to
poorer prognosis of over 70 year-old-patients compared with patients aged
4070 years when adjusting for disease stage [12]. Despite a growing interest
in this age group, currently no internationally agreed recommendation exists
G. Miconi ()
Department of General Surgery, Breast Unit,
Fano Hospital, Fano (PU), Italy
email: gumicon@alice.it
Updates in Surgery
163
G. Miconi
164
for the management of breast cancer in elderly patients, because of the paucity of evidence based clinical trial data for older patients. Many breast cancer
clinical trials tend to exclude elderly individuals mainly on the basis of age
alone, comorbidity or both [13]. The scarcity of robust data on breast cancer
in elderly people, particularly on modifying management for frail patients,
precludes recommendations based on level 1 evidence [14]. In terms of life
expectancy, data from the National Vital Statistics report from CDC (Centers
for Disease Control and Prevention) released in 2008 have shown that females
at the age of 70 have an average life expectancy of 16.2 years if they are relatively healthy and 6.8 years for those of 85 years old [15]. So, age alone should
not dictate any aspect of management for older individuals and all decisions
should consider physiological age, estimated life expectancy, risks, benefits,
treatment tolerance, potential treatment barrier and the patients preferences.
11.2
General Characteristics
Older women are more likely than younger women to develop breast cancer
with estrogen receptor (ER) and progesterone receptor (PR) expression with or
without HER2 overexpression [16]. ER-positive cancer increases from more
than 60% among women aged 3034 years to 85% among women 8084 years
old [17]. HER2 positive cancer decreases from 22% among women younger
than 40 years to 10% in over 70-year-old women [18]. Delayed diagnosis in
older women explains in part that the tumor size and nodal involvement
increase with age. The increasing involvement of nodals is frequently seen in
smaller tumors, suggesting more aggressive small tumors in older women [19].
11.3
Screening
Screening by mammography is generally regarded to be effective for women

aged 5070 years old [20]. The picture is less clear for over 70-year-old
women. Some studies show no association between screening and better survival for this class of age [21], whereas, other retrospective studies show a
potential benefit even over 80 years of age [22]. The accuracy of mammography increases with age and it is not biologically probable that mammography
screening is less effective in older women. Benefits of screening need to be
weighed against the presence of other medical conditions that limit a patients
life expectancy or limit the patients tolerance to cancer treatment. In North
America, where screening is practiced on an individual basis rather than being
population based, the decision to do screening over 70 years is based on the
clinical situation. The American Cancer Society advises to continue screening
till the patient is in good health and can tolerate cancer treatment [23].
The recommendation is that population-based breast cancer screening programs up to the age of 75 years could be appropriate but in individual patients
11 Breast Cancer in the Elderly
165
the physiological state, comorbidities, patient preference and life expectancy

should be considered.
11.4
Surgery
There is a general consensus that an older woman, affected by early-stage

breast cancer, with a life expectancy of 5 years or over, should be treated in
the same way as a younger patient [24]. This is concerning breast-conserving
surgery, mastectomy and breast reconstruction, as appropriate.
The paucity of data specifically looking at the management of elderly
patients does not permit trying strong recommendations. However, in a recent
study in which elderly patients were treated like younger, with surgery and
radiation therapy, if indicated, the 7 years survival was similar considering for
the different class of age [25].
In women with limited life expectancy (25 years), as a result of extreme
age or comorbidities, primary surgery is unlikely to impact overall survival
because of competing causes of death. In these patients, surgery can play a role
to alleviate symptoms of locally progressive disease. This is possible because
surgical morbidity from breast surgery remains low even in frail patients.
Patients who cannot undergo general anesthesia can often be managed with
local anesthetic approaches [24].
The benefit of surgery on primary endocrine therapy has been well-known
since the 1980 trials. Either tamoxifene or aromatase inhibitors can be offered
in primary therapy only to women deemed to be unfit to undergo surgery
[2426]. Surgery improves progression-free survival [26]. However, surgery
does not mean a significant better overall survival [26]. We need some trials
that take into consideration formal geriatric assessment and collected quality
of life, patient preference and cost-effectiveness data.
Breast-conservation treatment like lumpectomy, or partial mastectomy and
radiotherapy, is now recommended as the standard of care in patients of all ages
with early-stage breast cancer. Breast-conservation surgery in comparison with
total mastectomy is associated with a better quality of life and is preferred by
most elderly patients [27]. Nevertheless available data suggest that older
patients are less likely to receive conservative treatments [28]. Total mastectomy remains a surgical option for patients who prefer it and for those who
decline or are unfit for postoperative radiation therapy. Mastectomy is also
advised in the case of tumors with great dimensions, when cosmetic results are
unacceptable, or in multicentric disease. Finally, total mastectomy is indicated
in salvage treatment in tumor recurrence after conservative surgery.
A debate remains on axillary surgery in the elderly. Axillary nodal dissection may be associated with lymphedema. This is more frequent in younger
patients (50% in patients under 50 years) and less frequent in the elderly (40%
in patients aged 5079 years and 26% in those aged > 80 years) [29].
Generally, lymphedema is mild or moderate but can cause significant discom-
G. Miconi
166
fort and morbidity. Nodal dissection can also be associated with postoperative
numbness, paraesthesia, pain and weakness in the arm, which can cause a
reduction in the quality of life [30]. Generally axillary lymph node dissection
is considered a staging rather than therapeutic procedure. However, in elderly
people with small tumors, clinically node-negative and ER-positive, it rarely
affects the treatment. Several studies have shown no difference in outcome in
the older patient when nodal dissection was omitted [31, 32]. In elderly
patients, when the nodal state will not affect the adjuvant chemotherapy decision, it might be appropriate to omit axillary dissection.
Biopsy of the sentinel node has been introduced as an alternative, accurately predictive of axillary status, to lymph node dissection [17, 33]. Sentinel
node biopsy could negate the requirement of axillary node dissection and, as a
result, overtreatment in many patients [34]. Sentinel node biopsy is a safe procedure and it is particularly indicated in older women, however controversy
exists regarding the need for lymph node dissection in the case of positivity of
lymph node. Microscopic disease in the lymph node probably does not affect
the choice about a chemotherapeutic treatment [2].
In conclusion, surgery should not be denied in elderly patients and the treatment should not be different from the procedure for younger patients unless
patient preference dictates and a very poor prognosis due to comorbidities.
11.5
Radiotherapy
Tolerability is not a limiting factor for radiotherapy in older patients and toxicity is not superior in elderly people [35]. We must consider radiotherapy
after breast-conservative surgery and postmastectomy.
Local control rates after breast-conservative surgery followed by radiotherapy are equivalent of those of mastectomy. Omission of adjuvant radiation is
associated with a decrease in breast cancer, specifically survival [36]. Those
women who are unwilling or unable to undergo adjuvant radiotherapy may
benefit from mastectomy instead of breast-conservative surgery, in order to
minimize local relapse.
Contraindications to radiation that should be considered in older women
include significant pulmonary, skin or cardiac disease. Dementia and
decreased mobility can render the visits very difficult, as can upper limb
manipulation for the administration of the treatment.
Adjuvant radiation in breast cancer has been shown to have a modest
impact on the overall survival rate at 15 years [37]. Some studies have demonstrated the decrease in locoregional recurrence after radiation, but no advantage in decreasing distal metastasis or improving survival [38, 39]. To an elderly woman, who is expected to live 10 years or more, postBCS or mastectomy radiation therapy may be offered, as it would be offer to a younger woman
[24, 40]. Some data suggest that elderly women with low risk disease, that is,
stage 1 hormone receptor-positive cancers with free margins, can omit radio-
167
therapy [41]. High-risk patients, with T3 tumors, high-grade histology and

four or more involved nodes or positive resection margins, should undergo
radiation therapy [42]. Nevertheless, the survival advantage only emerges after
5 years and adjuvant radiotherapy should be considered only for a local control. ASCO guidelines indicate that there is insufficient evidence to recommend routine postmastectomy radiotherapy for patients with T1 or T2 tumors
and with a minimum of one to a maximum of three positive nodes [42].
Promising results in local control in elderly people are delivered by hypofractionated schedules of radiation therapy. Moreover some trials have shown the
same local control as the standard therapy, solving logistic problems of elderly people in submitting to therapy [43, 44].
Partial breast irradiation can be considered since the most of local recurrences occur at or close to the original tumor site. Techniques include postoperative brachytherapy, targeted intraoperative radiotherapy (TARGIT) and
electron intraoperative radiotherapy (ELIOT). For those methods, follow-up
(of maximum 4 years) is already too short to be recommended as a standard
therapy. Nevertheless, they are promising in older patients to avoid weeks of
tiring external beam therapy.
In conclusion, whether radiotherapy will improve overall survival, in elderly people, is unlikely, because overall survival is more affected by comorbidity, aging or the occurrence of distant metastases rather than local relapse.
The decision of offering radiotherapy must take into account patient health and
functional status, comorbidities and the risks of local recurrence.
11.6
Systemic Treatment
Systemic treatment in all ages is influenced by breast cancer biological subtype. There are no subtype specific treatment data for elderly patients that are
different from younger patients.
11.6.1 Endocrine Therapy

The goal of adjuvant therapy in general is to improve relapse and cure rates
after surgical treatment for early nonmetastatic cancer stage. The opportunity
and the efficacy of endocrine therapy in women with hormone receptor-positive cancer are well-known. This benefit is independent of age [45]. Most elderly patients have ER-positive tumors and HER2-negative disease. These are
likely to respond to endocrine therapy in adjuvant and neoadjuvant protocols.
Primary endocrine therapy refers to the systemic endocrine treatment as the
only treatment for early stages. Evidence of benefits exists only for patients
with short life expectancy (< 2 years), considered unfit for surgery. Local control by hormone therapy can be achieved only for 23 years [46]; therefore
geriatrician involvement is strongly recommended to estimate life expectancy,
168
G. Miconi
identify and guide management of reversible conditions, and to reduce the

risks of undertreatment or overtreatment. When life expectancy is 2 years or
more, surgery plus endocrine therapy permits a better local control than primary endocrine therapy alone [46].
Aromatase inhibitors have been compared with tamoxifen in several trials,
but only a few of them include elderly people [47]. Aromatase inhibitors are
more effective than tamoxifen in endocrine treatments either in neoadjuvant
protocol or in adjuvant protocol [48].The choice of the drug is between tamoxifen and aromatase inhibitors, it can be guided by potential toxicity and tolerability. Aromatase inhibitors are preferred to tamoxifen because of the lower
risk of thrombosis and endometrial cancer. Quality of life is similar for the two
drugs [49]. Nevertheless, aromatase inhibitors are associated with accelerated
bone loss and increased risk of fracture and muscle-skeletal syndrome, which
is irrespective of the age [49]. In elderly people, who generally have preexisting problems such as osteoporosis, it is very important to evaluate mineral
density and to consider implementation of vitamin D and calcium. In addition
antiresorptive therapies, like bisphosphonates and denosumab are generally
administered [49, 50].
11.6.2 Adjuvant Chemotherapy

Adjuvant chemotherapy improves survival from breast cancer, particularly in
patients with high-risk diseases such as node-positive or ER-negative patients.
Generally, the same regimens of therapy indicated for younger patients should
be indicated for elderly people [13]. These are composed of polychemotherapy administered in various regimens of therapy. Older women seem to derive
benefit from adjuvant chemotherapy although absolute benefit decreases with
age [45]. Despite this observation, the toxicity caused by therapy is much more
frequent in older women. In particular, anthracycline-based regimens show a
significant cardiotoxicity. The elderly people are particularly prone to develop
febrile neutropenia by myelosuppression. Trastuzumab therapy and other biological therapies show significant cardiotoxicity in elderly women. Important
factors of this cardiotoxicity are age > 50 years old, hypertension and baseline
cardiac dysfunction [51].
The use of molecular profiling is a promising field of study in predicting
effects of chemotherapy. Several molecular assays are emerging and, as soon
as they will be validated by prospective studies, elderly people will benefit
from the conclusions. In general, the utility of the assays, in predicting
chemotherapy benefit, is independent of age [52].
In this complex clinical picture, it is strongly recommended to do a geriatric assessment in order to establish whether an elderly patient will be able to
tolerate and which benefits will be able to achieve undergoing adjuvant systemic therapy, including targeted agents. Finally, patients preferences are very
important to decide the better therapy regimen. Older patients tend to overes-
169
timate toxicity of therapy in front of a limited benefit. It is important to provide clear information to elderly people and to discuss the diagnosis with
them. Need for information is age-independent [53]. Nevertheless, only a
small proportion of patients wants to have an active role in making decisions
and rely upon specialist recommendations [53]. Generally the acceptance of
therapies does not differ from that of younger patients, but elderly people tend
to prefer a good quality of life rather than a potential increase in survival.
11.7
Male Breast Cancer
Male breast cancer represents about 0.51% of all breast cancers. Median age
at the diagnosis is 64 years old [54]. Generally the disease is self-detected;
most cases are ER-positive while 1237% of cases are HER2-positive [55].
The surgical treatment consists of mastectomy and axillary dissection but
older men are less likely than younger to receive axillary dissection or radiotherapy [54, 55].
The systemic therapy is similar to the one administrated to postmenopausal
women with breast cancer, in indications and therapeutic regimens [56]. In
patients with nodal involvements, chemotherapy improves disease free survival and overall survival [57]. There are no trials regarding the use of
trastuzumab in male breast cancer with HER2 overexpression. However, it is
probable that the same benefit proven for women with breast cancer is valid
also for males.
11.8
Geriatric Assessment
From the concepts expressed till now, an important issue emerges: is breast
cancer the patients major illness?
The gold standard of outcome measurement in cancer clinical trials is the
overall survival. This standard might not be the most appropriate endpoint for
many cancer patients and in particular for older patients. For example, the
treatment of two 80-year-old patients with the same neoplasm (for stage and
biological characters) but different physical function, is very different because
their life expectancies are very different: the first, active and working late in
life; and the second, with mild dementia, in a nursing home and with poor
physical function.
The most important strategy to assess geriatric patients is to define the
physical function and the expectancy of life. Functional status includes
patients ability to perform daily tasks such as dressing themselves, walking,
cooking meals and other daily activities. Comorbidities are very important in
the evaluation because they affect the tolerance to cancer treatment, in particular to systemic treatment and to radiotherapy. Nutrition is an important issue:
whereas in younger people weight loss is desirable, in older people it may rep-
170
G. Miconi
resent a loss of muscle mass. This is associated with a poor function and a
shorter survival. Moreover, another essential element of evaluation is cognition because it implies a better understanding and the adherence to the proposed treatment. In addition, cancer treatments can affect the mental status.
Psychosocial support is essential in the ability to submit to the therapies and
play a role in the therapeutic decisions. Comorbidities increase with age and a
70-year-old has an average of two or three comorbidities; an 80year-old has
an average of five other pathologies affecting survival. These comorbidities,
like COPD (chronic obstructive pulmonary disease), diabetes, and hypertension, shorten life expectancy and compete and interfere with breast cancer and
the related therapies as well as with the survival.
Physical function impacts on survival. In a study of 4516 patients aged
over 70 years old, the functional morbidity index was evaluated, based on selfreported scoring of physical function. Scoring was based on ability to bathe,
shop, walk several blocks, push and pull objects. In those who reported a high
degree of functional loss, survival was not over 2 years for one-third and a low
mortality risk was reported in those with excellent function [58].
Comprehensive geriatric assessment (CGA) is a procedure, developed by
geriatricians, to evaluate elderly patients functional and global status. It is
useful to identify and manage age-related problems, allowing clinicians to
select patients more appropriately for therapy and avoiding futile therapies and
overtreatment as well as undertreatment [59]. According to the CGA results,
patients can be divided into three groups: (a) fit patients, (b) vulnerable
patients and (c) frail patients. Patients in the first group are fit to treatments as
well as their younger counterparts. Patients of the last group are fit only for the
best supportive care. For the patients in the second group, which is the biggest,
individualized approaches and specific trials are recommended. Results of retrospective studies of evidence show that CGA can predict morbidity and mortality in older cancer patients, detect previously unknown problems and allow
directed interventions toward the detected problems. CGA, if linked to geriatric interventions, can also reduce early re-hospitalization and mortality due
to therapies in older patients [59].
On the other hand, despite this value of CGA, there is the disadvantage that
the method is a time and manpower consuming procedure. Many other more
feasible approaches available in daily activity have been developed. These are
self-administered questionnaires that allow a baseline assessment of an elderly patient [60].
The research has identified new markers that from a simple blood test can
predict the likelihood of encountering myelosuppression or other problems. An
example is the expression of p16, a weak tumor suppression gene that has been
found to increase 10-fold between the ages of 20 and 80 years-old. This gene
is associated with the cellular senescence in almost all organ systems [61].
This marker, which is a marker of aging, in addition to the geriatric assessment, may help clinicians, with a molecular tool, to estimate survival as well
as treatment toxicity.
11.9
171
Conclusions
Breast cancer affects in particular elderly people but the age itself is a risk factor of not receiving adequate therapies or not standard therapies. This is true
in particular for 75-year-old patients or over, when breast cancer is more frequent.
Factors contributing to receiving nonadequate therapies are:
Reluctance of physician in treating a cancer apparently less aggressive than
in younger counterparts and the fear of important toxicities
Comorbidity, including cognitive status, depression and anxiety
Physical barriers like sensory impairment and poor mobility
Ethnic origin, socioeconomic status and sociocultural environment.
The transportation of the elderly patient to the radiotherapy unit can be a
problem and this may be a reason for omitting radiotherapy or opting for a mastectomy rather than breast-conservative surgery. In this latter consideration, an
important benefit could be gained by methods of partial breast irradiation like
intraoperative radiotherapy.
Family members are important in management and decision made by elderly people, but the patients need to be involved in decisions which often are
not the same as caregivers.
No aspect of management of elderly breast cancer patients can be guided
by chronological age alone. It is very important to evaluate the pathology, the
stage, the comorbidities and the physical impairment, the patients preferences
and the life expectancy. These factors are better evaluated by a multidisciplinary team composed of a geriatrician, oncologist, surgeon and radiotherapist.
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Locally Advanced Breast Cancer
12
Stefano P. Drago and Giovanni Battista Grassi
12.1
Introduction
Locally advanced breast cancer (LABC) has been the usual clinical presentation
in the past and still accounts for a sizable number of breast cancer cases in developing countries or in medically underserved populations of western countries.
Because of its poor clinical outcome even in the face of aggressive surgical treatment due to a prohibitive incidence of local relapse and distant failure, the treatment of LABC has rapidly evolved. In the past, single modality treatment, consisting of radical mutilating surgery or higher doses of radiation therapy (RT), was
used, but treatment now consists of multimodality management, which includes
systemic therapy along with surgery and radiation therapy. Systemic therapy, and
neoadjuvant chemotherapy in particular, have had a tremendous impact on the outcome of LABC thus affecting the local treatment planning.
Surgical options in the setting of LABC have likewise evolved, and should nowadays be tailored to the patient with the perspective of optimal multimodality management.
12.2
Definition
For management purpose, breast cancer is categorized into early breast cancer,
LABC and metastatic breast cancer.
LABC comprises a variety of tumors with extensive although variable locoregional involvement at clinical presentation, heterogeneous biological behavior and
S. P. Drago ()
Department of General Surgery and Surgical Oncology, San Filippo Neri Hospital,
Rome, Italy
e-mail: s.drago@tiscali.it
Updates in Surgery
175
S. P. Drago, G. B.Grassi
176
different prognosis. It includes advanced lesions within the breast (T3, T4) or in
ipsilateral nodes (N2, N3), in the absence of metastatic disease.
In the 2010 American Joint Committee on Cancer and the International Union
for Cancer Control TNM breast cancer staging system [1], LABC is defined by stage
IIB (T3N0) and stage III disease, which includes:
Advanced primary tumors
- Tumors larger than 5cm (T3)
- Tumors with direct extension to the chest wall (T4a) or with ulceration, skin
nodules and/or edema, including peau dorange (T4b)
- Inflammatory breast cancer (IBC, T4d)
Advanced regional nodal disease
- Ipsilateral level I or II lymph nodes that are clinically fixed or matted (N2a)
or clinically detected ipsilateral internal mammary nodes without clinically evident axillary node metastases (N2b)
- Involvement of ipsilateral infraclavicular lymph node(s) (N3a), or ipsilateral internal mammary node(s) with axillary node(s) (N3b), or ipsilateral supraclavicular lymph node(s) (N3c).
Besides the different clinical presentation, the heterogeneity of the LABC is also manifested in a variable biological aggressiveness and different prognosis. In
particular, inflammatory breast cancer (IBC, T4d) represents a distinct clinical entity, and should be considered separately.
Within the different editions of the TNM staging system, the recognition of subsets of clinical presentation with better prognosis has changed the staging system.
T3N0 tumors were downgraded from stage III to stage IIB, and ipsilateral supraclavicular node localization, initially considered M1 are now defined N3c and included in stage IIIC [2]. For this reason comparison of reports in the literature is
often difficult.
12.3
Epidemiology
In developed countries breast cancer is diagnosed as a locally advanced lesion in

5 to 20% of cases. According to the United States National Cancer Data Base
(NCDB) for the year 2006, about 10% of women diagnosed with breast cancer had
locally advanced (stage III) disease, while for the United Kingdom this figure was
about 15% [3].
There is evidence that the incidence of LABC has decreased in mammographically screened populations. As a matter of fact, the proportion of patients with LABC
is less than 5% in United States populations that receive regular screening mammography, while it is higher among younger women and in medically underserved
groups. In contrast, IBC, although accounting for less than 2% of invasive breast
cancers, appears to be increasing in incidence [4].
LABC is a very common clinical scenario in developing countries where it is
12 Locally Advanced Breast Cancer
177
encountered in 30 to 60% of newly diagnosed breast cancers. This difference may

be due not only to differences in socioeconomic status, poor education and lack of
medical facilities such as mammography screening, but also to variations in tumor
behavioral characteristics among different countries and ethnic groups [2, 4].
12.4
Historical Background
Historically, surgery has been the oldest treatment for women with breast cancer,
which was almost always presented to the physician with a clinically advanced tumor. Different strategies were devised over the centuries, but after William Halsted described his surgical technique of radical mastectomy with en-bloc removal
of the entire breast, axillary nodes and the chest muscles this rapidly became the
standard in the management of breast cancer.
Although the Halsted mastectomy represented a great scientific and surgical improvement, long-term survival remained poor, ranging from 13 to 20% at 5 years,
and enthusiasm in the surgical treatment declined over time up to the point when
Haagensen and Stout [5] in 1943 defined the criteria of inoperability of breast cancer. They recognized some clinical situations in which surgery, no matter how radical, did not lead to cure but was inevitably followed in the short run by local relapse or distant failure.
RT rapidly gained favor, first as a substitute for radical surgery, then in addition to surgical resections. Radiation doses higher than 70Gy were often applied
with the intent of radical treatment, but complications, such as cardiac and pulmonary
failure, breast and arm edema, fibrosis of the shoulder and chest wall, were common and equal if not worse than those of radical surgery [6].
When radiation was added to surgical resection, with the aim of a better local
control, initial results failed to demonstrate a survival benefit because the advantage of radiotherapy in cancer related mortality was lost due to a higher cardiac morbidity.
The first two trials that showed a significant advantage with postmastectomy
RT were the British Columbia trial and the Danish Breast Cancer Group trial [7,
8]. As other single institution large series confirmed, an optimal locoregional control given by the combination of radical surgery and RT, postmastectomy irradiation of chest wall and supraclavicular fossa became the standard treatment for women
with LABC.
Achieving a reasonable local control is only part of the management of LABCs.
The systemic component of the disease was long since considered important to
achieve long-term survival. Both adjuvant and neoadjuvant systemic therapy were
developed simultaneously in the setting of locally advanced lesions. Particularly
neoadjuvant chemotherapy (NACT), having shown to have an impact on both the
local and systemic component of the disease, has gained a major role in the management of LABC since its first use in early 1970 [2].
178
12.5
Radiation Therapy
Locoregional failure in women with LABC treated with mastectomy and without
radiotherapy has been reported to be about 20 to 30% [9].
Although few randomized trials have evaluated only stage III breast cancer and
the effect of radiation treatment, it is well established that combination of surgery
and radiotherapy is superior to either single treatment modality for local control
[6]. Postmastectomy radiation therapy (PMRT) has been recommended for highrisk patients after the Danish and the British Columbia trials have demonstrated
its benefit on local control and survival. Even after chemotherapy has been added
to the modality treatment, with further improvement in systemic control and longterm outcome, PMRT is still required to reach the best local control in high-risk
patients [10].
Patterns of failure have identified tumor size and number of positive nodes as
predictive of local failure. High-risk patients include those with tumors larger than
4cm and with more than four involved nodes [9].
Various studies suggest that even with a lower tumor burden in the metastatic
nodes (i.e., 13 positive lymph nodes) postmastectomy radiotherapy might be of
benefit [11, 12].
On the other hand, some reports are now suggesting that postmastectomy radiotherapy may not be necessary in subsets of patients with locally advanced tumors but low-risk of recurrence.
In fact, there is considerable variation in the practice pattern for postmastectomy radiotherapy in the node-negative patients.
A retrospective analysis from the Surveillance Epidemiology and End Results
(SEER) Database showed that an average of 30% of women with a stage T3N0 breast
cancer had radiation treatment after mastectomy [13].
Indeed, there is now evidence that tumor size alone does not warrant postmastectomy radiotherapy in otherwise node-negative women, as women with large tumor and negative nodes (T3N0) have no improvement in cancer specific survival
or local recurrence rate with the use of radiation. That is unless other risk factors
are present, such as multicentric disease, skin or nipple invasion, menopausal status, pectoralis fascia involvement, lymph vascular invasion, a high grade tumor and
close or positive margins [14].
Lymphovascular invasion (LVI) has consistently been shown to be an independent high-risk factor for recurrence [11, 14]. Tumor grade, premenopausal status,
absence of systemic therapy and close surgical margins have less consistently
found to impact on local recurrence in node-negative patients [9].
Positive surgical margins after mastectomy leave a small risk of local failure,
thus the benefit of PMRT in patients with otherwise favorable features might not
justify radiation treatment. A meta analysis from the UK suggests that only patients
with two or more risk factors other than size, including LVI, high tumor grade, premenopausal status and large tumor size, may benefit from PMRT [12].
Predictive models of local regional recurrence have been devised in order to
179
guide the choice of PMRT. Absolute quantification of local recurrence risk is important in order to identify the threshold for recommending PMRT, balancing the
risks and benefits of treatment in any single case.
If PMRT has become the standard in patients with LABC undergoing primary
surgical treatment, the role of radiation treatment after neoadjuvant chemotherapy is not well established, particularly in patients who experience a complete
pathological response [2].
Evidence from the NSABP trials on neoadjuvant chemotherapy B-18 and B27, in which PMRT was not allowed, suggested that predictors of local recurrence
were clinical tumor size and clinical nodal stage before chemotherapy, as well as
pathologic nodal status and breast tumor response after therapy. All these factors
can be used to optimize the indication for RT after mastectomy. Of note, dermal
lymphatic invasion remains a significant and independent predictor of outcome after neoadjuvant chemotherapy [15].
On the contrary, the MD Anderson review of a series of institutional prospective trials reports a high local recurrence rate after induction chemotherapy, even
in patients who experience pathologic complete response. PMRT is, therefore,
strongly supported in all patients with large tumors or positive axilla at presentation (stage III disease), no matter what response to chemotherapy is achieved [16].
Findings from an ASTRO directed survey on the recommendation of PMRT after neoadjuvant chemotherapy demonstrated a wide heterogeneity. For postmenopausal clinical stages T3N0, T3N1 and T4dN1 with partial response to
chemotherapy, 72.1%, 93.9% and 98.9% of the patients, respectively would have
been recommended PMRT. For patients with complete pathological response (pCR)
for the same cases, 56.1%, 84.8% and 96.7%, would have been recommended PMRT, respectively [17].
There is a need for a prospective study in this setting in order to guide the oncologist for optimal care for these patients specifically for all patients who achieve
pCR after chemotherapy. Most of the chemotherapy schedules studied included anthracyclin based regimens, with high clinical response, but limited complete pathological response [3, 18, 19].
When taxanes were introduced in the neoadjuvant setting, a tremendous increase
in the complete clinical and pathological response was observed [2, 10, 2022]. In
addition, although radiation related cardiovascular complications have been reduced
after modern techniques and fractionation schedules have been adopted, the introduction and extensive use of cardiotoxic drugs in standard chemotherapeutic regimens, such as anthracyclines and trastuzumab, adds another risk for cardiac ischemic events, and it is not known what might be the additional effect of radiotherapy on cardiovascular outcome.
Therefore, the role of radiation treatment in addition to surgery for local control must be continuously revisited in light of the higher complete pathological response obtained with modern chemotherapeutic regimens and in consideration of
the possible higher cardiovascular complication rate, not yet defined with the same
modern regimens.
180
12.6
Neoadjuvant Chemotherapy
Initial concerns with the upfront administration of systemic therapy included: an

unknown impact on survival after delayed surgery, particularly in nonresponder patients in whom local treatment might be delayed; the risk of chemoresistance, due
to the fact that the drugs had to act on a bulky tumor; a possible increase in surgical complication rates in patients that had received chemotherapy; and finally the
loss of axillary staging with alteration of its prognostic significance.
The issue of whether neoadjuvant chemotherapy (NACT) can improve survival in women with advanced breast cancer compared to adjuvant treatment is
controversial. Primary chemotherapy has never been proved to increase survival
in women with LABC; however, several prospective trials conducted in the 1980s
and 1990s have demonstrated a survival equivalence in locally advanced breast
cancer patients treated with either adjuvant or neoadjuvant chemotherapy [3, 18,
19, 23].
Response to chemotherapy is manifested by tumor shrinkage in both the breast
and axilla. Thus neoadjuvant chemotherapy has the advantage of an in-vivo assessment of chemotherapy effectiveness and has a predictive, rather that prognostic,
significance allowing the selection of patients with better outcome. Indeed, a survival benefit from induction therapy has been recognized in the subset of patients
that show a pathological complete response [19].
Findings from a Cochrane and a systematic review suggest that a better tumor
response is associated with better outcomes in patients with LABC who receive primary chemotherapy [24].
The response rate to induction chemotherapy has been variably reported, and
a discrete amount of patients experience a complete response, both clinical and
pathological, while only 2 to 3% show a tumor progression (Table 12.1) [2, 18,
2539]. Differences in the reported rates of clinical and pathological response are
related to different drug regimens and/or sequencing [21].
Anthracycline-based regimens yield 12 to 15% of complete pathologic response, as oppose to a clinical response rate as high as 80% [18]. Modern chemotherapeutic regimens with noncross resistant taxanes yield an even higher tumor response, in particular a complete pathological response [3, 40, 41].
In addition, the increase in the pathological complete response (pCR) has led
to an improved overall survival and disease free survival, confirming its relevance
as a surrogate for better outcome [10, 19].
The NSABP-B27 study demonstrated that preoperative administration of docetaxel following AC increased the pCR rate from 13.7 to 26.1% [22]. An MD Anderson study showed that adding paclitaxel prior to the preoperative fluorouracil,
doxorubicin and cyclophosphamide regimen, increased the pCR from 15.7 to
28.2% [41].
Taxanes in monotherapy appear less effective than given in a dose-dense or sequential regime [41]. In addition, tumor subtypes like HER2 positive tumors treated with trastuzumab, do show a higher pCR compared to HER2 negative tumors
[21, 30, 39]. Nonetheless, pCR still remains no higher than 20 to 30% overall.
Npts
clinPR
134
200
149
350
165
710
76
137
203
Institut Bergonie [25]

