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(BQ) Part 1 book “Breast cancer management for surgeons” has contents: Gross anatomy of the breast and axilla, breast cancer epidemiology, hereditary breast cancer genetics and risk prediction techniques, screening for high-familial- risk women, ductal carcinoma in situ,… and other contents.
Lynda Wyld · Christos Markopoulos Marjut Leidenius · Elżbieta Senkus-Konefka Editors Breast Cancer Management for Surgeons A European Multidisciplinary Textbook 123 Breast Cancer Management for Surgeons Lynda Wyld Christos Markopoulos Marjut Leidenius Elżbieta Senkus-Konefka Editors Breast Cancer Management for Surgeons A European Multidisciplinary Textbook Editors Lynda Wyld The Medical School Department of Oncology University of Sheffield Sheffield, United Kingdom Christos Markopoulos Athens University Medical School Athens, Greece Marjut Leidenius Helsinki University Hospital Helsinki, Finland Elżbieta Senkus-Konefka Department of Oncology & Radiotherapy Gdańsk Medical University Department of Oncology & Radiotherapy Gdańsk, Poland ISBN 978-3-319-56671-9 ISBN 978-3-319-56673-3 (eBook) https://doi.org/10.1007/978-3-319-56673-3 Library of Congress Control Number: 2017959196 © Springer International Publishing AG 2018 This work is subject to copyright All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed The use of general descriptive names, registered names, trademarks, service marks, etc in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Printed on acid-free paper This Springer imprint is published by Springer Nature The registered company is Springer International Publishing AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland V Foreword Foreword by: Professor Vassilios Papalois Imperial College Healthcare NHS Trust, London, UK Secretary General of the European Union of Medical Specialist (UEMS) It is a great honour to offer this forward for this world class textbook for the multidisciplinary management of breast cancer for surgeons I will first address with great pleasure the fact that this is a European textbook reflecting the widely known and well respected experience and expertise of Colleagues across Europe with whom I had the real privilege to work closely when I was President of the Section of Surgery of the Union of European Medical Specialists (UEMS) and over the last two years as UEMS Secretary General The UEMS is an organisation with almost 60 years of history, representing, through their National Medical Associations, 39 Countries in the EU and beyond, a total of 1.6 million medical specialists The UEMS work on the ground is being done by 43 Specialist Sections that also collaborate though 15 Multidisciplinary Joint Committees for areas of practice which are of interest to more than one Section The UEMS prides itself for being an organisation that develops real projects for real people in real life! The development of the UEMS European Training Requirements (ETRs) and Exams are two flagship projects for the UEMS. The ETRs and the Exams are developed by the UEMS Sections in close collaboration with the relevant European Scientific Societies This is being done through a truly wide and in depth consultation across Europe that embraces Universities, Scientific Societies and Professional Colleges and Associations; the final product has the review and approval of the National Medical Associations represented in the UEMS. I cannot really think of a more robust process for developing such quality control projects as the UEMS ETRs and Exams aiming to advance and harmonise specialist practice in Europe that will of course translate into top class clinical care for patients The Divisions of Breast Surgery of the Section of Surgery of the UEMS has been one of the most active and productive players in the field of UEMS ETRs and Exams They have also gone one step further and they have produced superb educational material in support of Colleagues across Europe who wish to ensure that their knowledge is up to speed and meets the standards of the UEMS ETRs and are also robustly prepared to apply for the relevant UEMS Exams The superb textbook that you have in your hands is testimony to this great effort I truly enjoyed reading each chapter that is written most clearly and elegantly and addresses all elements of modern practice: evidence based approach, multidisciplinary/ team work, state of the art experience, expertise and clinical pathways as well as constructive use of technology I was particularly impressed by the fact that the textbook combines scientific accuracy and robustness with the authors’ genuine interest and truly humane approach for the patients The textbook is inspired by the Hippocratic (and pan-European!) values of medical humanism I believe that Colleagues of all specialties and ranks who are actively involved in breast cancer treatment will find this textbook a powerful ally and compelling navigator that will guide them through the complexities of this ever evolving area of multidisciplinary practice that affects the lives of millions of patients around the world Congratulations and Kudos to the Editors and the Authors! Enjoy sailing through its pages! Preface from the UEMS – EBS – Division of Breast Surgery A few years ago, EUSOMA (the European Society of Breast Cancer Specialists) published a position paper on “Guidelines on the standards for the training of specialized health professionals dealing with breast cancer” Theoretical and practical requirements for the training of a “breast surgeon” were