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  • 1. Previous volumes in this seriesKleihues P., Cavenee W.K. Hamilton S.R., Aaltonen L.A. Jaffe E.S., Harris N.L., Stein Fletcher C.D.M., Unni K.K.,(Eds.): (Eds.): H., Vardiman J.V. (Eds.): Mertens F. (Eds.):World Health Organization World Health Organization World Health Organization World Health OrganizationClassification of Tumours. Classification of Tumours. Classification of Tumours. Classification of Tumours.Pathology and Genetics of Pathology and Genetics of Pathology and Genetics of Pathology and Genetics ofTumours of the Nervous Tumours of the Digestive Tumours of Haematopoietic Tumours of Soft Tissue andSystem. System. and Lymphoid Tissues. Bone.IARC Press: Lyon 2000 IARC Press: Lyon 2000 IARC Press: Lyon 2001 IARC Press: Lyon 2002ISBN 92 83 22409 4 ISBN 92 83 22410 8 ISBN 92 83 22411 6 ISBN 92 832 2413 2This book and all other volumes of the series can be purchased from:International Agency for IARCPress IARCPressResearch on Cancer (IARC) 150 Cours Albert Thomas 1775 K Street, NW, Suite 480 69008 Lyon (France) Washington, DC 20006 (USA) Tel. +33 4 72 73 85 15 Toll-free order line: 877 WHO-IARC Fax +33 4 72 73 83 02 Fax (202) 223 1782 iarcpress@who.intWorld Health Organization (WHO) WHO Marketing and Dissemination WHO Publications Center 1211 Geneva (Switzerland) Albany, NY 12210 (USA) Tel. +41 22 791 2476 Tel. (518) 436 9686 Fax +41 22 791 4857 Fax (518) 436 7433 qcorp@compuserve.comOxford University Press (OUP) OUP Oxford (UK) Tel. +44 1536 454534 24 hr. Hotline: Tel. +44 1 536 74 17 27 Fax +44 1 865 26 77 82 Blue Books on the web:
  • 2. World Health Organization Classification of Tumours WHO OMS International Agency for Research on Cancer (IARC) Pathology and Genetics of Tumours of the Breast and Female Genital Organs Edited by Fattaneh A. Tavassoli Peter Devilee IARCPress Lyon, 2003
  • 3. World Health Organization Classification of Tumours Series Editors Paul Kleihues, M.D. Leslie H. Sobin, M.D.Pathology and Genetics of Tumours of the Breast and Female Genital Organs Editors Fattaneh A. Tavassoli, M.D. Peter Devilee, Ph.D. Coordinating Editors Lawrence M. Roth, M.D. Rosemary Millis, M.D. Editorial Assistants Isabelle Forcier Christine Zorian Layout Lauren A. Hunter Sibylle Söring Pascale Dia Illustrations Georges Mollon Lauren A. Hunter Printed by Druckhaus Tecklenborg 48565 Steinfurt, Germany Publisher IARCPress International Agency for Research on Cancer (IARC) 69008 Lyon, France
  • 4. This volume was produced in collaboration with the International Academy of Pathology (IAP)The WHO Classification of Tumours of the Breast and Female Genital Organspresented in this book reflects the views of Working Groups that convened for Editorial and Consensus Conferences in Lyon, France, January 12-16 and March 16-20, 2002. Members of the Working Groups are indicated in the List of Contributors on page 365 The Working Group on Gynaecological Tumours greatly appreciates the participation of, and guidance by Dr. Robert E. Scully, Harvard Medical School
  • 5. Published by IARC Press, International Agency for Research on Cancer, 150 cours Albert Thomas, F-69008 Lyon, France © International Agency for Research on Cancer, 2003 Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved. The International Agency for Research on Cancer welcomes requests for permission to reproduce or translate its publications, in part or in full. Requests for permission to reproduce figures or charts from this publication should be directed to the respective contributor (see section Source of Charts and Photographs). The designations used and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city, or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The authors alone are responsible for the views expressed in this publication. Enquiries should be addressed to the Communications Unit,International Agency for Research on Cancer, 69008 Lyon, France, which will provide the latest information on any changes made to the text and plans for new editions.Format for bibliographic citations:Tavassoli F.A., Devilee P. (Eds.): World Health Organization Classification ofTumours. Pathology and Genetics of Tumours of the Breastand Female Genital Organs. IARC Press: Lyon 2003IARC Library Cataloguing in Publication DataPathology and genetics of tumours of the breast and female genital organs / editors, Fattaneh A. Tavassoli, Peter Devilee. (World Health Organization classification of tumours ; 5) 1. Breast Neoplasms—genetics. 2. Breast Neoplasms—pathology 3. Genital Neoplasms, Female—genetics 4. Genital Neoplasms, Female—pathology I. Tavassoli, Fattaneh A. II. Devilee, Peter III. Series ISBN 92 832 2412 4 (NLM Classification W 1)
  • 6. Contents1 Tumours of the breast 9 3 Tumours of the fallopian tube and Invasive breast carcinoma 13 uterine ligaments 203 Invasive ductal carcinoma, NOS 19 Tumours of the fallopian tube 206 Invasive lobular carcinoma 23 Tumours of the uterine ligaments 212 Tubular carcinoma 26 Invasive cribriform carcinoma 27 4 Tumours of the uterine corpus 217 Medullary carcinoma 28 Epithelial tumours and related lesions 221 Mucin producing carcinomas 30 Endometrial carcinoma 221 Neuroendocrine tumours 32 Endometrial hyperplasia 228 Invasive papillary carcinoma 34 Endometrial polyp 230 Invasive micropapillary carcinoma 35 Mesenchymal tumours and related lesions 233 Apocrine carcinoma 36 Endometrial stromal and related tumours 233 Smooth muscle tumours 236 Metaplastic carcinomas 37 Other mesenchymal tumours 242 Lipid-rich carcinoma 41 Mixed epithelial and mesenchymal tumours 245 Secretory carcinoma 42 Gestational trophoblastic disease 250 Oncocytic carcinoma 43 Sex cord-like, neuroectodermal / neuroendocrine tumours, Adenoid cystic carcinoma 44 lymphomas and leukaemias 255 Acinic cell carcinoma 45 Secondary tumours of the uterine corpus 257 Glycogen-rich clear cell carcinoma 46 Sebaceous carcinoma 46 5 Tumours of the uterine cervix 259 Inflammatory carcinoma 47 Epithelial tumours 262 Bilateral breast carcinoma 48 Squamous tumours and precursors 266 Precursor lesions Glandular tumours and precursors 272 Lobular neoplasia 60 Uncommon carcinomas and neuroendocrine tumours 277 Intraductal proliferative lesions 63 Mesenchymal tumours 280 Microinvasive carcinoma 74 Mixed epithelial and mesenchymal tumours 284 Intraductal papillary neoplasms 76 Melanotic, germ cell, lymphoid and Benign epithelial lesions 81 secondary tumours of the cervix 287 Myoepithelial lesions 86 Mesenchymal tumours 89 6 Tumours of the vagina 291 Fibroepithelial tumours 99 Epithelial tumours 293 Tumours of the nipple 104 Squamous tumours 293 Malignant lymphoma and metastatic tumours 107 Glandular tumours 297 Tumours of the male breast 110 Tumours of skin appendage origin 324 Mesenchymal tumours 3022 Tumours of the ovary and peritoneum 113 Mixed epithelial and mesenchymal tumours 306 Melanotic, neuroectodermal, lymphoid and Surface epithelial-stromal tumours 117 secondary tumours 308 Serous tumours 119 Mucinous tumours 124 7 Tumours of the vulva 313 Endometrioid tumours 130 Epithelial tumours 316 Clear cell tumours 137 Squamous tumours 316 Transitional cell tumours 140 Glandular tumours 321 Squamous cell lesions 143 Mesenchymal tumours 326 Mixed epithelial tumours 144 Melanocytic tumours 331 Undifferentiated carcinomas 145 Germ cell, neuroectodermal, lymphoid and Sex cord-stromal tumours 146 secondary tumours 333 Granulosa-stromal cell tumours 146 8 Inherited tumour syndromes 335 Sertoli-stromal cell tumours 153 Familial aggregation of cancers of the breast and Mixed sex cord-stromal tumours 158 female genital organs 336 Steroid cell tumours 160 BRCA1 syndrome 338 Germ cell tumours 163 BRCA2 syndrome 346 Primitive germ cell tumours 163 Li-Fraumeni syndrome 351 Biphasic or triphasic teratomas 168 Cowden syndrome 355 Monodermal teratomas 171 Hereditary non-polyposis colon cancer (HNPCC) 358 Mixed germ cell-sex cord-stromal tumours 176 Ataxia telangiectasia syndrome 361 Tumours and related lesions of the rete ovarii 180 Miscellaneous tumours and tumour-like lesions 182 Contributors 365 Lymphomas and leukaemias 191 Source of charts and photographs 370 Secondary tumours of the ovary 193 References 372 Peritoneal tumours 197 Subject index 425
  • 7. CHAPTER 1 Tumours of the BreastCancer of the breast is one of the most common human neo-plasms, accounting for approximately one quarter of all can-cers in females. It is associated with the Western lifestyle, andincidence rates are, therefore, highest in countries withadvanced economies. Additional risk factors include earlymenarche and late childbirth. Breast cancer is further charac-terized by a marked genetic susceptibility. Early detection andadvances in treatment have begun to reduce mortality rates inseveral countries. Through the use of cDNA expression pro-files, it may become possible to predict clinical outcome in indi-vidual patients.The typing of invasive breast cancer and its histological vari-ants is well established. More difficult is the classification ofpre-invasive breast lesions which are now increasingly detect-ed by mammography. The WHO Working Group agreed thatmore clinical follow-up and genetic data are needed for a bet-ter understanding of the natural history of these lesions.