Institut Curie [26]
Royal Marsden Hosp [27]

EORTC [28]
Bonadonna 1990 [29]
Penault-Llorca 2007 [30]
Swain 1987 [31]
Semiglazov 1994 [32]
ABCSG-07 trial [23]
57
44
54
78
61
42
30
42
43
45
30
270
20
174
50
47
455
458
ECTO trial [35]

Yao 2012 [36]
Buzdar 1999 [37]
Aberdeen trial [10]
GeparDuo study [21]
28
Alvarez 2002 [34]
39
56
Estevez 2003 [33]
Studies on taxanes with different regimens/protocols
743
NSABP B-18 [19]
Studies with various chemotherapeutic regimens
Study [Reference]
66
94
80
80
56
57
32
52
11
29
35
49
16
17
22
7
33
24
36
clinCR
16
16
34
8
8
16
23
25
16
29
30
14
7
4
13
pathCR
Table 12.1 Clinical and pathological response after neoadjuvant chemotherapy
ACDOC
CVAP 8
CVAP 4Doc 4
A+Doc
Pac 4
FAC 4
A+Pac x 4CMF 4
ECDoc
A+Pac
weekly Doc
CMF 3
TyMF + Radiotherapy
CAMF
various regimen
CMF / FAC
MiMx(M) Tam
FEC 4
EVM 3MiTyVd 3
FAC 4
AC x 4
regimen
(cont.)
Trial comparing sequential vs.

dose-dense anthracycline + taxane
Trial comparing anthracycline

vs. taxane
had RT after NACT
many had RT only

many had RT only
Notes

181
NSABP B-27 [22]
217
33
TECHNO trial [21]

Coudert 2006 [38]
42
clinPR
21
27
NR
NR
46
67
64
10
18
40
clinCR
23
7
39
42
19
45
19
pathCR
various regimen
without trastuzumab
EC 4Pac +Tz
Doc 6 + Tz
EC 4Doc + Cap+Tz
AC 4Doc
E+Pac 4
E 3Pac 4
AC 4
regimen
HER2 pos
HER2 neg
HER2 pos
HER2 pos
HER2 neg
HER2 pos
standard vs. dose dense regimen
Trial comparing anthracycline vs.

sequential anthracycline + taxane
Notes
25
Pac 4FEC 4
Her2 pos
67
Pac 4FEC 4 + Tz
A, doxorubicin; C, cyclophosphamide; Cap, capecitabina; Doc, docetaxel; E, epirubicin; F, fluorouracil; L, leucovorin; M, methotrexate; Mi, mitomycin; Mx,
mitoxantrone; P, prednisone; Pac, paclitaxel; Tam, tamoxifen; Ty, thiotepa; Tz, trastuzumab; V, vincristine; Vd, vindesine.
Buzdar 2007 [39]
Penault-Llorca 2007 [30] 51

287
456
GeparQuattro study [21]
AGO study 2002 [21]
752
233
242
Studies on Hercept positive tumors
Npts
762
Study [Reference]
Table 12.1 (continued)
182
183
Differences in the reported rates of complete clinical and pathologic response

reflect also differences in the criteria used for their definition. As for the pCR, some
trials have used the definition as the absence of residual cancer in the breast and
regional lymph nodes, whereas others have defined it as a complete response in the
breast, irrespective of axillary nodal involvement [22, 41]. In addition, some have
included the presence of focal invasive tumor or noninvasive cancer residual in their
definition of pCR, whereas others have defined it as the complete eradication of
all invasive and noninvasive cancer [41].
Discrepancies close to 10% in histopathological reports were found within
centers participating in a national multicenter randomized trial in UK [42]. Such
a methodologic limitation makes reporting and interpretation of data from neoadjuvant trials somewhat challenging, and highlights the need for consensus guidelines. A proposed operational definition of pCR and a 2006 Consensus statement,
defined a pathological complete response as the absence of any residual invasive
cancer in the resected specimen and in all sampled lymph nodes following completion of neoadjuvant systemic therapy [43, 44].
Downstaging of the primary tumor and lymph node metastases by induction
chemotherapy may in turn improve resectability and increase the rate of conservative surgery. Great emphasis has been given to this result and neoadjuvant
chemotherapy has indeed made an impact on the surgical management of the primary tumor [3, 18, 19, 45].
In addition, NACT certainly ensures early initiation of systemic treatment,
which might otherwise be delayed if postoperative complications arise, for example after immediate breast reconstruction. Although a delay in local treatment may
be of concern, new targeted chemotherapeutic drugs, can be tested in the minority of nonresponders or in subsets of patients with particular biologic characteristics.
For all these reasons, neoadjuvant chemotherapy has gained favor, and since
patients with bulky and locally advanced disease benefit from the tumor shrinkage and the improved resectability given by primary systemic therapy, this modality has become the treatment of choice in stage III disease [20].
12.7
Diagnosis and Work-up
Most of the locally advanced tumors are clinically evident and often have been noticeable for a long period, representing a neglected lesion rather than an aggressive
cancer. Psychic fragility, fear and refusal make women avoid seeking medical attention. Sometimes aggressive lesions may have a rapid and subtle growth. Inflammatory signs may initially be misleading and diagnosis of an aggressive tumor may thus
be challenging in the absence of a palpable or imaging detectable mass.
Initial work up, after a careful history and complete physical exam, always include bilateral mammography and breast ultrasound to evaluate the extension of
the disease within the breast and the presence of multicentric lesions or malignant
microcalcifications.
184
Magnetic resonance may be helpful in determining the extent of the disease,

although it may overestimate the real size of the tumor [46], and should always be
performed for baseline evaluation if induction chemotherapy is planned [47].
Tissue diagnosis is a priority and requires histological confirmation of an infiltrating lesion, as an extensive ductal carcinoma in situ may be palpable and mislead to the planning of induction chemotherapy, which is not appropriate in this
setting. Thus needle core biopsy is preferred over fine needle aspiration cytology.
In addition, microhistology by needle core biopsy allows evaluation of hormone
receptor status and HER2/neu expression, which are essential for the medical oncologist to plan the chemotherapy regimen.
At the time of needle core biopsy, it may be wise to leave a clip in place which
may serve as a marker for future resection, should a complete clinical response occur. Another useful practice is a visual record of the size and site of the lesion with
pictures.
Rarely, a large necrotic lesion with a negative needle core biopsy forces an open
biopsy to be performed. If skin involvement is present a punch biopsy may prove
useful.
Axillary status may be evaluated with ultrasound, which is helpful in detecting apical and infraclavicular involved nodes, which in turn has a relevant prognostic significance. In addition axillary ultrasound may provide a guide for fine
needle aspiration cytology of a suspected node, thus providing a clear diagnosis of a positive axilla. Even in experienced hands, ultrasound has at least a 20%
false negative rate, because small tumor deposits in a normal node are not detected.
An FDG-PET scan may be useful in determining the extent of axillary involvement and in revealing involvement of internal mammary nodes, that may be
involved in as much as 20% of cases, especially in IBC [48].
The best way to stage the lymph node status in the presence of a clinically and
imaging negative axilla is to perform a sentinel node biopsy. Sentinel node biopsy accurately stages the axilla even in patients with large or multicentric lesions.
It is not indicated in women with IBC due to a very low localization rate. When
performed as a single procedure it may be easily performed under local anesthesia and in an outpatient setting. Correct staging of the axilla prior to the pathological changes induced by chemotherapy results in optimal staging and avoids difficulties in lymphatic mapping and possible higher false negative rate of sentinel node
biopsy performed after primary chemotherapy [2, 49].
Sentinel node biopsy prior to induction chemotherapy in patients with clinical
and imaging negative axilla is the procedure of choice at our institution.
Additional imaging to evaluate for metastatic disease is not standardized and
practices vary accordingly. But in the presence of a clinically diagnosed stage III
breast cancer, subsequent work-up should always include a bone scan, liver ultrasound and chest x-ray, as about 10% of patients may present distant disease and
then would be restaged as a stage IV [50].
Work-up after neoadjuvant chemotherapy is important to estimate the residual
disease, but the extent of residual disease may be difficult to assess after induction
185
chemotherapy. Tumor shrinkage after neoadjuvant chemotherapy is better assessed

with sonography compared to mammography, but the former exam is operator dependent and not reproducible. Although ultrasound correlates well with complete
remission, residual ultrasound abnormalities are not always indicative of residual
disease. When both imaging modalities demonstrate no residual disease, likelihood
of a complete pathological response has been reported as high as 80%.
Magnetic resonance imaging has been shown to correlate well with pathological findings after neoadjuvant chemotherapy, as it represents the best and most reproducible imaging study to accurately document the occurrence of a downstaging of the tumor [51].
Positron emission tomography is under investigation as an indicator of tumor
response [52]. However, current imaging modality is insufficient for assessing complete pathological response.
12.8
Surgery
Primary surgery is an option only in those patients with operable disease, although
primary systemic therapy has gained wide favor in locally advanced breast tumors.
Patients with inoperable LABC may occasionally require a salvage surgical resection as initial treatment.
Radical mastectomy has long been the treatment of choice, but breast preservation is feasible in some patients who present with LABC. Those with small tumors and clinically advanced nodal disease may be amenable to conservative surgery, as well as those with larger tumor but a good breast to tumor ratio. Patients
with poor breast to tumor ratio may still be amenable to breast conserving resection after neoadjuvant chemotherapy has reduced the size of the tumor to a more
favorable ratio.
Several studies do report an increase in breast-conservative surgery (BCS) after the administration of neoadjuvant chemotherapy with low recurrence rates, comparable to those after BCS in patients with early stage disease [2, 3, 18, 19, 53].
Still some patients are poor candidates for breast preservation. Patients with multicentric disease, or with extensive malignant or suspect microcalcifications should
not undergo breast conservation [49]. Similarly patients with lobular histology, in
which the extent of residual disease is difficult to judge, are poor candidates for
conversion to breast preserving surgery after neoadjuvant chemotherapy. Moreover,
patients with pure invasive lobular carcinoma experience a lesser clinical benefit
from induction therapy, presenting a less frequent downstaging and a higher incidence of positive margins after breast conserving surgery, compared with patients
having an infiltrating ductal carcinoma.
Among other pathologic characteristics, initial tumor size and nodal status
give an increased, but not significant risk of local recurrence, thus do not predict
BCS feasibility [18].
Factors mainly associated with an increased risk of local recurrence are advanced
lymph node disease (N2 or N3) at initial clinical presentation, residual tumor size
186
> 2cm, a multifocal pattern of residual disease, and LVI [9, 12]. However, it remains unclear how these factors interact and how to best incorporate these data in
the context of clinical decision-making. Differences in reported outcomes between
series are likely to be due to a varying selection criteria used to determine BCS eligibility after neoadjuvant chemotherapy. According to their selection criteria,
Singletary at the MD Anderson Center found a potential 23% conversion rate in
143 women with LABC who underwent mastectomy having experienced a clinical response (84% partial and 16% complete) after neoadjuvant chemotherapy
(Table 12.2) [49].
Careful selection of patients to refer for breast conservation should be undertaken, because downsizing of the tumor may not always allow for a smaller resection. The pattern of tumor regression is somewhat irregular and unpredictable; it
does not necessarily shrink concentrically, but it may appear to occur with fragmentation of the mass, either in a concentric or diffuse way. In both cases residual foci of tumor may still be present and occupy an area not smaller then the initial tumor. This phenomenon has been explained as being due to irregular tumor
angiogenesis or tumor polyclonality with different exposure and susceptibility of
the tumor cells to the drug. Resections that are too limited may be at risk of leaving residual cancer cells, thus an adequate postneoadjuvant surgical resection shall
not be much smaller than the initial planned resection. Given this, the real benefit
of neoadjuvant chemotherapy in allowing breast conservative surgery is limited and
it concerns mainly patients that were borderline for breast conservative surgery before induction therapy.
As a matter of fact, only 5 to 19% of patients deemed as a candidate for mastectomy receive BCS down the line [3, 19, 45]. The randomized study from the NSABP B-18 [19] has demonstrated that only 7% of the women in which a mastectomy would have been the procedure of choice at presentation, were switched to
breast partial resection after neoadjuvant chemotherapy. Noteworthy is the observation that, although local relapse was not statistically different in women who had
BCS in the adjuvant chemotherapy setting compared to those who had BCS after
NACT overall, local relapse was higher among those in whom a BCS was undertaken after an initial indication for mastectomy and after tumor shrinkage by
Table 12.2 Overall clinical response rate and conversion rate to breast-conserving surgery (BCS)
after neoadjuvant chemotherapy (NACT) in patients with LABC
Study
[Reference]
Overall clinical response

(%) to NACT
Patients converted
to BCS (%)
NSABP B-18 [19]
80
Kling [45]
88
13
Hortobagy [20]
71
19
Makris [27]
83
11
EORTC 10902 [28]
49
5*
*23% of patients underwent BCS instead of the planned mastectomy, but 18% of patients underwent mastectomy instead of the planned BCS after NACT.
187
chemotherapy had occurred. Another large randomized trial from EORTC [18],
showed a 23% conversion rate from mastectomy to BCS after NACT. However,
at the same time 18% of patients who were planned for BCS prior to NACT, actually underwent mastectomy after treatment. In this trial as well, patients who were
initially planned for mastectomy, but were subsequently submitted to BCS because
of downstaging of the tumor, had a worse overall survival (HR 2.53; 95% CI, 1.02
to 6.25) compared to patients who underwent BCS accordingly to preNACT planning (Table 12.3).
Other randomized trials comparing preoperative chemotherapy to postoperative chemotherapy reported a similar observation of a higher local recurrence rate
in the preoperative chemotherapy treatment arm.
A meta-analysis from nine randomized studies did find a statistically significant 22% increase in the risk for local recurrence associated with neoadjuvant treatment. This risk was greater in those studies where radiotherapy was the only local
treatment in patients with apparent complete clinical response [18]. The local recurrence was likely to be related to the low rate of pathologic complete response
in these studies. Residual tumor foci present in the majority of patients, despite the
high clinical response, increase the risk of subsequent disease recurrence, especially if radiotherapy alone is used. Reported factors associated with recurrence after
neoadjuvant chemotherapy are: no surgery, no overall pathological complete response and diffuse inflammatory signs.
The question of close or positive margins is often debated. Although many report a low impact on local recurrence by the finding of close margins, others have
found a clear connection with local recurrence [14]. Certainly the risk of local recurrence is related to the presence of multiple microscopic foci left behind after
surgical resection [53], but margin status may not always be indicative of the presence and amount of residual disease. In particular, the uneven shrinkage of the tumor after chemotherapy makes the estimate of residual disease by margin evaluation even less predictable. A multidisciplinary guideline issued by the American
College of Radiology, the American College of Surgeons, the College of American Pathology and the Society of Surgical Oncology stated that in the setting of
BCS after neoadjuvant chemotherapy, the presence of viable tumor throughout the
specimen, even with clear margins, should require a re-excision.
The dilemma on how conservative surgery should be after NACT remains
open and has been approached differently. The question arises as to whether surTable 12.3 Conversion rate from Mastectomy to BCS after NACT and specific Local Recurrence
Rate (LRR)
Study
[Reference]
pts converted
to BCS
Overall LRR
after NACT
LRR in pts converted

to BCS
NSABP B-18 [19]
7%
6.9%
14.5%
Royal Marsden [27]
13%
2.7%
5.3%
Institut Bergonie [25] 30%

Institut Curie [26]
23%
18%
24%
188
gery is necessary at all in patients who achieve a complete response after primary
chemotherapy.
Such an approach may sometimes be a practical issue in those cases where the
primary tumor is no longer identifiable even by imaging studies and poses the problem on where to direct surgery. Other advantages may be identified in the avoidance of postoperative problems such as chronic arm morbidity, lymphedema and
the psychological and cosmetic impact of surgery. The downside of such an approach
is that of a possible increased risk of local relapse in untreated women with an impact on long term survival and a worse cosmetic outcome if salvage mastectomy
is required in the case of a local recurrence/persistence.
A review of published series demonstrated that the local recurrence rate is
higher when radiotherapy is the only local treatment after primary chemotherapy.
In a study from the Royal Marsden Hospital, no surgery was offered to patients
who achieved a complete clinical response, and they were given only breast radiotherapy, but the study was interrupted early on before complete accrual because a
trend toward a high local recurrence rate was noted. They reported a 5-year local
recurrence rate of 25% in the no surgery patients. Similarly, a 5-year local recurrence rate of 30% was reported from the Institute Gustave Roussy, and a 35% recurrence at 10 years was reported by the Institute Bergoni [18]. But in all these
studies the decision to avoid surgery was based only on the evidence of a complete
clinical response and no attempt was made to identify patients with pathological
complete response. A better outcome should be expected in those patients showing a complete pathological response, but the main problem in identifying this subgroup of patients, who may not have an additional benefit from surgery, is the assessement of complete pathological response.
In a reported study by Clouth [54], pathological complete response was identified by serial needle core biopsies on the site of the primary tumor, if complete
clinical response, confirmed by no ultrasound abnormalities, was detected after induction chemotherapy. In this study, an apparent pathological complete response
was detected in 16% of the patients treated with an anthracycline-based chemotherapy, and the local recurrence rate after 33 months follow-up was 12.5%.
Tumor response to induction therapy, manifested in a shrinkage of the tumor,
is reported to be as high as 80%, with around 30% of the patients achieving a complete clinical response, and only half of these having a complete pathological response. Reported rates of complete clinical and pathological response varies, depending on the study population, the treatment schedule, and the agents used [19].
Taxanes have shown a doubling in pCR with a parallel increase in BCS [10]. Still
the subset of patients in whom surgery might be avoided is limited.
One of the most recognized benefits of neoadjuvant chemotherapy remains improved resectability, the significance of which should be intended not only in an
increase in the feasibility of breast-conservative resections, but also in the increased possibility of conservative mastectomies.
Downsizing of the tumor or any good clinical response after induction
chemotherapy may allow a safer skin or nipple preservation, by clearing away the
nipple areolar complex from the tumor or by resolving a peau dorange, which by
189
itself may be expression of a neglected and long lasting tumor rather than a sign
of aggressive biological behavior. Complete resolution of skin changes represents
a favorable parameter for skin conservation [47].
Improved cosmetic outcome with the advent of the so-called conservative mastectomies and immediate breast reconstruction with definitive implant have increased
the number of total mastectomies even in the setting of early breast cancer. It may
be predictable that the same trend will occur in the case of LABC, returning to total mastectomy as the procedure of choice even in the face of a good clinical response to chemotherapy, but such a possible reversal of indications in this setting
poses different problems that need to be evaluated.
For women undergoing total mastectomy, breast reconstruction improves psychosocial well-being and body image and should always be considered and discussed
with the patient at the time mastectomy is planned. Type and timing of reconstruction may be different. Reconstruction may be performed with prosthetic implants
or with autologous tissues. It can be immediate or delayed after the completion of
all the treatments. In the case of prosthetic implants it can be performed in onestep with a definitive implant at the time of mastectomy or as a two-step procedure, with an expander placed at first and followed by a second procedure for the
placement of a permanent implant. The choice of the type of breast reconstruction
and the decision to proceed with immediate or delayed reconstruction depends on
several factors including patients anatomy, comorbidities, patient preference, life
expectancy, need for radiation and timing of planned chemotherapy, surgical expertise and costs (Table 12.4).
Autologous reconstruction offers the best cosmetic result, avoids problems related to radiation treatment and is considered, by many, as the best option. Still autologous reconstruction is performed in only 23% of all breast reconstructions in
the United States [55]. It requires a higher level of surgical expertise and involves
higher costs (Table 12.4). In addition, a potentially detrimental effect on the immune system from more extensive surgery and a delay in treatment should be considered when offering an autologous immediate reconstruction in a high-risk patient for distant relapse, thus free or pedicled flap type reconstruction are usually
offered as a delayed procedure.
Table 12.4 Comparison of factors involved in different surgical approaches in patients with locally advanced breast cancers
Breast-conserving
surgery
Mastectomy and
implant
reconstruction
Mastectomy and
autologous
reconstruction
Negative impact of RT
+++
Complications
++
++
Long lasting cosmetic

outcome
+++
+++
Impact on immune system
+++
Expertise required
++
+++
Cost
++
+++
190
Implant reconstruction has long been considered contraindicated with radiations,

these having shown a negative impact on the complication rate [56].
In the last few years the role of prosthetic reconstruction has been revisited and
several recent reports suggest an increased role for implant-based reconstruction
in the setting of adjuvant radiotherapy [57]. Improved techniques and the use of
biological (acellular dermal matrix) or synthetic grafts (Tiloop) have extended
the use of immediate prosthetic reconstruction particularly in patients previously
treated with radiation or in whom radiotherapy is planned [58].
Fat grafting to the irradiated chest wall prior to implant reconstruction enhances skin tropism and reduces radiation-induced complications rates. This might
be an alternative to flap reconstruction in selected patients who are not candidates
for this procedure [59]. Timing of reconstruction should also be considered alongside the timing of adjuvant treatments.
When a total mastectomy with reconstruction is planned one must weigh the possible risk of delaying systemic treatment, if surgical complications arise, toward the
increased risk of surgical complications in women who have been treated with cytotoxic drugs. Some prefer to place a definitive implant before radiation treatment
while others advocate the placement of an expander at the time of mastectomy,
which can be overinflated during radiotherapy, and then exchanged to a permanent
implant at completion of radiation treatment [60]. At the same time, breast reconstruction may interfere with the planning and administration of the radiation dose. In the
MD Anderson experience, the initial expander is used for temporary skin preservation, and is followed by autologous reconstruction if radiotherapy is required. A study
in progress from this center is evaluating the outcome of such an approach [61].
The best type of breast reconstruction and sequencing of radiation and reconstruction remains controversial. Since irradiation of the chest wall appears mandatory in a large number of patients with LABC, the effect of radiation on the reconstructed breast with an implant should always be taken into account during surgical planning, because a safe partial breast resection would have a better cosmetic
outcome compared to a good but irradiated breast prosthetic reconstruction.
12.9
Inflammatory Breast Cancer
Inflammatory breast cancer (IBC) is a distinct form of LABC with peculiar clinical features and a very aggressive clinical course with poor prognosis.
According to SEER statistics, IBC, while accounting for a limited although increasing percentage of breast cancers (less than 2%), has a high mortality rate, accounting for 7% of breast cancer specific mortality [4]. Overall 5-year survival has
increased from 5% before the advent of systemic therapy, to 3050% 5 years after widespread use of systemic therapy [62]. Higher incidences were reported in
North Africa and Asia with rates above 10% [62]. Clinical features that distinguish
IBC are a swelling of the breast with thickening of the skin which may be reddish
and warm, or present with the typical peau dorange; this is a fine dimpling of
the skin, due to a diffuse dermal infiltration by neoplastic emboli, which may be
191
present also in tumors with an extensive LVI or in neglected breast cancers. Essential for the diagnosis of IBC, which is defined only on clinical grounds, is the
rapid and progressive onset of the inflammatory signs. In the majority of cases, the
inflammatory signs are present without an underlying palpable mass [4]. Lymph
nodes are often involved and malignant cells frequently express no hormone receptors, have a high tumor grade and overexpress HER2 and p53 protein [63]. Ductal carcinoma is most common, although all histologic types have been described
as associated to IBC.
As IBC is a nonspecific clinicopathologic entity, minimum diagnostic criteria
have been set forth, by an international expert panel [40], which include:
Rapid onset of inflammatory signs, lasting no more than 6 months
At least 1/3 of the breast involved
Pathologic confirmation of invasive cancer.
Evaluation and staging of the disease should include, beside routine mammography, ultrasound and core biopsy, a skin punch biopsy and a total body CT scan
and bone scan, as distant disease may be present in up to 30% of patients [40].
IBC is a very aggressive disease and requires a likewise aggressive treatment.
Triple modality is the standard approach with chemotherapy being mandatory as
the primary treatment. Based on the available results, although not specifically designed for IBC, anthracycline-containing regimens induce a high response rate [40,
63] and are the drugs of choice, associated with taxanes. There is evidence from
the recent NOAH study that trastuzumab added to the primary systemic treatment
in HER2-positive patients improves significantly the pathologic complete response
and disease free survival, although presently there is agreement that it should not
used outside clinical trial [64]. Limitations lay in the fact that data on efficacy of
treatment in terms of locoregional control, distant failure and overall survival are
somewhat difficult to interpret because of the wide heterogeneity of the disease and
the frequent inclusion of patients with LABC and no inflammatory signs or with
secondary inflammatory symptoms in the reported studies.
On the other hand, there is a growing body of data suggesting a causal effect
of chronic inflammation on cancer formation. Several molecular mediators have
been recognized in the pathways involved in inflammation-associated cancer, and
mitochondria have been identified to function as central regulators in malignant
transformation [63]. This growing knowledge provides the basis for developing studies exploring the role of pharmacologic and genetic targeting in breast inflammatory cancer preventive and therapeutic strategies (Table 12.5).
Locoregional treatment can be faced after a substantial systemic treatment
with a minimum of six cycles of chemotherapy over a 46 month period [64]. Surgical ablation has been reported as effective in improving survival, but it is not clear
if this might be a selection bias, as surgery has been usually reserved to patients
who responded well to systemic treatment. As a matter of fact patients who respond
well to chemotherapy show a definite improvement in overall survival [20]. Mastectomy and axillary dissection is the recommended procedure with the aim of a
complete resection. Skin-sparing mastectomy, as well as primary reconstruction,
is not recommended [61].
192
Table 12.5 Recognized molecular targets in tumorigenesis pathways and therapeutic agents under
evaluation.
Molecular target
Therapeutic agent
HER2
Trastuzumab, lapatinib
EGFR
Lapatinib
VEGEF
Bevacizumab
VEGEF-R2
Semaxanib
RHO-C GTPase
Tipifarnib
IGF-1 pathway
Metformina, anti IGF-1 antibodies
COX-2
NSAID, coxibs
E-caderin
E-caderin antibodies
PMRT should always be included for locoregional control [3, 63] with the target being a wide chest wall field, supraclavicular nodes and internal mammary nodes.
A high dose of 66Gy is suggested in high-risk women (premenopausal, positive
margins, more than four involved nodes, poor response to chemotherapy). Patients who are nonresponders to chemotherapy should receive radiation treatment
first and should then be re-evaluated for surgical resection (Table 12.6).
12.10 Summary
LABC is a heterogeneous clinical entity, which includes large primary tumors or
extensive nodal involvement. LABC represents a challenging problem and its
management requires a multimodality treatment approach involving surgery, RT
and systemic therapy.
LABC has historically been divided in operable and nonoperable tumors, based on
local aggressiveness. In operable tumors, primary surgery may be offered and it should
be followed by RT and systemic therapy. Primary systemic therapy is mandatory in
those women with inoperable tumors and should be offered in those women in which
breast-conserving surgery might be an option, in order to improve resectability.
The best tumor response is achieved with anthracycline and taxane-based regimens, but the optimal drug sequence and duration is not yet defined. Different
chemotherapy regimens with targeted drugs in subsets of patients, including those
with HER2 positive or triple negative tumors, are under intense investigation.
Mastectomy is the procedure of choice in most of the patients, but breast-conserving surgery might be offered if macroscopically complete resection can be
achieved. Neoadjuvant chemotherapy has dramatically increased the possibility of
BCS, but strict selection criteria need to be applied should the local recurrence rate
remain acceptable. RT is routine after BCS and, except for a limited subset of patients with favorable prognosis, it needs to be added also after mastectomy, in order to achieve optimal local control.
193
Table 12.6 Overview of treatment options in LABC