described in detail, as well as an assessment strategy – specialist exams – on how a candidate could be qualified as a “specialist in breast surgery” Following that, the UEMS (European Union of Medical Specialists) expressed its support for proposals in the guidelines, and as a result, the breast surgery working group was established in the UEMS Section of Surgery, and the breast surgery examination was launched in 2010 The exam is part of the series of professional examinations offered by the European Board of Surgery (EBS) and results in the award of a European Board of Surgery Qualification (EBSQ) in breast surgery examination Graduates of the exam may use the post-nominal FEBS or Fellow of the European Board of Surgery Considering the recognized success of the project, the UEMS proceeded in 2015 to officially upgrade the breast surgery working group to a full division within the European Board of Surgery, the Division of Breast Surgery, recognizing its status as an increasingly important specialist group of surgeons The EBSQ in breast surgery exam is organized twice per year, and respected and recognized breast surgeons from all over Europe are invited to act as examiners In our common effort to improve the quality of health services for breast cancer patients across Europe, we strongly believe that the EBSQ exams play an important role A breast surgeon holding an EBSQ diploma has official recognition that she/he meets EBSQ application requirements with regard to specialist education, training and experience and has up-to-date knowledge of breast cancer management This textbook, written by European-based breast cancer specialists from all management disciplines involved in modern breast cancer care, will serve as the syllabus for the EBSQ in breast surgery exam Breast surgeons have a leading role in the management of patients with breast cancer, and all current necessary knowledge for evidence- based breast cancer management is included in its chapters Furthermore, this textbook will also serve as a helpful reference tool in everyday practice for everyone involved in the care of breast cancer patients On behalf of the UEMS-EBS-Division of Breast Surgery, I would like to express my deep appreciation to the editors and co-authors of the book for all their efforts and to Springer for this great edition Professor Christos J. Markopoulos President of the Division of Breast Surgery at the Section of Surgery of the UEMS-EBS VII Preface from the European Society of Surgical Oncology Half a million women develop breast cancer, and 100,000 women die of the disease each year in Europe This represents a massive health burden but one where outcomes are steadily improving Outcomes continue to vary widely across Europe due to differences in early detection and wide variance in therapy schedules Breast cancer surgeons play a leading role in the delivery of care to women with breast cancer, and over 60% of breast cancers are cured by surgery alone However, the increasingly complex treatment schedules require that surgeons have in-depth knowledge of evidence-based multidisciplinary practice Harmonization of outcomes across Europe requires education, training and quality assurance Specialist breast units are being set up across Europe as per European Parliament resolutions and European guidelines for quality assurance A programme of breast unit quality assurance is in progress in the EU at the moment This critically important action, implemented by the European Union, would be entirely useless if there was no quality assurance of surgical management and training in breast surgery ESSO (the European Society of Surgical Oncology) is committed to this task Numerous courses and masterclasses have been organized, specialists have set up a network to facilitate training across Europe, grants are available to train young breast surgeons, and the UEMS examination is solidly in place to certify competence and multidisciplinary understanding This textbook summarizes the expected knowledge which any breast cancer surgeon has to possess in order to pass the exam I congratulate the editors and all contributors to this ambitious editorial and educational project; it is here to reassure all breast cancer patients that they will receive the best management possible today and to lay the foundations for future research Professor Riccardo A. Audisio Immediate Past President of ESSO IX Contents I Basic Science Gross Anatomy of the Breast and Axilla Peter Palhazi 2 Physiology and Developmental Stages of the Breast 11 Theodore G Troupis, Adamantios Michalinos, George Skandalakis, and Panayiotis Skandalakis Breast Cancer Epidemiology 19 R.M Parks, M.G.M Derks, E Bastiaannet, and K.L Cheung 4 Effect of Oestrogen Exposure, Obesity, Exercise and Diet on Breast Cancer Risk 31 Eleni Th Petridou, Marios K Georgakis, and Constantine N Antonopoulos 5 Hereditary Breast Cancer Genetics and Risk Prediction Techniques 43 Helena Carley and Anju Kulkarni II Screening, High Risk Lesions, and Risk Management Screening for High-Familial-Risk Women 59 Athina Vourtsis Risk-Reducing Breast and Ovarian Surgery for Women at High Familial Risk 69 Inkeri Schultz and Kerstin Sandelin 8 The Role of Breast Cancer Chemoprevention in High-Risk Women 79 Lynda Wyld Molecular Profiling of Breast Cancer and DCIS 89 Christos Markopoulos 10 Pathology of High-Risk Breast Lesions 103 Sarah E Pinder and Abeer M Shaaban 11 Ductal Carcinoma in Situ 115 Stacey A Carter, Sarah E Pinder, and Alastair M Thompson 12 Imaging of the Breast 127 Petra