  • 8. WHO histological classification of tumours of the breast Epithelial tumours Adenomas Invasive ductal carcinoma, not otherwise specified 8500/3 Tubular adenoma 8211/0 Mixed type carcinoma Lactating adenoma 8204/0 Pleomorphic carcinoma 8022/3 Apocrine adenoma 8401/0 Carcinoma with osteoclastic giant cells 8035/3 Pleomorphic adenoma 8940/0 Carcinoma with choriocarcinomatous features Ductal adenoma 8503/0 Carcinoma with melanotic features Invasive lobular carcinoma 8520/3 Myoepithelial lesions Tubular carcinoma 8211/3 Myoepitheliosis Invasive cribriform carcinoma 8201/3 Adenomyoepithelial adenosis Medullary carcinoma 8510/3 Adenomyoepithelioma 8983/0 Mucinous carcinoma and other tumours with abundant mucin Malignant myoepithelioma 8982/3 Mucinous carcinoma 8480/3 Cystadenocarcinoma and columnar cell mucinous carcinoma 8480/3 Mesenchymal tumours Signet ring cell carcinoma 8490/3 Haemangioma 9120/0 Neuroendocrine tumours Angiomatosis Solid neuroendocrine carcinoma Haemangiopericytoma 9150/1 Atypical carcinoid tumour 8249/3 Pseudoangiomatous stromal hyperplasia Small cell / oat cell carcinoma 8041/3 Myofibroblastoma 8825/0 Large cell neuroendocrine carcinoma 8013/3 Fibromatosis (aggressive) 8821/1 Invasive papillary carcinoma 8503/3 Inflammatory myofibroblastic tumour 8825/1 Invasive micropapillary carcinoma 8507/3 Lipoma 8850/0 Apocrine carcinoma 8401/3 Angiolipoma 8861/0 Metaplastic carcinomas 8575/3 Granular cell tumour 9580/0 Pure epithelial metaplastic carcinomas 8575/3 Neurofibroma 9540/0 Squamous cell carcinoma 8070/3 Schwannoma 9560/0 Adenocarcinoma with spindle cell metaplasia 8572/3 Angiosarcoma 9120/3 Adenosquamous carcinoma 8560/3 Liposarcoma 8850/3 Mucoepidermoid carcinoma 8430/3 Rhabdomyosarcoma 8900/3 Mixed epithelial/mesenchymal metaplastic carcinomas 8575/3 Osteosarcoma 9180/3 Lipid-rich carcinoma 8314/3 Leiomyoma 8890/0 Secretory carcinoma 8502/3 Leiomyosarcoma 8890/3 Oncocytic carcinoma 8290/3 Adenoid cystic carcinoma 8200/3 Fibroepithelial tumours Acinic cell carcinoma 8550/3 Fibroadenoma 9010/0 Glycogen-rich clear cell carcinoma 8315/3 Phyllodes tumour 9020/1 Sebaceous carcinoma 8410/3 Benign 9020/0 Inflammatory carcinoma 8530/3 Borderline 9020/1 Lobular neoplasia Malignant 9020/3 Lobular carcinoma in situ 8520/2 Periductal stromal sarcoma, low grade 9020/3 Intraductal proliferative lesions Mammary hamartoma Usual ductal hyperplasia Flat epithelial atypia Tumours of the nipple Atypical ductal hyperplasia Nipple adenoma 8506/0 Ductal carcinoma in situ 8500/2 Syringomatous adenoma 8407/0 Microinvasive carcinoma Paget disease of the nipple 8540/3 Intraductal papillary neoplasms Central papilloma 8503/0 Malignant lymphoma Peripheral papilloma 8503/0 Diffuse large B-cell lymphoma 9680/3 Atypical papilloma Burkitt lymphoma 9687/3 Intraductal papillary carcinoma 8503/2 Extranodal marginal-zone B-cell lymphoma of MALT type 9699/3 Intracystic papillary carcinoma 8504/2 Follicular lymphoma 9690/3 Benign epithelial proliferations Adenosis including variants Metastatic tumours Sclerosing adenosis Apocrine adenosis Tumours of the male breast Blunt duct adenosis Gynaecomastia Microglandular adenosis Carcinoma Adenomyoepithelial adenosis Invasive 8500/3 Radial scar / complex sclerosing lesion In situ 8500/2 __________ 1 Morphology code of the International Classification of Diseases for Oncology (ICD-O) {921} and the Systematized Nomenclature of Medicine ( Behaviour is coded /0 for benign tumours, /2 for in situ carcinomas and grade 3 intraepithelial neoplasia, /3 for malignant tumours, and /1 for borderline or uncertain behaviour.10 Tumours of the breast
  • 9. TNM classification of carcinomas of the breast TNM Clinical Classification 1,2 M – Distant Metastasis T – Primary Tumour MX Distant metastasis cannot be assessed TX Primary tumour cannot be assessed M0 No distant metastasis T0 No evidence of primary tumour M1 Distant metastasis Tis Carcinoma in situ Tis (DCIS) Ductal carcinoma in situ pTNM Pathological Classification Tis (LCIS) Lobular carcinoma in situ pT – Primary Tumour Tis (Paget) Paget disease of the nipple with no tumour The pathological classification requires the examination of the primary car- Note: Paget disease associated with a tumour is classified according to the size of cinoma with no gross tumour at the margins of resection. A case can be the tumour. classified pT if there is only microscopic tumour in a margin. The pT categories correspond to the T categories. T1 Tumour 2 cm or less in greatest dimension Note: When classifying pT the tumour size is a measurement of the invasive compo- T1mic Microinvasion 0.1 cm or less in greatest dimensiona nent. If there is a large in situ component (e.g. 4 cm) and a small invasive component T1a More than 0.1 cm but not more than 0.5 cm in greatest dimension (e.g. 0.5 cm), the tumour is coded pT1a. T1b More than 0.5 cm but not more than 1 cm in greatest dimension T1c More than 1 cm but not more than 2 cm in greatest dimension pN – Regional Lymph Nodes 4 T2 Tumour more than 2 cm but not more than 5 cm in greatest pNX Regional lymph nodes cannot be assessed (not removed for dimension study or previously removed) T3 Tumour more than 5 cm in greatest dimension pN0 No regional lymph node metastasis* T4 Tumour of any size with direct extension to chest wall or skin pN1mi Micrometastasis (larger than 0.2 mm, but none larger than only as described in T4a to T4d 2 mm in greatest dimension) pN1 Metastasis in 1 - 3 ipsilateral axillary lymph node(s), and/or in Note:Chest wall includes ribs, intercostal muscles, and serratus anterior internal mammary nodes with microscopic metastasis detected muscle but not pectoral muscle. by sentinel lymph node dissection but not clinically apparent** T4a Extension to chest wall pN1a Metastasis in 1-3 axillary lymph node(s), including at least one T4b Oedema (including peau d’orange), or ulceration of the skin of the larger than 2 mm in greatest dimension breast, or satellite skin nodules confined to the same breast pN1b Internal mammary lymph nodes with microscopic metastasis T4c Both 4a and 4b, above detected by sentinel lymph node dissection but not clinically T4d Inflammatory carcinomab apparent pN1c Metastasis in 1 - 3 axillary lymph nodes and internal mammary Notes: a Microinvasion is the extension of cancer cells beyond the basement mem- brane into the adjacent tissues with no focus more than 0.1cm in greatest dimension. lymph nodes with microscopic metastasis detected by sentinel When there are multiple foci of microinvasion, the size of only the largest focus is used lymph node dissection but not clinically apparent to classify the microinvasion (Do not use the sum of all individual foci). The presence pN2 Metastasis in 4 - 9 ipsilateral axillary lymph nodes, or in of multiple foci of microinvasion should be noted, as it is with multiple larger invasive clinically apparent*** ipsilateral internal mammary lymph carcinomas. node(s) in the absence of axillary lymph node metastasis b Inflammatory carcinoma of the breast is characterized by diffuse, brawny induration pN2a Metastasis in 4-9 axillary lymph nodes, including at least one of the skin with an erysipeloid edge, usually with no underlying mass. If the skin biop- that is larger than 2 mm sy is negative and there is no localized measurable primary cancer, the T category is pTX when pathologically staging a clinical inflammatory carcinoma (T4d). Dimpling of pN2b Metastasis in clinically apparent internal mammary lymph the skin, nipple retraction, or other skin changes, except those in T4b and T4d, may node(s), in the absence of axillary lymph node metastasis occur in T1, T2, or T3 without affecting the classification. pN3 Metastasis in 10 or more ipsilateral axillary lymph nodes; or in infraclavicular lymph nodes; or in clinically apparent N – Regional Lymph Nodes 3 ipsilateral internal mammary lymph nodes in the presence of NX Regional lymph nodes cannot be assessed (e.g. previously one or more positive axillary lymph nodes; or in more than 3 removed) axillary lymph nodes with clinically negative, microscopic N0 No regional lymph node metastasis metastasis in internal mammary lymph nodes; or in ipsilateral N1 Metastasis in movable ipsilateral axillary lymph node(s) supraclavicular lymph nodes N2 Metastasis in fixed ipsilateral axillary lymph node(s) or in pN3a Metastasis in 10 or more axillary lymph nodes (at least one clinically apparent* ipsilateral internal mammary lymph node(s) in larger than 2 mm) or metastasis in infraclavicular lymph nodes the absence of clinically evident axillary lymph node metastasis pN3b Metastasis in clinically apparent internal mammary lymph node(s) N2a Metastasis in axillary lymph node(s) fixed to one another or to in the presence of one or more positive axillary lymph node(s); or other structures metastasis in more than 3 axillary lymph nodes and in internal N2b Metastasis only in clinically apparent* internal mammary lymph mammary lymph nodes with microscopic metastasis detected node(s) and in the absence of clinically evident axillary lymph by sentinel lymph node dissection but not clinically apparent node metastasis pN3c Metastasis in supraclavicular lymph node(s) N3 Metastasis in ipsilateral infraclavicular lymph node(s) with or Note: * Cases with only isolated tumour cells (ITC) in regional lymph nodes are clas- without axillary lymph node involvement; or in clinically sified as pN0. ITC are single tumour cells or small clusters of cells, not more than 0.2 apparent* ipsilateral internal mammary lymph node(s) in the mm in greatest dimension, that are usually detected by immunohistochemistry or presence of clinically evident axillary lymph node metastasis; molecular methods but which may be verified on H&E stains. ITCs do not typically or metastasis in ipsilateral supraclavicular lymph node(s) with or show evidence of metastatic activity (e.g., proliferation or stromal reaction). without axillary or internal mammary lymph node involvement ** not clinically apparent = not detected by clinical examination or by imaging stud- ies (excluding lymphoscintigraphy). N3a Metastasis in infraclavicular lymph node(s) *** clinically apparent = detected by clinical examination or by imaging studies N3b Metastasis in internal mammary and axillary lymph nodes (excluding lymphoscintigraphy) or grossly visible pathologically. N3c Metastasis in supraclavicular lymph node(s) Note: * clinically apparent = detected by clinical examination or by imaging studies pM – Distant Metastasis (excluding lymphoscintigraphy) The pM categories correspond to the M categories. 11
  • 10. Stage Grouping Stage 0 Tis N0 M0 Stage I T1 N0 M0 Stage IIA T0 N1 M0 T1 N1 M0 T2 N0 M0 Stage IIB T2 N1 M0 T3 N0 M0 Stage IIIA T0 N2 M0 T1 N2 M0 T2 N2 M0 T3 N1, N2 M0 Stage IIIB T4 N0,N1,N2 M0 Stage IIIC Any T N3 M0 Stage IV Any T Any N M1 _________ 1 {51,2976}. 2 A help desk for specific questions about the TNM classification is available at 3 The regional lymph nodes are: 1. Axillary (ipsilateral): interpectoral (Rotter) nodes and lymph nodes along the axillary vein and its tributaries, which may be divided into the following levels: (i) Level I (low-axilla): lymph nodes lateral to the lateral border of pectoralis minor muscle. (ii) Level II (mid-axilla): lymph nodes between the medial and lateral borders of the pectoralis minor muscle and the interpectoral (Rotter) lymph nodes. (iii) Level III (apical axilla): apical lymph nodes and those medial to the medial margin of the pectoralis minor muscle, excluding those designated as subclavicular or infraclavicular. Note: Intramammary lymph nodes are coded as axillary lymph nodes, level I. 2. Infraclavicular (subclavicular) (ipsilateral). 3. Internal mammary (ipsilateral): lymph nodes in the intercostal spaces along the edge of the sternum in the endothoracic fascia. 4. Supraclavicular (ipsilateral). 4 The pathological N classification requires the resection and examination of at least the low axillary lymph nodes (level I). Examination of one or more sentinel lymph nodes may be used for pathological classification. If classification is based solely on sentinel node biopsy without subsequent axillary lymph node dissection it should be designated (sn) for sentinel node, e.g. pN1(sn).12 Tumours of the breast
  • 11. Invasive breast carcinoma I.O. Ellis S.J. Schnitt C.J. Cornelisse A.J. Sasco X. Sastre-Garau R. Kaaks G. Bussolati P. Pisani F.A. Tavassoli D.E. Goldgar V. Eusebi P. Devilee J.L. Peterse M.J. Cleton-Jansen K. Mukai A.L. Børresen-Dale L. Tabár L. van’t Veer J. Jacquemier A. SapinoDefinition The risk of the disease had been increas- and Slovenia experiencing an increase inInvasive breast carcinoma is a group of ing until the early 1980s in both devel- risk that affects mainly younger genera-malignant epithelial tumours character- oped and developing countries and con- tions. If current trends persist, these gen-ized by invasion of adjacent tissues and tinues to increase in particular in the erations will maintain their higher risk anda marked tendency to metastasize to dis- developing countries {3068}. Thereafter, the age-specific curve will approach thattant sites. The vast majority of these tu- in developed countries, the advent of of Americans.mours are adenocarcinomas and are be- mammography and the previously men- Around 1990, breast cancer incidencelieved to be derived from the mammary tioned improvements in survival altered varied 10-fold world wide, indicatingparenchymal epithelium, particularly cells both incidence and mortality; the latter important differences in the distributionof the terminal duct lobular unit (TDLU). no longer appropriately reflect trends in of the underlying causes {2189}.Breast carcinomas exhibit a wide range the underlying risk of the disease. Geographical variations, time trends,of morphological phenotypes and specif- Breast cancer incidence, as with most and studies of populations migratingic histopathological types have particular epithelial tumours, increases rapidly with from low to high risk areas which showprognostic or clinical characteristics. age. Figure 1.02 shows age-specific inci- that migrant populations approach the dence rates for three selected popula- risk of the host country in one or two gen-Epidemiology tions representing countries with low erations {174,1478,3266}, clearly sug-Invasive breast cancer is the most com- (Japan), intermediate (Slovenia) and gest an important role of environmentalmon carcinoma in women. It accounts for high incidence rates (USA), just before factors in the aetiology of the disease.22% of all female cancers, 26% in afflu- screening was implemented. The curvesent countries, which is more than twice show a characteristic shape, rising Aetiologythe occurrence of cancer in women at steeply up to menopausal age and less The aetiology of breast cancer is multi-any other site {2188}. The areas of high rapidly or not at all afterwards. The differ- factorial and involves diet, reproductiverisk are the affluent populations of North ent behaviour at older ages is due to a factors, and related hormonal imbal-America, Europe and Australia where 6% cohort effect in the populations of Japan ances. From descriptive epidemiologicalof women develop invasive breast can-cer before age 75. The risk of breast can-cer is low in the less developed regionsof sub-Saharan Africa and Southern andEastern Asia, including Japan, where theprobability of developing breast cancerby age 75 is one third that of rich coun-tries. Rates are intermediate elsewhere.Japan is the only rich country that in year2000 still showed low incidence rates.The prognosis of the disease is verygood if detected at an early stage.Significant improvements in survival havebeen recorded in western countriessince the late 1970s {37,485}, butadvancements have been dramatic inthe 1990s due to the combined effect ofpopulation screening and adjuvant hor-monal treatment. As a result, the increas-ing mortality trend observed until the1980s leveled off or declined in severalhigh risk countries e.g. the United Statesof America (USA), the United Kingdom Fig. 1.01 Global incidence rates of breast cancer. Age-standardized rates (ASR) per 100,000 population andand the Netherlands {3155}. year. From Globocan 2000 {846}. Invasive breast cancer 13