Surgery
Operable
T3
N0
Adjuvant
O after good
response to
NACT
O (to
improve
resectability)
O (in
high-risk
patients)
O if good
tumor/breast
ratio
O (to
improve
resectability)
O after good
response to
NACT
O (to
improve
resectability)
R in N2,
O in N1
not R
O (after
NACT)
III A
T3
N12
Nonoperable
Radiation therapy
NACT
II B
T02
N2
Chemotherapy
Mastectomy BCS
T4
N02
III B
Tany
N3
III C
M
R
IBC
O if good
tumor/breast
ratio
feasible if
not R
achieve
macroscopic
complete
resection
M (as
primary
systemic
treatment)
O (after
NACT)
BCS, breast-conserving surgery; NACT, neoadjuvant chemotherapy; R, recommended; not R, not

recommended; M, mandatory; O, optional.
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50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
Prophylactic Surgery
13
13.1
Definition
Prophylactic breast surgery includes surgical options able to remove one or both
of the mammary glands, in order to reduce the risk of developing breast cancer;
in particular, it is subdivided in bilateral and contralateral prophylactic mastectomy. This group of procedures, according to the literature data, reduces by 90% the
probability of BC in women at high risk of developing it.
13.2
Who Can be Eligible for Prophylactic Mastectomy?
Given the high incidence of BC, all women are at risk simply from the fact of being female, and the risk increases with age. In Italy, a rate of 30,000 new cases/year
is reported and BC-related deaths reach 10,000 cases/year.
With the availability of the BRCA genetic testing and the development of statistical models for risk stratification, women that are more likely to develop BC
can now be identified. In such situations, among possible risk-reducing manoeuvres, prophylactic mastectomy can be considered after proper assessment of the
case, discussion with the patient about the pros and cons and adequate time to decide without haste and superficiality.
The major world cancer centers indicate the groups of patients given in Table
13.1 as potential candidates for prophylactic breast surgery.
M. Ghilli ()
Department of Oncology, Breast Surgery Unit, Pisa University Hospital,
Pisa, Italy
e-mail: m.ghilli@ao-pisa.toscana.it
Updates in Surgery
197
M. Ghilli, M. Roncella
198
Table 13.1 Potential candidates for prophylactic breast surgery
Patients with known BRCA
1 or 2 gene mutation
See below
Patients without personal history

of breast cancer, but with a significant
family history of breast cancer,
with test not carried out (for rejection)
or with negative test/no
diagnostic/uncertain
In particular, the number of first-degree relatives

affected by breast and/or ovarian cancer, in maternal
or paternal line, and the age at which they got sick
(regardless of the outcome of their illness) must be
considered, paying attention to the presence of any
males with breast cancer or bilateral cancer cases
and/or breast and ovarian cancer in the same subject.
Patients with breast cancer
This group must be distinguished into:

Patients with unilateral BC that is still present
(recent diagnosis)
Patients with a previous breast cancer history (and
eventual adjuvant treatments) that months/years later
decide for a contralateral prophylactic mastectomy or
for a bilateral one (in case of previous quadrantectomy)
Patients with (surgical or

percutaneous) breast biopsies that
reveal histological situations with
increased risk of developing
breast cancer
Patients with (surgical or percutaneous) breast

biopsies that reveal histological situations with
increased risk of developing breast cancer.
In particular intraductal lobular carcinoma (LCIS)
or other borderline disease like atypical hyperplasia.
LCIS has a risk of 11.5% per year and 2030% in a
lifetime of subsequent development of invasive cancer
in either breast. The relative risk of invasive BC is
5.4 the rate in general population, decreasing with
increasing age [1]. Atypical hyperplasia increases the
relative risk to 4 that of the general population and
to 8.9 in those with a family history [2].
Previous thoracic radiotherapy
For the treatment of lymphomas
Dense breast
Recent studies seem to demonstrate a risk not simply

linked to the difficulty of diagnosis (which often
means a delayed diagnosis), but also a real increase of
developing cancer due to the breast structure [3].
13.3
BRCA1/2 Mutation Carriers
The literature suggests that 510% of all breast cancers have an inherited maternal or paternal basis [4, 5]; 50% of hereditary breast cancer is inherited from the
fathers side. In the USA, more than 500,000 women are mutation carriers. Mary
Claire King and colleagues localized the BRCA1 gene in 1990: studying families
with early-onset breast cancer, they demonstrated that the disease had a marker on
chromosome 17q. The newly discovered gene was considered to be a tumor suppressor gene (p53 related) since its loss was found in more than 90% of BRCA1
mutation carriers with BC. In 1994, the sequence of the BRCA1 gene was completely characterized and the research of BRCA2 gene started [6]. Thus a relation
13 Prophylactic Surgery
199
Table 13.2 The peculiar characteristics of BRCA1/2 mutation carriers [7]

BRCA 1 and 2
They are autosomal dominant, tend to be highly penetrant. BC mutation

inheritance can be maternal or paternal, following the Mendelian model
Their function is linked to DNA damage repair. In vitro and animal
BRCA models have been shown to be radiosensitive: it is therefore
important to combine the need of regular and frequent controls and the
risk of RX damage
Frequently early-onset and bilateral tumors
The lifetime probability of a second breast cancer (after a previous one)
is 60% in absence of risk-reducing maneuvers, if the patient survives the
first BC
BRCA1
BRCA1 carriers have a 5080% lifetime risk of BC and a 3040% of

OC. BRCA1 mutated cancer account for 3040% of inherited BC.
Mapped to a region on chromosome 17
BRCA1 tumors (compared with sporadic ones) are often triple-negative,
poorly differentiated, high proliferative rate tumors, and frequently
medullary tumors; overexpression of p53 is common
BRCA2
BRCA2 mutation carriers have a 4070% lifetime risk of BC and 20%

of OC. Its mutation is also linked to prostate cancer (4), uterine, pancreatic and gastric cancer and melanoma
Mapped to a region on chromosome 13
Men who are mutation carriers are more frequently BRCA2 carriers
BRCA2 tumors (compared with sporadic ones) are often well differentiated, with a medium-low mitotic rate and tend to be ER-positive with the
same frequency as sporadic ones
between BRCA1/2 mutations and BC or other carcinoma (pancreatic, prostatic),

or some particular inherited syndromes like Li-Fraumeni, Peutz-Jeghuers and ataxia-telangiectasia, was demonstrated. Table 13.2 shows the peculiar characteristics
of BRCA1 or 2 mutation carriers [7].
13.3.1 Genetic Testing

Genetic testing should be accompanied by a genetic counselling team [4], whose
members must be prepared to deal with a spectrum of medical, psychological and
social consequences of a positive, negative or ambiguous result of the test itself.
There are clear indications (see Table 13.3, according to The Italian FONCaM
2006 recommendations) for referring the patients (or healthy subject) to genetic
counselling where, after careful history taking and calculation of the risk of being
carriers of a mutation, genetic testing could be proposed (on peripheral blood, since
genes BRCA1 and 2 are present in all cells).
The DNA study normally takes quite a long time (months), however, in selected cases, it may be reduced to a few weeks: this is particularly important in patients eligible for
conservative surgery, when the eventual mutation could be a reason for demolitive surgery. It is necessary that the patient who takes the test is adequately informed that:
A positive test should not be read as a condemnation but as an opportunity to
200
Table 13.3 Indications for referring the patients (or healthy subject) to genetic counselling
BREAST CANCER PATIENTS
Women with a personal history
of BC/OC at any age IF
Breast cancer diagnosed at age 36 or younger OR

Breast AND ovarian cancer in the same subject at any age OR
Bilateral breast carcinoma at age 50 or younger OR
Male breast carcinoma at any age OR
Ovarian or fallopian cancer at age 45 or younger

of BC at age 50 or younger AND
One first-degree-relative with a history of BC at age

50 or younger OR
One first-degree-relative with a history of bilateral BC at any
age
One first-degree-relative with a history of OC at any age

of BC at age 50 or older AND
Two first-degree-relatives, both with a history of BC

at any age

of OC at any age AND
One first-degree-relative with a history of OC at any age
HEALTHY SUBJECTS WITH A FAMILIAR HISTORY OF:

At least one first-degree relative
with BC, IF
Breast cancer diagnosed at age 36 or younger OR

Breast AND ovarian cancer in the same subject at
any age OR
Bilateral breast carcinoma at age 50 or younger OR
Male breast carcinoma at any age OR
Ovarian or fallopian cancer at age 45 or younger
Two first-degree relatives
With a history of BC at age 50 or younger

With a history of OC at any age
One with a history of BC at age 50 or younger and one
with a history of bilateral BC
One with a history of BC at age 50 or younger and one
with a history of OC
Three first-degree relatives
With a history of BC at any age
learn of a risk and put in place the maneuvers that can reduce it (but not cancel). The patients reactions are heterogeneous in this sense; for their proper management, it is necessary to provide psychological support
A negative test (for mutations known up to now) does not exclude the possibility of being considered at high risk of hereditary BC
The presence of a negative genetic test in a patient with a mutation clearly established in other family members excludes this mutation and takes us back to
a risk comparable to the general population.
The test should be performed, in families with multiple cases, on the youngest subject (referring to the age at the moment of the diagnosis) with a personal story of BC
because she/he has, in that family, the highest probability of carrying the mutation.
Before performing the test, the patient must be properly informed (this must be
documented in the informed consent) that there is no procedure that can reset the
risk, in the case of a positive test. There are tools for primary (surgery and chemoprevention) or secondary prevention, essentially represented by clinical and instru-
201
mental monitoring. The important role of MRI in the surveillance of these subjects
has been demonstrated. In fact, it is very sensitive and can pick up cancer at an earlier stage, but the impact on survival is unknown. The Dutch National Study [8]
on more than 1,900 high-risk women (358 of which BRCA1/2 mutation carriers)
concluded that MRI had a higher overall sensitivity, except for ductal carcinoma
in situ (DCIS), a condition that was better detected by mammography.
13.3.2 Radiological Screening

In addition to risk-reducing surgery, which is the object of our present article
and which will be discussed below, there are other strategies to reduce the risk,
the main one of which is represented by the radiological monitoring in these patients, using traditional methods and breast MRI. The recommendations regarding radiological screening at different ages, according to Italian FONCaM 2006,
are reported in Table 13.4.
In male mutation carriers, the risk of BC at 70 years of age is 6%; for this reason a radiological screening is not indicated: the subject must be informed of the
risk and warned that in presence of the slightest suspicion he should consult a specialist. He must also be informed of the increased risk of prostate cancer and colon
cancer, and of the advisability of a regular check-up.
13.3.3 Chemoprevention
Chemoprevention uses hormonal drugs able to block the effects of estrogens,
which are responsible for the development and growth of a significant proportion
Table 13.4 Recommendations about radiological screening at different ages, in high risk patients
Between 2535 years old (or 10 years
younger than the youngest affected relative)
Clinical examination twice a year, breast

ultrasound twice a year, breast MRI every 12
months, one x-ray bilateral mammography
projection every 12 months
Semi-annual OC screening with pelvic
examination, transvaginal ultrasound and
CA-125 test
Between 3650 years old
Clinical examination twice a year, breast

ultrasound every 12 months or twice a year
in case of dense breast, breast MRI every 12
months, two x-ray bilateral mammography
projections every 12 months.
Semi-annual OC screening with pelvic
examination, transvaginal ultrasound and
CA-125 test
50 years old or older
Clinical examination twice a year, breast MRI

every 12 months, two x-ray bilateral mammography projections every 12 months, breast
ultrasound if needed
202
of tumors: among them, tamoxifen and raloxifene (active against osteoporosis and
reduction of LDL-cholesterol) can be used, keeping in mind that their risk-reducing effect is about 50% and that they are accompanied by side effects. The randomized placedo-control Breast Cancer Prevention Trial [9] demonstrated a 50% reduction of invasive BC incidence among high-risk healthy women who took tamoxifen (in women with lobular carcinoma in situ (LCIS) the incidence of invasive BC
decreased by 56%; and in cases with atypical hyperplasia, the decrease was 86%).
There were no proven effects in terms of mortality, but an increased risk of developing an endometrial stage I carcinoma. Other more recent trials found a minor effect in particular in cases at low risk. Actual recommendations are:
Tamoxifen employment in chemoprevention must be individualized and used
in cases with a risk of BC superior to 1.66 using the Gail model.
Patients with DCIS, LCIS and atypical hyperplasia, or BRCA1/2 mutation carriers could be considered for the treatment.
The treatment must be avoided if a history of stroke or cardiovascular disease
is present.
Some studies have evaluated or are evaluating the protective role of the administration of raloxifene, aromatase inhibitors, non steroidal anti-inflammatory drugs,
statins and more recently retinoids (fenretinide) without definitive and unequivocal results.
13.3.4 Bilateral Salpingo-oophorectomy

Finally, without going into details which are far from the goals of this chapter, it is important to mention the bilateral salpingo-oophorectomy (BSO); if performed between
35 and 40 years, it results in a 98% reduction in the risk of ovarian cancer (OC) and
5070% of BC. Given that in mutation carriers OC occurs more frequently between 45
and 50 years old, performing the intervention after 35 years to allow a possible pregnancy is recommended. The BSO is a risk-reducing maneuver that is strongly recommended (much more than the mastectomy) because difficulties in diagnosis of OC, the
absence of effective screening measures and poor prognosis are well known. However, there are also some adverse effects among which are decreased libido, the early-onset of osteoporosis and cardiac problems, all typical of postmenopausal women.
13.4
Looking at the Literature: Effectiveness of Bilateral

Prophylactic Mastectomy
13.4.1 BRCA Carriers

In BRCA carriers, three milestone studies confirmed that bilateral prophylactic mastectomy (BPM) reduces the incidence of breast cancer. Meijers-Heijboer and colleagues [10] conducted a prospective study on 139 BRCA1 or BRCA2 mutation
carriers. Seventy-six women underwent BPM, and 63 remained under close sur-
203
veillance. No BC developed in the BPM group; however, the risk reduction effect
of BPM in this study cannot be isolated from the risk-reducing effect of prophylactic BSO. In this study, a statistically greater proportion of women in the BPM
group underwent premenopausal prophylactic salpingo-oophorectomy (PSO) (58%)
compared with the surveillance group (38%).
Hartmann and colleagues [11] reported no case of BC at a median follow-up
of 13.4 years in 26 BRCA mutated women who underwent BPM. Using various
statistical models, the relative risk reduction due to BPM was estimated at 85100%.
In the more recent Prevention and Observation of Surgical Endpoints (PROSE)
study of Rebbeck and colleagues [12], 105 BRCA carriers were followed after BPM
and compared with 378 matched BRCA controls, who did not undergo the procedure. With a mean follow-up of 6.4 years, BC was diagnosed in 2 (1.9%) of those
who had BPM versus 184 (48.7%) of those who did not. Cases and controls in this
study were matched based on PSO, with a relative breast cancer risk reduction of
95% in those who had PSO and 90% in the other group.
Taken together, these studies confirm a 9095% reduction in breast cancer risk
after BPM in BRCA carriers.
13.4.2 High-risk Women Regardless of BRCA Status

Several studies provide evidence on the efficacy of BPM for high-risk women regardless of BRCA status. Hartmann and colleagues [13] retrospectively studied BPM
among high-risk women based on a positive family history of breast cancer. In their
cohort of 639 women from 1960 to 1993, 90% underwent bilateral subcutaneous
mastectomy with preservation of the nipple-areolar complex (NAC), whereas it was
removed in the remaining 10%. The cohort was divided into high- and moderaterisk groups, and the incidence of breast cancer in these groups was compared with
that of a control group consisting of their sisters, who did not undergo BPM. With
a median follow-up of 14 years, the incidence of breast cancer was reduced by
9094% in the high-risk group and 90% in the moderate-risk group.
The efficacy of BPM in community practice was evaluated in a population-based
study by Geiger and colleagues [14]. In this retrospective case-cohort study, BPM
reduced breast cancer risk by 95%, although the absolute risk of BC in the control
population was low (4%).
13.5
Looking at the Literature: Effectiveness of Contralateral

Prophylactic Mastectomy
Women who are facing early-stage diagnosis of BC may choose to have a contralateral prophylactic mastectomy (CPM) to reduce the risk of developing BC. In the
United States, according to the SEER Cancer Registry, the CPM rate among patients with unilateral invasive breast cancer has increased from 1.8% to 4.5%
(+150% ) over the period 19932003 [15].
204
In a BRCA mutation carrier with unilateral BC already operated or waiting for

the intervention, the risk of contralateral BC is 3040% within 10 years after the
first diagnosis [16]. CPM has been shown to reduce the risk for developing contralateral BC but the significant increase in the CPM rate is worrying especially
among women with early-stage sporadic BC who have a minimal annual risk of
developing contralateral disease. In fact, for many of these women with early-stage
sporadic BC, the risk of distant metastasis outweighs the risk of contralateral
breast cancer [15]. The potential benefit of CPM in terms of disease-free survival
will be observed only among certain subgroups of patients, for example in ER-negative cancer. In fact, in patients with an ER+ breast cancer, CPM is not associated
with longer breast cancer-specific survival after consideration of the positive effect of adjuvant hormonal therapy [17].
There is conflicting evidence on whether or not CPM reduces BC mortality or
overall death. Boughey et al. [18] reported a 95% lower incidence of contralateral BC at a long follow-up among patients with a family history of BC who underwent CPM, compared to patients who did not undergo CPM. PM was also associated with statistically significant superior disease-free and overall survival. However, in a population of breast cancer patients with mutations, Van Sprundel et al.
[19] showed that CPM led to a 91% lower incidence of contralateral breast cancer, but there was no association with longer overall survival after adjusting for
oophorectomy. A recently updated Cochrane review of six observational studies concluded that CPM resulted in a lower risk for contralateral breast cancer but did not
convey a survival benefit [20].
In an indirect way, using statistical models, Schrag estimated a gain after mastectomy of 2.85.3 years of life if PM was carried out before 30 years of age, 2.6
years if performed between 30 and 40 years of age and 2.3 years at 50 years [21].
In 2007, the Surgical Oncology Society indicated when CPM may be appropriate in patients with a personal history of breast cancer [22]:
(a) To reduce contralateral breast cancer risk in high-risk patients
(b) For whom radiological surveillance is difficult due to breast density or diffuse
calcifications, and
(c) To improve symmetry in women undergoing unilateral mastectomy.
Given that patients may overestimate their risk of developing contralateral breast
cancer, physicians should counsel patients appropriately [22]. The increased use
of preoperative breast MRI has changed the surgical treatment of patients with unilateral breast cancer, and in some studies, it appears to have resulted in higher rates
of CPM, in addition to the well-known effect of an increase in mastectomies. Concerning the decision-making process in the case of CPM, a recent study has been
conducted at the MD Anderson Cancer Institute on more than 2,500 women with
BC; the target of the trial was to determine which factors were associated with the
decision of undergoing CPM. Of 2,504 breast cancer patients, 1,223 (48.8%) underwent total mastectomy, 284 (23.2%) underwent immediate or delayed CPM. Univariable analyses revealed that factors reported in Table 13.5 were significantly associated with undergoing CPM [23].
205
Table 13.5 Factors significantly associated with the choice of undergoing CPM, according to [23]
Age < 50
White ethnicity
Marital status
Family history of breast cancer
Use of hormone replacement therapy
Undergoing BRCA1/2 genetic testing before surgery
Higher clinical tumor stage
Multicentric primary tumor
Invasive lobular histology
Use of reconstructive surgery
Most studies concerning CPM have been conducted among high-risk women
and BRCA1 and BRCA2 mutation carriers; thus, their conclusions may not reflect
the experiences of breast cancer patients without familiar risk. Nonetheless, some
researches suggest that a small proportion of women who undergo CPM experience low satisfaction with their appearance and adverse effects on their sexuality.
There are several psychosocial predictors that may influence a womans decision
to have CPM, including: knowledge about the treatment options, perceived risk,
empathy with the doctor, anxiety, body image, and uncertainty of illness. Moreover, the approach that physicians use to communicate with the patients, regarding treatment options, is an important determinant of patients treatment decisions
and satisfaction.
13.6
Decision-making Process: How to Get to the Decision

of Prophylactic Surgery?
After establishing that the case is at medium/high risk of BC, the decision about
what to do is a complex process that requires time. A specialized multidisciplinary
team is needed in order to have a complete, detailed, balanced and nonpartisan assessment concerning what to do and how technically to achieve it. The team must
include a geneticist, a psychologist and a clinical doctor (for discussion of technical options, it is essential to have a breast surgeon and a reconstructive plastic surgeon).
The decision must be balanced and absorbed by the patient after the pros and
cons of PM have been discussed and after the details related to the reduction of risk
and type of reconstruction have been clarified. The patient must be clearly informed
that the risk reduction does not coincide with its own reset. Considering that PM
reduces the risk of BC by 90% in high-risk patients, for every 100 patients who
undergo it according to data of the literature 10 develop the disease anyway.
In fact, the whole breast tissue is not always surgically removed: islands of glan-
206
dular tissue may remain in the flap of skin and subcutaneous tissue, in the retroareolar tissue, in the axillary extension, in the axilla, in the supraclavicular region or,
in the context, the very cranial portion of the abdominal wall.
So the patient must come to understand:
The risks linked to the probability of a cancer after performing a PM (significantly reduced, but not reset)
The general risks related to surgery (bleeding, infections (1020%), seroma
(17%), retracting scars or keloids or any form of delayed healing)
The specific risks related to mastectomy and to reconstruction (ischemia/necrosis of the flap, or of the NAC, varying degrees of capsular contracture which
are described in up to 30% of procedures). According to EUSOMA guidelines
[24], the capsular contracture occurs in 1520% of the reconstructions in the
absence of radiotherapy and occurs even after years, more frequently when the
prosthesis is not completely covered by the muscle. A variable degree of durable
pain is variously described in 35% of cases.
Finally, clear elements about the outcome of reconstruction must be provided
to the woman: in general, any kind of surgery, even if performed with the greatest
skill, is unable to return to the same overall situation, in terms of sensitivity and
subjective response (body projection). No reconstructive result is guaranteed forever, and the result may change over time, in a totally unpredictable way, often necessitating further operations (rate of reinterventions reported: 49%). According to
EUSOMA, PM gets excellent results in 60% of cases, with 5% of the patients not
being satisfied with the choice. EUSOMA best practice indicators are: excellent
results in at least 75% of cases, minor complications (infection, small area of
necrosis) in less than 10%, asymmetry in less than 20% and contracture in less than
10% of cases [24].
In summary, the patient who wants to start a project of prophylactic surgery (especially, if she is not at high genetic risk, certificated with a positive test for BRCA mutation) must be warned (and it must be written in the informed consent) that:
PM is a permanent and irreversible act.
On one hand, it is predictable that a psychological benefit linked to the achievement of the risk reduction could be obtained; on the other hand, a negative impact on the quality of life related to the partial or full loss of sensibility, its effect on the body projection (meaning the way you see and feel regardless of how
it is objectively) and on the sexual life can happen in some subjects. Sometimes
anxiety and depression have been reported.
The breast-operated on can no longer breastfeed.
The risk of developing breast cancer is significantly reduced but not reset.
The ideal time to propose PM is between 30 and 50 years.
13.7
Risk-reducing Surgery of the Breast: Techniques
There are different technical approaches of prophylactic mastectomy. The main techniques belong to the new generation-mastectomies; the so-called conservative
207
mastectomies (skin-sparing and nipple-sparing) are usually associated with immediate reconstruction with implants or with expander. The currently most suitable
option within the prophylactic setting is certainly the nipple-sparing mastectomy,
first described by Crowe, in which the whole skin envelope is conserved.
Prophylactic mastectomy, unlike the curative one, having to avoid significant
changes in the body projection, is always accompanied by breast reconstruction with
expander or sometimes with implants directly, except on occasions where the patient refuses the reconstructive option: this particular situation must be discouraged
and performed only after a multi-step decision-making process, accompanied by
psychological evaluation and documented in the written informed consent.
In the prophylactic breast surgery, it is rare to use autologous flaps for reconstruction.
13.7.1 Subcutaneous Mastectomy

The subcutaneous mastectomy (SM) is a progenitor of the nipple-sparing mastectomy (NSM). SM differs from NSM as there is an increased possibility of leaving
breast tissue in thicker skin flaps and of the retroareolar region having a thickness
of up to 1 cm. The SM, described for the first time in the 1950s by Strickler and
Rice, made it possible to remove the 9095% of breast tissue vs 9799% in properly conducted NSM. The SM appears therefore, today, less secure under the oncologic profile: it has lost indications and should be discouraged.
13.7.2 Nipple-sparing Mastectomy