Steyerova 13 Breast Cancer Screening 147 John Mathew and Mark Sibbering III Early Breast Cancer: Diagnosis and Management 14 Clinical Presentation, Diagnosis and Staging of Breast Cancer 159 Janez Zgajnar X Contents 15 Pathology of Breast Cancer 177 Frederique Penault-Llorca and Nina Radosevic-Robin 16 The Breast and Oncoplastic Multidisciplinary Team 193 Fiona MacNeill, Marios Konstantinos Tasoulis, and Melissa Ley Hui Tan 17 Surgery to the Breast: Mastectomy 203 Petros Charalampoudis and Tibor Kovacs 18 Surgery to the Breast: Breast Conservation Techniques 213 Marjut Leidenius 19 Oncoplastic Breast-Conserving Therapy 229 Elias E Sanidas and Florian Fitzal 20 Fat Transfer in Oncoplastic and Reconstructive Breast Surgery 245 Riccardo Bonomi, I Fabio Rapisarda, Gilles Toussoun, and Loraine Kalra 21 Breast Surgery after Primary Systemic Treatment 255 Thorsten Kuehn 22 Surgery for Locally Recurrent Breast Cancer 263 Roberto Agresti, Andrea Spano, Giulia Bianchi, and Giovanna Trecate 23 Management of the Axilla: Sentinel Lymph Node Biopsy 275 Leif Bergkvist and Jan Frisell 24 Axillary Node Clearance 285 Tuomo J Meretoja 25 Axillary Management in the Neoadjuvant Setting 291 K Wimmer, F Fitzal, R Exner, and M Gnant 26 Axillary Reverse Mapping: ARM 303 Isabel T Rubio, Ernest J.T Luiten, and V Suzanne Klimberg IV Reconstructive Surgery 27 Immediate Reconstruction: General and Oncological Considerations 315 Maria João Cardoso and Giuseppe Catanuto 28 Delayed Breast Reconstruction: General and Oncological Considerations 325 Zoltán Mátrai 29 Breast Implants: Design, Safety and Indications for Use 355 Jana de Boniface and Inkeri Schultz 30 Specific Implant-Based Techniques for Breast Reconstruction 365 Lorna J Cook and Michael Douek 31 Specific Autologous Flap Techniques 381 Sinikka Suominen and Maija Kolehmainen XI Contents 32 Goldilocks Procedure 393 Fiona MacNeill 33 Nipple Reconstruction 401 Valentina Lefemine and Kelvin F Gomez 34 Complications of Breast Surgery and Their Management 411 Michalis Kontos and Christos Markopoulos V Adjuvant Therapy for Early Breast Cancer 35 Adjuvant Endocrine Therapy 427 Manuela Rabaglio and Monica Castiglione 36 Adjuvant Chemotherapy 439 Giuseppe Curigliano, Angela Esposito, and Carmen Criscitiello 37 Adjuvant Molecular Therapies in Breast Cancer 447 A Prove, L.-A Teuwen, and L Dirix 38 Primary Systemic Therapy for Breast Cancer 453 Cornelia Liedtke and Hans-Christian Kolberg 39 Radiotherapy for Breast Cancer 463 Barbara Alicja Jereczek-Fossa, Maria Cristina Leonardi, and Samantha Dicuonzo VI Breast Cancer in Special Groups 40 Breast Cancer in Special Groups: Young Women with Early Breast Cancer 487 Rossella Graffeo and Olivia Pagani 41 Hereditary Breast Cancer 499 Teresa Ramón y Cajal, Anna Virgili, and Nuria Dueñas 42 Breast Cancer in Special Groups: Breast Cancer in Pregnancy 511 Matteo Lambertini, Hatem A Azim Jr, and Fedro Alessandro Peccatori 43 Fertility Preservation in Women with Breast Cancer 521 Anna Rachelle Mislang, Matteo Lambertini, and Laura Biganzoli 44 Breast Cancer in Older Patients 529 Anne Shrestha and Lynda Wyld 45 Breast Cancer in the Male Patient 541 M Umit Ugurlu and Bahadir M Gulluoglu 46 Sarcoma of the Breast 551 Erkki Tukiainen and Andrew Lindford 47 Desmoid (Aggressive) Fibromatosis of the Breast 559 Nicholas C Eastley, Jaroslaw Krupa, and Robert U Ashford 297 Axillary Management in the Neoadjuvant Setting A secondary endpoint of the ACOSOG Z1071 (Alliance) trial was to determine the impact of axillary ultrasound (AUS) after PST. Patients with a suspicious US result after PST had significantly more often a SLN metastasis and had a greater number of positive lymph nodes and a greater size of the metastasis than those with normal US findings Additionally, a reduction of the FNR from 12.6% to 9.8% could be found in those patients with a normal AUS after PST and at least two removed SLNs On the basis of these findings, axillary US after PST allows selection of patients with the greatest likelihood to benefit from the omission of ALND [39] and should be considered a standard procedure Moorman and colleagues stated that AUS is an accurate staging tool in the preoperative setting when it is combined with fine-needle aspiration cytology A sensitivity and specificity of 42.4% and 97.1%, respectively, were achieved in this study population including 1,124 patients In 18.9%, a false- negative US result was found Patients with false-negative US findings were significantly younger and more frequently had oestrogen-receptor-positive tumours, larger tumours and lymphovascular invasion The sensitivity of AUS and fine- needle aspiration cytology increased with an increasing number of lymph node metastases In conclusion, AUS in combination with cytology has a greater sensitivity in patients with more than three lymph node metastases, whereas in younger patients with larger and oestrogen-receptor-positive tumours, higher false-negative rates must be expected [40] The Z0011 trial also addressed the question of whether US is still an appropriate tool for staging of the axilla In total 679 patients underwent AUS, and in cases with a suspicious US, lymph nodes were biopsied Patients with a negative AUS underwent SLNB. They reported a sensitivity of 86.2%, a specificity of 100%, a positive predictive value of 100% and a negative predictive value of 71.9% for AUS with sampling of suspicious nodes and concluded that AUS is an important guiding tool for the management of the axilla in patients with breast cancer [41] Schipper and colleagues