  • 12. More than most other human neoplasms, breast cancer often shows familial clus- tering. Two high penetrance genes have been identified (BRCA1/2) which greatly increase the breast cancer risk (see Chapter 8). However, it is anticipated that multigenic traits also play a significant role in the inherited susceptibility to breast cancer. Reproductive lifestyleFig. 1.02 Incidence of female breast cancer by age For almost half a century, the events of Fig. 1.04 Female breast cancer mortality selected populations 1988-1993. From M. Parkin reproductive life have been considered Source: WHO/ al. {2189}. to be risk factors for breast cancer in women. Breast cancer occurs more fre-data it has clearly emerged that breast quently among women who have an finding an increased risk for inducedcancer is a disease of affluent societies early menarche, remain nulliparous or, if abortion. Similarly, the protective effect ofwhich have acquired the Western parous, have few children with a late age lactation, once considered quite a stronglifestyle, characterized by a high-caloric at first delivery. Infertility per se appears factor, was later given less importance;diet rich in animal fat and proteins, com- to be a risk factor as may be lack of its impact appears limited to long-termbined with a lack of physical exercise. breast-feeding. Finally, late age at cumulative breast feeding, preferablyRegions which have featured this menopause also increases the risk exceeding two years {435}.lifestyle for a long period of time (North {1430}.America, Northern Europe, Australia) Most of these factors have also been Exogenous hormoneshave reached a plateau of an incidence found relevant in populations at low risk Two major types of hormonal com-rate of 70 to 90 new cases per 100,000 of breast cancer such as the Japanese pounds have been evaluated in relationpopulation/year while countries that and Chinese. Although the data is limited to breast cancer: oral contraceptiveshave more recently become industrial- in Africa, at least one study confirmed and menopausal replacement therapy.ized and affluent show a marked the negative impact of late age at first The evidence suggests a small increaseincrease in incidence and mortality. In delivery, reduced number of pregnan- in the relative risk associated with the useaddition to breast cancer, the Western cies and shorter breast feeding time of combined oral contraceptives, espe-lifestyle carries a high risk of cancer {2770}. Recent data indicates that the cially among current and recent users,of the prostate, colon/rectum, and age at any delivery, not just the first is which is not related to duration of useendometrium. Specific environmental associated with breast cancer risk, with and type or dose of preparation, andexposures operative in the development deliveries occurring before the age of 30 may be partly linked to detection biasof breast cancer (e.g. radiation, alcohol, having a protective effect {3137}. {1296}. Data on injectable pure progesto-exogenous hormones) have been iden- Controversies still surround the issue of gen contraceptives shows relative riskstified but carry a lower risk. abortion, some studies, but not others, from 1.0 to 1.3, which are not statistically significant {1294}. Epidemiological studies on postmeno- pausal estrogen therapy show a small increase in risk with longer duration of use in current and recent users {1298}. Information on the effect of postmeno- pausal estrogen-progestogen therapy was provided in only a minority of studies, but indicates that the increased relative risk in long-term users is not significantly different from that for long-term use of estrogens alone {1297}. Yet it should be noted that, among hormone replacement therapy users, there is an over representa- tion of tumours that, with regard to tumour stage, type and grade are associated with a more favourable prognosis {1760}. Nutrition High intakes of fruit and vegetables are probably associated with a slightlyFig. 1.03 Aetiological factors involved in the development of breast cancer. reduced risk of breast cancer {3153}.14 Tumours of the breast
  • 13. Rapid growth and greater adult height,reflecting in part, the total food intake inearly years, are associated with anincreased risk {674}. Similarly a highbody mass, also linked to a high totalcaloric intake, or intake not counterbal-anced by caloric expenditure, is a riskfactor for postmenopausal breast cancer.Total fat, as well as saturated animal fat,also possibly increases the risk {674,3153}.Meat consumption is possibly associat-ed with an increased risk. Red meat wasmore frequently cited as a risk factor anddiets rich in poultry possibly have nolinks {3153}. In countries with differentmeat consumption levels within the pop-ulation, higher risks were associated withhigher total meat, red meat or processed Fig. 1.06 Insulin, IGF-I, bioavailable sex steroids, and breast cancer.meat intake in most studies, although thiswas not always statistically significant. Inconclusion there is considerable consis- was found with number of drinks per day, While risk ratios have levelled off at BMItent evidence that higher meat consump- including a low level of consumption levels near 25 kg/m2 in high risk coun-tion, particularly red or fried/browned {1691}. Hormone use or other factors tries, this is not the case in low to moder-meat is associated with a higher risk of potentially including genetic polymor- ate risk countries, where risk has contin-breast cancer {674}. phism {2182} may modify the risk. ued to increase across a wider range ofRecent studies, however, tend to sug- body weight. The association betweengest that several associations, either Smoking BMI and breast cancer is strongerpreventive for vegetables and fruit, or The evidence on smoking and breast among women who have never usedrisk for fat may have been overstated cancer remains inconclusive {787,816, postmenopausal hormone replacement{804,815,817}. 784,402}. Tobacco has been viewed as therapy, suggesting that the risk fromOther questions remaining unsolved an anti-estrogen and a potential protec- being overweight may be mediated byinclude the long term cumulative effects tive factor {182}. the elevations in endogenous estrogenof exposure to contaminants, either production among heavier women. Adultformed during cooking, such as hetero- Body weight weight gain is a strong and consistentcyclic amines in well-done meat or pesti- It has long been known that the influence predictor of postmenopausal breast can-cide residues. of weight on breast cancer risk depends cer risk particularly among women who on the menopausal status {1292}. More have never used hormone replacementAlcohol than 100 studies over nearly 30 years in therapy {1292}.The consumption of alcohol has been rel- many countries have established that In populations with a high incidence ofatively consistently found to be associat- higher body weight increases breast breast cancer, the overall associationed with a mild increase in risk of breast cancer risk among postmenopausal between BMI and breast cancer riskcancer {2729,3153}. A dose-response women. This is largely independent of among premenopausal women is the reproductive and lifestyle risk factors and inverse. The reduction in risk with exces - of the effect of physical activity. The sive weight is modest and not observed association appears to increase in a until a BMI of 28 kg/m2. Despite this, stepwise fashion with advancing age however, the breast cancer mortality rate after menopause. is not lower among heavier pre- The increase in risk with body-mass menopausal women {1292}. index (BMI) has been somewhat modest in the majority of studies {1292}. Above a Physical activity BMI of 24 kg/m2, the incidence rate The association between physical activi- increases among postmenopausal ty and breast cancer risk is independent women. The greatest slope of increases of menopausal status {1292}. The in risk across higher BMI levels is in low decrease in risk among the most physi-Fig. 1.05 Breast cancer risk by increasing levels and moderate risk countries suggesting cally active women was about 20-40%.of circulating insulin-like growth factor (IGF-1) in that increases in BMI now being Activity that is sustained throughout life-women <50 years. Blue columns, IGF-1, orange observed in those countries may time, or at a minimum performed aftercolumns, IGF-1 binding protein (IGFBP-3). From S.E. become a major factor contributing to menopause, may be particularly benefi-Hankinson et al. {1127}. future increases in breast cancer rates. cial. It appears that physical activity has Invasive breast cancer 15
  • 14. similar effects within different popula-tions. Although lifetime physical activityis desirable, beginning recreationalphysical activity after the menopausecan probably be beneficial for bothweight control and breast cancer riskreduction {1292}.Endogenous hormonesThere is overwhelming evidence fromepidemiological studies that sex steroids(androgens, estrogens, progestogens)have an important role in the develop-ment of breast tumours. Breast cancerincidence rates rise more steeply withage before menopause than after, whenovarian synthesis of estrogens and prog-esterone ceases and ovarian androgenproduction gradually diminishes {1447}.The estrogen excess hypothesis is cen-tral, stipulating that breast cancer riskdepends directly on breast tissue expo- Fig. 1.07 Age distribution of benign and maligmant breast lesions in patients presenting with a discrete breast lump. From Dixon and Sainsbury {707}.sure to estrogens. In vitro studies showincreased breast cell proliferation andinhibition of apoptosis. Animal studies gens, and decrease the hepatic synthe- Some specific exposuresshow increased rates of tumour develop- sis and circulating levels of SHBG Only limited data is available on specificment when estrogens are administered. {1376}. Especially in postmenopausal exposures in relation to breast cancer.The risk is higher among postmenopausal women, elevated plasma androgens Long-term follow-up of women exposedwomen who have elevated plasma levels lead to increased estrogen formation in to the Hiroshima or Nagasaki nuclearof testosterone and androstenedione, adipose tissue, and hence to increased explosions indicates an increased risk ofreduced levels of sex hormone-binding levels of oestrone and oestradiol. The breast cancer, in particular for womenglobulin (SHBG), and increased levels of hypothesis that chronic hyperinsulinemia exposed around puberty {2938}.oestrone, oestradiol, and bioavailable might explain the observed associations Similarly, exposure as a result of treat-oestradiol not bound to SHBG. of breast cancer risk with low plasma ment and surveillance of tuberculosis isA second major theory, the estrogen SHBG and elevated androgens and associated with risk {304}. Yet there is lit-plus progestogen hypothesis {255, estrogens, among postmenopausal tle evidence for a different pattern of risk1446}, postulates that, compared to women {1376} has, however, received as a function of fractionated versus oneexposure to estrogens alone (as in post- only limited support {661,1377}. Insulin- time only irradiation {1678}. Systematicmenopausal women not using exoge- growth factor-I (IGF-I) and IGF-binding reviews on occupation and breast can-nous hormones), risk of breast cancer is proteins (IGFBP) appear to be significant cer are few, indicating an increased riskfurther increased in women who have risk predictors {1127,1377}. for selected occupations and specificelevated plasma and tissue levels of Future adult cancer risk is in part set by chemical and physical exposures. Thisestrogens in combination with progesto- conditions of exposure in utero. The pre- data contrasts with the long-held viewgens. This theory is supported by obser- ventive effect of gravidic toxaemia is rec- that risk of breast cancer is related tovations that proliferation of mammary ognized {1288} and since the 1950s stud- social class, with higher risk for execu-epithelial cells is increased during the ies have incriminated high birth weight asluteal phase of the menstrual cycle, a risk factor for cancer, in particular of thecompared to the follicular phase. breast {1857}. Similarly, among twins, the Table 1.01 Frequency of symptoms of women presenting in aAmong premenopausal women, several risk of breast cancer may be affected by breast clinic {288,698}.studies have not shown any clear asso- the type of twinning (dizygotic versusciation between breast cancer risk and monozygotic) and sex of the dizygotic Lump 60-70%circulating levels of androgens, estro- twin {429}. A study of maternal pregnan- Pain 14-18%gens, or progesterone {255,1183,2448, cy hormone levels in China and the2613,2909}. United States of America (USA) did not Nipple problems 7-9%A metabolic consequence of excess find, however, the expected higher levelsbody weight and lack of physical activity in the USA but rather the reverse {1676}. Deformity 1%is development of insulin resistance. Another important period is adolescence, Inflammation 1%Elevated insulin levels, may lead to where diet may play a role either directlyincreased ovarian and/or adrenal synthe- or possibly indirectly through a modifica- Family history 3-14%sis of sex steroids, particularly of andro- tion of growth velocity {242}.16 Tumours of the breast