In NSM, the skin flap thickness is minimal and the NAC, especially, is completely deprived of the glandular portion. Essential conditions for an NSM are:
Checking the distance between the NAC and the disease, by using radiological and clinical instruments (the ideal distance is considered > 2cm at mammography and MRI). This criterion is obviously not applicable to the prophylactic setting.
Evaluating during surgery the absence of disease in the retroareolar region, with
an intraoperative examination (frozen sections) performed on the disc of
retroareolar tissue, that must be adequate in thickness and oriented for the
pathologist.
Using the superficial fascia as a dissection plane, because it is bloodless and
allows the minimization of the risk of leaving residual glandular component.
Especially in young subjects, this plan is hardly distinguishable. Moreover, it
does not exist in correspondence of the retroareolar region, where it is useful
to hydrodissect the structures.
Evaluating the shape and the size of the breast: regardless of oncologic reasons,
the very voluminous and/or ptotic breasts do not allow a good reconstructive
result. In medium-sized breasts with a moderate degree of ptosis and with good
208
projection, the use of synthetic (titanium) or biological, cross-linked or not, dermal collagen patches can have a role. These tools replace the muscle function
in the coverage of the lower half of the prosthesis (the muscle, in this case disengaged inferiorly, covers the higher half), allowing interventions in one step,
often avoiding contralateral symmetrization and achieving more natural results
in terms of ptosis. The risk of infections or of inflammatory reactions has been
described sometimes as a potential disadvantage. It is therefore important to make
careful use of these expansive devices and to appropriately select patients: in
fact, one of the greatest limitations of such tools is represented by the high cost,
partly offset by savings due to a single-step operation. The experience with these
devices is fairly recent, at least in Italy, and therefore reliable data concerning
safety, behavior over time and reconstructive results are not available, even if
the experiences gathered so far are encouraging.
There are several types of incision for the NSM, including the lateral (in the
inframammary fold, laterally), the upper periareolar with two horizontal extensions on the sides (more risky because it reduces by 50% the blood supply to
the nipple-areola complex) or the radial s italic incision in the upper-outer quadrant (Figs. 13.1 and 13.2).
Despite the potential aesthetic and psychological benefits of NSM, there are some
doubts about a possible increased recurrence rates or higher postoperative complications. In a recent review, twenty-seven studies were identified that met inclusion
criteria, representing a total of more than 3000 mastectomies. It has been found,
with documented mean/median follow-up of 2 years, an overall local-regional recurrence rate of 2.8%. Concerning ischemic complications involving the NAC and
the skin flap, 9% of cases were reported to have some degree of NAC necrosis and
2% a complete NAC loss. Sixteen studies (representing more than 2000 mastectomies) reported rates of skin flap necrosis, in less than 10%. There is now a significant body of literature demonstrating acceptable rates of early locoregional recurrence and postoperative complications after NSM.
These data support its use, when indicated, because NSM has been shown to
improve psychological and esthetic outcomes without compromising therapeutic
efficacy [25].
13.7.3 Skin-sparing Mastectomy

Another surgical option is represented by the skin-sparing mastectomy (SSM) in
which most of the skin is preserved, but not the NAC. First described by Toth and
Lappert in 1991, it typically provides removal of the entire breast and NAC while
preserving the skin envelope and the inframammary fold (Fig. 13.3) [26].
The dissection should be carefully carried out in the same plane as the Madden Mastectomy. Some authors evaluated that skin flaps >5mm were associated
with an unacceptable presence of residual disease [27, 28]. The traditional SSM
also involves excision of the skin overlying superficial tumors, as well as previous biopsy entry sites to decrease chances of LR.
209
Fig. 13.1 Prophylactic bilateral nipple-sparing mastectomy: preoperative, intraoperative and

postoperative phases
Fig. 13.2 Prophylactic nipple-sparing
mastectomy: one-step reconstruction by
employing collagen patch and prosthesis
210
Fig. 13.3 Skin-sparing mastectomy: intraoperative phases
Despite some papers showing relatively high rates of residual tissue, many studies over the past two decades have determined that SSM is a safe treatment without significant difference in LR than nonSSM [29]. The LR after nonSSM in tumors up to 4cm was shown to be less than 10% after 20 years of follow-up, and
SSM recurrence rates range from 07% [30].
13.7.4 Skin-reducing Mastectomy

Another possibility is represented by the skin-reducing mastectomy, first described
by G. Querci della Rovere and M. Nava [31]; it is a useful technique in the case
of big and ptotic breasts, in patients with good microcirculation (smokers, diabetics, and people affected by connective tissue disease should be excluded). The technique provides a de-epithelialized dermal flap that is used to cover the implant in
the lower quadrants, while the pectoralis major muscle is inferiorly disengaged and
employed to cover the upper part (Fig. 13.4). The approach is mediated by a breast
reduction technique with inverted-T scars. The NAC could be grafted at the end
of the procedure. This new technique, reserved for particular cases, allows a onestep reconstruction with prosthesis and usually it requires a contralateral symmetrization (in the prophylactic setting, SRM is obviously bilateral).
211
Fig. 13.4 Skin-reducing mastectomy: preoperative, intraoperative and postoperative phases
13.8
Prophylactic Surgery of the Axilla
The overall estimated risk of finding an occult invasive carcinoma after histological study of breasts from prophylactic mastectomies is less than 5%, so a routine
use of SNB is not recommended. In particular subgroups of patients over the age
of 60, with biopsies positive for in situ and invasive lobular carcinoma and BRCA
mutation carriers, this risk increases and the sentinel node biopsy can (but not, must)
be executed. Advanced cancers, multicentricity, or receptor status on the therapeutic side or a finding of atypical hyperplasia in prophylactic breast specimen yielded no positive sentinel node. Routine sentinel node biopsy in pure bilateral PM can
be safely omitted, reducing axillary morbidity and operative time and/or cost [32].
13.9
Conclusions
BPM has been proven as a possible option, in the risk-reducing setting, indicated
for women with a family history of breast and/or ovarian cancer, increased Gail
risk, carriers of BRCA1 or BRCA2 gene mutations, personal history of biopsies
positive for high-risk breast lesions. Regarding CPM, a personal actual or previous history of invasive/in situ cancer represents a possible indication. From a technical point of view, there are different options for mastectomy and for reconstruction (Fig. 13.5).
NSM appears to be the best approach, when indicated. The role of SNB in the
setting of PM is still controversial. Overall high satisfaction with the decision regarding the concern, worry and fear related to BC is reported, even if a small proportion of women, who undergo PM, experience less satisfaction with their appearance, or adverse effects on their sexuality and on their body projection with psy-
212
Subcutaneous
mastectomy
Inframammary incision with nippleareola complex sparing. Important

residual tissue in: skin flaps, axillary
extension and in the Retro Areolar.
Total mastectomy
NO immediate reconstruction.
Possible minimal residual tissue
in the skin flaps.
Skin-sparing
mastectomy
Periareolar incision. NO nippleareola complex sparing. Complete

resection. Minimal residual tissue
in the axillary extension.
Nipple-sparing
mastectomy
NAC conservation. Minimal Retro

Areolar residual tissue. Possible
minimal residual tissue in the skin
flaps and axillary extension.
Skin-reducing
mastectomy
A new optiof for medium-large,

ptotic breast. Tissue-expander or
directly prosthesis. Possible minimal
residual tissue in the skin flaps and
in the dermo-subcutaneous pouch.
Fig. 13.5 Mastectomies: different approaches
chologically poor effects. Prophylactic breast surgery is in fact an irrevocable BC

prevention strategy that carries both medical and psychological benefits and risks.
The decision-making process leading to the PM must be rigorous and managed by
a multidisciplinary medical team. The patient should be supported psychologically and even doctors of the counselling team must be properly instructed on how to
address these talks. Some recently published papers show that if the vast majority of patients after PM reported judgments such as: For years I felt like a walking time bomb and after the surgery I felt a high sense of relief. It was the best decision I ever made; there are also other evaluations like I had unrealistic ideas
as to what the final cosmetic result would be or if I had known what I was waiting for, I would not have done it that cannot be underestimated [33].
213
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Intraoperative Radiotherapy
14
14.1
Definition
The techniques grouped under the name of Accelerated Partial Breast Irradiation
(APBI) provide, with different technical approach and different technological instruments, direct irradiation of the target volume during surgery (as a boost or as
a complete treatment) or in the following days, with an accelerated scheme. APBI approaches have the peculiarity of irradiating only the breast tissue closest to
the resection cavity.
Before going into the detail of APBI, some theoretical considerations are necessary to understand the rationale for this approach, which began in the mid 1990s
with interstitial brachytherapy.
14.2
Introduction
Breast-conservation therapy (BCT) is a safe, effective alternative to mastectomy

for early-stage breast cancer. This approach involves local excision of the cancer
with tumor-free margins, followed by external beam whole-breast radiotherapy (RT)
to minimize the risk of an in-breast recurrence.
Prospective, randomized trials confirmed that the combination of breast-conservation surgery (BCS) with whole-breast (WB) radiotherapy (known as breastconservation therapy BCT) produced effective local control and equivalent survival when compared directly to radical mastectomy (see Table 14.1a and 14.1b).
What is the role of radiotherapy in breast cancer? The rationale for treating the
breast with radiotherapy, after BCS, is to destroy any residual microscopic malignant cells or additional occult foci anywhere in the breast.
M. Ghilli ()
Department of Oncology, Breast Surgery Unit, Pisa University Hospital, Pisa, Italy
e-mail: m.ghilli@ao-pisa.toscana.it
Updates in Surgery
215
216
Table 14.1a Local recurrences: role of radiotherapy according to the biggest trials
Trial (year)
Local recurrences %
Breast-conserving
Breast-conserving
surgery
therapy
Follow-up
(years)
NSABP B06 (2002)
39.2
14.3
> 20
Milan III (2001)
23.5
5.8
10
Swedish (1999)
24
8.5
10
British (1996)
35
13
Scottish (1996)
24.5
5.8
5.7
Table 14.1b Survival: role of radiotherapy according to the biggest trial

Survival %
Trial (year)
Breast-conserving
Breast-conserving
surgery
therapy
Follow-up
(years)
NSABP B06 (2002)
46
46
> 20
Milan III (2001)
76.9
82.4
10
Swedish (1999)
78
77.5
10
British (1996)
Scottish (1996)
5.7
New studies were undertaken in an attempt to identify subgroups of patients,

tumor characteristics, and surgical techniques that might achieve adequate local control using breast conservation without irradiation [1, 2]. Surgery alone has failed
to obtain local control as effectively as that seen with surgery followed by WB irradiation in trials with long-term follow-up. The latest Early Breast Cancer Trialists Collaborative Group (EBCTCG) systematic review confirmed a 75% reduction in local recurrence (LR) risk after radiotherapy, and showed that the prevention of four local recurrences prevents one cancer-related death at 10 years, corresponding with 15 fewer deaths per 100 node-negative patients and 510 fewer
deaths per 100 node-positive patients treated [3].
Subsequently the local-regional management of BC has arrived at another
crossroad. The standard radiotherapy is being replaced, in several clinical trials,
by shorter courses of postoperative irradiation lasting only 15 days or intraoperative irradiation (accelerated), and focused solely on the breast tissue around the
surgical cavity (partial breast).
If APBI is demonstrated as safe and effective in selected women compared to
WBRT in ongoing trials, this will represent a new option for selected women with
early-stage BC.
14.3
APBI: Theoretical Bases
14.3.1 Whole-breast Radiotherapy Criticisms

The daily visits that women must make to a treatment facility over 5 weeks are disruptive, especially in these situations:
14 Intraoperative Radiotherapy
217
Women with family or work obligations

Elderly women
Women with important comorbidity, and
Distance from the facility, especially in case of a lack of reliable transportation
[4].
In these situations, an important percentage of patients must choose between
avoiding postoperative radiotherapy (undertreatment) or deciding for a mastectomy (overtreatment). Another topic, especially in a period of economical crisis, is
represented by consumption of resources: breast irradiation may constitute 2530%
of patients for a radiation oncology service and it can create stress for a health-care
delivery system.
In addition, APBI provides a better integration with chemotherapy for women
who require such treatment. Finally, it has been demonstrated that external boost
may often miss the target (simply because it is more difficult for the radiotherapist to know the exact tumor site than for the surgeon during the operation).
14.3.2 Topographical Distribution of Tumor Recurrences

After BCS, most breast cancer recurrences are localized at the site of the original
tumor rather than elsewhere in the breast [56]. Accordingly, the WBRT approach
is potentially unnecessary and may introduce avoidable toxicity.
BCT trials have demonstrated that the majority of in-breast tumor recurrences
take place near the original tumor site in or around the surgical site, within 2cm
(known as true recurrences) and those recurrences which develop away from the
initial tumor (elsewhere failures, or new or second, ipsilateral primary breast
cancer) may not be significantly reduced by radiotherapy. 7086% of the local recurrences after BCS without radiotherapy are true recurrences, according to the trials reported in Table 14.1 (Milan III: 85%; NSABP B06: 70%; Swedish group:
72.7%)
14.3.3 Radiobiological, Clinical, and Psychological Aspects

During or immediately after surgery, the tissue is maximally vascularized and
oxygenated, since radiotherapy acts with a mechanism of ionization and free radical liberation that causes DNA damage, the effect in the case of APBI is optimized.
In addition, DNA damage can be repaired between each delivery while this cannot happen in the case of single-step irradiation.
Using a mathematical model known as the linear-quadratic equation, it has been
concluded that shorter plans require more intense doses of radiation per fraction
to achieve the same effect on the tissue. In addition, higher doses are better tolerated as the target volume decreases.
The therapeutic effect seen with a standard course of 50Gy to the whole breast
at 2Gy per day (plus a boost to the tumor bed) might be seen equally well with
21Gy in a single fraction using intraoperative radiotherapy (IORT). The dose is
218
delivered to the target under direct vision. The adjacent tissues are spared: they can
be easily shielded or moved away from the radiation field, finding a solution to the
problem of cardiac and lung exposure and the related sequelae. Moreover, skin and
subcutaneous tissue are also spared, with possible improvement of cosmesis [7].
It is obviously better for a woman to complete the treatment (surgery and radiation therapy) at the same time or in a short period instead of in many weeks [8].
14.4
Techniques
There are some possibilities of performing an APBI approach.
14.4.1 Interstitial Brachytherapy

Studies with longer follow-up started with this approach, in the mid 1990s by Frank
Vicini. The rates of local recurrence in the APBI arm versus the standard arm have
been demonstrated to be similar, equally disease free survival (DFS) and overall
survival (OS).
Up to 20 catheters are inserted in the breast tissue surrounding the tumor cavity under direct control during surgery. Radioactive sources (High Dose Rate
(HDR) unit or Low Dose Rate (LDR) iridium seeds) are loaded afterward in the
catheters to irradiate the cavity plus a margin. For HDR, a schedule with 34Gy in
10 fractions (twice daily) over 5days is the most frequently used. At the end of
treatment, the catheters are removed.
Interstitial brachytherapy is a complex procedure that requires specialized, expensive equipment and high experience. Dose heterogeneity inside the catheter can
potentially lead to fat necrosis and subcutaneous toxicity; however, this technique
provides good sparing of heart and lung [9, 10].
14.4.2 MammoSite Balloon Catheter Using HDR Brachytherapy

An inflatable balloon linked to a single- or multi-lumen catheter is inserted into
the surgical cavity, during or after surgery, under ultrasound guidance. The balloon
is inflated and the source (usually iridium) is inserted. The balloon-to-skin distance
should be 57mm: a shorter distance may lead to poorer cosmetic results or skin
necrosis. For this reason, it is not indicated for patients with small breasts or superficial tumor. It is important to make the walls of the cavity adhere to the device
and then inject contrast for radiographic verification of the correct positioning, with
respect to the target and to the structures that are to be spared. This technique respects the heart and lungs, but can also potentially lead to fat necrosis within the
breast. The most frequently used schedule is 34Gy in 10 fractions (twice daily)
over 5days. Harper published data that revealed acceptable toxicity and comforting cosmetic results [11, 12].
219
14.4.3 External Beam Radiation with 3D-Conformal Radiation

Therapy (3D-CRT) and Intensity-modulated Radiation
Therapy (IMRT).
APBI can also be performed with the new generation linear accelerators of that
are already present in most RT departments. These methods require external
beams but, with the use of an accurate study of sagittal, coronal and transverse
planes, it is possible to reconstruct with extreme precision the target volumes
excluding important anatomical structures. With sophisticated software even synchronization with the respiratory movements can be taken into consideration.
The most frequently used schedule is 38.5Gy in 10 fractions (twice daily) over
5days [10, 13].
14.4.4 Intraoperative Radiotherapy Using the Photon

Radiosurgery System (TARGIT)
Intraoperative radiotherapy using the photon radiosurgery system (TARGIT) uses low-energy x-rays directed through an applicator sphere (intrabeam) placed
in the surgical cavity with breast tissue sutured around it. The tumor bed, with
no supplementary margin, is irradiated to a dose of 20Gy. This technique requires dedicated equipment, operating room time and technical expertise. Critical points are the low penetrability, the difficulty (for the steric dimensions) of
a correct positioning and an adequate distance from the skin. Treatment schedule: two doses per day for 5/7 days [14].
14.4.5 Intraoperative Radiation Therapy Using Electrons (IORT)

Intraoperative radiation therapy using electrons (IORT) is used to deliver a single fraction (one-step treatment) in the operating room during BCS. A mobile
linear accelerator producing 310MeV electron beams is used in combination
with an electron applicator placed over the surgical cavity, delivering a single
fraction of 21Gy to the tumor bed plus a margin of 1.53cm. Like TARGIT, it
requires dedicated equipment, operating room time and technical expertise.
Compared to other APBIs, IORT with electrons offers the most homogeneous
dose distribution, with an average dose inside the target volume closest to the
prescribed dose [7, 15]. In addition, IORT, as the other all-in-one approaches,
avoids any delay in local and systemic treatments. Frozen section analysis is clearly the most important weakness of intraoperative technique, as the definitive
pathology may reveal contraindications to a limited radiation field [7]. For
more details see Section 14.6.
220
14.5
APBI: Selection of Patients
The APBI treatment currently cannot be considered as the gold-standard approach

[7]. The standard is still represented by the external postoperative treatment. Up
to now, there is not enough evidence to perform APBI as the first choice in any patients: it should be undertaken within clinical trials, after obtaining the informed
consent of the patient, or in out-trials but in a selected group of patients. Thus, the
take home message must be: select patients with great care. Obviously those subjects with high risk-factors for LR must be excluded.
14.5.1 General Eligibility Criteria [1626]

The eligibility criteria are summarized in Table 14.2. Before and during the operation, it is important to assess the absence of an extensive intraductal component (EIC;
defined as 25% or more of the area encompassed by the infiltrating tumor) that is
considered to be an important risk factor for LR in breast-conserving therapy.
The margins involvement is the other factor to evaluate before starting the treatment. It is well known that the presence of margins with disease significantly reduces the effectiveness of radiation therapy in general and of the partial treatment
in particular, in terms of prevention of LR.
For these reasons, it is mandatory to have a good collaboration with the pathologists in a multidisciplinary approach in order to assess the margin-status as well
as possible: some trials require an intraoperative evaluation of the margins and in
the case of positive/close margins a postoperative standard treatment is indicated.
The most important disadvantage of all intraoperative techniques is that a definitive histology of margins is not available at the time of treatment.
Table 14.2 APBI: criteria for the selection of the eligible patients
Age and hormonal status
Post menopausal status, 4875 years: age has a primary

role in the development of local recurrences. The incidence is greater in pre-menopausal women where the risk
of occult multicentricity of the tumor is higher, due to different anatomy/biology of breast gland
Histology
Invasive carcinoma (in situ carcinoma is often multifocal/multicentric). Ductal better than lobular carcinoma
(more likely multifocal)
Foci
Unifocality
Dimensions (T)
Tumor diameter 25mm: the bigger the size, the higher

the risk of other foci of tumor
Axillary status
No significant involvement of the axilla present: in such

a case it will be necessary to perform radiotherapy on the
lymphatic regional stations
Radiotherapy contraindications
No factors contraindicating RT in general (i.e., a previous

treatment already done in the same site)
221
Fig. 14.1 Breast MR is particularly useful in order to exclude multifocality, especially in the
case of a dense breast
Oncoplastic techniques, performed after APBI, can significantly improve cosmetic outcome and they allow the surgeon to perform removal with wide margins
that are more likely to be negative.
Because of the difficulty of obtaining a secure evaluation of the margins during the operation, it is essential to perform an accurate preoperative assessment of
the disease and the type of breast. For this purpose, a magnetic resonance of the
breast is particularly useful in order to exclude, with good approximation, multifocality (22%) and/or contralateral breast involvement (5%): its use results in a
change of surgical approach in approximately 15% of patients (Fig. 14.1) [2224].
However magnetic resonance cannot exclude with absolute certainty the presence
of peritumoral disease (which means positive margins). In this sense, a selection
of patients is mandatory to avoid doubtful cases.
American ASTRO and European GEC-ESTRO have published guidelines analyzing three categories of patients [25, 26]:
1. Low-risk of local recurrence. APBI suitable, also acceptable outside a clinical
trial; including patients > 50 or 60 years, with unicentric, unifocal, lesions
< 3cm, nonlobular invasive breast cancer without EIC and lymphovascular invasion (LVI), with negative surgical margins (> 2mm) and without axillary node
involvement
2. Intermediate-risk or cautionary group, for whom APBI is considered acceptable
only in the context of prospective trials
3. High-risk or unsuitable group, for whom APBI is considered contraindicated;
patients 4050 years of age or younger, with involved margins, and/or multi-
222
centric or large tumors, and/or presence of EIC or LVI, and/or >three positive
lymph nodes or unknown axillary status.
Other factors may have a significant relation with local recurrence, even if they
are not part of the guidelines, such as HER2 amplification, proliferation index, biological subtype (basal cell vs. luminal A type).
14.6
IORT
There are different experiences, most advanced of which (in terms of follow-up and
enrollment sample size) is the study ELIOT at IEO, Milan [27, 28]. In Italy, there
have also been other experiences, including ours in Pisa (as part of a multicenter
national trial) that started in 2003.
A mobile linear accelerator with a robotic arm is used to deliver electron beams
able to produce energies from 3 to 9MeV. Through a perspex applicator (collimator) of 410cm diameters (usually 57 cm, 0 angle), radiation is delivered directly to the mammary gland.
The advantages are:
Short treatment duration
Radiation treatment can be concluded before adjuvant medical treatment, avoiding the delay of RT that often occurs in patients submitted to chemotherapy
The collimator is placed under the direct visual control of the surgeon and the
radiotherapist
Radiation exposure to the skin, subcutaneous tissue, lung and contralateral
breast is dramatically reduced
Better rationalization of radiotherapy resources (waiting list)
The problem of difficult access to radiotherapy facilities is solved.
The treatment requires a dedicated operating room with a mobile linear accelerator, a multidisciplinary staff able to discuss the cases before the treatment (eligibility), to perform the treatment together and to evaluate the pathological results
and the follow-up.
These are the steps of the treatment:
The surgeon performs a standard lumpectomy, considering from the beginning
the radiation treatment, that means an incision directly over the tumor, longer
than usual
Then the surgeon concentrates on the breast mobilization: the gland must be accurately separated from the subcutaneous tissue and pectoralis major fascia
The perspex/aluminium disk should be at least 12cm bigger in diameter than
the collimator used for IORT, to ensure good protection. The gland reconstruction can now be performed obtaining a homogenous thickness (to be verified
with a precise measurement): the suture of the gland for target exposure
should create an homogeneous area without differences in thickness and
shape (Fig.14.2)
The mobile linear accelerator is now easily moved close to the patient
A robotic arm can take the correct positions for irradiation
223
Fig. 14.2 The perspex/aluminium disk
should be at least 12cm bigger in
diameter than the collimator used for
IORT, to ensure a good protection
(arrow). The gland reconstruction is
performed obtaining a homogenous
thickness
The collimator is placed under direct vision, perpendicular to the thoracic wall,
being careful of the skin (Fig. 14.3)
Radiation treatment lasts for 12min.
The technique is safe, with a low rate of acute and delayed side effects: negligible rates of infections, hematomas, transient edema, partial wound dehiscence have
been reported. More often there is a moderate/high degree of fibrosis that determines a lump in the breast, sometimes pain and unsightly scars that require a particular attention and ability by the radiologist during the follow-up (differential diagnosis between liponecrosis and local relapse). This reminds us once again how
necessary it is to have a multidisciplinary approach and cooperation with the entire staff.
The peculiarities of the IORT treatment make it also suitable in particular subgroups of patients such as those with vitiligo, some rheumatologic diseases (scleroderma), severe heart disease or pulmonary fibrosis, or previous radiotherapy to
the thorax for the treatment of lymphomas.
As mentioned above, the most important experience concerning IORT is the
ELIOT trial at the IEO in Milan [27, 28]; the results on 1822 patients treated in
the period of 20002008, report, after a mean follow-up of 4years, a 4.8% rate of
LR (annual rate of 1.2%), two-thirds of which were in the same quadrant of the
primary tumors. Reported side effects were mild (1.8% of fibrosis and 4.2% of
224
Fig. 14.3 The collimator is placed under direct vision, perpendicular to the thoracic wall, being
careful of the skin
liponecrosis). The IEO trial and other experiences, and also our own experience
in Pisa, show IORT as a safe technique: no acute grade 3 toxicities have been observed. When before-treatment quality-of-life scores were maximal, no significant
decrease was observed during follow-up. Cosmesis was good to excellent at 6
months (Fig. 14.4). The rate of patients that experienced recurrence and underwent
mastectomy is comparable to the expected rate (similar to postoperative radiotherapy). In conclusion, IORT may be considered an alternative treatment for a selected population and offers a safe one-step treatment [7].
14.7
Trials State of the Art
Several advantages have been reported by using APBIs. A reduction in overall treatment duration is convenient for patients and may increase the use of BCT, particularly for subjects that live far from RT facilities or in familiar/socially difficult
situations. Cutting down the volume treated may lessen normal tissue toxicity and
cardiac/pulmonary toxicity. Reducing the treatment duration may impact favorably
on radiotherapy waiting times and treatment costs.
225
Fig. 14.4 Final cosmetic
result is usually good to
excellent
However, the use of APBI has a number of potential disadvantages. The risk
of local recurrence may increase for occult foci elsewhere in the breast. The higher radiation dose per fraction may enhance late toxicity with adverse effects on
cosmesis. At the present time, there are unanswered questions concerning the role
of APBI; these topics, well-summarized by Lehman and Hickey [29] in their recent paper, are under investigations and include:
1. Selection of patients: considered the limited volume of breast tissue irradiated, patients should only be considered if they have a low risk of clinically occult disease far from the lumpectomy site. The clinical and pathological (also
molecular) criteria are still under investigation
2. Definition of target volume in APBIs
3. Optimal technique of administration of APBIs
4. Ideal radiation dose/fractionation regimen
5. Long-term effects on local control, survival and toxicity.
Currently, there are few Level 1 evidences, without sufficiently long follow-up.
The results coming from a recent matched-pair analysis, published by F. Vicini and his group, comparing 199 patients treated with WBRT and 199 patients with
interstitial APBI, revealed equivalent results in the 12-year follow-up rates in
terms of LR (3.8% vs. 5.0%); regional recurrence, DFS and OS between the WBRT
and APBI groups are not statistically different [30].
226
Multiple retrospective, single institution experiences have been published evaluating the use of APBI in relatively low-risk patients. Different APBIs have been
employed including interstitial brachytherapy, balloon and applicator-based
brachytherapy, single-fraction intraoperative RT (IORT), and 3D-CRT. Despite
the good results obtained in the majority of these analyses, very little phase III data are available comparing APBI versus a standard regimen of 6 weeks of WBRT.
Polgar et al. [31] published their results from a small phase III trial: 258 patients were randomized to receive either WBRT (50 Gy/25 fractions) or APBI
(36.4Gy/7 fractions, twice daily) with multi-catheter HDR (69%) or limited electron field irradiation (31%). They found no difference in local control at 5years
and improved excellent/good cosmesis in the APBI arm. Vaidya et al arrived at the
same conclusion using single-fraction IORT with 2-year follow-up; they found no
difference in terms of LR (IORT 1.2% vs. WBRT 0.95%), with the same rate of
complications or toxicity [32].
There are additional phase III trials that are either ongoing or have recently completed accrual addressing the use of APBI vs WBRT using a variety of APBI techniques. The largest phase III trial using three different APBI techniques is NSABP
B39/RTOG 0413 trial. In this study, eligible patients include Stage III IDC or DCIS
(ductal carcinoma in situ), that are randomized to adjuvant whole-breast RT or APBI delivered via interstitial, 3-D conformal, or intracavitary techniques. The results
will be available in a few years [33, 34]
Veronesi and colleagues have also completed accrual to their not randomized
trial of single-fraction IORT (ELIOT) after quadrantectomy. They treated 1822 cases and recently classified them according to GECESTRO groups: 573 patients met
the criteria to be in the good candidates group, 468 patients possible candidates
and 767 patients in the contraindication group. Median follow-up length was 3.5
years (range 010.5years). The 5-year rate of in-breast tumor LR for good candidates, possible candidates and contraindication groups were 1.9%, 7.4% and
7.7%, respectively (p=0.001). While the regional node relapse showed no difference, the rate of distant metastases was significantly different in the contraindication group compared to the other two categories, having a significant impact
on survival, as shown in Table 14.3 [35].
14.7.1 Molecular Markers