investigated whether AUS accurately predicts pN0, pN1 and pN2–3 status In patients with a negative AUS (cN0), a NPV of 95.5% could be achieved, whereas in patients with one to three suspicious nodes (cN1), a NPV of 58.5% was described In conclusion, a negative AUS can generally exclude pN2/pN3 disease, though it cannot accurately differentiate between pN1 and pN2–3 [42] The predictive value of a negative AUS was evaluated by Jackson and colleagues It was reported that the combination of normal findings on physical examination and a negative AUS could reliably exclude patients with “heavy” nodal disease The sensitivity and specificity for AUS to predict three or more lymph node metastases were 71% and 83%, respectively [43] Figure 25.2 demonstrates the conversion from radiologically node-positive to node-negative disease during PST The diagnostic abilities of 18F-FDG PET/CT compared to those of US and MRI were evaluated by An and colleagues Before PST After PST Date 07.04.2016 11.10.2016 Size 16.4 mm 8.7 mm Fig. 25.2 Initial radiologically node-positive disease converting to node negative under the influence of PST (Source: Department of Diagnostic and Interventional Radiology, Hospital Barmherzige Schwestern, Linz, Austria, by Courtesy of Maria Miesbauer, MD) 25 298 K Wimmer et al 25 Fig. 25.3 An 18F-FDG-positive lymph node in PET-CT prior to PST (Source: Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Austria) The PPV and the NPV were 66.7% and 81.6% for US, 65.9% and 79.2% for MRI and 77.6% and 79.1% for 18F-FDG PET/ CT. Among the imaging modalities, no significant differences in diagnostic ability could be observed However, combining 18F-FDG PET/CT with US or MRI could improve the diagnostic ability compared to 18F-FDG PET/CT alone [44], while it has to be admitted that PET-CT may not be available in most centres for this purpose Figure 25.3 shows an image of an 18F-FDG-positive lymph node in PET-CT prior to PST To summarize, 18F-FDG PET/CT and/or AUS combined with fine-needle aspiration or core biopsy represent the methods with the highest PPV for diagnosis of metastatic lymph node involvement For confirmation of node-negative disease, AUS is – with its high NPV – an accurate alternative to more invasive staging procedures Clinical assessment alone is often associated with high error rates 25.8 Adjuvant Radiotherapy The increasing number of patients undergoing PST and the higher rates of axillary pCR make it necessary to consider how to optimize locoregional treatment after PST. The role of radiotherapy to the nodal basins in the neoadjuvant setting remains unclear The effect of radiotherapy on survival if axillary pCR is achieved after PST is questionable, and further evaluation is needed The DEGRO practical guidelines 2014 stated that in patients who converted from clinical node-positive to ypN0 disease after PST, the decision for regional nodal irradiation should depend on the pre- neoadjuvant stage, irrespective of the response to chemotherapy [45] If no remnant tumour cells are expected, the disadvantages of RT might outweigh its benefits In contrast, if ALND could be omitted in patients who convert from node positive to node negative, axillary radiotherapy might play an important role in adjuvant axillary treatment In the non-neoadjuvant setting, the AMAROS trial showed that axillary radiotherapy can achieve equal locoregional control with a lower morbidity than ALND in patients with a positive SLNB [46] – however, the trial was criticized for poor results in the surgery arm (wound infections, frequency of level III dissections) The ongoing NSABP B-51 trial may more accurately answer some of the remaining questions This trial plans to evaluate the effect of radiotherapy on axillary lymph node basins in patients who convert from node positive to node negative after PST Another study may provide insights into potential treatment strategies in patients with lymph node metastases who not convert following PST. The Alliance A11202 trial will randomize patients with histologically proven remaining SLN metastasis after PST to either ALND and additional chest wall and nodal RT or chest wall and nodal RT alone 25.9 Conclusion The controversy about the feasibility and accuracy of SLNB after PST is currently ongoing Evidence to date suggests that SLNB is a useful staging tool in patients with clinically node- negative disease, both prior and after PST. In patients who convert from node-positive to node-negative disease, SLNB should be scheduled after PST, even if the detection of the SLN is more difficult and associated with higher FNRs than if performed before PST. The most important advantage of this sequence is the potential to safely avoid ALND in cases where the SLNB is negative due to pCR. To achieve a lower FNR, at least three SLNs should be removed; the use of dual-tracer mapping and immunohistochemistry are mandatory to increase the accuracy of the SLN surgery For patients with node-positive disease after PST, ALND continues to be the best surgical approach although “definitive” radiotherapy forges ahead as a locoregional treatment alternative The recommended surgical management of the axilla in the neoadjuvant setting is illustrated by a flowchart in Fig. 25.4 299 Axillary Management in the Neoadjuvant Setting Fig. 25.4 Axillary management in the neoadjuvant setting Clinically node-positive (cN1 or cN2) Clinically node-negative (cN0) Neoadjuvant chemotherapy ycN0 ycN1 SLNB ALND Remove at least SLNs Use dual tracer mapping place Clip in initial cN1 node References Gradishar WJ, Anderson BO, Balassanian R, Blair SL, Burstein HJ, Cyr A, et al Breast cancer, version 1.2016 J Natl Compr Cancer Netw JNCCN 2015;13(12):1475–85 Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, et al The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27 J Clin Oncol Off J Am Soc Clin Oncol 2003;21(22):4165–74 van der Hage JA, van de Velde CJ, Julien JP, Tubiana-Hulin M, Vandervelden C, Duchateau L. 