  • 15. tives, administrative and clerical jobs{387}. A recent hypothesis deals with cir-cadian disruption through night work,with an increased risk in women workingpredominantly at night {632,2556}.Over the last ten years concerns havearisen as to the potential risks of exposureto, not only hormones, but to artificialproducts mimicking hormonal activities.This led to the concept of xeno-hor-mones, mostly represented so far by Bxeno-estrogens. The exact role they playis unknown. Most epidemiological studiesdeal with various pesticides, essentiallyorganochlorines which remain in the envi-ronment for a very long time and theresidues of which may be found in adi-pose tissue of various species, includinghumans {628}. Studies have producedconflicting results with some suggesting apossibly increased risk, some no risk andothers showing a negative effect. For the A Ctime being, many consider these links as Fig. 1.08 A Mammogram of infiltrating carcinoma, clinically occult, less than 1 cm. B Mammographic detailspeculative and unfounded {1951,2503} of small, non-palpable, infiltrating carcinoma (<1 cm). C Macroscopic picture.or as markers of susceptibility {1951}.Finally, based on animal experience, a tumour virus, is a recognized cause of benign and malignant disease does dif-viral hypothesis has been put forward. In mammary tumours, transmitted with milk fer between age cohorts, benign condi-mice, a retrovirus, the murine mammary from mothers to daughters. Another can- tions being more common in younger didate is the Epstein-Barr virus, although women and breast cancer the common- data from the USA are not particularly est cause of symptoms in older women.Table 1.02Conditions requiring referral to a specialist clinic. supportive {1015}. Other potential viral The most common findings in sympto- candidates remain to be searched for. matic women are breast lumps, which may Lump or may not be associated with pain. Nipple Any new discreet mass Localization abnormalities (discharge, retraction, dis- A new lump in pre-existing nodularity Breast carcinoma arises from the mam- tortion or eczema) are less common and Asymmetrical nodularity that persits at review after menstruation mary epithelium and most frequently the other forms of presentation are rare. Abscess on breast inflammation which does not epithelial cells of the TDLU. There is a Some symptoms have a higher risk of settle after one course of antibiotics slightly higher frequency of invasive underlying malignancy for which hospital Cyst persistently refilling or recurrent cyst (if the breast cancer in the left breast with a referral is recommended. patient has recurrent multiple cysts and the GP reported left to right ratio of approximate- Breast abnormalities should be evaluat- has the necessary skills, then aspiration is ly 1.07 to 1 {1096}. Between 40 and 50% ed by triple assessment including clinical acceptable) of tumours occur in the upper outer examination, imaging (mammography Pain quadrant of the breast and there is a and ultrasound) and tissue sampling by If associated with a lump decreasing order of frequency in the either fine needle aspiration cytology or Intractable pain that interferes with a patient’s other quadrants from the central, upper needle core biopsy. lifestyle or sleep and which has failed to respond to inner, lower outer to the lower inner quad- Clinical examination should be systema- reassurance, simple measures such as wearing a rant {1096}. tic and take account of the nature of the well supporting brassiere and common drugs Unilateral persistent pain in postmenopausal women lump and, if present, any skin dimpling or Clinical features change in contour of the breast and also Nipple discharge Symptoms and signs assessment of the axilla. All women > 50 The majority of women with breast can- Women < 50 with: cer present symptomatically, although Imaging bilateral discharge sufficient to stain clothes bloodstained discharge the introduction of breast screening has Imaging should include mammography persistent single duct discharge led to an increasing proportion of asym- except in women under age 35, where it tomatic cases being detected mammo- is rarely of value, unless there is strong Nipple retraction, distortion, eczema graphically. Breast cancer does not have clinical suspicion or tissue/needle biopsy specific signs and symptoms, which evidence of malignancy. Change in skin contour allow reliable distinction from various The mammographic appearances of Family history of breast cancer forms of benign breast disease. breast carcinoma are varied and include However, the frequency distribution of well defined, ill defined and spiculate Invasive breast cancer 17
  • 16. A B CFig. 1.09 Mammographic demonstration of the evolution of a poorly differentiated invasive ductal carcinoma, a circular tumour mass on the mammogram.A Non-specific density in the axillary tail of the right breast, undetected at screening. B 18 Months later: >30 mm ill defined, high density lobulated tumour, mam-mographically malignant. Metastatic lymph nodes are seen in the axilla. C Large section histology of the tumour.masses, parenchymal deformity and cal- histologically proven malignancies. As phism and mitotic counts. A numericalcification with or without a mass lesion. seen in Table 1.03, the mammograms of scoring system of 1-3 is used to ensureBy far the most common manifestation of these breasts cancer showed: that each factor is assessed individually.breast cancer on the mammogram is 1) Stellate or circular tumour mass with When evaluating tubules and glandulartumour mass without calcifications. The no associated calcifications in 64% of the acini only structures exhibiting clear cen-mammographic histological correlation cases. tral lumina are counted; cut off points ofof 1,168 open surgical biopsies at Falun 2) An additional 17% had both calcifica- 75% and 10% of glandular/tumour areaCentral Hospital, Sweden, included 866 tions and tumour mass. are used to allocate the score. 3) Only calcifications without associated Nuclear pleomorphism is assessed byTable 1.03 tumour mass accounted for less than reference to the regularity of nuclear sizeMammographic appearance of histologically 20% of all malignancies detectable on and shape of normal epithelial cells inmalignant breast lesions. the mammogram. adjacent breast tissue. Increasing irregu- larity of nuclear outlines and the number Stellate and circular 64% Grading of invasive carcinoma and size of nucleoli are useful additional without calcifications Invasive ductal carcinomas and all other features in allocating scores for pleomor- Stellate and circular 17% invasive tumours are routinely graded phism. with calcifications based on an assessment of tubule/gland Evaluation of mitotic figures requires care formation, nuclear pleomorphism and and observers must count only defined Calcifications only 19% mitotic counts. mitotic figures; hyperchromatic and Many studies have demonstrated a sig- pyknotic nuclei are ignored since they nificant association between histological are more likely to represent apoptosisTable 1.04 grade and survival in invasive breast car- than proliferation. Mitotic counts requireSpectrum of histological diagnosis corresponding cinoma. It is now recognized as a power- standardization to a fixed field area or byto mammographic circular/oval lesions. ful prognostic factor and should be using a grid system {1984}. The total Invasive ductal carcinoma, NOS 59% included as a component of the minimum number of mitoses per 10 high power data set for histological reporting of fields. Field selection for mitotic scoring Medullary carcinoma 8% breast cancer {779,1190}. Assessment of should be from the peripheral leading histological grade has become more edge of the tumour. If there is hetero- Mucinous carcinoma 7% objective with modifications of the Patley geneity, regions exhibiting a higher fre- & Scarff {2195} method first by Bloom quency of mitoses should be chosen. Intracystic carcinoma 5% and Richardson {293} and more recently Field selection is by random meander by Elston and Ellis {777,2385}. through the chosen area. Only fields with Tubular carcinoma 4% a representative tumour cell burden Invasive lobular carcinoma 4% Method of grading should be assessed. Three tumour characteristics are evaluat- The three values are added together to Other diagnoses 13% ed; tubule formation as an expression of produce scores of 3 to 9, to which the glandular differentiation, nuclear pleomor- grade is assigned as follows:18 Tumours of the breast
  • 17. Grade 1 - well differentiated: 3-5 points Table 1.05Grade 2 - moderately differentiated: Semi-quantitative method for assessing histological grade in breast. From Elston and Ellis{777}. 6-7 points Feature ScoreGrade 3 - poorly differentiated: 8-9 points Tubule and gland formation Majority of tumour (>75%) 1Invasive ductal carcinoma, Moderate degree (10-75%) 2not otherwise specified (NOS) Little or none (<10%) 3 Nuclear pleomorphismDefinition Small, regular uniform cells 1Invasive ductal carcinoma, not otherwise Moderate increase in size and variability 2specified (ductal NOS) comprises the Marked variation 3largest group of invasive breast cancers. Mitotic countsIt is a heterogeneous group of tumours Dependent on microscope field area 1-3that fail to exhibit sufficient characteris- Examples of assignment of points for mitotic counts for three different field areas:tics to achieve classification as a specif- Field diameter (mm) 0.44 0.59 0.63ic histological type, such as lobular or Field area (mm2 ) 0.152 0.274 0.312tubular carcinoma. Mitotic count* 1 point 0-5 0-9 0-11ICD-O code 8500/3 2 points 6-10 10-19 12-22 3 points >11 >20 >23Synonyms and historical annotationInvasive ductal carcinoma, no specifictype (ductal NST); infiltrating ductal car-cinoma. tion {2548,3154}. This perpetuates the single entity from the point of view of theMany names have been used for this traditional concept that these tumours site of origin of most breast carcinomasf o rm of breast carcinoma including are derived exclusively from mammary {147,3091}. Some groups {874,2325}scirrhous carcinoma, carcinoma sim- ductal epithelium in distinction from lobu- have retained the term ductal but addedplex and spheroidal cell carcinoma. lar carcinomas, which were deemed to the phrase not otherwise specifiedInfiltrating ductal carcinoma is used by have arisen from within lobules for which (NOS), whilst others {2147} prefer to usethe Armed Forces Institute of Pathology there is no evidence. In addition it has no specific type (NST) to emphasize{1832,2442} and was the nomenclature been shown that the terminal duct-lobu- their distinction from specific typeadopted in the previous WHO classifica- lar unit (TDLU) should be regarded as a tumours. This latter view is increasinglyA B CFig. 1.10 Well differentiated infiltrating ductal carcinoma, Grade 1. A First screen. Intramammary lymph node and small (<5 mm), nonspecific density. B Secondscreen: 20 months later. The density has grown a little. C Third screen: after another 29 months. The 10 mm tumour is more obvious but still not palpable. Invasive breast cancer 19
  • 18. mixed category, preferring to include Classically, ductal NOS carcinomas are them in the no special type (ductal NOS) firm or even hard on palpation, and may group. have a curious gritty feel when cut with Ductal NOS tumours, like all forms of a knife. The cut surface is usually grey- breast cancer, are rare below the age of white with yellow streaks. 40 but the proportion of tumours classi- fied as such in young breast cancer Histopathology cases is in general similar to older cases The morphological features vary consid- {1493}. There are no well recognized dif- erably from case to case and there is fre- ferences in the frequency of breast can- quently a lack of the regularity of struc- cer type and proportion of ductal NOS ture associated with the tumours of spe- cancers related to many of the known cific type. Architecturally the tumour cells risk factors including geographical, cul- may be arranged in cords, clusters and tural/lifestyle, reproductive variables (see trabeculae whilst some tumours are aetiology). However, carcinomas devel- characterized by a predominantly solid oping following diagnosis of conditions or syncytial infiltrative pattern with little such as atypical ductal hyperplasia and associated stroma. In a proportion of lobular neoplasia, recognized to be cases glandular differentiation may be associated with increased risk include a apparent as tubular structures with cen- higher proportion of tumours of specific tral lumina in tumour cell groups. type specifically tubular and classical Occasionally, areas with single file infil- lobular carcinoma {2150}. Familial breast tration or targetoid features are seen but cancer cases associated with BRCA1 these lack the cytomorphological char-Fig. 1.11 Invasive ductal carcinoma, not otherwise mutations are commonly of ductal NOS acteristics of invasive lobular carcinoma.specified. 84 year old patient, mastectomy specimen. type but have medullary carcinoma like The carcinoma cells also have a variable features, exhibiting higher mitotic counts, appearance. The cytoplasm is oftenaccepted internationally, but since duc- a greater proportion of the tumour with a abundant and eosinophilic. Nuclei maytal is still widely used the terms invasive continuous pushing margin, and more be regular, uniform or highly pleomorphicductal carcinoma, ductal NOS or NST lymphocytic infiltration than sporadic with prominent, often multiple, nucleoli,are preferred terminology options. cancers {1572}. Cancers associated with mitotic activity may be virtually absent or BRCA2 mutations are also often of ductal extensive. In up to 80% of cases foci ofEpidemiology NOS type but exhibit a high score for associated ductal carcinoma in situDuctal NOS carcinoma forms a large tubule formation (fewer tubules), a high- (DCIS) will be present {147,2874}.proportion of mammary carcinomas and er proportion of the tumour perimeter Associated DCIS is often of high gradeits epidemiological characteristics are with a continuous pushing margin and a comedo type, but all other patterns maysimilar to those of the group as a whole lower mitotic count than sporadic can- be seen.(see epidemiology). It is the most com- cers {1572}. Some recognize a subtype of ductalmon type of invasive carcinoma of the NOS carcinoma, infiltrating ductal carci-breast comprising between 40% and Macroscopy noma with extensive in situ component.75% in published series {774}. This wide These tumours have no specific macro- The stromal component is extremely vari-range is possibly due to the lack of scopical features. There is a marked vari- able. There may be a highly cellularapplication of strict criteria for inclusion ation in size from under 10 mm to over fibroblastic proliferation, a scanty con-in the special types and also the fact that 100 mm. They can have an irregular, stel- nective tissue element or marked hyalini-some groups do not recognize tumours late outline or nodular configuration. The sation. Foci of elastosis may also bewith a combination of ductal NOS and tumour edge is usually moderately or ill present, in a periductal or perivenousspecial type patterns as a separate defined and lacks sharp circumscription. distribution. Focal necrosis may be pres-A B CFig. 1.12 A Infiltrating ductal carcinoma, grade I. B Infiltrating ductal carcinoma, grade II. C Invasive ductal NOS carcinoma, grade III with no evidence of glandular dif-ferentiation.Note the presence of numerous cells in mitosis, with some abnormal mitotic figures present.20 Tumours of the breast