Recent DNA microarray profiling has identified different subtypes of BC with peculiar clinical and biological behavior, from the good prognosis of patients with
luminal A tumors to the worst prognosis of basal-like and HER2 tumors.
The ELIOT study described a different behavior of the molecular subgroups,
regarding the risk of true local recurrence, which was:
Really low for luminal A (0.15/100-year)
Higher for luminal B carcinoma (0.96/100-year)
Even higher when considering basal-like and HER2 positive carcinoma (1.19
and 3.88/100-year, respectively).
227
Table 14.3 ELIOT trial: results (5-year rate) in the 1822 enrolled women, classified in subgroups,
according to GECESTRO criteria
(%)
In breast tumor recurrence
Good
candidates
1.9
Possible
candidates
7.4
Contraindication
group
7.7
True local recurrence
1.6
4.0
4.7
Ipsilateral breast cancer
0.3
3.3
3.0
Regional node failure
2.2
0.7
1.3
Distant metastases
1.4
1.7
3.9
Disease free survival
90.8
85.9
81.5
Overall survival
98.6
97.0
94.4
The same conclusion has been reached by other works [36, 37]. So, molecular
markers should be taken into account as a variable for risk-adapted RT to help proper patient selection and should be evaluated on the biopsy before deciding to opt
for APBI [7].
14.7.2 Elderly Patients

Recently, the role of radiotherapy in elderly patients has been discussed and investigated in trials. It has been evaluated that the use of RT decreases substantially with
age, although the majority of cases of BC occur in women aged 65years. Current
data suggest that the risk of LR after BCS and endocrine therapy may decline with
age [38]. The updated results of the CALGB trial [39] showed that for elderly patients with ER-positive Stage I tumors, the association with RT resulted in an absolute
reduction of 6% in LR when compared to tamoxifen alone. At the same time, as also shown in the EBCTCG overview [40], the absolute effect of WBRT on LR was
greater in younger than in older women, but significant at any age, as you can see in
Table 14.4.
Furthemore, WBRT may not represent the optimal standard of care for these
patients. Some randomized trials evaluated the quality of life (QoL) in irradiated
and nonirradiated old patients: WBRT was found associated with increased breast
problems, which persisted for 5years or more after treatment [7, 41].
Some authors have considered that APBIs can adapt to elderly patients for whom
radiation treatment is more likely to be avoided than for younger patients. In these
patients, APBI might be a better alternative than WBRT or no irradiation. A phase
II study [42] started in 2004 to investigate the role of IORT as the sole modality
in elderly patients, aged 65 or older, with T1N0 unifocal ductal carcinoma. At a
sufficiently long follow-up of 30 months, only two patients (0.42%) experienced
LR; questionnaires about QoL indicated a very good result. In the ELIOT study [28],
patients over 60 years represented an interesting subgroup (43.3%, 789 out of
1822): LR was 2.28% at 3years median follow-up.
228
Table 14.4 Effect of WBRT on LR, in subgroup of patients of different ages
5-year risk reductions (%)
Age (years)
22
< 50,
16
5059
12
6069
11
70
14.8
Conclusions
APBIs are different techniques having in common the fact that they allow a partial and accelerated radiotherapy. Experiences with different follow-up, almost all
under 10 years, show that the technique is safe in low-risk patient. APBI does not
seem to influence survival and may be used as an alternative to whole-breast radiation. Nevertheless the issue of locoregional recurrence needs to be further addressed. The careful selection of patients must be considered mandatory: the technique cannot currently be considered as the gold standard and it must be used within studies or in any case for subgroups of patients at low risk of local relapse.
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Primary Surgery in Metastatic

Breast Cancer
15
James O. Murphy and Virgilio S. Sacchini
15.1
Introduction
The widespread uptake of breast cancer screening, together with heightened population awareness, mean that most breast cancers in the Western world are detected
at an early stage. Recent tumor registry studies from the United States and Europe
have shown that metastatic breast cancer (MBC) accounts for 45% of all cases [1,
2]. However, in developing nations, the proportion of patients with MBC at diagnosis is greater, ranging from 10% in Malaysia [3] to 24% in Nepal [4] and 44%
in Nigerian men [5].
In early breast cancer, high-quality evidence from randomized controlled trials
and meta-analyses is available to support the majority of treatments we perform. In
comparison, there is a lack of level I evidence and accepted standard-of-care therapies available for patients with MBC. Despite some advances, the median overall
survival has remained at 23 years for the past two decades. The first international consensus conference for advanced breast cancer (Lisbon 2011) was convened
in an attempt to address these. The published guidelines that were produced, outline important general principles for managing this complex patient group, and also
consider the evidence for specific diagnostic and therapeutic interventions [6]. The
role of multidisciplinary team care is of particular importance. Treatment goals and
expectations should be fully discussed with patients and their caregivers. To counteract our lack of robust evidence, it is a priority to include patients in welldesigned prospective randomized trials when these are available.
There is immense interest in the evolving role of primary surgery in MBC. Historically, there is a very limited role for the surgical treatment of a primary cancer
V. S. Sacchini ()
Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center,
New York, USA
e-mail: sacchinv@mskcc.org
Updates in Surgery
231
232
J. O. Murphy, V. S. Sacchini
in patients with metastatic disease. Cases where surgery was deemed appropriate have
included the palliation of an offensive, infected, or bleeding breast cancer with a toilet mastectomy, or the resection of a perforated or obstructing gastrointestinal cancer. The notion that surgery could change a patients prognosis did not exist. The publication of a prospective randomized controlled trial in 2001 forced us to reconsider this preconception. Patients with metastatic renal cell cancer who were treated with
nephrectomy and interferon had a median survival of 11 months compared to 8
months in patients who received interferon alone (p 0.05) [7]. Primary surgery had
improved the prognosis for patients with metastatic renal cell cancer.
In the last 10 years, the role of primary surgery in MBC has been investigated in
multiple tumor registry studies, institutional studies, and a meta-analysis. It has been
considered in numerous review articles and is now being investigated in several
prospective trials. In this chapter, we will consider the arguments for and against primary breast cancer surgery in patients with metastases. We will critically analyze the
trials that have been published to date to consider if they have shown a benefit from
surgery-overall or in certain subgroups. We will then discuss the ongoing prospective trials and how their results may alter the future role of surgery in MBC.
15.2
Arguments Against and In Favor of Primary

Surgery in MBC
There are several arguments against performing primary surgery in MBC.

Traditional teaching tells us that surgery may not provide any survival advantage,
but may be associated with postoperative complications; by not performing surgery, we can avoid potential complications. Secondly, the primary breast cancer is
easily accessible and provides measurable disease that can be used to gauge the
response to systemic treatment; removing this makes the clinical assessment of
response to therapy more difficult. Patients with MBC may represent an anesthetic
challenge because of debilitation, as well as a surgical challenge because of locally advanced cancer with bulky lymph node involvement; the likelihood of adverse
outcomes may be increased. Additionally, in a rodent cancer model, the primary
tumor has been shown to inhibit its remote metastases. Following excision of the
tumor, neovascularization and growth of the metastases occurred; it is feared that
perhaps this could also happen in patients after primary surgery in MBC [8].
The validity of these arguments has been challenged. Several retrospective studies have now shown an association between primary breast cancer surgery and
improved overall survival in MBC. Improvements in imaging technology, especially combined positron emission tomography with computed tomography (PET-CT),
now enable the detection of minute foci of metastases that previously would have
remained undetected. Todays patients with MBC are frequently asymptomatic and
systemically well. They often have small primary breast cancers rather than locally advanced cancers. An operation may therefore not represent any increased surgical or anesthetic risk compared to patients without metastases. Regular PET-CT
scans enable accurate assessment of the metabolic activity, size, and number of
15 Primary Surgery in Metastatic Breast Cancer
233
metastases in response to systemic treatment; an intact primary cancer does not provide as much information. In addition, the progression of metastatic disease noted
in the rodent cancer model has not been observed in humans. In fact, proponents of
surgery suggest that removing the primary cancer burden may reduce tumor shedding and the development of further metastases.
15.3
Studies of Primary Surgery in MBC
The association between primary surgery in MBC and overall survival is currently
a subject of great interest and has been comprehensively reviewed [912]. This
relationship has been examined recently in at least six tumor registry studies [1, 2,
1316] (Table 15.1), 15 institutional studies [3, 1730] (Table 15.2), and one metaanalysis [31]. The tumor registry study by Nguyen and colleagues [13] scrutinized
the effects of locoregional treatment (LRT) of the primary cancer rather than surgery alone; however, we have included this in our review because 78% of patients
received surgery as part of their LRT. The study by Lang and colleagues [17] is an
update of an earlier study by Babiera et al. [32].
15.3.1 Study Strengths

One obvious advantage of these studies is the number of patients included in them.
The outcomes of more than 27,000 patients and 4,000 patients have been analyzed
in the published registry studies and institutional series, respectively. These include
patients not only from the United States and Canada, but also from several
European countries as well as Malaysia and Japan. They provide valuable epidemiological information, for example, the overall incidence of MBC, which ranges
from 45% in recent United States and European reports. They also illustrate which
treatments patients with MBC are actually receiving. The first and largest report, by
Khan et al, was received with surprise; 57% of 16,023 patients with MBC had surgical excision of the primary cancer performed [1]. This percentage was much
greater than anticipated. It proved not to be unique; between 4052% of women in
other cancer registry studies, and 2760% in institutional studies, also had surgical
resection of their primary breast cancer. The proportion of patients who underwent
breast-conserving surgery (BCS) varied widely among the 16 studies that recorded
this information. In 12 of these, between 2259% of patients had BCS; however, in
four studies, the rate of BCS was < 10%.
15.3.2 Study Weaknesses

The published reports on primary surgery in MBC are all retrospective. By their
nature, they frequently contain incomplete and uncertain information. This is especially true in the case of tumor registry studies; for example, in the report by
234
Table 15.1 Cancer registry studies of primary surgery in metastatic breast cancer (MBC) (cont.)
Study
[Reference]
Cancer
registry
Study period Patients

(follow-up)
Group differences
Nguyen 2012
[13]
British
Columbia,
Canada
19962003, LRT, 378 (52%);

surgery, 255
(median,
(67%); RT, 82
1.9 y)
(22%); both, 41
(11%); no LRT,
355
LRT group: younger age,

better ECOG status, lower T
and N stage, lower grade,
less LVI, more ER+, less
sites metastases, less
visceral metastases
Dominici
2011 [14]
NCCN, USA
19972007
Surgery, 54 (19%); Matched non-surgery

no surgery, 236
patients to surgery patients.
Surgery group: more lung
metastases, less treatment
with trastuzumab
Ruiterkamp
2009 [2]
South
Netherlands
19932004
Surgery, 288
(40%); BCS, 85
(30%); Mast, 189;
no surgery, 440
Surgery group: younger age,

less comorbidity, smaller T
size, less sites of metastases,
less visceral metastases,
more radiotherapy and
systemic therapy
Gnerlich
2007 [15]
SEER, USA
19882003
Surgery, 4,578
(47%);
BCS, 1,844 (40%);
Mast, 2,485; no
surgery, 5,156

more likely to be white and
married, lower T stage,
higher grade, more ER+ and
PR+
Rapiti 2006
[16]
Geneva,
Switzerland
19771996
Surgery, 127
(42%); BCS 40
(31%); Mast, 87;
no surgery, 173

more likely private, lower T
and N stage, more single
site metastasis, less visceral
metastases, less chemotherapy
Khan 2002
[1]
NCDB, USA
19901993
Surgery, 9,162
(57%); BCS, 3,513
(38%); Mast,
5,649; no surgery,
6,861
Mastectomy more likely in

women with a single
metastasis. Higher
proportion of women with
soft-tissue/bone metastases
vs visceral metastases
received mastectomy
BCS, breast-conserving surgery; CNS, central nervous system; CI, confidence interval;
ECOG, Eastern Cooperative Oncology Group; DSS, disease-specific survival; ER, estrogen
receptor; HR, hazard ratio; LRT , locoregional treatment; LVI, lymphovascular invasion;
235

Overall survival
(OS)
Surgery vs. no surgery
Other comments
5-year OS: LRT 21%;

no LRT 14%
Improved OS with LRT: HR

0.78; 95% CI 0.640.94;
p = 0.009
Improved OS in LRT group: < 50 y, with

higher performance status, ER+, clear
surgical margins, single metastasis, 14
metastases and bone-only metastasis
Median survival:
surgery, 3.5 y; no
surgery, 3.4 y
No difference: HR, 0.94; 95%

CI 0.831.08; p = 0.38
Median survival:
surgery, 31 m; no
surgery, 14 m
Improved OS with surgery:

HR, 0.62; 95% CI 0.510.76
OS at end of study:
surgery, 24%; no
surgery, 16%

adjusted HR, 0.63; 95% CI,
0.600.66; p < 0.001
5-year DSS: surgery

(margins-), 27%;
surgery (margins+),
16%; no surgery, 12%
Improved DSS, surgery with

neg. margins vs. no surgery:
adjusted HR, 0.6; 95% CI
0.41.0; p = 0.049
Improved DSS also in younger, LN-, ER+,

nonsymptomatic and nonCNS or visceral
metastases. Percentage of patients with
stage IV cancer: 6.5%
3-year OS: mastectomy,

32% (+/-margins: 26%/
36%); BCS, 28% (+/margins: 26%/35%); no
surgery, 17%
Improved OS with surgery (p <

0.0001):
negative margins HR, 0.61
(95% CI 0.580.65); positive
margins HR, 0.75 (95% CI
0.710.79)
Improved OS also with a single metastasis,

without visceral metastases and with
systemic therapy.
Percentage of patients with stage IV
cancer: 4.1%

cancer: 4.6%
m, month; Mast, mastectomy; N, node; NCCN, National Comprehensive Cancer Network;

NCDB,National Cancer Data Base; OS, overall survival; PR, progesterone receptor; RT, radiotherapy; SEER,Surveillance, Epidemiology, and End Results; T, tumor; y, year.
236
(cont.)
Table 15.2 Institutional studies of primary surgery in MBC

Study
[Reference]
Institution
Study period Patients

(follow-up)
Group differences
Lang 2013 [17] M.D. Anderson 19972002

(update of
Cancer Center, (med. 74 m)
Babiera
USA
2006 [32])
Surgery, 74 (36%);
BCS, 33 (45%);
Mast, 41;
no surgery, 134
Surgery group: lower T

and N stage, less sites of
metastases, less multiorgan
metastases, more received
chemotherapy only, more
received RT
Rashaan
2012 [19]
Hospitals in
19892009
Leiden and sHertogenbosch,
Netherlands
Surgery, 59 (35%);
BCS, 11 (19%);
Mast, 48;
no surgery, 112
Surgery group: younger, less

medication use, smaller T
size, more with a single site
of metastasis
Samiee
2012 [18]
Ottawa and
Queensway
Carleton
Hospitals,
Canada
Roche
2011 [20]
Universitts19862007
medizin, Berlin,
Germany
Prez-Fidalgo
2011 [21]
Hospital Clinico 19822005 Surgery, 123 (59%);

Universitario,
(med. 30 m) BCS, 10 (8%);
Mast, 113;
Valencia, Spain
no surgery, 85
Pathy
2011 [3]
University
19932008
Malaya Medical
Centre, Malaysia
Surgery, 139 (37%); Surgery group: less likely

BCS, 6 (4%); Mast, to be Malay, lower T and N
133; no surgery, 236 stage, more with a single
site of metastasis, more
likely to receive RT and
hormone therapy
Leung
2010 [23]
Medical College 19902000

of Virginia, USA
Surgery, 52 (34%);
no surgery 105
Surgery group: younger

patients and lower N stage
Neuman
2010 [22]
Memorial Sloan- 20002004

Kettering Cancer
Center, USA
Surgery, 69 (37%);
BCS, 41 (59%);
Mast, 28;
no surgery, 117
Surgery group: more likely

to have a smaller tumor, be
negative for HER2/neu and
have a solitary metastasis
McGuire
2009 [25]
Moffitt Cancer
Center, USA
20052007 Surgery, 48 (43%);

(med. 40 m) no surgery, 63
Surgery, 35 (57%);
BCS, 13 (37%);
Mast, 22;
no surgery, 26
No significant differences,
but lower proportion of
patients with visceral
metastasis and advanced T
and N stages in surgery
group.
Surgery group: younger,
more with single site of
metastasis, more
received RT
Surgery group: better
performance status, more
with single site of metastasis,
less with visceral metastasis
19902007 Surgery 154 (27%); Surgery group:

(med. 37 m) BCS, 56 (36%);
older patients
Mast, 98;
no surgery, 412
237

Overall
survival (OS)
Surgery vs. no surgery
Median survival: surgery, Improved OS with surgery:

56 m; no surgery, 37 m HR 0.58; 95% CI 0.350.98;
p = 0.04
NR
Other comments
Improved OS also in ER+ and a single

site of metastasis. Surgery before
stage IV diagnosis: 30 patients (41%)
No overall difference on
Improved OS in younger patients and
multivariate ana-lysis: HR 0.9; patients without comorbidity that
95% CI 0.61.4; p = 0.5
received surgery. Surgery before
stage IV diagnosis: 21 patients (36%)
Mean survival: surgery, Improved OS with surgery:

49 m; no surgery, 33 m p = 0.016
Surgery before stage IV diagnosis:

29 patients (60%)
NR
No difference: p = 0.253
Median survival:
surgery, 40 m;
no surgery, 24 m

HR 0.52; 95% CI 0.350.77;
p = 0.001
Improved OS also in ER+.

78 patients (63%)
Median survival:
surgery, 21 m;
no surgery, 10 m

adjusted HR 0.72; 95% CI
0.560.94)
Improved OS in surgery patients who

had negative margins and were < 65 y.
cancer: 10.2%
Median survival:
surgery, 25 m;
no surgery, 13 m
12 m survival incre-ased in
surgery group by Wilcoxin
test but not by log-rank
Chemotherapy was the only factor

associated with improved survival on
multivariate analysis
Median survival:
surgery, 40 m;
no surgery, 33 m
No difference on multivariate
analysis: HR 0.71; 95% CI
0.471.1; p = 0.1
Improved OS in ER+, PR+, HER2/neu

amplified and without visceral metastases.
Surgery before stage IV diagnosis: 34
patients (49%)
OS at median 37 m:
surgery, 33%;
no surgery, 20%

p = 0.0012
Improved OS in surgery group seen

in mastectomy patients (preoperative
chemotherapy more likely)
(cont.)
238
Shien
2009 [24]
National Cancer 19622007 Surgery, 160 (47%); Surgery group: younger

Center Hospital, (med. 33 m) BCS, 4 (3%); Mast, patients, less with visceral
Okayama, Japan
156; no surgery, 184 metastases, most diagnosed
before 1990, more likely to
receive hormonal therapy
Hazard
2008 [27]
Lynn Sage
19952005
Comprehensive (med. 27 m)
Breast Center,
USA
Surgery, 47 (42%);
BCS, 17 (36%);
Mast, 30;
no surgery, 64
Cady
2008 [28]
Massachusetts 19702002
General (MGH),
Brigham and
Women's (BWH)
Hospitals, USA
Surgery, 234 (38%); Analysis of all patients

no surgery, 388
performed. Then further
analysis following case
matching of surgery and
no surgery patients
Laboratory
19711991
database
(University of
Texas Health
Science Center),
USA
Surgery, 242 (61%);

BCS, 54 (22%);
Mast, 188;
no surgery, 153
Surgery group: older patients,

more likely to be white, T1
tumors more likely to have
surgery, less likely to have
multiple metastases and
visceral metastases
Bafford
2008 [26]
MGH, BWH and 19982005

Dana-Farber
Cancer Institute,
USA
Surgery, 61 (60%);
BCS, 21 (34%);
Mast, 40;
no surgery, 40
Surgery group: more likely

to have fewer sites of
metastasis, but more likely
to have brain metastasis,
more likely to receive RT
Fields
2007 [30]
Washington
University
School of
Medicine, USA
Blanchard
2008 [29]
19952005 Surgery, 187 (46%);

(med. 142 m) BCS, 61 (33%);
Mast, 126; no
surgery, 222

patients, higher proportion
of hormone receptor
negative tumors, more likely
to receive radiotherapy

patients, smaller tumor size
and less likely to have
metastases to
bone other sites
Khan et al., detailed histological information was unavailable, the tumor (T) stage
was collected instead of the tumor size, data on margins were unavailable for 30%
who had surgery, and although external beam radiation therapy was used to treat
36% of patients, it is unknown whether this was administered to the breast or to
sites of metastatic cancer [1]. Additionally, the institutional studies are often small,
and patients were often recruited over a prolonged period of time. Of the 15 institutional studies presented in this chapter, eight contain fewer than 200 patients, and
in a further eight studies, patients were accrued over 15 years or more. The ethos
and biases of each institution also determine what treatment patients received and
how the data are presented.
239

Median survival:
surgery, 27 m;
no surgery, 22 m

p = 0.049
Improved OS with surgery not observed

for women aged > 50 y or with visceral
metastases
Median survival:
surgery, 26 m;
no surgery, 29 m
No difference between groups: Chest-wall control: improved with surgery

HR 0.798; 95% CI 0.41.52; but associated with OS, regardless if
surgery or not. Surgery before stage IV
p = 0.52
diagnosis: 26 patients (55%)
NR
Analysis of all patients:

improved OS with surgery,
p < 0.0001
Case matching reduced or eliminated

the apparent benefits of surgery.
cancer: 4.2%
Median survival:
surgery, 27 m;
no surgery, 17 m

multivariate analysis,
p = 0.006
Improved OS also in ER+, PR +, and

with a lower number of metastases.
Percentage of patients with Stage IV
cancer: 4.9%
Median survival:
surgery, 3.5 y;
no surgery, 2.4 y

adjusted HR, 0.47,
p = 0.003
Improved OS in ER+, HER2/neu+,

and without CNS/liver metastases.
Improved OS only seen in those who
had surgery before stage IV diagnosis
(36 patients, 59%)
Median survival:
surgery, 27 m;
no surgery, 13 m

adjusted HR, 0.53; 95% CI
0.420.67; p < 0.0001

81 patients (43%)
BSC, breast-conserving surgery; CI, confidence interval; CNS, central nervous system; ER, estrogen receptor; HR, hazard ratio; m, month; Mast, mastectomy; Med, median; N, node; NR, not
recorded; PR, progesterone receptor; RT, radiotherapy; T, tumor; y, year.
15.3.3 Overall Survival: Surgery vs. No Surgery

Two-thirds of the studies reviewed in this chapter show an improvement in overall
survival following primary surgery in patients with MBC. This includes four of the
six registry studies [1, 2, 13, 15], and 10 of the 15 institutional studies [3, 17, 18,
21, 2426, 2830]. Two further studies show equivocal benefit [23] or benefit in a
subgroup of patients [16]. A meta-analysis of 15 of these studies found that surgery
appeared to be an independent factor for an improved survival (hazard ratio [HR],
0.69; 95% confidence interval [CI], 0.630.77; p < 0.00001) [31].
240
15.3.4 Group Differences

The main drawback to the published retrospective trials is the absence of patient randomization to surgical or non-surgical treatment. In two studies, patients who did not
receive surgery were matched to those who did, in an attempt to reduce selection bias
[14, 28]. In these studies, overall survival was either not improved with surgery, or
else case matching reduced or eliminated the apparent benefits of surgery.
There are obvious differences between the surgery and no-surgery groups in all
of the other trials, which are statistically significant in all trials except one [18]
(Tables 15.1 and 15.2). The patients who underwent surgery were frequently
younger, with better performance scores and less comorbidity. They often had smaller primary tumors with a lower nodal (N) stage, and were less likely to have multiple sites of metastases or visceral metastases. In addition, they were regularly more
likely to receive radiation therapy, hormonal therapy, and chemotherapy. Therefore,
the patients who were chosen to undergo surgery had more favorable features and a
better baseline prognosis than those who did not. Despite using multivariate analysis, only some of these differences were corrected for, and it is not surprising that
surgical patients had an improved survival.
15.3.5 The Timing of Surgery

As well as being diagnosed before surgery, MBC may also be diagnosed after
breast surgery has been performed. Adverse pathologic features, for example, a
greater burden of axillary lymph node metastases, may be uncovered and prompt
staging investigations which reveal unsuspected stage IV disease. The greater sensitivity of modern staging with PET-CT means that limited metastatic disease that
would have previously remained undetected can now be found. The timing of surgery relative to the diagnosis of MBC is recorded in 7 out of the 15 institutional
studies presented in this chapter; between 3663% of patients were diagnosed with
distant metastases following surgery. One study has examined whether this timing
is important; Bafford and colleagues found that the improved overall survival in
patients with MBC treated with surgery was only seen in those who had surgery
before being diagnosed with stage IV cancer [26]. For commentators who are skeptical about the role of surgery in MBC, there is no evidence that patients diagnosed
postoperatively with stage IV cancer have been harmed by surgery.
15.3.6 The Relevance of Surgical Margins

The original report by Khan et al found that for BCS or mastectomy patients, the
median 3-year survival was 3536% for patients with clear margins, 26% for those
with positive margins, and 17% in non-surgical patients (p < 0.0001) [1]. Two further tumor registry studies [13, 16] and an institutional study from Malaysia [3]
also demonstrated that survival was improved in patients with negative margins.
241
While these findings may be explained by differences between groups, they perhaps suggest that we should aspire to clear surgical margins when we perform surgery in MBC.
15.3.7 Other Factors Associated with Survival

On multivariate analysis of studies, factors other than surgery, associated with
improved overall survival, have been found (Tables 15.1 and 15.2). These include
younger age, higher performance status, and less comorbidity. Those who received
systemic treatment and patients with a treatment target, that is, estrogen or progesterone receptor positive (ER+ or PR+) and with HER2/neu amplification, were
more likely to survive longer. A single site of metastasis and the absence of visceral metastases were other factors associated with enhanced survival.
Improved chest-wall control is an important goal in the palliation of women with
stage IV breast cancer, and was found by Hazard et al to be associated with surgery in
MBC [27]. However, chest-wall control was found to be more likely in patients with
improved overall survival (OS) regardless of whether surgery was performed or not.
15.4
Ongoing Prospective Trials of Primary Surgery in MBC
Because of the limitations of retrospective studies, it is unclear whether surgery in