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J Am Coll Surg 2005;200(1):10–4 39 Boughey JC, Ballman KV, Hunt KK, McCall LM, Mittendorf EA, Ahrendt GM, et al Axillary ultrasound after Neoadjuvant chemotherapy and its impact on sentinel lymph node surgery: results from the American College of Surgeons Oncology group Z1071 trial (Alliance) J Clin Oncol Off J Am Soc Clin Oncol 2015;33(30): 3386–93 40 Moorman AM, Bourez RL, de Leeuw DM, Kouwenhoven EA. Pre- operative Ultrasonographic evaluation of axillary lymph nodes in breast cancer patients: for which group still of additional value and in which group cause for special attention? Ultrasound Med Biol 2015;41(11):2842–8 41 Farrell TP, Adams NC, Stenson M, Carroll PA, Griffin M, Connolly EM, et al The Z0011 trial: is this the end of axillary ultrasound in the pre-operative assessment of breast cancer patients? Eur Radiol 2015;25(9):2682–7 42 Schipper RJ, van Roozendaal LM, de Vries B, Pijnappel RM, Beets-Tan RG, Lobbes MB, et al Axillary ultrasound for preoperative nodal stag- 301 Axillary Management in the Neoadjuvant Setting ing in breast cancer patients: is it of added value? Breast 2013;22(6): 1108–13 43 Jackson RS, Mylander C, Rosman M, Andrade R, Sawyer K, Sanders T, et al Normal axillary ultrasound excludes heavy nodal disease burden in patients with breast cancer Ann Surg Oncol 2015;22(10):3289–95 44 An YS, Lee DH, Yoon JK, Lee SJ, Kim TH, Kang DK, et al Diagnostic performance of 18F-FDG PET/CT, ultrasonography and MRI. Detection of axillary lymph node metastasis in breast cancer patients Nuklearmedizin Nucl Med 2014;53(3):89–94 45 Sautter-Bihl ML, Sedlmayer F, Budach W, Dunst J, Feyer P, Fietkau R, et al DEGRO practical guidelines: radiotherapy of breast cancer III-radiotherapy of the lymphatic pathways Strahlenther Onkol Organ der Deutschen Rontgengesellschaft [et al] 2014;190(4):342–51 46 Donker M, van Tienhoven G, Straver ME, Meijnen P, van de Velde CJ, Mansel RE, et al Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase non-inferiority trial Lancet Oncol 2014;15(12):1303–10 25 303 Axillary Reverse Mapping: ARM Isabel T. Rubio, Ernest J.T. Luiten, and V. Suzanne Klimberg 26.1 Introduction – 304 26.1.1 Lymphatic’s Pathways – 304 26.2 Description of the ARM Technique – 304 26.2.1 ARM Node Location – 305 26.2.2 Identification of ARM Lymphatics and Nodes During SLNB and ALND – 306 26.2.3 Crossover – 306 26.3 Metastatic Involvement of ARM Nodes – 307 26.3.1 Involvement of ARM Node in Patients Undergoing SLNB – 307 26.3.2 Involvement of ARM Nodes in the Pathologically Positive Axilla – 307 26.3.3 Involvement of ARM Nodes in Patients with a Positive SLN and ALND – 307 26.3.4 Involvement of ARM Nodes in the Neoadjuvant Setting – 309 26.4 The Impact of ARM on Lymphoedema Rates – 309 26.4.1 Oncological Safety of Preserving ARM Nodes – 309 26.5 Other Techniques to Reduce Lymphoedema – 311 26.5.1 Microvascular Anastomosis – 311 26.6 Conclusion – 311 References – 311 © Springer International Publishing AG 2018 L Wyld et al (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_26 26 26 304 I.T Rubio et al 26.1 Introduction Despite improvements in the last two decades in the management of breast cancer, axillary lymph node dissection (ALND) remains a common surgical intervention for some women with clinically involved nodes or positive sentinel nodes (see Chap 24 for a detailed review of indications) One of the most functionally debilitating morbidities from ALND is lymphoedema [1] Axillary dissection is associated with a more than threefold increased risk of lymphoedema compared with no dissection Lymphoedema has been reported to develop from 7% to 77% of patients although the true incidence is uncertain due to wide variations in measurement techniques and diagnostic criteria When ALND is combined with radiation therapy (RT), lymphoedema rates are higher than with ALND alone and are reported to range from 30% to 50% [2] Studies have shown that an increased risk of lymphoedema following breast cancer treatment may be related to mastectomy (rather than lumpectomy), axillary dissection, radiotherapy, chemotherapy and lymph node status Lymphoedema is known to have detrimental effects on quality of life due to body image changes, alterations in arm function and increased complications such as infection and cellulitis [3, 4] With the incorporation of sentinel lymph node biopsy (SLNB) into routine protocols for staging of the clinically uninvolved axilla, rates of lymphoedema have decreased, although lymphedema has not been avoided completely In most studies, rates of lymphoedema after SLN are significantly lower when compared to ALND (20%, respectively) [5, 6] Even in those patients with a positive SLN biopsy who undergo RT, the 2-year cumulative incidence of lymphoedema was 10%, compared with 19% for ALND without RT and 30% for ALND with RT as it has been shown in the study by Miller and colleagues [7] So although the rate of lymphoedema is much less with the use of SLNB, it remains clinically significant (range, 0–13%), and in the randomized National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-32, lymphoedema