  • 19. ent and this is occasionally extensive. Ina minority of cases a distinct lympho-plasmacytoid infiltrate can be identified.Mixed type carcinomaFor a tumour to be typed as ductal NOSit must have a non-specialized pattern inover 50% of its mass as judged by thor-ough examination of representative sec-tions. If the ductal NOS pattern compris-es between 10 and 49% of the tumour,the rest being of a recognized specialtype, then it will fall into one of the mixedgroups: mixed ductal and special type ormixed ductal and lobular carcinoma.Apart from these considerations thereare very few lesions that should be con-fused with ductal NOS carcinomas.Pleomorphic carcinoma Fig. 1.13 Mixed infiltrating ductal and infiltrating lobular carcinoma. Two distinct morphologic patterns areICD-O code 8022/3 seen in this tumour, ductal on the left and lobular on the right.Pleomorphic carcinoma is a rare variant The tumour giant cells account for more high S-phase (>10%) is found in 63%.of high grade ductal NOS carcinoma than 75% of tumour cells in most cases. Axillary node metastases are present incharacterized by proliferation of pleo- Mitotic figures exceed 20 per 10 high 50% of the patients with involvement of 3morphic and bizarre tumour giant cells power fields. All these tumours qualify as or more nodes in most. Many patientscomprising >50% of the tumour cells in grade 3 carcinomas. The intraepithelial present with advanced disease.a background of adenocarcinoma or component displays a ductal arrange-a d e n o c a rcinoma with spindle and ment and is often high grade with necro- Carcinoma with osteoclastic giantsquamous differentiation {2683}. The sis. Lymphovascular invasion is present cellspatients range in age from 28 to 96 in 19% of cases.years with a median of 51. Most Generally BCL2, ER and PR negative, ICD-O code 8035/3patients present with a palpable mass; two thirds of these pleomorphic carcino-in 12% of cases, metastatic tumour is mas are TP53 positive, and one third are The common denominator of all thesethe first manifestation of disease. The S-100 protein positive. All are positive for carcinomas is the presence of osteo-mean size of the tumours is 5.4 cm. CAM5.2, EMA and pan-cytokeratin clastic giant cells in the stroma {1089}.Cavitation and necrosis occur in larger (AE1/AE3, CK1). A majority (68%) is ane- The giant cells are generally associatedtumours. uploid with 47% of them being triploid. A with an inflammatory, fibroblastic, hyper-A BFig. 1.14 Invasive ductal carcinoma: pleomorphic carcinoma. A Poorly differentiated cells without distinctive architecture often lead to misinterpretation of thelesion as a sarcoma. B Immunostain for keratin (AE1/AE3 and LP34) confirms the epithelial nature of the process. Invasive breast cancer 21
  • 20. year survival rate is around 70%, similar Carcinoma with to, or better than, patients with ordinary choriocarcinomatous features infiltrating carcinomas {3062}. Prognosis is related to the characteristics of the Patients with ductal NOS carcinoma may associated carcinoma and does not have elevated levels of serum human appear to be influenced by the pres- β−chorionic gonadotrophin (β-HCG) ence of stromal giant cells. {2649} and as many as 60% of ductal The giant cells show uniform expression NOS carcinoma have been found to con- of CD68 (as demonsrated by KP1 anti- tain β-HCG positive cells {1243}. body on paraffin sections) {1200} and Histological evidence of choriocarcino-Fig. 1.15 Invasive carcinomas with stromal osteo- are negative for S100 protein, actin, and matous differentiation, however, isclastic giant cells often have vascular stromal tis- negative for cytokeratin, EMA, estrogen exceptionally rare with only a few casessue with haemosiderin pigment accumulation giv- and progesterone receptors {2869}. reported {993,1061,2508}. All were ining them a brown macroscopic appearance. The giant cells are strongly positive women between 50 and 70 years old. for acid phosphatase, non-specific esterase and lysosyme, but negative Carcinoma with melanotic featuresvascular stroma, with extravasated red for alkaline phosphatase indicative ofblood cells, lymphocytes, monocytes morphological similarity to histiocytic A few case reports have describedalong with mononucleated and binucle- cells and osteoclasts {2423,2869,2952, exceptional tumours of the mammaryated histiocytes some containing 3025}. parenchyma that appear to representhaemosiderin. The giant cells are vari- A number of ultrastructural and immuno- combinations of ductal carcinoma andable in size and appear to embrace the histochemical studies have confirmed malignant melanoma {2031,2146,2485}epithelial component or are found within the histiocytic nature of the osteoclastic and in some of these cases, therelumena formed by the cancer cells. The cells present in these unusual carcino- appeared to be a transition from one cellgiant cells contain a variable number of mas {2632,2869,2952,3025}. In vitro type to the other. A recent genetic analy-nuclei. The giant cells and hypervascu- studies have recently shown that osteo- sis of one such case showed loss of het-lar reactive stroma can be observed in clasts may form directly from a pre- erozygosity at the same chromosomallymph node metastases and in recur- cursor cell population of monocytes loci in all the components of the tumour,rences {2952}. and macrophages. Tumour associated suggesting an origin from the same neo-The carcinomatous part of the lesion is macrophages (TAMs) are capable of dif- plastic clone {2031}.most frequently a well to moderately dif- ferentiating into multinucleated cells, The mere presence of melanin in breastferentiated infiltrating ductal carcinoma which can affect bone resorption in cancer cells should not be construed asbut all the other histological types have metastases {2313}. Osteoclastic giant evidence of melanocytic differentiation,been observed particularly invasive cells in carcinoma are probably also since melanin pigmentation of carcinomacribriform carcinoma {2003,2241}, and related to TAMs. Angiogenesis and cells can occur when breast cancersalso tubular, mucinous, papillary {3062}, chemotactic agents produced by the invade the skin and involve the dermo-lobular {1274,2837}, squamous and carcinoma may be responsible for the epidermal junction {150}. In addition,other metaplastic patterns {1200,2044, migration of histiocytes to the area care must be taken to distinguish tumours3062}. involved by cancer and their ultimate showing melanocytic differentiation fromAbout one-third of the reported cases transformation to osteoclastic giant cells breast carcinomas with prominent cyto-had lymph nodes metastasis. The five {2638,2869}. plasmic lipofuscin deposition {2663}.A BFig. 1.16 A Invasive ductal carcinoma with stromal osteoclastic giant cells and haemosiderin-laden macrophages. B The invasive ductal carcinoma is low grade.Multinucleated giant cells are evident in the stroma.22 Tumours of the breast
  • 21. Most melanotic tumours of the breastrepresent metastases from malignantmelanomas originating in extra-mamma-ry sites {2694}. Primary melanomas mayarise anywhere in the skin of the breast,but an origin in the nipple-areola com-plex is extremely rare {2168}. The differ-ential diagnosis of malignant melanomaarising in the nipple areolar region mustinclude Paget disease, the cells of which A Bmay on occasion contain melanin pig- Fig. 1.17 Carcinoma with choriocarcinomatous features. A,B Multinucleated tumour cells with smudgedment {2544}. This is discussed in the nuclei extend their irregular, elongated cytoplasmic processes around clusters of monocytic tumour cells,section on Paget disease. mimicking the biphasic growth pattern of choriocarcinoma. B Note the abnormal mitotic figures in this high grade carcinoma.GeneticsThe genetic variation seen in breast can-cer as a whole is similarly reflected in Approximately 70-80% of ductal NOS radiological {1599} analysis (see bilateralductal NOS tumours and has until recent- breast cancers are estrogen receptor breast carcinoma section). An 8-19%ly proved difficult to analyse or explain. positive and between 15 and 30% of incidence of contralateral tumours hasThe increasing accumulation of genetic cases ERBB2 positive. The management also been reported {699,725,834}, repre-alterations seen with increasing grade of ductal NOS carcinomas is also influ- senting an overall rate of 13.3 %. This(decreasing degree of differentiation) enced by these prognostic and predic- may be higher than that for IDChas been used to support the hypothesis tive characteristics of the tumour as well {1241,2696}. However, no significant dif-of a linear progression model in this type as focality and position in the breast. ference in the rate of bilaterality wasand in invasive breast cancer as a whole. observed in other series of cases {648,The recent observation by a number of 1168,2186}. At mammography, architec-groups that specific genetic lesion or Invasive lobular carcinoma tural distortion is more commonlyregions of alteration are associated with observed in ILC than in IDC whereashistological type of cancer or related to Definition microcalcifications are less common ingrade in the large ductal NOS group An invasive carcinoma usually associa- ILC {895,1780,3066}.does not support this view. It implies that ted with lobular carcinoma in situ is com-breast cancer of ductal NOS type posed of non-cohesive cells individually Macroscopyincludes a number of tumours of unrelat- dispersed or arranged in single-file linear ILC frequently present as irregular anded genetic evolutionary pathways {365} pattern in a fibrous stroma. poorly delimited tumours which can beand that these tumours show fundamen- difficult to define macroscopicallytal differences when compared to some ICD-O code 8520/3 because of the diffuse growth pattern ofspecial type tumours including lobular the cell infiltrate {2696}. The mean diam-{1085} and tubular carcinoma {2476}. Epidemiology eter has been reported to be slightly larg-Furthermore, recent cDNA microarray Invasive lobular carcinoma (ILC) repre- er than that of IDC in some seriesanalysis has demonstrated that ductal sents 5-15% of invasive breast tumours {2541,2696,3133}.NOS tumours can be classified in to sub- {725,771,1780,2541,2935,3133}. Duringtypes on the basis of expression patterns the last 20 years, a steady increase in its Histopathology{2218,2756}. incidence has been reported in women The classical pattern of ILC {895, over 50 {1647}, which might be attributa- 1780,3066} is characterized by a prolife-Prognosis and predictive factors ble to the increased use of hormone ration of small cells, which lack cohesionDuctal NOS carcinoma forms the bulk replacement therapy {312,1648,2073}.(50-80%) of breast cancer cases and its The mean age of patients with ILC is 1-3prognostic characteristics and manage- years older than that of patients with infil-ment are similar or slightly worse with a trating ductal carcinoma (IDC) {2541}.35-50% 10 year survival {771} comparedto breast cancer as a whole with around Clinical featuresa 55% 10 year survival. Prognosis is The majority of women present with ainfluenced profoundly by the classical palpable mass that may involve any partprognostic variables of histological of the breast although centrally locatedgrade, tumour size, lymph node status tumours were found to be slightly moreand vascular invasion (see general dis- common in patients with ILC than withcussion of prognosis and predictive fac- IDC {3133}. A high rate of multicentrictors at the end of this chapter) and by tumours has been reported by somepredictors of therapeutic response such {699,1632} but this has not been found in Fig. 1.18 Macroscopy of an invasive lobular carci-as estrogen receptor and ERBB2 status. other series based on clinical {2541} or noma displays an ill defined lesion. Invasive breast cancer 23
  • 22. A BFig. 1.19 Mammography of invasive lobular carcinoma. A Architectural distortion in the axillary tail, corre- Fig. 1.20 In situ and invasive lobular carcinoma.sponding to a palpable area of thickening. B Magnification view of the architectural axillary distortion. The larger cells on the left and lower part of the field are invasive tumour cells.and appear individually dispersed arranged in globular aggregates of at The admixture of tubular growth patternthrough a fibrous connective tissue or least 20 cells {2668}, the cell morphology and small uniform cells arranged in a lin -arranged in single file linear cords that and growth pattern being otherwise typi- ear pattern defines tubulo-lobular carci-invade the stroma. These infiltrating cal of lobular carcinoma. Pleomorphic noma (TLC) (ICD-O 8524/3) {875}. LCIScords frequently present a concentric lobular carcinoma retains the distinctive is observed in about one third of TLC.pattern around normal ducts. There is growth pattern of lobular carcinoma but Comparison of the clinico-pathologicaloften little host reaction or disturbance of exhibits a greater degree of cellular atyp- features of TLC and pure tubular carci-the background architecture. The neo- ia and pleomorphism than the classical noma (TC) has shown that axillary metas-plastic cells have round or notched ovoid form {808,1858,3082}. Intra-lobular tases were more common in TLC (43%)nuclei and a thin rim of cytoplasm with an lesions composed of signet ring cells or than in TC (12%) {1062}. A high rate ofoccasional intracytoplasmic lumen pleomorphic cells are features frequently estrogen receptor (ER) positivity has also{2312} often harbouring a central mucoid associated with it. Pleomorphic lobular been reported in TLC {3141}. Furtherinclusion. Mitoses are typically infre- carcinoma may show apocrine {808} or analysis of TLC, especially regarding E-quent. This classical form of ILC is asso- histiocytoid {3047} differentiation. A cadherin status, should help to deter-ciated with features of lobular carcinoma mixed group is composed of cases mine whether TLC should be categorizedin situ in at least 90% of the cases showing an admixture of the classical as a variant of tubular or of lobular{705,2001}. type with one or more of these patterns tumours. Without this data these tumoursIn addition to this common form, variant {705}. In about 5% of invasive breast are best classified as a variant of lobularpatterns of ILC have been described. cancers, both ductal and lobular features carcinoma.The solid pattern is characterized by of differentiation are present {1780} (seesheets of uniform small cells of lobular Mixed type carcinoma, page 21). Immunoprofilemorphology {835}. The cells lack cell to Analysis of E-cadherin expression may About 70-95% of lobular carcinomas arecell cohesion and are often more pleo- help to divide these cases between duc- ER positive, a rate higher than the 70-morphic and have a higher frequency of tal and lobular tumours but the 80% observed in IDC {2541,3235}.mitoses than the classical type. In the immunophenotype remains ambiguous Progesterone receptor (PR) positivity isalveolar variant , tumour cells are mainly in a minority of cases {34}. 60-70% in either tumour type {2541,A B CFig. 1.21 A Invasive lobular carcinoma. B Loss of E-cadherin expression is typical of lobular carcinoma cells. Note immunoreactivity of entrapped normal lobules.C Large number of signet ring cells and intracytoplasmic lumina (targetoid secretion).24 Tumours of the breast