MBC confers a survival advantage above systemic therapy alone. The association
that has been demonstrated certainly does not prove causality. This question is currently being considered in six prospective trials [3338]. A summary of these can
be seen in Table 15.3. One of these is an observational cohort study, which aims to
collect more accurate information on the response to first-line systemic therapy, the
frequency of surgical referral, and the proportion of patients with MBC who undergo primary surgery [37]. This study has finished recruiting patients, and follow-up
and data analysis are ongoing.
The role of surgery in stage IV breast cancer is being investigated in five prospective randomized trials, which are being undertaken in India, Turkey, Japan, the
Netherlands, and the United States [3336, 38]. These aim to randomize between 281
and 880 patients presenting with MBC at diagnosis to receive surgery and systemic
treatment, or surgery alone. In total, these studies aim to enroll more than 2,500 patients. In two studies, patients are being randomized to receive initial surgery, followed by systemic therapy or else systemic therapy alone [33, 34]. In the remaining
three trials, patients receive systemic treatment first, followed by randomization to
either undergo surgery or not [35, 36, 38]. The multicenter Eastern Cooperative Oncology Group (ECOG) E2108 trial is recruiting patients with stage IV breast cancer
at diagnosis or after commencing systemic therapy [35]. Patients who demonstrate
a response to treatment or stable disease after receiving optimum systemic treatment
will be randomized to receive continued systemic therapy or else surgery. The surgery performed should be the same as that performed on a patient without MBC. Sur-
Clinical trial
identification
NCT00941759
NCT01392586
NCT00557986
NCT00193778
Study
[Reference]
Multicenter, USA [37]
Multicenter, Netherlands
[33]
Multicenter, Turkey [34]
Tata Memorial Hospital,

India [36]
Prospective randomized.
Patients initially receive
anthracycline-based
chemotherapy followed
by randomization to
locoregional treatment
(LRT) or no LRT
Randomization to
immediate surgery
followed by systemic
treatment or systemic
treatment alone
Prospective
randomized.
Randomization to
immediate (up front)
surgery followed by
systemic treatment,
or systemic treatment
alone
Prospective, cohort,
single-arm
Design
350
281
516
100
Estimated
No. of patients
Table 15.3 Prospective randomized studies of primary surgery in metastatic breast cancer (MBC)
Overall survival
and disease-free survival
Overall survival
(all cause mortality)
Overall survival
Measure response to
first-line therapy,
frequency of surgical
referral and proportion
who undergo surgery
Primary endpoint
Recruiting
patients
Completed.
In follow-up
Recruiting
patients
Ongoing, not
enrolling
Status
242
UMIN000005586
Multicenter, Japan [38]
3 months of systemic
therapy. Those without
progression randomized
to surgery and systemic
therapy, or systemic
therapy alone
1632 weeks of systemic
therapy. Those without
progression randomized
to standard palliative
therapy or else surgery
500
880
NCT, National Clinical Trial; UMIN, University Hospital Medical Information Network.
NCT01242800
Multicenter, USA [35]
Overall survival
Overall survival
Recruiting
patients
Recruiting
patients

243
244
geons should aim for negative margins, and standard indications for axillary lymph
node dissection and adjuvant radiotherapy should be followed. An update of the
ECOG-E2108 trial was presented at the Society of Surgical Oncologys Cancer
Symposium, National Harbor, Maryland, USA on March 7, 2013. To date, 95 patients
have been accrued, which is somewhat fewer than expected; it is hoped that the accrual rate will increase. The Turkish trial has finished recruiting patients and is currently in follow-up to measure study outcomes. In 2009, the Indian trial presented
early results after accruing 125 out of 350 patients; with a median follow-up of 18
months, there was no survival difference in patients treated with or without surgery
[39]. The completion of accrual and the results of these prospective randomized trials are awaited with anticipation. These will give us a clearer picture whether or not
primary surgery in MBC results in prolonged survival.
15.5
Conclusions
In numerous retrospective tumor registry and institutional studies, a considerable

proportion of patients with stage IV breast cancer had surgery performed on the primary tumor. Additionally, an association has repeatedly been found between primary surgery and improved survival in these patients. However, this does not mean
that surgery has been proven to improve survival. In almost all of the published
reports, there are significant differences in the characteristics of patients who
undergo surgery and the patients who do not. Surgical treatment has mainly been
performed on patients with more favorable prognostic factors and who would be
expected to have a longer life expectancy. In an attempt to definitively answer this
question, there are five ongoing prospective randomized trials of surgery compared
to no-surgery for patients with MBC. While awaiting the results of these prospective trials, international consensus guidelines suggest that removal of the primary
tumor may be considered in selected patients [6]. However, the guidelines stress the
importance of including patients in well-designed, prospective trials whenever
these are available and the patient is willing to participate. This will be the only way
to clarify the role of primary surgery in stage IV breast cancer.
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Reconstructive Surgery
16
Carlo Mariotti, Gabriele Bianchelli, Michele Riccio,

Angelica Aquinati, and Elisa Sebastiani
16.1
Introduction
Breast reconstruction after a mastectomy is a surgery of extreme importance to

women and it has many psychosocial effects besides the physical ones.
For women, the breast is the main symbol of femininity as it undergoes a
morphodynamic development in all the main psychosocial development phases:
puberty, sexual maturity and maternity. It is indeed a means to establish intimate
interpersonal relationships, drawing fundamental sensations, both in sexual intimacy and in maternal rapport with the newborn.
Based on these considerations, it is easy to understand the physical and psychorelational relevance surgical mutilation has to women. It follows that breast
reconstruction is a fundamental moment, which is perceived by women not simply as the recovery of an anatomical profile, but, above all, an essential psychoaffective-relational restoration.
Surgical reconstruction techniques must meet two specific needs: to adapt the
reconstruction to the indispensable needs resulting from oncologic radicality
and, simultaneously, to have a reconstruction that allows the woman to have the
shape of her breast back, her femininity, a satisfying emotional and sexual life
and a complete social one.
Today, mastectomies amount to about 2025% of the oncologic breast surgery, and only 70% of them are followed by reconstruction.
For many years, breast reconstruction meant the use of prosthetic implants;
in fact, the use of implants, except for some years (when FDA banned the placement of silicone gel implants for esthetic purposes, in April 1982), is a widely
C. Mariotti ()
Ancona, Italy
Updates in Surgery
247
C. Mariotti et al.
248
spread technique; even if the most ideal reconstruction or the closest to

womens expectations is the one that involves the use of autologous tissues.
Today many reconstructive options are being used and it is only through a
careful interview with the patient that the plastic surgeon and breast surgeon can,
and has the duty to, follow a reconstruction procedure that is truly tailor-made to
each single case.
16.2
Historical Outline
The first breast reconstruction is historically attributed to Czerny [1], who, in

1895, used a massive lumbar lipoma to fill an area of wide mammary gland
removal.
Since then, experimental attempts and scientific and technological research
have been carried out throughout the last century, reaching the present possibilities. From the pioneering transplant of autologous tissue, carried out by Czerny,
to the liquid alloplastic material implants (paraffin, 1903; liquid silicone, Rees
1965)[2] or the pre-shaped sponge (Ivalon ,Grindlay 1949)[3], and, finally, the
prosthetic implant using autologous tissue (flaps) or lipofilling.
1906 is a historical date, when Igino Tansini [4], a Professor of Surgery from
the University of Padova, described, for the first time, a latissimus dorsi musculocutaneous flap, that until the 1920s was used to repair defects secondary to radical mastectomy. In 1920, Halsted [5] criticized this technique and promoted the
use of free skin grafting or the healing by second intention, arguing that the flap
described by Tansini could in some ways be an obstacle for the diagnosis of local
breast cancer recurrence. Developments on reconstructive techniques stopped for
a long time, until the 1960s, when Cronin [6] introduced the first breast prosthesis, bringing about a true innovation to reconstructive surgery, triggering a kind
of rivalry between progress of technical surgery, with its ever refined reconstructions using autologous tissue, and the progress of biomedical engineering, with
its prosthetic implants constantly developing in biocompatibility, safety and
esthetics. Since the 1960s, efforts were aimed at improving the cosmetic outcome
of the reconstructed breast, that is, trying to make the reconstructed breast look
as similar as possible to the contralateral breast in terms of shape, volume, consistency, symmetry and profile. In 1971, Shyderman and Guthrie [7] described a
case of postmastectomy breast reconstruction, which involved the positioning of
a subcutaneous silicon prosthesis. Breast reconstruction with prosthetic implants
rapidly became the most common reconstruction technique due to its many
advantages: the relative simplicity of the technique, the short operating period,
the absence of further scarring, the use of local skin tropism with excellent coloring and the absence of disease transmission to the donor site. However, since
the end of the 1970s, surgeons started to re-evaluate reconstruction with autologous tissue, since the use of prosthetic implants was not without problems. This
is how, in 1976, Olivari [8] designed the latissimus dorsi myocutaneous flap
again and it became the basic technique to cover the skin and the muscle. In 1978,
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Bostwick [9] presented reconstruction combined with the latissimus dorsi flap
and prosthesis. In 1982, Radovan [10] introduced prosthesis expansion and published his experience with 68 patients who were treated with a temporary
expander, before the permanent breast prosthesis was introduced. Later, immediate breast reconstruction started to be used. Robbins [11] was the first to use the
rectus abdominis muscle for breast reconstruction in 1979. While in 1982,
Dinner, Labandter and Dowden [12] and Scheflan, Hartrampf and Black [13]
described the vertical myocutaneous flap with the rectus adbominis and transverse rectus abdominis mycutaneous flap (TRAM). In 1986, Holmstrom [14]
described the thoracodorsal flap and then in 1989, Koshima and Soeda [15] introduced the technique of perforator flaps (DIEP). Yousif [16] described the transverse musculocutaneous gracilis flap (TMG) in 1992. Then a year later, in 1993,
Allen [17] described the gluteal myocutaneous flap on the superior gluteal artery
perforator (SGAP).
16.3
Reconstruction
1. Psychological aspects
Willing to heal
Femininity restore
Improvement of humor
Familiar life
Social life
2. Goals
Shape
Volume
Consistency
Symmetry
Profile
3. Timing
Immediate reconstruction
Delayed reconstruction
Immediate reconstruction is today the preferred choice, since it is oncologically safe and also ensures better esthetics since it uses elastic tissue. In addition,
this type of reconstruction has an important psychological impact on the patient,
reducing the psychological impact of mastectomy and the effect of mutilation.
Last, but not least, it reduces hospitalization, duration of hospitalization and operations. Delayed reconstruction is suitable for cases in which neoadjuvant therapy
is necessary within a short time and in cases of a clinical-oncologic context of
disease remission.
4. Type of reconstruction
With prosthetic implant
Single-stage (implant or adjustable postoperative implant)
Single-stage (implant and synthetic or biological mesh)
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Two stages (expander, then implant)

With autologous implant
Flap
Fat grafting
With flap and implant
5. Treatment of contralateral breast
No treatment
Reduction
Augmentation
Mastopexy
Prophylactic mastectomy
6. Factors influencing the choice of technique
Patient clinical condition (ASA)
Type and size of the defect
Contralateral breast
Autologous tissue availability
Need for radiotherapy
Patient needs and wishes
16.3.1 Reconstruction with Prosthetic Implants

Implants have undergone an incredible evolution since their first appearance.
Reconstruction with prosthesis is a rapid and a relatively simple reconstruction;
however, implants have a limited duration, which may result in more operations
for the patient. In fact, implants often present decreased naturalness and have
scarce compatibility with radiotherapy. In 1962, Cronin and Gerow introduced
silicone gel implants. Over the years, the silicone implants have undergone
changes aimed at improving implant biocompatibility and cosmetic outcomes.
The first generation implants (1960) had a thick coating with a back support made
of Dacron, filled with viscose silicone gel, an anatomical shape and a smooth surface, and they were characterized by a high frequency of capsular contracture;
during this period, there was also a saline prosthesis. The second generation
implants (1970) had a thin coating, a less viscose gel, which resulted in capsular
ruptures and oozing oil. For this reason, during the 1970s, the double-lumen
implants appeared, with an internal chamber with silicone and an external one
with a saline solution to prevent the gel from oozing. Then in 1980, the third generation implants had a capsule reinforced with multi-layered casing, a more cohesive gel and a round shape. By 1992, there were fourth generation implants,
which had a thick coating, resistance and a low permeability, a smooth and texturized surface, a round and anatomical shape, and a more viscose gel (cohesive).
In 1993, the last generation implants had a thick coating, resistance and low permeability, a smooth or texturized surface, a round and anatomical shape, a highly cohesive gel with a stable implant shape. To date the silicone gel implant has
the largest part of the market, due to its characteristics of biocompatibility (ther-
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mal and oxidative stability, chemical and biological inertness, hydrophobic

nature and sterilizablity). Variations in length, crosslink and molecular weight
characterize its mechanical properties that can change from the oil-like viscosity
(< 30 monomers) to a solid consistency (> 3000 monomers). The implants currently used are made of gel, they have a double chamber with a silicone gel nucleus surrounded by a chamber that contains a physiological saline solution;
implants with a permanent expansion with the external part made of silicone gel,
an internal part filled with physiological solution; saline implants filled with
physiological solution at the time of reconstruction; hydrogel implants; implants
with polyurethane coating (the coating should reduce the periprosthetic fibrous
reaction). The shape of the implants may be round or anatomical. The anatomical
implants are tear-shaped which makes them esthetically more natural. Both the
anatomical and the round implants can have a high (more projecting), an intermediate or a low profile [1822].
16.3.2 Measurements and Preoperatory Drawing

In order to choose the best implant, it is necessary to measure the chest and the
breast with a measuring tape and a demographic pen, which the patient in an
orthostatic position. The umbilical jugular midline, the inframammary folds, the
front axillary lines and the corvicular line are drawn and the midpoint, that is
810 cm away from the ensiform process, is marked. The distance between the
nipple and the mammary fold, with or without upward skin traction, and the distance between the nipple and the midline, with and without lateral skin traction,
are measured. The distance between the nipple and the midclavicular point and
that between the nipple and the ensiform process are measured. The distance
between the nipple and jugular is measured. The width of the breast is measured.
The thickness of the lower pole at the inframammary fold and the upper pole are
measured. The breast circumference is measured and a note of the bra cup size is
taken.The first reconstruction phase consists of creating a submuscular pocket;
specifically, a pocket is formed under the pectoralis major muscle where the
implant will be placed (temporary or definitive); the complete implant cover is
realized with pectoralis major and serratus anterior, ensuring that it is not exposed
(alternatively the cover with pectoralis muscle and biological (acellular dermal
matrices) or synthetic mesh is proposed) [23]. The second reconstructive phase,
when reconstruction involves two different sessions, is usually carried out after
about 46 months and it depends mainly on the characteristics of the patients
contralateral breast. The main aim of this phase is to obtain symmetry. The surgeons decision whether to perform an additive or reductive plastic surgery or a
breast lift or not to operate on the contralateral breast, is based on an informed
choice and the patients awareness. This second reconstruction stage involves
reopening of the mastectomy, capsulotomy or capsulectomy incision, replacing
the first implant with a new one, possible adjustment of the inframammary fold
and the contralateral symmetrization. After about six months, the third recon-
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structive phase is carried out, once the reconstructed breast takes its final shape
and position, it is ready for the reconstruction of the nipple-areola complex
(NAC). There are many NAC reconstruction techniques and interested readers
are referred to other sources.
16.3.3 Complications Related to Prosthetic Implants

16.3.3.1 Capsular Contracture
A connective capsule forms around the prosthetic implant (spherical fibrous capsular contracture), and it depends on the type of prosthesis used, the position in
which the implant is positioned and the prosthetic implant packaging. For various reasons, such as inflammation, infection, hematoma, oozing of the silicone
gel, the rupture of the prosthesis or an unspecific organism reaction to the
implant, a contracture of this periprosthetic capsule develops causing pain,
induration, palpability and/or dislocation of the prosthesis itself. The capsular
contracture can be measured in different grades (Baker classification) [24] and
may need surgical correction:
Grade I: soft capsule, normal breast appearance, no evidence of implant
Grade II: minimal capsule, palpable implant but not visible
Grade III: moderate, firm breast, visible implant
Grade IV: severe, breast hard, breast distorsion and discomfort/tenderness
16.3.3.2 Infection
Infection has an incidence of between 2% and 13% and it is usually caused by
Staphylococcus aureus and Staphylococcus epidermidis. Symptoms are the onset
of fever, erythema, pain, tenderness and the accumulation of inflammatory fluid,
and this may make it necessary to remove the prosthesis.
16.3.3.3 Hematoma/Seroma
The occurrence of hematoma varies between 23%, while the occurrence of seroma oscillates between 7% and almost 15%. They are always linked to surgical
error. In cases with large dimensions, a new surgical operation or the removal of
the breast implant may be necessary.
16.3.3.4 Implant Rupture
Rupture might take place in the presence of certain conditions, such as a violent
trauma, lacerations in the implant packaging, mammography, age and the type of
implant, iatrogenic maneuvers. Following the rupture of an implant, the contained gel can spread inside the capsule or it may seep through the latter and
reach the locoregional lymph nodes. Usually the prosthetic rupture is not accompanied by particular signs and symptoms and, therefore, its diagnosis happens
accidentally, usually at US or MRI.
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16.3.3.5 Granulomas
Granulomas are mostly associated with the use of liquid silicone that migrates to
other sites by infiltrating the subcutaneous tissues to cause lysis and ulcerations.
16.3.3.6 Folds
Folds are probably caused by insufficient filling of the implant or the tissue thinning in patients, due to a continuous mechanical action of the prosthesis itself on
the surrounding tissues.
16.3.3.7 Breast Sensitivity
Breast sensitivity is caused by lesions that occur to some nerve endings during
surgery or to the nerve compression by the prosthesis phenomenon, which may
cause temporary or permanent dysesthesia.
16.3.3.8 Implant Dislocation
Implant dislocation is the displacement of the prosthesis from the surgically prepared pocket or the rotation of the prosthesis on itself: the latter phenomena can
only be observed in anatomical prosthesis. In this case, a new surgical intervention is necessary to place the implant in the correct position and to resolve any
errors in the packaging of the pocket.
16.3.3.9 Implant Extrusion
Implant extrusion consists of the surfacing of the prosthesis towards the skin,
causing erosion until the implant itself comes out. Among the causes of this phenomenon are, above all, infection, the malpositioning and/or the presence of damaged tissues following, for example, radiotherapy or burns. In such cases more
surgery is necessary. It is a dreaded complication that requires the removal of the
implant, and indicates a temporary failure of the reconstructive procedure, and it
often involves a series of complex operations to obtain a new reconstruction.
16.4
Reconstruction Using Autologous Tissue
Breast reconstruction using autologous tissue involves the transfer of flaps, that
is, a large amount of tissue, usually made of skin and subcutaneous tissue, sometimes even muscular tissue. Flaps can be lifted and rotated towards the receiving
area starting from the adjacent donor site, with, therefore, the persistence of a
vascular pedicle originating from the donor site that connects the receiving area
with the donor site of origin (isolated pedicle flaps). Conversely they can be taken
from other regions further away from the donor site and transferred to the recipient area by means of arteriovenous vascular anastomoses performed using
microsurgical techniques (traditional free flaps/perforator free flaps).
Initially, the flaps were used for selected cases of breast surgery characterized
by wide tissue excisions, and where prosthetic reconstruction was not possible or
had failed, with the aim of having a simple cover for the thoracic wall. However,
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Table 16.1 Flaps classification
Latissimus dorsi flap
Olivari [8]
1976
Vertical rectus abdominis myocutaneous flap (VRAM)
Drever [25]
1977
Transverse rectus abdominis myocutaneous flap (TRAM)
Scheflan [13]
1982
Transverse rectus abdominis myocutaneous free flap (TRAM free)
Holmstrom [28]
1979
Deep inferior epigastric perforator flap (DIEP)
Koshima [15]
1989
Superficial inferior epigastric artery flap (SIEA)
Grotting [29]
1991
gradually the use of flaps obtained the predominant role of recreating the skin
coating and the volume of the breast without using an implant.
The main advantage of reconstruction using autologous tissue is that of reconstructing a dynamic breast, that is, one that can vary in shape and volume when
moving and with variations in weight or age, similarly to what happens in a
healthy breast. This has a more natural and long-lasting effect, with greater symmetry when compared to the contralateral breast, with a good reproduction of the
adipose-glandular structure from where the adipose component of the flap is
transferred and therefore of greater esthetic value.
The surgeon will therefore find it easier to reproduce a well-defined inframammary fold, symmetrical to the contralateral one. Autologous tissue does not
interfere with radiotherapy.
In addition, even though implants are characterized by the reconstruction of a
static breast, the use of implants is still the most widely used reconstruction
method worldwide since they involve a less complex surgical technique.
In literature many types of flaps have been proposed for postmastectomy
reconstruction. They can be divided into pedicle flaps and free flaps (Table
16.1).
When selecting the most suitable flap for breast reconstruction, two fundamental aspects must be given consideration.
Characteristics of recipient site:
1. Location and size of tissue defect
2. Quality and vascularization of surrounding tissues
3. Presence of uncovered muscloskeletal structures
4. Esthetical and functional aspects
Characteristics of donor site:
1. Location
2. Anatomical integrity of flap angiosoma
3. Type of tissue requested
4. Functional and esthetical morbidity
The evaluation of the aforementioned parameters, applied to the most recent
anatomical acquisition on the lower angiosomes of the lower abdomen, explains
the growing tendency to use preferably free perforator flaps taken from this donor
site.
Flaps are classified on the basis of innervation and vascular supply:
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Classification according to mode of innervation [26]

Type I single unbranched nerve enters muscle
Type II single nerve, branches prior to entering
Type III multiple branches from same nerve trunk
Type IV multiple branches from different nerve trunks
Classification according to vascular supply [27]
Type I single vascular pedicle
Type II dominant pedicle, minor pedicle
Type III dual dominant pedicles
Type IV segmental pedicles
Type V dominant pedicle with secondary segmental pedicles
16.4.1 Considerations Regarding Recepient Vessels of Free Flaps

During recent years, the internal mammary artery and its veins have become the
first choice as pedicle vascular receivers for free flaps transferred from the breast
region. Its central position in the thoracic wall facilitates the microsurgical anastomosis and provides maximum flexibility during the process of breast remodeling. The isolation and dissection of the internal mammary vessels takes place
more easily and vessels are more protected against damage from radiotherapy.
Although the artery almost always has sufficient caliber, the diameter of the vein
is very variable. In general, the veins on the left side of the thoracic wall are
smaller than the ones on the right. For this reason, it is better to dissect the vessels on the left, at the level of the third rib on the left side, and the fourth rib on
the right side. A small piece of cartilage can be removed together with some intercostal muscles to allow adequate vessel exposure and recipient vessel length.
The thoracodorsal artery and vein have long been the first choice as recipient
vessels. Even the subscapular vessels, the circumflex scapular and the axillary
vessels can be used as recipient vessels for free flaps. Although these vessels
always have great caliber and the flow is always reliable, the distance from the
breast is larger than that of the internal mammary vessels. The microanastomosis
at the armpit, with an abducted arm, can present more problems than those situated at the level of the internal mammary vessels.
16.4.2 Autologous Tissue Flaps

16.4.2.1 Major or Latissimus Dorsi Flap
The myocutaneous dorsi flap was described, for the first time, by Tansini [4] in
1906 for the reconstruction of the thoracic wall following mammary amputation.
Abandoned for several years, it was later proposed again by Olivari [8] in 1976,
and at the end of the 1970s it became the basic breast reconstruction technique.
It continued to be the basic technique until TRAM was introduced.
In 1978, Bostwick [9] carried out the first series of breast reconstructions com-
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bining the latissimus dorsi flap with the placement of an implant. The musculocutaneous dorsi latissimus flap used in the classic method provides a muscular and
cutaneous supply; if on one hand the tissue contribution is sufficient to partially
reconstruct the breast, on the other hand, in a total reconstruction it requires the
placement of a silicone implant to give volume and projection to the reconstructed
breast. The silicone implant is responsible for long-term complications.
The latissimus dorsi flap without implant, as proposed by Hokin, was used for
the first time in 1983 [28]. This surgical technique is suitable for patients who
must undergo reconstruction of the anterior axillary pillar, but cannot cope with
the reconstruction of TRAM due to specific contraindications (advanced age,
obesity, previous reconstructions with TRAM flap or abdominoplasty issues and
abdominal scars), or patients who have undergone radiotherapy and who have
issues at tissue level. More recently lipofilling has made it possible to obtain optimized results, very often resulting in a reconstructed breast with a good volume,
shape and similar texture.
The flap is very vascularized and has a significant trophic effect on the local
tissue, especially noticeable in radiated areas. The vascular reliability allows the
flap to be molded in numerous ways to recreate a shape that is similar to the contralateral breast, both base and projection. Therefore it is possible to obtain a
reconstructed breast with a similar shape to the contralateral one more easily and
contralateral symmetrization is less often necessary. This allows a good reconstruction of the anterior axillary pillar and good filling of the subclavian area of
the reconstructed breast.
The dorsal sequelae, represented by a dorsal scar and a moderate dorsal modification, are well accepted as long as the dorsal scar is of excellent quality with
regards to the tension lines of the curvilinear pattern and for the absence of skin
tension upon closure.
Disadvantages include:
Minimal but possible functional loss in the movement of the upper arm
Due to the intraoperative patients positioning, the flap can hardly be removed
at the same time of the removal surgery
In the case of obese patients, the subcutaneous flap can be too thick
Despite the attention given to the handling of tissue, the distal part of the flap
can suffer from necrosis.
16.4.2.2 Thoracodorsal Flap

The thoracoductal flap is a fasciocutaneous flap from the thoracic lateral wall,
described by Holmtrom in 1986 [14]. Its vascularization is provided by the superficial epigastric artery and the perforator branches of the intercostal VI and VII.
This technique is used in case of an inadequate quantity of good quality skin
that can cover the breast implant.
The flap, that includes a muscle fascia, starts from the inframammary fold and
extends laterally. It is transferred by a rotation of about 90 to fill in the scar area.
The flap fascia is sutured medially to the pectoral muscle and laterally to the serratus fascia, creating a complete muscular fascia pocket to hold the implant.
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The implant is then placed underneath the muscle layer. This technique allows
breast reconstruction to take place in a single procedure without expansion. The
scars are bigger but mostly limited to the bra cup.
16.4.2.3 Transverse Rectus Abdominis Myocutaneous Flap (TRAM)

The TRAM was first described by Holmstrom in 1979 [29], and later made popular by Grotting [30] and Elliott [31].
The rectus abdominis muscle flap has assumed a central role in reconstructive
surgery. Easily removed, even simultaneously to the removal phase or the preparation of the recipient area, the length of the pedicle with a good vessel caliber,
as well as the large quantity of available tissue, have made the flap widely used.
The versatility of this flap is due to the fact that it is possible to use various types
with various shapes depending on the reconstructive needs. According to the tissue used, it is possible to prepare a myofascial, myocutaneous or condromyocutaneous flap.
As mentioned above, the TRAM flap can be lifted in two ways:
Pedicle TRAM flap. This can be obtained by the dissection of skin, adipose tissue and the abdominal rectus; its subsequent transposition to the mastectomy area
occurs through a subcutaneous tunnel and it is possible to recreate the original
shape and volume of the removed breast. This technique makes it possible to
reconstruct breasts with big volumes and to adjust it to contralateral ptosis (sagging) or a voluminous breast. In fact, it is possible to transfer a large area of skin
and adipose tissue to the breast region, taken from the lower abdomen below the
navel. This is used for patients who have excess skin and adipose tissue in the
lower abdomen.
Advantages:
The significant skin supply with the subcutaneous adipose mantle is sufficient
to recover a good breast volume and to guarantee a good esthetic result with
a natural breast ptosis
No implant is used, only tissue from the patients themselves.
The breast reconstructed with TRAM, compared with the use of implants, has
a more natural aspect and a soft consistency and the abdominal damage is not
very visible and is sometimes desired (abdominoplaty).
Disadvantages:
An extensive horizontal abdominal scar in the donor site of the flap
Abdominal wall weakness with the possibility of a secondary incisional hernia
A long operation time (45hours).
Free TRAM Flap. This consists of the transferring of a lozenge-shaped free
TRAM flap from the abdominal to the mastectomy region. The sectioned blood
vessels are anastomosed to the pre-prepared recipient vessels. Therefore, it
allows the transferring of a large amount of autologous tissue with a larger degree
of freedom and flexibility compared to the pedicle flaps. It is an invasive surgery
that requires microsurgical expertise, long operative time and a long postoperative course. The dominant vascular axis is represented by the deep inferior epigastric vessels.
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16.4.2.4 Deep Inferior Epigastric Perforator Flap (DIEP)

The deep inferior epigastric perforator flap (DIEP) was described for the first
time in 1989, by Koshima and Soeda [15], and later, in 1994, Allen and Treece
[32] highlighted the efficacy of breast reconstruction.
Initially, it was a development of the TRAM, but today it is the first choice for
breast reconstruction, supplanting the TRAM itself due to the lower morbidity of
the abdominal wall.
The flap consists of thin adipose skin, vascularized by perforating vessels
that flow from the deep inferior epigastric artery towards the vertical course
supplying the integuments of the lower abdomen.
Unlike the TRAM, the flap dissection preserves the muscles and the abdominal wall fascia, lifting only the part of skin and subcutaneous tissue situated between the navel and the pubis.
Therefore, it is unnecessary to place a net to strengthen the abdominal wall as
the donor site is closed. Also, saving the abdominal rectus muscles reduces the
morbidity of the donor site, postoperative pain and the hospital stay. Currently,
this flap is the best method for breast reconstruction.
The fundamental principle that guides the DIEP flap project is that of centering the flap onto suitable muscular perforators with enough caliber to supply the
integuments, which are identified preoperatively by a Doppler or an echoDoppler flowmetry; to recover the skin of the abdominal wall, the position and
the caliber of the revived vessels. Some authors have also proposed the use of a
CT angiography or MR angiography.
The Doppler ultrasonography test is an essential step of the project as it provides valuable information regarding the position, the flow and the diameter of
the deep inferior epigastric artery, that is, the pre-operative map of the perforators with the highest caliber situated in the most favorable position of the flap dissection, usually in the periumbilical area. This makes it possible to reduce the
operating time by about 3050minutes.
16.4.2.5 Superficial Inferior Epigastric Artery Flap (SIEA)
The superficial inferior epigastric artery flap (SIEA) is a lower abdominal wall
free flap, which is vascularized by the superficial inferior epigastric artery, a
branch of the femoral artery. Its removal does not damage the muscular or fascial
structure of the abdominal wall. The operation is easy and quick.
The superficial inferior epigastric artery originates from 23 cm beneath the
inguinal ligament, or directly from the common femoral artery (17%) or from an
origin that is common to the superficial circumflex iliac artery (48%). The skin
ellipses of the lower abdomen may be transferred, without muscle dissection, placing the flap on the artery and the superficial inferior epigastric vein, branches of the
femoral artery.
Advantages:
It does not damage the muscular and the aponeurotic structures of the abdominal walls
The operation is faster
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The dissection of the vascular peduncle is easier.