in the SLNB group was found to be 8% at 36 months [8] Measures to reduce damage to the lymphatic drainage to the arm during both procedures are therefore highly desirable 26.1.1 Lymphatic’s Pathways ALND has been described as the removal of level I and II axillary nodes, and this dissection is done following anatomical boundaries The findings from multiple studies support the common belief that only treatments which disrupt the flow of lymph through the axilla will lead to the development of lymphoedema This disruption can happen during ALND or, to a lesser extent, SLNB Suami and colleagues [9] described the gross lymphatic anatomy of the lymphatic drainage and lymph node connections in the arm using a radiologic technique which involved injecting hydrogen peroxide into the fingertips of cadavers to identify lymphatic vessels in the arm They found that the superficial lymphatic vessels course within the subcutaneous fat in close proximity to the main subcutaneous veins Most lymph vessels from the hand and the forearm always flow into the lymph nodes in the axillary region Some go above the axillary vein and/or directly into the subclavian vein They showed that in the axilla, more than one lymph node was always detected that received lymph channels from the upper limb, although it appeared that the major lymphatic drainage from the upper limb is usually to one lymph node Nevertheless this main or dominant lymph node connects with other lymph nodes situated more proximally in the axilla Subsequent to the publication of the axillary reverse mapping (ARM) procedure [10, 11], Pavlista and colleagues [12] used direct contrast lymphography of the lymphatic drainage of the upper extremity and demonstrated that it was fully separable from the lymphatic drainage of the chest and breast in an effort to find an explanation for lymphoedema after SLNB. They found that the first SLN image, which was usually localized most laterally in the axilla, was the one into which the afferent lymphatic drainage of the upper extremity flowed They also showed contrast media was not limited to flowing centrally towards higher nodes in a sequential manner but could drain into any of the axillary nodes including the sentinel nodes of the breast In another study, the same group [13] showed that a certain portion of lymph is fed into the caudal part of the axilla near to the sentinel nodes of the breast (24% of all cases) and, in five cases, even entered them directly The concordance of the sentinel node of the upper extremity and the sentinel nodes of the breast or their intimate vicinity is the probable cause of lymphoedema after SLN biopsy in breast cancer They assumed that any surgical intervention in the axilla may potentially result in the development of lymphoedema of the upper extremity, the severity of which is dependent upon the variability and location of damage to the lymphatics The potential to identify afferent lymphatics and nodes coming from the lymphatics draining the arm and to prevent damaging or removing them in order to prevent or reduce lymphoedema is the main concept underpinning the ARM technique 26.2 Description of the ARM Technique Two separate authors (Klimberg and colleagues [10] and Nos and colleagues [11]) simultaneously developed the concept that modification of the surgical procedure may prevent lymphoedema following axillary surgery The concept of ARM [10] described the split mapping of the drainage of the arm with blue dye and radioisotope from the breast to determine the existence of distinct SLNs for the arm and the breast and to assess the anatomical variation in these lymphatics and how much overlap there would be By mapping the lymph channels and nodes draining the arm, it is feasible to 305 Axillary Reverse Mapping: ARM Fig. 26.1 Split mapping of the drainage of the arm and the breast SLN and ARM node identify and preserve them ( Fig. 26.1) The preservation of these lymphatics should consequently prevent disruption of lymphatic drainage from the arm and resulting lymphoedema The concept of ARM must include this split mapping from the breast and the arm to determine when the ARM node is also the SLN and should be excised and remaining lymphatics re-approximated The original ARM technique [10, 11] was performed by injecting 1–5 mL of blue dye (isosulfan blue, patent blue or methylene blue) subcutaneously in the inner upper part of the ipsilateral arm The injection can be made subcutaneously or intradermally although the preferred technique is subcutaneous injection as there are rich lymphatics in this area and the drainage is rapid Also the time to visualization as well as the tattoo from the blue dye injection is less visible if injected in the upper inner volar surface of the arm versus the hand After injection, massage is performed in the area of injection, and the arm is elevated in order to facilitate drainage, similar to the injection of blue dye in the breast for SLNB [10, 11, 14–16] In the early reports, a time interval of at least 15 min between the injection and surgery was recommended [17], although from other reports, it seems that the arm massage and elevation are more important for drainage than the time interval since the injection [18] Other authors have not reported improved detection when massaging the arm [14] In patients undergoing SLNB and an ARM technique, it is crucial that technetium-99 (99Tc) is injected for SLN identification and blue dye for the ARM technique [10] The SLNB can be performed through a mastectomy