  • 23. A BFig. 1.22 A Classic invasive lobular carcinoma with uniform, single cell files compared to (B). B Invasive pleomorphic lobular carcinoma with characteristic pleomor-phic, atypical nuclei.3235}. ER was found to be expressed in immunostaining can be related to the ranging from 3-10% {1327,1578,2541,the classical form and in variants {1994}, presence of protein truncation mutations 2696,2935}. Metastatic involvement bybut the rate of positivity was higher {260,1394,2380}, together with the inacti- scattered isolated cells may simulate(100%) in alveolar {2668} and lower vation of the wild type allele. Alternative sinusoidal histiocytes and re q u i re(10%) in pleomorphic ILC {2318} than in mechanisms may also be involved in immunohistochemical detection.the classical type. The proliferation rate the alteration of E-cadherin {723,3190} The metastatic pattern of ILC differs fromin ILC is generally low {2027}. With the and/or of E-cadherin-associated proteins that of IDC. A higher frequency of tumourexception of pleomorphic lobular carci- {723,1892,2337,2374}. extension to bone, gastro-intestinal tract,noma ERBB2 overexpression in ILC Analysis of neoplastic lesions correspon- uterus, meninges, ovary and diffuse{2274,2477,2750}, is lower than reported ding to early steps of tumour develop- serosal involvement is observed in ILCin IDC {2358}. ment has shown that both loss of het- while extension to lung is more frequent erozygosity of the 16q chromosomal in IDC {319,1142,1327,2541,2696,2935}.Genetics region {800} and of E-cadherin expres- IHC using antibodies raised againstUsing flow cytometry, ILCs were found sion {649,3034} were also observed in GCDFP-15, cytokeratin 7, ER, andnear diploid in about 50% of the cases LCIS and in mixed ductal-lobular carcino- E-cadherin may help establish a female{887}. This fits with the finding that chro- ma {34}. Inactivation of the E-cadherin genital tract tumour as a metastatic ILC.mosomal abnormalities, assessed by gene may thus represent an early event in Several studies have reported a morecytogenetical {887} or comparative oncogenesis and this biological trait indi- favourable disease outcome for ILC thangenomic hybridization (CGH) analysis cates that LCIS is a potential precursor of for IDC {705,725,771,2696,2935} where-{2027}, are less numerous in ILC than in ILC. However, other molecular events as others found no significant differencesIDC. In ILC, the most common genetic must be involved in the transition from {2205,2541,2696,2731} or a worse prog-alteration, found in 63-87% of the cases in situ to invasive lobular tumours. nosis for ILC {126}.{887,2027}, is a loss of the long arm of Furthermore, genetic losses concerning When the histological subtypes of ILCchromosome 16. other parts of the long arm of chromo- were analysed separately, a moreThe E (epithelial)-cadherin gene, which some 16 than the locus of E-cadherin favourable outcome was reported for themaps in 16q22, is implicated in main- have been found in IDC and in ILC {2960}, classical type than for variants {699,taining coherence of adult epithelial as well as in DCIS {460}. This strongly 705,725}. However, alveolar ILC hastissues {1217}, and acts as a cell diffe- suggests that several genes localized in been considered as a low grade tumourrentiation and invasion suppressor factor this chromosomal region, and presenting {2668}, whereas a poor prognosis of{922,3030}. A correlation has been found tumour suppressive properties, may be pleomorphic ILC has been reported inbetween deletion of 16q and the loss of involved in breast oncogenesis. some series {808,3082}. No difference inE-cadherin expression {2027}. Immu- A combination of mutation analysis and the outcome of different subtypes hasnohistochemical analysis has shown E-cadherin protein expression may offer been observed in other series {2935}.complete loss of E-cadherin expression a method for identification of lobular Furthermore, a large extent of lymphin 80-100% of ILC {956,1892,2094, carcinoma. node involvement has not been found to2152,2336}. This contrasts with the increase significantly the risk of localm e re decrease in staining intensity Prognosis and predictive factors relapse {2570}. A link between lack ofobserved in 30-60% of IDC. A lower frequency of axillary nodal E-cadherin expression and adverse out-Molecular analysis has shown that, in metastasis in ILC than in IDC has been come of the disease has also beenmost cases, the lack of E-cadherin reported in several series, the difference reported {125,1176}. Invasive breast cancer 25
  • 24. Treatment of ILC should depend on the epithelial atypia {915,1034}. In addition,stage of the tumour and parallel that of an association with radial scar has beenIDC. Conservative treatment has been proposed {1668,2725}.shown to be appropriate for ILC {327,2205,2269,2541,2570,2696}. Macroscopy There is no specific macroscopical fea- ture which distinguishes tubular carcino-Tubular carcinoma ma from the more common ductal no special type (NOS) or mixed types, otherDefinition than small tumour size. Tubular carcino-A special type of breast carcinoma with a mas usually measure between 0.2 cm Fig. 1.23 Tubular carcinoma. Specimen X-ray.particularly favourable prognosis com- and 2 cm in diameter; the majority are 1posed of distinct well differentiated tubu- cm or less {772,1829,2081}.lar structures with open lumina lined by a Two morphological subtypes have been A secondary, but important feature issingle layer of epithelial cells. described, the pure type which has a the cellular desmoplastic stroma, which pronounced stellate configuration with accompanies the tubular structures.ICD-O code 8211/3 radiating arms and central yellow flecks Calcification may be present in the inva- due to stromal elastosis and the sclero- sive tubular, associated in situ or theEpidemiology sing type characterized by a more dif- stromal components.Pure tubular carcinoma accounts for fuse, ill defined structure {410,2190}. DCIS is found in association with tubularunder 2% of invasive breast cancer in carcinoma in the majority of cases; thismost series. Higher frequencies of up Histopathology is usually of low grade type with ato 7% are found in series of small T1 The characteristic feature of tubular carci- c r i b r i f o rm or micro p a p i l l a ry pattern .breast cancers. Tubular cancers are noma is the presence of open tubules Occasionally, the in situ component isoften readily detectable mammographi- composed of a single layer of epithelial lobular in type. More recently an associ-cally because of their spiculate nature cells enclosing a clear lumen. These ation has been described with flat epithe-and associated cellular stroma and are tubules are generally oval or rounded and, lial atypia and associated micropapillaryseen at higher frequencies of 9-19%, in typically, a proportion appears angu- DCIS {915,1034}.mammographic screening series {1853, lated. The epithelial cells are small and There is a lack of consensus concerning2192,2322}. regular with little nuclear pleomorphism the proportion of tubular structuresWhen compared with invasive carcino- and only scanty mitotic figures. Multi- required to establish the diagnosismas of no special type (ductal NOS), layering of nuclei and marked nuclear of tubular carcinoma. In the previoustubular carcinoma is more likely to occur pleomorphism are contraindications for WHO Classification {1,3154} and ain older patients, be smaller in size and diagnosis of pure tubular carcinoma, number of published studies {410,1350,have substantially less nodal involve- even when there is a dominant tubular 1832} no specific cut-off point is indicatedment {691,1379,2166}. architecture. Apical snouts are seen in as although there is an assumption that allThese tumours are recognized to occur many as a third of the cases {2874}, but the tumour is of a tubular association with some epithelial prolif- are not pathognomonic. Myoepithelial Some authors have applied a strict 100%erative lesions including well differentiat- cells are absent but some tubules may rule for tubular structures {409,552, 2190},ed/low grade types of ductal carcinoma have an incomplete surrounding layer of some set the proportion of tubular struc-in situ (DCIS), lobular neoplasia and flat basement membrane components. tures at 75% {1668,1829, 2224,2442}, andA BFig. 1.24 Tubular carcinoma. A There is a haphazard distribution of rounded and angulated tubules with open lumens, lined by only a single layer of epithelial cellsseparated by abundant reactive, fibroblastic stroma. B The neoplastic cells lining the tear-drop shaped tubules lack significant atypia.26 Tumours of the breast
  • 25. yet others at 90% {97,2147}. For pragma-tic reasons, a 90% purity requirementoffers a practical solution.Tumours exhibiting between 50 and 90%tubular growth pattern with other typesshould be regarded as mixed type ofcarcinoma (see Mixed type carcinomas).Differential diagnosisSclerosing adenosis (SA) can be distin-guished from tubular carcinoma by itsoverall lobular architecture and themarked compression and distortion ofthe glandular structures. Myoepithelialcells are always present in sclerosingadenosis and can be highlighted byimmunostaining for actin. Similarly, a fullyretained basement membrane can beshown by immunohistological staining forcollagen IV and laminin in tubules of SA.Microglandular adenosis (MA) can be Fig. 1.25 Invasive cribriform carcinoma. The haphazard distribution of irregularly shaped and angulated invasivemore difficult to differentiate because of areas is in contrast with the rounded configuration of the ducts with cribriform DCIS on the left side of the field.the rather haphazard arrangement of thetubules, and lack of myoepithelial cells in of breast cancer are not seen, which ICD-O code 8201/3the tubules. However, the tubules of MA implies that tubular carcinoma of theare more rounded and regular and often breast is genetically distinct. Epidemiologycontain colloid-like secretory material, at Invasive cribriform carcinoma (ICC)least focally, compared to the often angu- Prognosis and predictive factors accounts for 0.8-3.5% of breast carcino-lated tubules of tubular carcinoma. Pure tubular carcinoma has an excellent mas. The mean age of patients is 53-58Furthermore a ring of basement mem- long term prognosis {409,410,552,771, years {2148,2670,3017}.brane is present around tubules of MA. 1829,2081,2224} which in some series isComplex sclerosing lesions/radial scars similar to age matched women without Clinical featureshave a typical architecture with central breast cancer {691}. Recurrence follow- The tumour may present as a mass butfibrosis and elastosis containing a few ing mastectomy or breast conservation is frequently clinically occult. At mam-small, often distorted, tubular structures in treatment is rare and localized tubular mography, tumours typically form awhich myoepithelial cells can be demon- carcinomas are considered to be ideal spiculated mass frequently containingstrated. The surrounding glandular struc- candidates for breast conservation tech- microcalcifications {2670,2806}. Multi-tures show varying degrees of dilatation niques. Following breast conservation, focality is observed in 20% of the casesand ductal epithelial hyperplasia. the risk of local recurrence is so low that {2148}. some centres consider adjuvant radio-Immunophenotype therapy unnecessary. Axillary node HistopathologyTubular carcinoma is nearly always metastases occur infrequently, and when The pure ICC consists almost entirelyestrogen and progesterone receptor observed rarely involve more than one (>90%) of an invasive cribriform pat-positive, has a low growth fraction, and low axillary lymph node. There is little tern. The tumour is arranged as inva-is ERBB2 and EGFR negative {691, adverse effect of node positivity in tubu- sive islands, often angulated, in which1379,2166}. lar carcinoma {691,1471} and the use of well defined spaces are formed by systemic adjuvant therapy and axillary arches of cells (a sieve-like or cribri-Genetics node dissection are considered un- form pattern). Apical snouts are a reg-Tubular carcinomas of the breast have a necessary by some groups {691,2166}. ular feature. The tumour cells are smalllow frequency of genetic alterations and show a low or moderate degree ofwhen compared to other types of breast nuclear pleomorphism. Mitoses arecarcinoma. Using LOH and CGH tech- Invasive cribriform carcinoma rare. A prominent, reactive appearing,niques, alterations have been found fibroblastic stroma is present in manymost frequently at chromosomes 16q Definition ICC. Intraductal carcinoma, generally(loss), 1q (gain), 8p (loss), 3p FHIT An invasive carcinoma with an excellent of the cribriform type, is observed in asgene locus, and 11q ATM gene locus prognosis that grows in a cribriform pat- many as 80% of cases {2148}. Axillary{1754,1779,2476, 3046}. Of particular tern similar to that seen in intraductal lymph node metastases occur in 14.3%interest is the observation that other cribriform carcinoma; a minor (<50%) {2148}, the cribriform pattern beingsites of chromosomal alteration previ- component of tubular carcinoma may be retained at these sites. Lesions show-ously found at high levels in other types admixed. ing a predominantly cribriform arrange- Invasive breast cancer 27