Disadvantages:
A short vascular peduncle of small caliber that can be easily damaged by previous operations in the inguinal region (vessels of such small caliber can lead
to an increased risk of partial or total necrosis of the flap)
These vessels might be absent in a third of the patients.
16.4.2.6 Gluteal Free Flaps

A good second choice for breast reconstruction consists of skin and adipose tissue taken from the gluteal region. The myocutaneous gluteus flaps were not
extensively used in the past due to their short peduncle, the large caliber discrepancy of their vessels for anastomosis, the difficult dissection, the possibility of
damage to the sciatic nerve and the sacrificing of a conspicuous part of the maximus gluteus muscle.
Gluteal perforator flaps are the ultimate evolution of the musculocutaneous
variants. By eliminating the muscular component of the traditional myocutaneous
flap of the gluteus maximus, the vascular peduncle elongates up to 8 cm.
Vascularization depends on the perforator vessels of the SGAP or the inferior one
(IGAP).
Between the two types of flaps, the SGAP is given preference since the exposure of the sciatic nerve can be avoided.
Superior Gluteal Artery Perforator Flap (SGAP)
The microvascular transfer of the tissue taken from the gluteal region was introduced in 1975 by Fujino [33]. The SGAP includes the skin and the subcutaneous
tissue of the gluteal region, with an acceptable scar at the donor site.
The reconstruction using SGAP is a rather complex technique and, therefore,
scarcely used. However, it can be suitable for cases in which both breasts need to
be reconstructed, the patient is thin and has insufficient abdominal tissue, or else,
if a previous abdominoplasty was carried out.
Inferior Gluteal Artery Perforator Flap (IGAP)
The transfer of the inferior gluteal artery perforator flap (IGAP) flap was introduced in 1978 by Le-Quang [34]. The use of this flap with the gluteal muscle lifting has often caused the exposure of the sciatic nerve, with significant sequelae
for the patients. The advantages of the IGAP are the position of the scars, the constant anatomy, the presence of donor sites with adequate volumes, the ease with
which modeling in breast reconstruction takes place and the possibility of having
a sensitive flap.
16.4.2.7 Alternative Donor Sites

There are other types of free flaps that can be used for breast reconstruction
which, however, require more skills and expertise, with a greater risk of failure.
They are used for cases in which the traditional techniques are deemed inappropriate: for example, they are appropriate when the abdominal and dorsal tissue is
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insufficient, already used or unusable due to previous surgery damaging the vascular pedicle, or in the case where the patient does not want scars in the abovementioned sites.
Transverse Lateral Thigh Flap (TLT)
The TLT represents the horizontal variant of the most common myocutaneous
flap of fascia lata based on the lateral circumflex femoral artery that perforates
the muscle approximately 10cm lower than the anterior superior iliac spine. As
regards the direct closure of the donor site, the quantity of skin that can be used
is limited to a height of 68cm.
Transverse Myocutaneous Gracilis Flap (TMG)
The TMG is a musculocutaneous flap removed from the inner side of the thigh,
just below the inguinal fold, where the vascular pedicle is made up of the ascending branch of the circumflex femoral veins with two concomitant veins.
Anterolateral Thigh Flap (ALT)
The ALT was proposed as a subcutaneous flap for the first time by Song in 1984
[35]. It is a perforator flap, which is vascularized by perforator arteries flowing
from the descending branches of the lateral circumflex femoral artery.
The flaps of the skin and the subcutaneous tissue, based on the subcutaneous and
musculocutaneous perforators of the descending branch of the lateral circumflex
femoral artery, can be used for immediate or deferred reconstructions of smallsized breasts if other alternative donor sites are not available.
The ALT flap can be prepared as a cutaneous flap or a fascia-cutaneous flap or
else a composite or a chimera flap including a portion of lateral vastus.
16.4.2.8 Omental Flap and Mesh After Conservative Mastectomy

The omental flap, whose blood supply is provided by the gastroepiploic arteries,
was initially used by reconstructive surgeons in breast reconstruction surgery to
cover implants; the entire covering was obtained from cutaneous grafts. The cosmetic outcome was unsatisfactory, due to the final shape and the quality of the
cutaneous covering.
By using an omental flap and a synthetic mesh after conservative mastectomy, the volume of the neobreast is obtained by inserting a flap of omentum,
which is dissected via laparoscopy; the shape of the breast is defined and above
all supported by an internal bra made of a synthetic mesh that wraps around and
supports the flap. Moreover, conservative mastectomy (skin-sparing mastectomy
or nipple-sparing mastectomy) offers a high quality cover with original skin and
reduced and well-placed scars.
The pedicle length (approximately 12cm) ensures the movement of the flap
toward the mastectomy area without tension, producing satisfactory results since
the reconstructed breasts have a natural volume and consistency [36].
16.5
261
Fat Grafting
The idea of carrying out breast reconstruction using autologous tissue is not new
but coincides with the introduction of plastic surgery in Europe and North
America. Hereby, it is worth mentioning the first publications on fat grafting
produced by Czerny (1845) [37], Lexer (1919) [38], and later that of the Italian
author Pennisi [39] who, in 1920, described Grafting using adipose tissue for
surgical purposes. It was only in the 1980s that this method experienced a significant impetus, especially thanks to the French school. In 1989, Fournier [40]
described his Liposculputure, ma technique, a liposuction method using a
syringe and cannula aspiration, and liposculpture for augmentation, which
involves the self-transplantation of adipose tissue removed with a syringe from
the donor site and then inoculated, for esthetic purpose, on the face, hands and
breasts. The genius of the intuition to increase volume by grafting adipose tissue
became quickly evident. Nevertheless, this method had major limitations because
of the significant and rapid reabsorption of the transplanted adipose tissue that after
some time made the surgical result very poorly significant. In 1987, another issue
was added to this, the American Society of Plastic and Reconstructive Surgeons,
with particular reference to breast fat grafting, declared it inadequate due to
feared calcifications that could interfere with the diagnosis of breast cancer.
For such reasons, in the 1980s, the lipofilling method in breast surgery suffered a setback. In the 1990s, an innovative technique was designed in the United
States, making fat grafting more stable. Coleman [41], at the Congress of
Lipoplasty Society of North America (Seattle, 1991), presented the method of
centrifugation of sampled tissue (3000 rpm per 3 minutes), demonstrating the
systematization of the technique (bloodless sampling, purification via centrifugation and a blunt injection), to obtain optimal results with reabsorption of the
grafted adipose tissue limited to 2030% of the sampled volume. The rationale of
Colemans innovative technique coincided with the abandonment of the traditional idea developed by Fournier. The use of grafted adipose tissue became the filling means on which the concept of grafting using tissue, enriched with adiposederived adult stem cells, was developed. Besides the technical attention given to
this technique during the fat aspiration and inoculation phase, to ensure a larger
quantity of fat availability, according to Colemans rationale, the enrichment with
adult stem cells in the grafted fat, was to be carried out using a centrifugation
method (3000rpm in 3minutes). By separating the liquid-oily part of the sample
from the cellular one, this method makes it possible to inoculate a denser adipose
tissue, where the clusters are certainly richer in adult stem cells. Even if to date
it is still unclear, and a source of intense experimental research, whether the persistence of the grafted adipose tissue is due to the regenerative tissue effect of the
grafted stem cells or that this grafting causes more complex cell regeneration
processes, it is certain that the excellent reconstructive and cosmetic results presented by Coleman are due to the amount of stem cells present in the graft. In the
2000s, there have also been many international publications that have shown scientific and speculative interest in applying this breast surgery method, all of
262
C. Mariotti et al.
which are in favor of applying this method, including Italian authors. Based on the
spur of published experimental and clinical novelties and adhering to Colemans
specific request to abolish the promulgated ostracism; in 2007, the American
Society of Plastic and Reconstructive Surgeons established a new commission
(ASPS fat grafting task force), which critically revisited scientific research developed practical recommendations, and while acknowledging the validity of the
methodology, recognized that fat transplantation is a valid indication to achieve an
increase in breast volume and the correction of surgical outcomes.
Following these events, the use of lipofilling in breast surgery, both for cosmetic and reconstructive purposes, has experienced an exponential growth characterized by intense research aimed at obtaining two fundamental objectives: the
reduction of transplanted adipose tissue absorption and an improvement in the
final cosmetic outcome. Therefore, there has been a wide debate regarding alternative methodologies such as condensation and the body jet system, which, revolutionizing the fat removal and treatment methodologies, have constantly tried
to increase the quantity of adipose tissue that is resistant to reabsorption. In this
regard, a recent study by Choi (2013) [42] evidenced how the stable amount of
transplanted adipose tissue, that is, not absorbed, is volume and time dependent. In particular, this study has shown that the immediate result of lipofilling is
always satisfactory if evaluated within the first 7 days, with a persistent fat
amount with a volume that is greater than 86% of the transplanted adipose tissue.
However, the residual amount that can be reabsorbed within 5 months is directly
proportional to the volume of grafted fat, varying between 5152% of residual fat
(volume of grafted fat > than 150cm3) to reach residual volumes < than 30% for
smaller volumes of transplanted fat.
However, it was the Italian School that proposed the use of lipofilling in surgical breast reconstruction, moving away from a mainly esthetic perspective aimed at
increasing the volume of a healthy breast, with or without implant, to the idea of
reconstructing the breast after a mastectomy, or to treat the outcome of radiotherapy. Rigotti [4345], in 2007, proposed breast lipofilling as a main indication for
radiodermitic lesions and, subsequently, an ambitious objective was set, that of
completely reconstructing a new breast, after mastectomy, using adipose tissue
grafting. Obviously, the first phase of this method is external skin expansion, using
the Brava system, that creates the anatomical space for the positioning of the fat,
followed by a lipostructure phase in various operative phases. The ideal candidate,
according to Rigotti, is someone with a large donor site of adipose tissue (lower
abdomen, thighs), with an adequate thickness of breast skin, a thickness of more
than 1.5cm, without skin tension. Rigottis cases, require two to four adipose grafting sessions, spaced by the use of the Brava system; however, in some cases, it is
necessary to have more sessions, especially for those patients with more complications. If we now consider the acquired concept by which it is possible to reconstruct
the breast using just a fat transplant, the question that remains is, whether and in
what ways, can the adipose grafting interfere with the prognosis of a breast cancer.
Even if the first results of statistical research seems reassuring, numerous trials are
currently being carried out with the aim of clarifying the doubt regarding the oncologic risk of breast lipofilling.
263
16.5.1 The Technique

The lipofilling surgical technique has three fundamental phases: the removal of
fat, its purification by centrifugation or alternative methodologies, and infiltration in the treatment area.
16.5.1.1 Considerations Regarding the Donor Site

One of the fundamental requirements of the ideal candidate for breast lipofilling
is the presence of donor sites rich in adipose tissue. Traditionally, these sites are
those that have always been subjected to liposuction for cosmetic reasons, such
as the lower abdomen, the thighs and the medial region of the knee. The first
authors mainly used the abdominal subumbilical region as a donor site to be able
to hide the scar in the navel. However, the fundamental principle when choosing
a donor site, is to take into consideration the quality of the fat to be removed in
terms of a higher amount of engraftment to the recipient site, as well as its ability to offer a better lipostructure and greater persistence of transplanted fat with
time. For this reason, in 2010, Sbarbati [46] carried out experimental research on
the characteristics of the adipose tissue sampled from various donor sites, evaluating their structural and ultrastructural characteristics and the concentration of
adult stem cells. This study led to the identification and the classification of three
types of white adipose tissue (WAT), which can be used as donor sites:
1. DWAT (Deposite WAT): this can be found mostly in large abdominal and
periumbilical deposits. The cells in these areas are tightly packed and have a
tenuous collagen fiber net with scarce vascularization. In addition, the deepest fat layer seems to be more fibrous than the superficial one and the scarce
capillary vessels forming the microcirculation have fewer stem cells;
2. SWAT (Structural WAT): is mostly found in the limbs and the trochanteric
regions; this fat is definitely richer in stroma, structured in such a way to form
a dense network of collagen fibers that surround the adipocytes as in a basket.
The stroma is widely present and richly vascularized, as well as being rich in
stem cells. These characteristics are mainly present in the medial region of the
knee and the trochanteric regions;
3. FWAT (Fibrous WAT): is mainly characterized by a fibrous structure, which
is poorly vascularized. It has a scarce presence of stem cells. It is typically
present in the anatomical areas where mechanical stress develops.
Ultimately, this study has provided surgeons with excellent structural references
when selecting the most suitable donor sites that can generate a good lipostructure.
Therefore, the idea that donor sites can be chosen randomly has been abandoned
and priority for removal is given to the medial regions of the knee and the tronchanteric regions that have abundant SWAT tissue, using the abdomen as a second
choice, when larger quantities of adipose tissue are necessary.
16.5.1.2 Consideration Regarding the Fat Treatment
The current state of art, has four methods of treating the sampled fat:
1. Centrifugation according to Coleman
The Coleman technique uses centrifugation as a purification procedure. Once
264
2.
3.
4.
5.
6.
C. Mariotti et al.
the syringe is filled with aspirated fat, the cannula is removed and a Luer-Lok
is placed on the syringe to seal the opening. The next stage is purification: the
plunger is removed, the syringe is placed in a sterilized centrifuge and centrifugation takes place for 3minutes at 3000rpm.
Washing
Generally, washing is carried out using a lactate Ringer solution. This technique is not a very appreciated one since it may damage the adipocytes both
from a mechanical and an osmotic point of view.
Decanting
Decanting allows the purification and isolation of adipose tissue from unnecessary and potentially harmful material, which may cause the onset of an
inflammatory process, without traumatizing the adipocytes. Therefore, it
involves a rather advantageous method, even though the procedure is longer
when compared to centrifugation.
Filtration
Filtration is not a recommended method if carried out with metallic filters or
filters placed inside the aspiration tube, since it increases the trauma of adipose cells. However, it is preferred to centrifugation, because it is considered
to be less traumatic if the fat is collected on a gauze placed over a container,
with repeated washing (45 times) of the tissue collected with a physiological
solution and a slight applied pressure to eliminate excessive liquids. If we
compare the filtration method with centrifugation, it is necessary to realize
that the latter does not cause damage to the adipose cells, but it has been
noticed that the material obtained with this method has 13% less of adipocytes
than the material obtained with decanting/filtration, even if centrifugation has
the advantage of eliminating a larger amount of the destroyed adipose cells.
In addition, the intermediary layer obtained via centrifugation, the one that is
rich of integral and vital adipose cells, can in turn be divided into three layers, of which the bottom and the intermediary one contain 250% and 140%
more vital adipocytes compared to the superficial one.
Lipocondensation
The fat is removed by a particular technique which uses a special microcannula linked to a device called Lipokit. With this method, the adipose tissue is
treated before the reimplantation with the possibility of determining a real
predigestion of the fluid fraction, represented by triglycerides, which in any
case will be reabsorbed by the organism within a short time. Therefore, it is a
pretreatment, or a real condensation of the adipose tissue before injecting it in
the breast. The adipose tissue is transformed into a dense and homogeneous
natural gel, that maintains its volume and shape over time and is not absorbed
or just in little quantities.
Body jet system
The body jet system is an innovative method, designed to aspire and treat considerable volumes of adipose tissue, and therefore complementary to the
breast external expansion system Brava. The removal of fat takes place via
a pressurized water jet with a laminar shape (with five steps of adjustment),
265
mediated by specific cannulas at every stage, which enables it to carry out

both the infiltration (saline solution containing epinephrine and anesthetic)
and the delicate fat aspiration phase, simultaneously and under closed circuit.
The saline solution, the epinephrine and the anesthetics are diffused between
the adipocytes and not in them, which makes them available for a later fat
grafting surgery. This way the adipose tissue is delicately removed respecting
the adjacent tissue structures, minimizing bruising and edema of the treated
area. With this method, the adipose cells are not destroyed but are transformed
into gelatin making aspiration easier and non-traumatic. The fat removed with
this method has 76% intact and active adipocytes and is capable of transforming itself into a new adipose tissue of significantly higher quantities when
compared to that obtained from centrifugation and washing processes. The
inoculation phase of the removed fat can also be completely compared to
Colemans method.
16.5.1.3 Considerations Regarding Fat Inoculation

Although literature is divided on the proposals of various fat sampling and treatment techniques, there is general agreement about the inoculation technique and
the aim of this method. There is an unanimous consensus on the reliability of a
method that obtains brilliant results both from a cosmetic and a reconstructive
aspect, even though the intimate biological mechanisms of its results are still
unknown. The most debated issue is the lipostructure obtained via lipofilling,
both as a result of the rearrangement of the injected adipose tissue itself and the
complex restructuring process of the transplanted fat from the stem cells that
starts as a result of lipofilling, modulated by the existing growth factors. The
study of Yoshimura (2010) [47] tends to confirm the second hypothesis as the
most probable one, but still today there is a lack of definite experimental data validating the formulated hypothesis and, above all, we are still unable to explain
how adult transplanted stem cells can encourage the structuration of the shape
and volume of adipose tissue, and whether the injected adipose tissue behaves
like a useful temporary matrix that guides the structure of the new tissue.
Certainly, there is no consensus on the fat inoculation method. During reimplantation, to protect the adipocytes, the removal must maintain the lobular structural architecture of the fat: the fragments must be big enough to maintain their
structure, but small enough to pass through a 1718G cannula. The inoculation
must follow precise criteria: the adipose tissue is distributed on various dissection planes (a blunt dissection carried out with the injecting cannula itself) and
wide areas that allow a better revascularization of the grafted tissue, with a better chance to take root. Therefore, in order to obtain a good lipostructure outcome, the technique involves the infiltration of fat through many small canals situated at various levels, in each of which a small needle is linked to a syringe
which deposits a small amount of adipose tissue, so as to create a three-dimensional structure that encourages revascularization and an increased longevity of
the graft.
C. Mariotti et al.
266
16.5.1.4 Considerations Regarding the Oncologic Risk of Fat Grafting

The placement of regenerated tissue in a tumor resection site raises questions
about the possibility of promoting tumor recurrence. Literature highlights the
effectiveness of this technique, but experimental studies raise important questions about the potential effects that adipocytes might have on stimulating the
growth of cancer and possible recurrence. All the authors agree that, despite the
growing interest in autologous fat grafting in breast reconstruction, the potential
effects on the tumor bed are currently unclear. With regard to the problem of
cancer risk related to lipofilling, few publications have focused on the possibility of tumor recurrence. However, we know from experimental studies that
adipocytes and preadipocytes residing in white adipose tissue are capable of producing various growth factors that may act on the tumor cells via paracrine
activity. This condition raises the question of the risk of recurrence for patients
who undergo lipofilling in the area that was previously treated for breast cancer,
especially after conservative treatment. Rigotti [48], in 2010, compared the incidence of local and regional recurrence of breast cancer in a population of 137
patients who underwent postmastectomy adipose grafting. This study showed
that when the curves of disease-free survivors are statistically compared, there
are no significant differences in the recurrence rate between the time phase that
precedes the adipose grafting and the one after the lipofilling surgery. Rigotti
concludes that, even though it requires further confirmation through multicentric randomized clinical studies, the obtained results support the hypothesis that
autologous fat grafting can combine surprising regenerative properties with the
marginal or the very little significant risks of locoregional tumor recurrence.
After a study carried out on 321 patients, Petit [49], in 2011 , also concluded that
lipofilling seems to be a safe procedure for patients who have already been treated for breast cancer. Nevertheless, he proposed a longer follow-up and further
studies to confirm these results. The indications given by the ASPS task force,
dated 2009, are on the same lines, stressing that since no evidence of an increase
in cancer recurrence following breast lipofilling has been recorded or published
until now, it is not possible to give a definitive recommendation regarding the
oncologic risks.
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Preoperative Systemic Therapy
17
Massimiliano DAiuto and Giuseppe Frasci
17.1
Introduction
Neoadjuvant (preoperative) therapy is defined as the first systemic treatment a

patient receives when nonmetastatic breast cancer is diagnosed. Neoadjuvant
treatment has the ability to shrink tumors and was first used, in the 1970s, in
patients with inoperable locally-advanced or inflammatory disease. Data from
several retrospective analyses showed that the application of multimodal treatment consisting of neoadjuvant chemotherapy, surgery, radiotherapy, and hormonal therapy improved survival for patients with locally-advanced breast cancer (LABC) [12]. The role of neoadjuvant treatment has evolved since this
time; indeed, in the last two decades, preoperative chemotherapy has also been
performed in women with large operable breast cancer in order to downstage the
tumor and thus enabling breast-conservative surgery. More recently, the preoperative approach has also been tested in patients with early breast cancer, suitable for conservative surgery, in order to allow a more rapid evaluation of new
therapies without the need for long-term follow-up to demonstrate a survival
advantage [327]. The absence after neoadjuvant chemotherapy of residual
tumor (pCR; pathologic complete response) is associated with a very favorable
long-term outcome, suggesting that pCR could be a marker for long-term effects
on disseminated tumor cells [28]. However, different definitions of pCR have
been reported in the past (i.e. no residual tumor in breast, no residual tumor in
breast and axilla, only residual DCIS), since there was not a general agreement
about the prognostic impact of residual carcinoma in situ in the breast, and of
the persistence of residual tumor only in the axillary nodes.
M. DAiuto ()
Department of Senology, Breast Surgery Unit,
Istituto Nazionale dei Tumori, Naples, Italy
e-mail: massimiliano.daiuto@gmail.com
Updates in Surgery
269
270
M. DAiuto, G. Frasci
The Breast International Group (BIG) and the National Cancer Institutesponsored North American Breast Cancer Group (NABCG) have recently recommended that in neoadjuvant clinical trials, pCR should be defined as the
absence of residual invasive cancer within both the breast and lymph nodes [29].
The achievement of pCR is quite frequent in patients with a triple-negative
and HER2 positive tumor, otherwise it is very uncommon in patients with an ERpositive tumor, who represent the majority of women with breast cancer. In spite
of that, the long-term outcome is better in this last cohort [30]. It has recently
been shown that pCR is more highly predictive of relapse-free survival within
every established receptor subset than overall, demonstrating that the extent of
outcome advantage conferred by pCR is specific to tumor biology [31, 32].
The investigators of the German Breast Group have recently reported the
long-term outcome of 6,377 patients with primary breast cancer receiving
neoadjuvant anthracycline-taxane-based chemotherapy in seven randomized
trials. They observed that pCR was a suitable surrogate endpoint for patients
with luminal B/HER2-negative, HER2-positive (nonluminal), and triple-negative disease, but not for those with luminal B/HER2-positive or luminal A
tumors [32].
In view of these considerations, pCR cannot be considered the unique surrogate endpoint after neoadjuvant therapy, especially in patients with a lowproliferating tumor, since a relevant proportion of them have very favorable
prognosis even in presence of residual tumor. However, the achievement of
pCR can be associated with a substantial risk of relapse, in patients who had
advanced clinical stage at diagnosis.
Investigators from the MD Anderson Cancer Center previously described a
novel breast cancer staging system for assessing prognosis after neoadjuvant
chemotherapy on the basis of pretreatment clinical stage (CS), estrogen receptor status (E), grade (G), and post-treatment pathologic stage (PS). This clinical-pathologic stage (CPS) plus EG staging system, assigned and summed
points for each factor, allowing for better determination of breast cancer-specific survival than clinical stage or pathological stage alone (Table 17.1) [33].
The CPS+EG staging system has been recently validated in two independent
cohorts (Table 17.2) [34].
To date, in spite of the high number of clinical trials carried out, many
issues on neoadjuvant chemotherapy are still open. In the present chapter, we
analyze all the available data in order to provide the appropriate answers to the
following questions:
1. Does primary chemotherapy result in a substantial prognostic advantage
when compared to a standard adjuvant approach?
2. Are we able to define the best regimen, dose, timing, and sequence today?
3. What is the current role of targeted therapy, and what will it be in the near
future?
4. Can we deliver a treatment other than chemotherapy in some ER-positive
patients?
5. How do locoregional treatments change after neoadjuvant therapy?
17 Preoperative Systemic Therapy
271
Table 17.1 CPS+EG (Clinical and pathological staging + post-treatment Estrogen and grading) score
Score
Pretreatment
clinical stage
Score
Score
Post-treatment
pathological stage
Post-treatment
biomarkers in the
residual tumor
ER negative
IIA
G3
IIB
IIA
IIIA
IIB
IIIB
IIIA
IIIC
IIIB
IIIC
Table 17.2 Validation of the CPS+EG score in three different cohorts for a total of 1901 patients
Score
Initial cohort
Internal validation
External validation
(932 pts.)
(804 pts.)
(165 pts.)
N. pts
5-yr
DSS (%)
N. pts
5-yr
DSS (%)
N. pts
5-yr
DSS (%)
73
100
32
97
10
100
155
98
108
98
17
94
245
96
223
88
60
93
226
88
186
72
45
74
151
72
169
73
27
88
51
57
64
52
33
22
22
17
DSS,Disease-specific Survival.
17.2
Preoperative vs. Postoperative Chemotherapy in