incision or an incision in the axilla The ARM procedure always includes both radioactivity in the breast and blue dye in the arm because, in a small fraction of patients, the ARM node will also be the SLN from the breast [10, 19] In cases where the SLN is positive and a mastectomy is performed, the ALND can be completed through the same incision; otherwise, a separate axillary incision can be made For patients undergoing only ALND, other groups injected patients with 99Tc-labelled nanocolloid alone or combined with blue dye, into the back of the hand on the ipsilateral side or in the upper inner part of the arm [18, 20, 21] However, it must be emphasized that injecting into the arm only does not allow identification when the ARM node is also draining the breast and would be more likely to contain tumour cells Split mapping is recommended in all cases In those cases where an ALND is performed, an anatomic resection of levels I and II lymph nodes is completed, taking care to identify and preserve blue lymphatics [17–19, 22] One of the complications of the ARM technique has been the temporary blue tattooing at the injection site The tattoo fades away but may last from days to years [10, 23, 24] although usually after the first 6 months it is practically invisible [22] Other authors have used fluorescence imaging technique with subcutaneous injection of indocyanine green (ICG) in the upper inner arm to avoid the blue dye tattoo and to try to improve ARM node identification rates [25–29] The ICG is injected subdermally into the inner side of the wrist [27] or intradermally in the upper inner ipsilateral arm [26], and the doses used have varied between 0.1 and 1.0 mL [26–28] In 372 patients, ICG was used combined with blue dye: more than 2 h before surgery, 0.15 mL of ICG was subcutaneously injected into the interdigital area, and immediately before surgery, 1.5 mL of blue dye was subcutaneously injected in the upper third of the arm [28] The fluorescence signal flowing to the axilla from the upper extremity was detected using a near-infrared fluorescence imaging system as the wavelength is not visible to the naked eye One of the disadvantages of using an invisible tracer is that the lymphatic channels cannot be followed during surgery and therefore are more likely to be damaged which may increase lymphoedema rates In the study by Noguchi [29] using a fluorescence imaging system, the SLN was the same as the ARM node in 77 (27%) of 286 patients, and the mean number of removed ARM nodes was 7.2 (range 0–25) in patients who underwent ALND, whereas the mean number of SLNs removed was 1.6 (range 1–7) The clinical importance of the first ARM node or secondary ARM nodes in the lymphatic drainage of the arm is still unknown, but the chances of preserving the ARM node will decrease if the concordance rate between the SLN and the ARM node is higher However, preserving up to seven nodes while doing an ALND may impact on the oncological safety of the procedure 26.2.1 ARM Node Location The lymphatic pathway of the arm is usually described as crossing the lower part of the axilla below the axillary vein, although there is significant variability in reported studies Most studies have shown that the ARM blue node usually lies in the lateral pillar of the axillary dissection, lateral to the thoracodorsal bundle [14, 25, 30, 31] The most common pattern identified during SLN is the sling pattern, occurring in 26 306 I.T Rubio et al 26 Fig. 26.2 Axillary reverse mapping sling 71.4% of the cases as showed by Tummel and colleagues [32] ( Fig. 26.2) The ARM lymphatics have been described to be as low as 3–4 cm below the axillary vein, in the medial or lateral apron or even positioned above the vein, although less commonly [19, 22] The size of the ARM lymphatics is also variable, and they may be as large as 6 mm in diameter [23, 26] Boneti and colleagues reported that blue lymphatics draining from the arm were visible through the SLNB incision and were located near the field of the SLN in 42% of the 131 patients they reported This may explain why even with SLNB there are cases of lymphoedema [14] Regardless of the tracer used for the ARM technique, almost all of the ARM nodes are located in the same area, between the axillary vein and the second intercostobrachial nerve, lateral to the thoracodorsal bundle and close to the latissimus dorsi muscle or in the vicinity 26.2.2 I dentification of ARM Lymphatics and Nodes During SLNB and ALND Early studies describing the technique showed ARM identification rates of only 61% [10], but with more experience using the technique and increased knowledge of the variations in lymphatics, blue arm drainage identification increased to nearly all patients [31] Other studies have reported rates of ARM lymphatic and node identification rates of between 27% and 100% [15, 16, 23] In the meta-analysis by Han and colleagues [33] in eight studies, they found that the pooled results revealed an overall identification rate of 38.2% (95% CI 32.9–43.8%), with statistically significant heterogeneity (I2 = 70.5%, P 1 cm Boneti et al (2009) [14] 36 (L) 15 (N) 0/36 (0) 2/15a (13) N/A Water displacement method and clinical diagnoses An asymmetrical increase >20% from baseline or clinical diagnoses Boneti et al (2012) [31] 140 (N) 16 (L) 4/140 (2.9) 3/16 (18.7) 0.003 14.6 Water displacement method An asymmetrical increase >20% from baseline Han et al (2012) [16] 80 (N) 17 (N) 0/80 (0) 1/17 (5.9) N/A 9.6 Arm circumference As measurement change of >2 cm during follow-up Tausch et al (2013) [18] 61 (N) 55 (N) 14/61 (23) 22/55 (40) 0.046b 19 Water displacement method Difference in volume > 10% between two arms Gennaro et al (2013) [20] 45 (L) 15 (N) 4/45 (8.9) 5/15 (33.3) 0.035 16 Arm circumference, clinical diagnoses or comparative lymphoscintigraphy As measurement change of >2 cm during follow-up Ochoa et al (2014) [19] 120 (L) 22 (L) 4/120 (3.3) 1/22 (4.5) N/A 12 Water displacement method Volume increase of the affected side over the opposite side of >20% Ikeda et al (2014) [26] 19 (N) 57 (N) 5/19 (26) 19/57 (33) NS 24 Arm circumference A 2 cm increase at any level relative to the baseline or the healthy opposite arm Yue et al (2015) [21] 118 (N) 127 (N) 7/118 (5.9) 42/127 (33.1) 0.001 20 Arm circumference Difference between two arms increased >2 cm Pasko et al (2015) [43] 22 (N/A) 24c 6/22 (27) 12/24 (50) N/A N/A Questionnaire Patients identified themselves as suffering from LE Tummel et al (2016) [32] 103 50 5/72 33/154 N/A 26 Water displacement method Volume increase of the affected side over the opposite side of >20% ARM-P patients where ARM lymph nodes (N) or ARM lymphatics (L) were preserved, ARM-R patients where ARM lymph nodes (N) or ARM lymphatics (L) were removed or transected, LE upper extremity lymphoedema, N/A not applicable, NS not significant aOne patient had clinical diagnosis of lymphoedema but did not have arm volume checked bIn the multivariate logistic regression model, this correlation was not evident c24 patients underwent non-ARM procedure but a normal ALND 311 Axillary Reverse Mapping: ARM In summary, despite the small size of some of the studies, different measurement methods, short follow-up and/or different definitions of upper extremity lymphoedema, saving ARM lymph nodes and lymphatics may contribute to the reduction of upper extremity lymphoedema rates following axillary surgery for breast cancer Ongoing randomized multicentre trials (ALND with or without preservation of ARM lymph nodes and corresponding lymphatics in SLN+ patients) will further contribute to the debate about the value of these procedures [46] 26.5 Other Techniques to Reduce Lymphoedema 26.5.1 Microvascular Anastomosis In those cases where the ARM nodes need to be excised, other surgical options are available in order to try to decrease rates of lymphoedema Ochoa and colleagues [19] re- anastomosed the remaining afferent and efferent lymphatics by re-approximation of the transected ends of the lymphatic channels These transected lymphatics underwent end-to- end re-approximation by the operating breast surgeons using 6–0 to 9–0 prolene, dependent upon size [19, 32] Of the three patients in whom the blue lymphatics were re- anastomosed, there were no cases of lymphoedema Tummel and colleagues [32] from the same group reported that of the 15 (48.3%) patients in whom the blue lymphatics were re- anastomosed at the time of the SLNB and of the 18 (36%) patients at the time of ALND, there were no cases of lymphoedema Other studies have shown that lymphatic-venous microanastomoses using the lymphatic channels coming from the arm and one of the collateral branches of the axillary vein (named LYMPHA) may reduce lymphoedema when the ARM nodes are excised Casabona and colleagues [15] and Boccardo and colleagues [47] performed lymphatic-venous microanastomosis whenever the blue lymphatics and nodes are well seen In their series, in out of patients (88.9%), the procedure was performed At 6-month and 9-month followup, none of them had a diagnosis of lymphoedema Further studies with larger numbers of patients are warranted to fully evaluate whether these techniques are really effective in the prevention of lymphoedema 26.6 Conclusion Preservation of ARM lymph nodes and corresponding lymphatics is oncologically safe in patients scheduled for SLNB if ARM lymph nodes are not concordant with the SLN, as well as in SLN-positive breast cancer patients who are advised to undergo a complementary ALND. In case of clinical node- 26 positive disease, proper selection of patients scheduled for ALND and a combined ALND plus ARM should be considered Although still with only short-term follow-up, the ARM procedure has been shown to reduce the incidence of upper extremity lymphoedema without compromising oncological outcomes Longer-term follow-up of patients in whom the ARM nodes were preserved and a surgical refinement of combined ALND and the ARM technique will provide a real insight into the scope of this technique References DiSipio T, Rye S, Newman B, Hayes S. Incidence of unilateral arm lymphoedema after breast cancer: a systematic review and meta- analysis Lancet Oncol 2013;14(6):500 Tsai RJ, Dennis LK, Lynch CF, Snetselaar LG, Zamba GK, Scott-Conner C. The risk of developing arm lymphedema among breast cancer survivors: a meta-analysis of treatment factors Ann Surg Oncol 2009;16(7):1959–72 Ahmed RL, Prizment A, Lazovich D, Schmitz KH, Folsom AR. 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Postmenopausal Breast – 16 2.3 Conclusions – 16 References – 17 © Springer International Publishing AG 2 018 L Wyld et al (eds.), Breast Cancer Management for Surgeons, https://doi.org /10 .10 07/978-3- 319 -56673-3_2... Development – 12 2.2 .1 Prenatal Development – 12 2.2.2 Congenital Anomalies – 13 2.2.3 Infant Breast – 13 2.2.4 Peripubertal Breast – 14 2.2.5 Adult Breast, Pregnancy and Lactation – 14 2.2.6 The... of the Breast 12 7 Petra Steyerova 13 Breast Cancer Screening 14 7 John Mathew and Mark Sibbering III Early Breast Cancer: Diagnosis and Management 14 Clinical Presentation,