  • 26. ment associated with a minor (<50%) Epidemiology Besides these typical histologic traits,component of tubular carcinoma are Medullary carcinoma (MC) represents the presence of an intraductal compo-also included in the group of classic between 1 and 7% {294,2334} of all nent is considered as a criterion forICC {2148}. Cases with a component breast carcinomas, depending on the exclusion by some authors {2370,3064},(10-40%) of another carcinoma type, stringency of diagnostic criteria used. but acceptable by others {2334}, espe-other than tubular carcinoma, should The mean age of women with MC ranges cially when it is located in the surround-be called mixed type of carcinoma from 45 to 52 years {623,2204,2334, ing tissue or reduced to small areas with-{2148,3017}. 3064}. in the tumour mass. These diagnostic criteria, particularly theImmunoprofile Clinical features status of the margin, may be difficult toICC is estrogen receptor positive in The tumour is well delineated and soft on assess in practice, and may explain the100% and progesterone receptor in 69% palpation. Mammographically MC is typ- low reproducibility in the diagnosis of MCof cases {3017}. ically well circumscribed and may be observed in certain series {950,2203, confused with a benign lesion. 2372}. To overcome this difficulty, a sim-Differential diagnosis plified scheme has been proposedICC should be differentiated from carci- Macroscopy {2202}. Syncytial growth pattern, lack ofnoid tumour and adenoid cystic carcino- MC has distinctive rounded, well defined tubule formation and lymphoplasmacyticma; the former has intracytoplasmic margins and a soft consistency. Fleshy infiltrate, together with sparse tumourargyrophilic granules, while the latter has tan to grey in appearance, foci of necro- necrosis (<25%) were found to be thea second cell population in addition to a sis and haemorrhage are frequent. The most reproducible and characteristicvariety of intracystic secretory and base- median diameter varies from 2.0-2.9 cm features of MC. However, the prognosticment membrane-like material. The lack of {2334,2370,3064}. significance of this simplistic schemelaminin around the cribriform structures needs to be assessed {1339}.also differentiates ICC from adenoid cys- Histopathology Tumours showing the association of atic carcinoma {3092}. ICC is distin- Since the early descriptions of MC predominantly syncytial architecture withguished from extensive cribriform DCIS {895,1908,2367}, the histological fea- only two or three of the other criteria areby the lack of a myoepithelial cell layer tures of this tumour have been further usually designated as atypical medullaryaround its invasive tumour cell clusters, specified {2334,2370,3064}. carcinoma (AMC) {2334,2370}. However,its haphazard distribution and irregular Classically, five morphological traits strictly defined morphological criteria areconfiguration. characterize MC. necessary to preserve the entity of MC 1. A syncytial architecture should be characterized by its relatively favourablePrognosis and predictive factors observed in over 75% of the tumour prognosis {2334,2478} which is notICC has a remarkably favourable out- mass. Tumour cells are arranged in shared by AMC. Several works {2334,come {771,2148,3017}. The ten-year sheets, usually more than four or five 3064} have advocated the elimination ofoverall survival was 90% {771} to 100% cells thick, separated by small amounts the AMC category in order to avoid con-{2148}. The outcome of mixed invasive of loose connective tissue. Foci of necro- fusion with MC and the term infiltratingcribriform carcinoma has been reported sis and of squamous differentiation may ductal carcinoma with medullary featuresto be less favourable than that of the be seen. seems to be more appropriate for theseclassic form, but better than that of com- 2. Glandular or tubular structures are not tumours.mon ductal carcinoma {2148}. The bio- present, even as a minor component.logical behaviour of ICC is very similar to 3. Diffuse lymphoplasmacytic stromal Immunoprofile and ploidythat of tubular carcinoma {771}. It has infiltrate is a conspicuous feature. The Flow cytometry and immunohistochemi-been suggested that cribriform elements density of this infiltrate varies among cal analysis has shown that most MCmight correspond to tubules {2148}. cases, mononuclear cells may be scarce are aneuploid and highly proliferativeHowever, many ICC have no definite or so numerous that they largely obliter- tumours {551,1244,1345,1766,2108,tubular structures and separation of this ate the carcinoma cells. Lymphoid folli- 2201}. A high apoptosis rate has alsotumour as a distinct clinicopathological cles and/or epithelioid granuloma mayentity is justified. be present. 4. Carcinoma cells are usually round with abundant cytoplasm and vesicular nucleiMedullary carcinoma containing one or several nucleoli. The nuclear pleomorphism is moderate orDefinition marked, consistent with grade 2 or 3.A well circumscribed carcinoma com- Mitoses are numerous. Atypical giantposed of poorly differentiated cells cells may be observed.arranged in large sheets, with no glandu- 5. Complete histological circumscriptionlar structures, scant stroma and a promi- of the tumour is best seen under lownent lymphoplasmacytic infiltrate. magnification. Pushing margins may delimit a compressed fibrous zone at the Fig. 1.26 Medullary carcinoma. Mammogram showingICD-O code 8510/3 periphery of the lesion. a typical rounded, dense tumour without calcifications.28 Tumours of the breast
  • 27. notype of BRCA1 germline associated tumours, but not all BRCA1 mutations lead to medullary phenotype. MC are also characterized by a high rate of TP53 alterations. Somatic mutations were found in 39% {1766} to 100% {643} of MC, together with protein accumula- tion in 61-87% of the cases {643, 711,1345}. This contrasts with the 25- 30% rate of TP53 alterations found in common ductal carcinomas {643,711, 1345}. No specific TP53 mutation was found to characterize MC {643} but TP53 overstaining may be considered as a biological marker of MC. Both TP53 and BRCA1 are involved in the process of DNA repair and the alteration of these genes, together with a high proliferation rate, may account for the high sensitivity of MC to radio- and/or chemotherapy.Fig. 1.27 Medullary carcinoma. The tumour is composed of a syncytial sheet of large pleomorphic cells. Thereis no glandular differentiation. The adjacent stroma contains numerous plasma cells and mature lymphocytes. Prognosis and predictive factors MC has been reported to have a better prognosis than the common IDC {1339,been reported {1386,3170}. MC typically of polyclonality of the B-cell infiltrate has 1740,1908,2204,2334,2352,2367,2370,lack estrogen receptors (ER) expression been obtained {1510}. Plasma cells 3064} but this has been questioned by{1244,1340,2204,2272}, and have a low were found to express IgG {1310} or others {285,771,876}. The overall 10-year-incidence of ERBB2 overe x p re s s i o n IgA {1254}. The recent finding of an survival reported for MC varies between{2439,2746,2750}. increased number of activated cytotoxic about 50% {285,771,1740} to more thanThe cytokeratin profile is similar in typical lymphocytes in MC may correspond to 90% {1339,2334,3064}. Differences inand atypical MC, and does not differ sig- an active host versus tumour response diagnostic criteria may account for thisnificantly from that of common ductal {3169}. Expression of HLA class I and disparity and several reports underlinetumours {610,1340,2943}. The cell co- class II molecules by carcinoma cells, that stringency in diagnostic criteria ishesiveness of MC, contrasting with the as a cause or a consequence of the required to preserve the anatomo-clinicalpoorly differentiated pattern and high immune response, was reported to char- identity of MC {876,2334,2370,3064}mitotic index, has been characterized by acterize MC {840}. Although EBV-associ- which is justified by the characteristicthe expression of the intercellular adhe- ated lymphoepithelioma shares some prognosis of this tumour. The outcome ofsion molecule-1 {156} and of E-cadherin morphological features with MC, only a MC associated with more than three{444}. This feature might account for the few cases were found associated with metastatic axillary lymph nodes has beengood limitation of the tumour and the late EBV, in contrast with the 31-51% rate of reported to be poor {285,1740,2202} oraxillary lymph node extension. EBV-positive common ductal carcinomas no different from that of common ductalImmunophenotyping of the lymphoid {310,857}. tumours {876,2352}. However, less thaninfiltrate of MC has shown that most cells 10% of MC {876,1339,2334,2352,2370}correspond to mature T lymphocytes, a Genetics present with node metastases, and thisprofile similar to that observed in com- A high frequency of MC has been report- might account in part for the relativelymon ductal carcinomas {214}. Evidence ed in patients with BRCA1 germ line favourable overall prognosis of MC. mutation, whereas this observation was less common among patients with Table 1.06 BRCA2 mutation or with no known germ Histological criteria required for a diagnosis of MC. line mutation. Typical MC were observed in 7.8% {1767} to 13% {8} of BRCA1- > Syncytial growth pattern (> 75%) associated carcinomas, versus 2% in control populations. However, the pres- > Absence of glandular structures ence of medullary features was found in 35% {1767} to 60% {121} of tumours aris- > Diffuse lymphoplasmacytic infiltrate, moderate to marked ing in BRCA1 carriers. Reciprocally, in a population of MC, germ line mutations of > Nuclear pleomorphism, moderate to marked BRCA1 was observed in 11% of theFig. 1.28 Medullary carcinoma. Note multinucleated cases {764}. There is thus a large overlap > Complete histological circumscriptionmalignant cells with atypical mitoses. between medullary features and the phe- Invasive breast cancer 29
  • 28. readily recognizable. The tumours range in size from less than 1 cm to over 20 cm, with an average of 2.8 cm {1498,2338, 2447,2934}. Histopathology Mucinous carcinoma is characterized by proliferation of clusters of generally uni- form, round cells with minimal amounts of eosinophilic cytoplasm, floating in lakes B of mucus. Delicate fibrous septae divide the mucous lake into compartments. The cell clusters are variable in size and shape; sometimes with a tubular arrangement; rarely, they assume a pap- illary configuration. Atypia, mitotic figures and microcalcifications are not common, but occur occasonaly. An intraepithe- lial component characterized by a mi- cropapillary to solid pattern is present in 30-75% of the tumours. The lakes of mucin are mucicarmine positive, butA C intracytoplasmic mucin is rarely present.Fig. 1.29 Mucinous carcinoma. A Mammogram showing small rounded density of less than 10 mm diame- A notable proportion of the lesions haveter in the upper-outer quadrant. B Ultrasound suggests mucinous carcinoma. C Low power view of the neuroendocrine differentiation {150,855}mucinous carcinoma. easily demonstrable by Grimelius stain or immunoreaction for chromogranin andMucin producing carcinomas ICD-O code 8480/3 synaptophysin (see also neuroendocrine carcinoma of breast).Definition Synonyms The descriptive term cellular mucinousA variety of carcinomas in the breast are Colloid carcinoma, mucoid carcinoma, carcinoma has been used by somecharacterized by production of abundant gelatinous carcinoma. {1751} to differentiate the endocrine vari-extracellular and/or intracellular mucin. ant of mucinous carcinoma from the non-Among these are mucinous (colloid) car- Epidemiology endocrine one; presence of intracyto-cinoma, mucinous cystadenocarcinoma, Pure mucinous carcinoma accounts for plasmic neuroendocrine granules doescolumnar cell mucinous carcinoma and about 2% of all breast carcinomas not always correlate with the degree ofsignet ring cell carcinoma. {2338,2590,2934}. It occurs in a wide cellularity, however. age range, but the mean and median Traditionally, pure and mixed variantsMucinous carcinoma age of patients with mucinous carcinoma of mucinous carcinoma have been in some studies is somewhat higher than described {1498,2934}. A pure tumourMucinous carcinoma is characterized by that of regular infiltrating carcinomas, must be composed entirely of mucinousa proliferation of clusters of generally being often over 60 years {2447,2590}. carcinoma. The pure mucinous carcino-small and uniform cells floating in large mas are further subdivided into cellularamounts of extracellular mucus often vis- Clinical features and hypocellular variants. The former isible to the naked eye. The tumours usually present as a pal- more likely to have intracytoplasmic pable lump. The location is similar to mucin and argyrophilic granules. As that of breast carcinomas in general. soon as another pattern becomes evi- Mammographically, mucinous carcinoma dent as a component of the tumour appears as a well defined, lobulated mass, the lesions qualifies as a mixed lesion. On magnification or compression tumour (the proportion of the different views {547}, a less defined margin components should be noted). The most may become more evident. The mam- common admixture is with regular inva- mographic resemblance to a benign sive duct carcinoma. process (circumscription and lobulation) increases with increasing mucin content. Differential diagnosis The two lesions most likely to be con- Macroscopy fused with mucinous carcinoma are myx- The typical glistening gelatinous appear- oid fibroadenoma and mucocoele likeFig. 1.30 Mucinous carcinoma. 38 year old patient, ance with bosselated, pushing margins lesion {2417}. The presence of com-tumour excision. and a soft consistency make the lesion pressed spaces lined by epithelial and30 Tumours of the breast