Operable Breast Cancer
Because of the possibility that a preoperative treatment may improve the outcome
by exposing micrometastases to early chemotherapy, neoadjuvant chemotherapy
was investigated in patients with primary operable disease. Several randomized trials have been conducted, which compared neoadjuvant chemotherapy with the standard adjuvant approach in women with early disease [46]. Since it is known from
the advanced setting that neoadjuvant treatment has the ability to shrink tumors, this
treatment approach may also allow for breast-conserving treatment in patients who
otherwise would have needed a mastectomy. The pioneer trial investigating these important issues was the B18 trial of the NSABP (National Surgical Adjuvant Breast
and Bowel Project) [4]. In this study, 1,523 women with operable breast cancer were
randomized to four cycles of AC (adriamycin, cyclophosphamide) either before or
272
after definitive surgery. A pCR, which was defined as the absence of malignant tumor cells at the site of the primary tumor irrespective of nodal status, was seen in
13% of the patients. A higher rate of breast-conserving treatment was observed with
neoadjuvant surgery (67 vs. 60%; p=0.002). In tumors larger than 5cm in diameter, the difference was more obvious in favor of the neoadjuvant approach (22 vs. 8%).
There were no significant differences in disease free survival (DFS) and overall survival (OS), even though updated results with follow-up exceeding 15 years indicated a trend in favor of neoadjuvant treatment in women younger than 50 years for DFS
(hazard ratio (HR), 0.85; p=0.053) [10]. There were also no significant differences
in ipsilateral breast cancer relapse rates between the neoadjuvant and adjuvant group
(7.9 vs. 5.8%; p=0.23). Two further trials [5, 6], one of which used not only anthracyclines but an anthracycline/taxane-containing regimen, confirmed the findings of
the B18 trial. A recent meta-analysis of nine randomized trials involving 3,946 patients confirmed that no differences exist between neoadjuvant and adjuvant
chemotherapy in terms of OS [7].
In view of these considerations, although a clear survival advantage has not
been demonstrated yet, neoadjuvant chemotherapy can be considered a standard approach in the management of operable breast cancer in routine practice.
There are limited contraindications to its use, that is, patients with small
tumors with low aggressive features for whom systemic chemotherapy would
not be a suitable approach. However, if the pretreatment information is sufficient to recommend a systemic approach, there is no risk of overtreatment with
neoadjuvant chemotherapy.
17.3
Searching for the Best Neoadjuvant Chemotherapy
The more recent neoadjuvant trials have focused on the addition of taxanes
and alternative schedules such as dose-dense chemotherapy. To study the role
of docetaxel in the neoadjuvant setting, the NSABP-27 trial [9] randomized
2,411 women with operable breast cancer (excluding patients with T4 tumors)
to four cycles of AC alone, four cycles of AC followed by four cycles of docetaxel (Doc) before surgery, and in the third arm to four cycles of neoadjuvant
AC followed by four cycles of adjuvant Doc after surgery. The addition of Doc
preoperatively to AC increased significantly the pCR rate in the breast (14 vs.
26%; p > 0.001), and the proportion of patients with negative nodes (51 vs.
58%; p > 0.001) compared to four cycles of AC. However, despite the pCR
rate being almost doubled by the addition of taxanes to AC preoperatively, the
study did not demonstrate a significant improvement in outcome in terms of
DFS and OS [10]. On the basis of these results, many investigators have concluded that early improvements in pCR rates cannot yet act as surrogate endpoints. However, there is another possible explanation for the lack of survival
advantage, despite the significant pCR gain. The NSABP B-27 study was powered to detect a 25% reduction in the hazard ratio for mortality. None of the
trials testing the addition of a taxane in the adjuvant setting has demonstrated
benefits of this magnitude. If we take relapse-free survival into consideration,
273
there were 231 events in the AC docetaxel arm as compared to 258 events in
the AC arm. This 10% event rate reduction would have required > 10,000
patients enrolled to be detected statistically.
Paclitaxel has also been tested in the neoadjuvant setting. To evaluate the
prognostic impact of the addition of paclitaxel to doxorubicin-based neoadjuvant chemotherapy, Mazouni et al. [11] performed a pooled analysis of results
from seven consecutive neoadjuvant chemotherapy trials conducted at MD
Anderson Cancer Center from 1974 to 2001, including 1079 patients. Patients
with ER-negative cancer had higher overall pCR rate than those with ER-positive tumors (20.1% vs. 4.9%, p < 0.001). In ER-negative patients, the pCR
rates were 29% and 15% with or without a taxane (p < 0.001), respectively. In
ER-positive patients, the pCR rates were 8.8% and 2.0% with or without a taxane (p < 0.001). In multivariate analysis, clinical tumor size (p < 0.001), ERnegative status (p < 0.001), and inclusion of a taxane (p = 0.01) were independently associated with pCR. The best results were observed with the
administration of 12 weekly cycles of paclitaxel followed by four cycles of
fluorouracil-epirubicin-cyclophosphamide (FEC) given every 3 weeks [12].
The superiority of weekly over q3wk paclitaxel has also been confirmed in the
adjuvant setting [13].
It has been hypothesized that the administration of standard doses at shorter intervals (dose-dense approach) is more effective in avoiding tumor
regrowth than the delivery of a single very high dose treatment. A meta-analysis of all randomized trials comparing dose-dense with standard chemotherapy
in the neoadjuvant and adjuvant setting has been recently performed [14].
Patients who received dose-dense chemotherapy had better OS (HR of
death=0.84, 95% confidence interval [CI]=0.72 to 0.98, p=0.03) and better disease-free survival (HR of recurrence or death=0.83, 95% CI=0.73 to
0.94, p=0.005) than those on the conventional schedule. However, no benefit
was observed in patients with hormone receptor-positive tumors.
Three decades of neoadjuvant trials have failed to define the best chemotherapy approach. Breast cancer is a heterogenous disease, and it is now widely accepted that the disease is divided into several subtypes with different biological behaviors, and different chemosensitivity [2830]. The efficacy of chemotherapy is
scarce (or even absent) in the low-proliferating, highly endocrine-sensitive tumors
(luminal A subtype); otherwise chemotherapy has a relevant antitumor effect in the
majority of patients with highly proliferant tumor (Luminal B, triple negative,
HER2 positive). Since all these kinds of intrinsic subtypes were included in the
neoadjuvant trials, this heterogeneity may have diluted (and sometimes hidden) the
differences between the different regimens.
17.4
Beyond Chemotherapy: the Targeted Agents
In the last few years many trials, evaluating the role of targeted agents in the neoadjuvant setting, have been carried out (Table 17.3). The combination of trastuzumab
274
Table 17.3 Neoadjuvant randomized trials with targeted agents
Trial [Reference] Drug
Randomization
pCR rate
MD Anderson
[15]
Paclitaxel 4 FEC 4
trastuzumab
65% vs. 25% 0.02
NOAH
[17]
Adriamycin-paclitaxel
3paclitaxel 3
CMF 3 trastuzumab
43% vs. 23%* 0.002
Trastuzumab
Lapatinib
NeoALTTO
[18]
Paclitaxel 12+Trastuzumab 27.6%
Geparquinto [19]
HER2+
Paclitaxel 12 + Lapatinib
20%
Paclitaxel 12 +
Trastuzumab + Lapatinib
46.8%*
EC 4 Docetaxel 4 +
Trastuzumab or Lapatinib
30.3%
22.7%**
0.0001
(Arm 3 vs. 1)
0.04
Pertuzumab
NeoSphere [20]
Pertuzumab + trastuzumab
16.8%
Docetaxel 4 + pertuzumab
24%
Docetaxel 4 + trastuzumab
29%
Docetaxel 4 + trastuzumab
+ pertuzumab
45.8%*
Geparquinto [21]
HER2-
EC 4 docetaxel 4
Bevacizumab
18.4%
14.9%**
0.04
NSABP B40
[22]
Docetaxel or docetaxelcapecitabine or docetaxelgemcitabine 4AC 4

+ bevacizumab
34.5%
0.02
< 0.05
(Combination
vs. others)
Bevacizumab
28.2%*
FEC, fluorouracil-epirubicin-cyclophosphamide; CMF, cyclophosphamide-methotrexate-fluorouracil; EC, epirubicin-cyclophosphamide; AC, adriamycin-cyclophosphamide.

*Absence of invasive tumor only in the breast; **Absence of residual tumor in breast and axilla
with chemotherapy is the standard adjuvant treatment for HER2-positive breast

cancer and has also been widely investigated in the preoperative setting. The first
randomized trials evaluating the addition of trastuzumab to chemotherapy were
conducted at the MD Anderson Cancer Center, and patients with stage II and IIIa
HER2-overexpressing tumors randomized to four cycles of paclitaxel followed by
four cycles of FEC with or without trastuzumab [15]. After treating 42 patients, the
study was stopped prematurely due to the remarkably high pCR rate in the
trastuzumab arm (65 vs. 25%; p=0.02). This preliminary data was confirmed by
two large studies [16, 17]. In the GeparQuattro study, the pCR rate (ypT0 ypN0)
was 31.7% compared to 15.7% in the HER2-negative reference group [16]. The
275
NOAH trial compared 1 year of treatment with trastuzumab (given as neoadjuvant

and adjuvant treatment) with no trastuzumab, in women with HER2-positive locally-advanced or inflammatory breast cancer treated with a neoadjuvant chemotherapy regimen consisting of doxorubicin, paclitaxel, cyclophosphamide, methotrexate, and fluorouracil. Trastuzumab significantly improved event-free survival (3year EFS 71 vs. 56%; hazard ratio, 0.59 [95% CI, 0.380.90]; p=0.013) [17].
The efficacy of neoadjuvant lapatinib (a dual tyrosine kinase inhibitor of both
HER1 and HER2), given alone or in combination with trastuzumab has been tested in two large randomized trials. The NeoALTTO [18] was a three-arm randomized trial which compared lapatinib-paclitaxel versus trastuzumab-paclitaxel versus
concomitant lapatinib and trastuzumab plus paclitaxel. The pCR was 25 and 30%
with lapatinib or trastuzumab, respectively (without statistically significant differences; p=0.34) and almost doubled (pCR 51%) when both agents were added to
paclitaxel.
In the GeparQuinto trial, 615 HER2-positive patients were treated with EC and Doc,
each given for four cycles, and randomly assigned to trastuzumab or lapatinib given
for the entire 24-week treatment period until surgery. In this trial, the pCR rate was significantly higher with trastuzumab than with lapatinib (31 vs. 22%; p < 0.05) [19].
Pertuzumab is a recombinant humanized monoclonal antibody which binds to a
different HER2 epitope than trastuzumab, and has shown activity in trastuzumabresistant disease. In the NeoSphere trial, 417 patients with HER2-overexpressing
breast cancer were randomized to 12weeks of docetaxel-trastuzumab, docetaxelpertuzumab, docetaxel-trastuzumab-pertuzumab, or trastuzumab-pertuzumab. The
highest pCR rate (46%) was observed in the arm which combined both biological
agents with chemotherapy [20].
An alternative way to target breast cancer is through the inhibition of neoangiogenesis. In the HER2-negative part of the GeparQuinto trial, the concept of antiangiogenesis was investigated [21]. In total, 1,948 patients were randomized to
receive four cycles of EC followed by four cycles of docetaxel with or without concomitant bevazicumab. Whereas no effect of bevazicumab in HR-positive patients
was seen, bevazicumab significantly increased the pCR rate in triple-negative
tumors. Conflicting results were observed in the NSABP B40 trial [22]. In this
study, patients received one of three taxane-based regimens preoperatively (docetaxel, docetaxel plus capecitabine, or docetaxel plus gemcitabine followed by AC
4) with or without bevazicumab given every 3weeks. The addition of bevazicumab to chemotherapy improved pCR rates (28.4 vs. 34.5%; p=0.027 but the effect
was predominantly seen in the HR-positive subset.
17.5
Beyond Chemotherapy: the Neoadjuvant Endocrine

Treatment
Aromatase inhibitors (anastrozole, letrozole and exemestane) represent the

standard adjuvant treatment in postmenopausal HR-positive patients. They
have also shown a clear superiority over tamoxifen in the preoperative treat-
276
ment of postmenopausal women with clinical stage 2 or 3 ER-positive breast

cancer. In the IMmediate Preoperative Arimidex, tamoxifen, or Combined
with Tamoxifen (IMPACT) study, in which a comparison was done of neoadjuvant anastrozole vs. tamoxifen vs. the combination of the two, there was a
significantly higher rate of patients who were deemed feasible for breast-conservation surgery (BCS) by their surgeon in the anastrozole arms (46 vs. 22%,
respectively; p=0.03) [23].
In the P024 trial, postmenopausal patients with HR-positive primary breast cancer who were ineligible for breast-conserving surgery were randomly assigned to
4months of neoadjuvant letrozole or tamoxifen. The rate of breast-conserving surgery was significantly higher with letrozole (48% vs. 36%; p=0.036). Differences
in response rates between letrozole and tamoxifen were most marked for tumors
that were positive for ErbB-1 and/or ErbB-2 (88% vs. 21%, p=0.0004) [24].
Despite these promising results with preoperative endocrine treatment,
neoadjuvant chemotherapy is still widely used in postmenopausal HR-positive
patients with large operable or locally-advanced disease. The lack of a practice
standard reflects the absence of a phase III trial definitively comparing neoadjuvant aromatase inhibition with neoadjuvant chemotherapy. Unfortunately,
the design of such a study is not straightforward, because pCR rates are low in
ER-positive disease regardless of treatment modality, suggesting other primary endpoints must be considered. However, the clinical response rate (cRR)
traditionally used in neoadjuvant endocrine studies is not verifiable, and radiologic response endpoints are not standardized. Surgical outcome improvement is a logical primary endpoint, but surgical decisions are subject to bias
when blinded treatments are not possible. An alternative to conventional primary endpoints for neoadjuvant endocrine therapy trials is the Ki67 proliferation biomarker. Follow-up data of patients enrolled in IMPACT indicated that
the Ki67 level measured 2 weeks after treatment was a better predictor of
relapse-free survival than pretreatment levels [23]. These findings suggest that
Ki67 could be used as an intermediate endpoint, able to provide evidence of
therapeutic effectiveness during endocrine treatment. The Ki67 data have been
integrated into a post-treatment model that also includes pathologic stage and
ER levels, referred to as the Preoperative Endocrine Prognostic Index (PEPI).
Patients with pathologically node-negative T1 or T2 disease with a fully suppressed Ki67 level (02.7%) and persistent ER expression after completion of
neoadjuvant endocrine therapy (PEPI of 0) were found to have such a low risk
of relapse that adjuvant chemotherapy after neoadjuvant endocrine therapy
may not be necessary (Table 17.4) [25].
An integration of pretreatment biomarkers, either genomic or immunohistochemical, with early Ki67 assessment, and post-treatment PEPI score could
improve prognostic algorithms and help to identify patients for whom neoadjuvant
endocrine therapy is appropriate, because adjuvant chemotherapy is unnecessary
treatment. To investigate these issues, the ACOSOG (American College of
Surgeons Oncology Group) Z1031 trial, was conducted. Three hundred and seventy-seven postmenopausal women with clinical stage II to III, strongly ER-positive
277
Table 17.4 The Preoperative Endocrine Prognostic Index (A) and its correlation with the outcome
in the P024 and IMPACT trials (B)
A
Post-treatment pathology
and biomarkers status
Relapse-free survival
Disease-specific survival
(score)
(score)
T12
T34
Negative
Positive
02.7%
> 2.7%7.3%
> 7.3%19.7%
> 19.7%53.1%
> 53.1%
02
38
T size
Axillary nodes
Ki67 level
ER Status (Allred score)
B
Risk score
13
P024 median follow-up 62 months

Relapse
4 (10%)
15 (23%)
25 (48%)
IMPACT median follow-up 37 months

Relapse
1 (3%)
5 (5%)
13 (17%)
breast cancer (Allred score 68) were randomly assigned to receive neoadjuvant
exemestane, letrozole, or anastrozole. The primary endpoint was clinical response.
Secondary endpoints included BCS, Ki67 proliferation marker changes, the PEPI,
and PAM50-based intrinsic subtype analysis. Fifty-one percent of patients who
were designated candidates for mastectomy only before therapy received BCS, and
83% of those considered marginal for BCS at baseline experienced successful
breast conservation, with no significant differences between arms. Post-treatment
pathologic findings were also similar. A PEPI of 0 was observed in 17.3%, 15.9%,
and 15.6% of anastrozole, letrozole and exemestane patients, respectively. In univariable analysis, a baseline Ki67 level less than or equal to 10% (p=0.018) and
luminal A subtype status (p=0.004) were significantly associated with an increased
likelihood of a PEPI of 0. In multivariate analysis, luminal A subtype assignment
was the dominant factor predicting the likelihood of PEPI-0 status [26].
278
Fig. 17.1 Multistep personalized approach in HR-positive patients
The neoadjuvant endocrine therapy has also been tested in premenopausal HRpositive patients. Japanese investigators randomized 197 premenopausal women
with operable breast cancer to receive goserelin combined with either tamoxifen or
anastrozole for 24 weeks before surgery. The overall response rate was 70.4% and
50.5% in the anastrozole and tamoxifen arm, respectively (p=0.004) [27].
On the basis of these data, it could be hypothesized a prognostic algorithm
for patients with HR-positive breast cancer (either pre- or postmenopausal)
which includes baseline, on-treatment and post-treatment biomarkers. This
model could allow to select HR-positive patients who independently of their
age or tumor size, could never require chemotherapy (Figure 17.1).
17.6
The Locoregional Treatment
One important benefit of neoadjuvant chemotherapy is that selected patients with

large primary tumors at the time of diagnosis can be treated with breast-conservation therapy after responding to preoperative treatment. Defining the optimal selection criteria for breast-conservation therapy after preoperative chemotherapy
remains a clinically relevant area of research. Advanced primary breast cancers
respond to preoperative chemotherapy in a heterogeneous fashion. Some primary
tumors shrink concentrically to a solitary nidus, which can be completely resected
with breast-conserving surgery. However, other responding cancers leave scattered
disease over the original tumor bed volume. In such cases, a surgery directed at the
center of the residual primary may risk leaving a high burden of microscopic disease, which may predispose to breast cancer recurrence.
Precious insights concerning selection criteria for breast conservation have
come from investigators at The University of Texas MD Anderson Cancer Center
(Houston, TX), who retrospectively evaluated the outcome of 340 patients with
stage II or III noninflammatory disease, who underwent breast-conservation thera-
279
py after neoadjuvant chemotherapy [35]. In this series, the 10-year in-breast recurrence rate was 10%. Four factors were independently associated with locoregional
recurrence: clinical N2 or N3 disease, lymphovascular space invasion, a multifocal
or break-up pattern of residual disease, and residual disease larger than 2 cm.
Patients with three or more factors had very high rates of recurrence (5-year rate of
18%), and may have been better served by undergoing a completion mastectomy.
In aggregate, the available data concerning breast conservation after preoperative
chemotherapy suggests that this treatment approach can be performed successfully
for selected patients, who initially would have required mastectomy. However,
careful selection criteria are necessary, and the treatment complexity necessitates a
careful coordination among multidisciplinary team members. The primary tumor
location should be marked early in the course of preoperative chemotherapy to
ensure that the tumor bed can be localized at the time of surgery in cases of complete clinical and radiologic response. Radiographic evaluation and biopsy of suspicious areas, before chemotherapy initiation, are required, and restaging of the disease should be performed before the surgical procedure. Breast-conserving surgery
should be limited to those cases in which the surgical procedure is able to achieve
clearly negative margins and should be followed by whole-breast irradiation in all
cases. Patients with inflammatory breast cancer should not be considered for
breast-conservation therapy if they are being treated with curative intent. In addition, patients who present with gross multicentric disease or diffuse calcifications
throughout the breast should undergo a mastectomy.
The increasing use of preoperative chemotherapy in patients with clinically
negative lymph nodes has created a controversy with respect to the timing of sentinel lymph node surgery.
A meta-analysis of 21 published studies that investigated 1,273 patients, who
underwent sentinel lymph node biopsy with subsequent axillary dissection after
preoperative chemotherapy, reported a pooled identification rate of 90% and a
false-negative rate of 12%, which were similar to the reported rate for sentinel node
biopsy before systemic therapy [36]. Whether sentinel node biopsy after neoadjuvant chemotherapy is accurate in patients, who present with clinically involved
axillary nodes before neoadjuvant chemotherapy, but convert to clinically nodenegative afterward remains controversial, and additional prospective data are needed before this approach can be considered a standard of care. However, in NSABP
B-27, the false-negative rate was not different for clinically node-positive patients
compared with clinically node-negative patients [37].
The sentinel node biopsy performed before starting chemotherapy allows a
more accurate assessment of the extent of disease; however, the delay of procedure
after chemotherapy provides some more relevant advantages. If chemotherapy
downstages the disease in the axillary nodes (as expected in up to 40% of patients
treated with an anthracycline-/taxane-based regimen), a patient, who would otherwise normally require an axillary dissection, might be treated with sentinel node
biopsy alone, thus decreasing surgical morbidity. In addition, with this approach,
most patients require only one surgical procedure rather than two. Furthermore, if
a component of nodal disease is removed before chemotherapy, then the prognos-
280
tic value of achieving a pCR (breast and axilla) is less certain. Finally, performing
surgery before chemotherapy delays the administration of systemic treatments, particularly if an axillary metastasis is found and the patient then undergoes pretreatment axillary dissection.
17.7
Conclusions
Several randomized trials have shown that in patients with operable breast cancer
neoadjuvant chemotherapy provides similar survival and higher breast-conservation rate in comparison with adjuvant treatment. Thus, this procedure can now be
offered as a valid treatment option to patients with operable breast cancer, irrespective of tumor size, when adjuvant chemotherapy is indicated. The combined preoperative administration of targeted agents and chemotherapy can substantially
improve prognosis in HER2 positive patients. A gentle neoadjuvant treatment,
consisting of hormone therapy alone can be indicated in some HR-positive patients.
Important goals for the future are to identify biomarkers whose early changes can
predict both pathologic response and long-term outcome, in order to tailor neoadjuvant treatment, so obtaining an optimal therapeutic result at the lowest possible
toxicity. In conclusion, the neoadjuvant setting gives the unique opportunity to get
insights in breast cancer biology and to evaluate not only new therapies but to find
predictive factors for better individualization of the treatment.
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Afterword
At forty-two years old, in the fullness of a life rich in commitments and interests,
I felt a strange sensation at the side of my breast and, instantly, I became aware that
something odd had taken form. Quickly, there were the examinations (mammography, ultrasound), the first visit to a senologist and, thus, began my parenthetic life
with a new travel companion: cancer.
I wasnt new to the disease, Id seen it in my family with my father and had
already viewed it from every perspective, from the drama of its discovery, to the
faith in surgical interventions, to the rekindling of hope with every improvement
in the general prognosis during chemotherapy, up to its most devastating epilogue,
when, in its terminal phase, no further actions are possible, no therapy practicable,
but only the containment of pain brought on by the free rein of metastasis
Now, I find myself living through this in first person, with a less ominous prognosis than my father, yet still quite serious because of a particularly aggressive
form of the cancer, my age and the burden of having to irreparably mar that part of
my body that I had always held as a most beautiful gift that mother nature had ever
bestowed upon me.
Speaking with other women, I discovered that, for many, the disease was an
occasion to esthetically change a part of themselves with which they were less than
satisfied. But for someone who already has lovely breasts, having to operate on
them is an added violence of the disease, finding oneself obliged to undo an intimate part of oneself and accept the subsequent handicap, in as much as one can
rationally relegate the situation to dealing with just a part of the body that needs
repair, deep down, its not so easy to adjust.
Of all the sensations that could have run through me, I would never have imagined that the disease could have been transformed into an extraordinary force,
capable of overcoming every physical difficulty, turning an undeniably difficult
period into the most dynamic, the most intense, the height of my existence.
E.F.
Updates in Surgery
DOI: 10.1007/978-88-470-5438-7, Springer-Verlag Italia 2014
May 2013
283

Oncologic Breast Surgery (2014) Veronesi Italia 290 Str.

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Updates in Surgery

Oncologic Breast Surgery

ISBN 978-88-470-5438-7 (eBook)

Springer-Verlag Italia S.r.l. Via Decembrio 28 I-20137 Milan

Surgical treatment of malignant diseases of the breast represents an exemplary

Thanks to my everyday coworkers Gabriele Bianchelli, Enrico Lenti, and

Part I - Preliminary Remarks on Modern Surgical Treatment

2 The Pathology of Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3 The Breast Unit and the Organization of Health Care . . . . . . . . . . .

Part II - Conservative Program

6 Sentinel Node Biopsy and Axillary Dissection . . . . . . . . . . . . . . . . . . 101

8 Radioguided Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

Breast Cancer in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

12 Locally Advanced Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

Massimiliano DAiuto Department of Senology, Breast Surgery Unit, Istituto

Guglielmo Miconi Department of General Surgery, Breast Unit, Fano Hospital,

Instrumental and Interventional

1 Instrumental and Interventional Diagnostics

The method of sampling for cytological examination is relatively simple although

Cytological Diagnostic Conclusions

Inadequate for diagnosis - the cause shall be indicated (little or no cellularity,

1 Instrumental and Interventional Diagnostics

(complicated cysts, papillomatous lesions) [12], or localized in particularly difficult

Percutaneous biopsy (PB), performed by US or stereotactic guide needle size

1 Instrumental and Interventional Diagnostics

US-guided Breast Biopsy

1 Instrumental and Interventional Diagnostics

Stereotactic Breast Biopsy

1 Instrumental and Interventional Diagnostics

MR Guided Breast Biopsy

As magnetic resonance became the imaging technique of choice in senology, due

1 Instrumental and Interventional Diagnostics

Sample Handling for the Pathologist

1 Instrumental and Interventional Diagnostics

Complications like hematoma, vagal crisis and sporadic pneumothorax may

1 Instrumental and Interventional Diagnostics

During surgery a gamma radiation absorbing probe (gammaprobe) is used,

Zuiani C et al (2004) Biopsie citologiche. Radiol Med 107:4752

1 Instrumental and Interventional Diagnostics

The Pathology of Breast Cancer

Proliferative Epithelial Lesions of the Breast:

The main proliferative epithelial breast lesions can be schematically subdivided in

Ductal Hyperplasia (Usual and Atypical) and Columnar Cell

2 The Pathology of Breast Cancer

Atypical Lobular Hyperplasia and Classic Lobular

In Situ Ductal and Lobular Carcinoma of the Breast

Ductal Carcinoma in Situ

DCIS is a neoplastic, malignant proliferation of epithelial cells confined to the

2 The Pathology of Breast Cancer

ductal-lobular system, without evidence of stromal invasion. It accounts for

Some prognostic and predictive factors seem to be important to help to guide

2 The Pathology of Breast Cancer

tors, over-express HER2 and harbor HER2 gene amplification, occasionally

Lobular Carcinoma in Situ

cLCIS is discussed in Section 2.2.5. Pleomorphic lobular carcinoma in situ (pLCIS)

2 The Pathology of Breast Cancer

Invasive Breast Carcinoma: Histological Classification

NST Carcinoma (Ductal Carcinoma NST)

Invasive lobular carcinoma

Classic lobular carcinoma

Carcinoma with aprocrine differentiation

Low-grade adenosquamous carcinoma

2 The Pathology of Breast Cancer

Mucinous carcinoma is more frequent in postmenopausal women, with a mean age