  • 29. myoepithelial cells in fibroadenomas, {2590,2934}. In general, pure mucinous mucin that appears either cystic (muci-along with mast cells within the myxoid carcinomas have a favourable prognosis nous cystadenocarcinoma) or solidstroma, helps in its recognition. {844,2590,2934}. The ten-year survival (columnar cell mucinous carcinoma) toIn mucocoele-like lesions, the presence ranges from 80% {1498} to 100% the naked eye.of myoepithelial cells adhering to the {844,2053}. Pure mucinous carcinomasstrips of cells floating in the lakes of have a far better prognosis than the ICD-O codemucus serves as an important clue to mixed variety with at least a 18% differ- Mucinous cystadenocarcinoma 8470/3their benign nature; the cell clusters in ence in survival rates noted in severalmucinous carcinoma are purely epithe- studies {1498,2053,2934}. About 10% of Epidemiologylial. The presence of ducts variably dis- women with the pure form die of their Only four examples of mucinous cys-tended by mucinous material adjacent to cancer compared to 29% of those with tadenocarcinoma and two of the solida mucocoele is another helpful clue in the mixed type {1498,2053}. A similar dif- columnar cell type have been reporteddistinguishing mucocoele-like lesions ference also exists in the incidence of {1486}. They occurred in women 49 to 67from mucinous carcinomas. axillary node metastases for pure and years of age. mixed types; only 3-15% of the pure vari-Immunoprofile and ploidy ety show axillary node metastases com- Clinical featuresTypically mucinous carcinoma is estro- pared to 33-46% of the mixed type The clinical features of mucinous cys-gen receptor positive {2669}, while less {82,1498,2338}. Late distant metastases tadenocarcinomas are similar to com-than 70% {691} are progesterone recep- may occur {502,2447,2934}. mon infiltrating ductal carcinomas.tor positive. Nearly all pure mucinous car- A rare cause of death among womencinomas are diploid, while over 50% of with mucinous carcinoma is cerebral Macroscopythe mixed variety are aneuploid {2933}. infarction due to mucin embolism to the The tumours vary in size from 0.8 to 19 cerebral arteries {2944}. cm, are cystic and display a gelatinousPrognosis and predictive factors appearance with abundant mucoidPrognostic factors relevant to breast car- Mucinous cystadenocarcinoma material simulating an ovarian mucinouscinomas in general are also applicable to and columnar cell mucinous tumour.pure mucinous carcinomas. Tumour cel- carcinomalularity has also been implicated in that Histopathologycellular tumours are associated with a Definition Microscopically, both of these variants,worse prognosis {502}. The presence or A carcinoma composed of generally tall, are composed of tall columnar muci-absence of argyrophilic granules had no columnar cells with basally located bland nous cells with abundant intracyto-prognostic significance in two studies nuclei and abundant intracytoplasmic plasmic mucin and basal nuclei. In theA A BB C DFig. 1.31 Mucinous carcinoma. A Hypercellular Fig. 1.32 A Mucinous cystadenocarcinoma. Papillary processes lined by mucinous columnar cells protudevariant with large clusters of densely packed into cystic spaces. B Mucinous cystadenocarcinoma. Many of the invasive cells are immunoreactive tomalignant cells. B Hypocellular variant. Lakes of CK34βE12. C Combined mucinous and infiltrating ductal carcinoma. A favourable prognosis associated withmucus are separated by fibrous septae. A few iso- pure mucinous carcinoma is no longer expected when it is admixed with regular infiltrating duct carcino-lated or clusters of carcinoma cells are floating in ma. D Signet ring cell carcinoma. The invasive cells assume a lobular growth pattern and contain abundantthe mucus lakes. intracytoplasmic mucin conferring a signet-ring cell appearance to the cells. Invasive breast cancer 31
  • 30. Table 1.07 Endocrine hormone related syndromesCriteria for the differential diagnosis of mucin producing carcinomas. are exceptionally rare. Of interest is the Histological type Location of mucin Growth pattern In situ component increase in the blood of neuroendocrine markers such as chromogranin A. Mucinous (colloid) Extracellular Clusters of cells Ductal carcinoma in mucus lakes Macroscopy NE breast carcinomas can grow as infil- Mucinous Intracellular and Large cysts, columnar Ductal trating or expansile tumours. The consis- cystadenocarcinoma extracellular cells, epithelial tency of tumours with mucin production stratification, papillae, is soft and gelatinous. solid areas Columnar mucinous Intracellular Round and convoluted Ductal Histopathology carcinoma glands lined by a single Most NE breast carcinomas form alveolar layer of columnar cells structures or solid sheets of cells with a tendency to produce peripheral palisad- Signet ring cell carcinoma Intracellular Isolated cells, cords, Mainly ing. However, they may present as differ- clusters lobular ent subtypes, depending on the cell type, grade, degree of differentiation and presence of mucin production. The lattercystic variant numerous cysts of vari- the cell. This type of signet ring cell car- is observed in 26% of cases {2535}.able size are formed, some with papil- cinoma can be seen in association withlary fronds lined by a single layer of pre- the signet ring cell variant of DCIS Solid neuroendocrine carcinomadominantly bland appearing, columnar {1143}.mucinous cells. Focal atypia character- These tumours consist of densely cellu-ized by nuclear pleomorphism (but lar, solid nests and trabeculae of cellssparse mitotic activity), loss of polarity Neuroendocrine tumours that vary from spindle to plasmacytoidand eosinophilic cellular transformation and large clear cells {2536} separatedis invariably present, as is invasion of Definition by delicate fibrovascular stroma. Insurrounding stroma by most often the Primary neuroendocrine (NE) carcino- some tumours, the nests are packedeosinophilic cells. Axillary node metas- mas of the breast are a group, which into a solitary, well defined to lobulatedtases occur in a quarter of mucinous exhibits morphological features similar mass; the tumour cells rarely formcystadenocarcinomas. to those of NE tumours of both gastroin- rosette-like structures and displayThe columnar cell variant is composed testinal tract and lung. They express peripheral palisading reminiscent ofof a compact to loose aggregation of neuroendocrine markers in more than carcinoid tumour.round and convoluted glands lined by a 50% of the cell population. Breast carci- Some of these appear to originate fromsingle layer of generaly tall, columnar noma, not otherwise specified, with focal solitary, solid papillary intraductal carci-mucimous epithelium with bland, basal endocrine differentiation, revealed by nomas. Others form multiple, often round-nuclei and rare mitotic figures. immunocytochemical expression of neu- ed solid nests separated by a dense, col- roendocrine markers in scattered cells, lagenous stroma resembling the alveolarPrognosis and predictive factors is not included this group. pattern of invasive lobular carcinoma.After a maximum follow-up of only 2 Mitotic activity ranges from 4 in the carci-years, none of the patients has deve- Synonym noid-like tumour to 12 in the alveolar vari-loped a recurrence or metastasis. Endocrine carcinoma. ant; focal necrosis may be seen. The tumour cells contain NE granules.Signet ring cell carcinoma Epidemiology NE breast carcinomas represent about Small cell / oat cell carcinomaICD-O code 8490/3 2-5% of breast carcinomas. Most patients are in the 6th or 7th decades of life {2535}. ICD-O codesSignet ring cell carcinomas are of two N e u roendocrine diff e rentiation also Small cell carcinoma 8041/3types. One type is related to lobular car- occurs in male breast carcinoma {2591}. Oat cell carcinoma 8042/3cinoma and is characterized by largeintracytoplasmic lumina which com- Clinical features This is morphologically indistingui-press the nuclei towards one pole of the There are no notable or specific diffe- shable from its counterpart in the lungcell {1849}. Their invasive component rences in presentation from other tumour on the basis of histological andhas the targetoid pattern of classical types. Patients often present with a pal- immunohistochemical features {2662}.lobular carcinoma. The other type is pable nodule, which usually appears as The tumours are composed of denselysimilar to diffuse gastric carcinoma, and a circumscribed mass on mammo- packed hyperchromatic cells with scantis characterized by acidic mucosub- graphic and ultrasound examination. cytoplasm and display an infiltrativestances that diffusely fill the cytoplasm Patients with small cell carcinoma growth pattern. An in situ componentand dislodge the nucleus to one pole of often present at an advanced stage. with the same cytological features may32 Tumours of the breast
  • 31. A BFig. 1.33 Neuroendocrine carcinoma. A Tumour cells are polarized around lumina; some cells show eosinophilic granules – carcinoid-like pattern. B IHC stainingis positive for present. Areas of tumour necrosis apocrine marker GCDFP-15, which is pression for neuroendocrine markers incontaining pyknotic hyperc h ro m a t i c frequently expressed by well and mod- scattered cells; this feature is noted innuclei are rarely detectable. Crush arte- erately differentiated endocrine breast 10-18% of breast carcinomas of thefact and nuclear streaming occur, but carcinomas {2535}, are supportive of a usual type. Such focal neuroendocrineare more typical of aspiration cytology primary breast carcinoma. differentiation does not seem to carry asamples. Lymphatic tumour emboli are Mammary small cell carcinoma can be special prognostic or therapeutic signif-frequently encountered. confused histologically with lobular car- icance {1876}. cinoma. The negative immunoreactionLarge cell neuroendocrine for E-cadherin in lobular carcinomas, in Immunoprofilecarcinoma contrast to a positive reaction in 100% Argyrophilia demonstrated by Grimelius of small cell carcinomas, is useful in the silver precipitation is a feature of neu-ICD-O code 8013/3 differential diagnosis {2661}. roendocrine breast carcinomas. Only It is also important to differentiate neu- darkly granulated cells should be con-These poorly differentiated tumours are roendocrine breast carcinomas from sidered as argyrophilic {2536}.composed of crowded large clusters of carcinomas with neuroendocrine differ- Expression of chromogranin proteinscells, with moderate to abundant cyto- entiation. The latter have immunoex- and/or synaptophysin also confirmedplasm, nuclei with vesicular to finelygranular chromatin and a high number ofmitotic figures ranging from 18 to 65 per10 hpf. Focal areas of necrosis are pres-ent {2535}. These tumours exhibit neu-roendocrine differentiation similar tothose encountered in the lung (see alsobelow).Differential diagnosisA nodule of NE carcinoma in the breastmay reflect metastatic carcinoid orsmall cell carcinoma from another site{2022}. Immunohistochemistry mayhelp to distinguish between metastaticand primary small cell carc i n o m a s .Mammary small cell carcinomas arecytokeratin 7-positive and cytokeratin20-negative, whereas, for example, pul-monary small cell carcinomas are neg-ative for both {2662}. The presence ofDCIS with similar cytological features issupportive of breast origin. In addition,the expression of estrogen (ER) and Fig. 1.34 Neuroendocrine carcinoma of the breast.Alveolar pattern with rounded solid nests of spindle cellsprogesterone receptors (PR) and of the invading a dense collagenous stroma. Invasive breast cancer 33
  • 32. evidence of neuroendocrine differentia- The presence of clear vesicles of pre- Invasive papillary carcinomation {2533}. These proteins are identifi- synaptic type is correlated with theable by immunohistochemical and expression of synaptophysin. Definitionimmunoblot analysis. Poorly and mod- Both dense core granules and mucin When papillary intraductal carcinomaserately differentiated endocrine breast vacuoles are present in neuroendocrine invade, they generally assume the pat-carcinomas of the alveolar subtype, in mucinous carcinomas {1265}. tern of infiltrating duct carcinoma andgeneral, express chromogranin A. The lack a papillary architecture. Most of themRNA specific for chromogranin A is Genetics published literature concerning papillarydetectable by in situ hybridization tech- N e u roendocrine breast carc i n o m a s carcinomas of the breast probably in-nique {2535}. About 50% of well or have not been correlated to specific clude both invasive and in situ papillarymoderately diff e rentiated tumours gene mutations. lesions as they do not generally specifyexpress chromogranin B and A and features of an invasive process {413,only 16% express synaptophysin Postulated normal counterpart 603,969,1269,1604,1618,1834}. In this{2535}. A monoclonal antibody against Argyrophilic and chromogranin A-reac- section, however, only data concerningn e u rone-specific enolase (NSE) has tive cells, located between the basal invasive papillary carcinomas will bealso been used and is expressed in myoepithelial and the luminal epithelial reviewed. Invasive papillary carcinomas100% of small cell carcinomas of the cells, have been demonstrated in histo- comprise less than 1-2% of invasivebreast {2662}, whereas chromogranin A logically normal breast tissue surround- breast cancers, and are characterized byand synaptophysin are expressed in ing infiltrating and in situ neuro e n- a relatively good prognosis {879,2567}.about 50% of such cases. In addition, docrine breast carcinomas {382,1995,20% of small cell mammary carcinomas 2542,2956}. ICD-O code 8503/3express thyroid transcription factor-1(TTF-1) {2661}. Prognosis and predictive factors Clinical featuresImmunodetection of pan-endocrine Histological grading is one of the most Invasive papillary carcinomas are diag-markers may fail to recognize endo- important prognostic parameters. nosed predominantly in postmenopausalcrine tumours, which produce but do NE breast carcinomas may be graded patients. Fisher et al. {879} noted a dis-not retain the specific antigen in the using classical criteria described else- proportionate number of cases in non-cells. Estrogen (ER) and progesterone where. Caucasian women. Similar to medullaryreceptors (PR) are expressed in the Excluding the rare small cell variety, carcinomas, Fisher et al. noted that amajority of tumour cells in well differen- 45% of NE breast carcinomas are well significant proportion of patients withtiated tumours {2535}, and in more than differentiated, 40% are moderately dif- invasive papillary carcinoma exhibit axil-50% of small cell carcinomas {2662}. ferentiated, and only 15% are poorly dif- lary lymphadenopathy suggestive ofExpression of somatostatin receptors ferentiated. Small cell NE carcinomas metastatic disease, but which on patho-(SSR), a known feature of tumours should be considered as undifferentiat- logical examination is due to benignshowing neuroendocrine differentiation, ed carcinomas {2535}. reactive changes {879}.has been demonstrated in endocrine Mucinous differentiation is a favourable Mammographically, invasive papillarybreast carcinomas as well {2169}. prognostic factor {2535}. carcinoma is usually characterized by The prognosis of primary small cell car- nodular densities which may be multiple,Ultrastructure cinomas of the breast depends on the and are frequently lobulated {1880, 2567}.Different types of dense core granules, stage of disease at the time of diagno- These lesions are often hypoechoic onwhose neurosecretory nature is con- sis. It has been demonstrated that low ultrasound {1827}. One study noted thefirmed by ultrastructural immunolocal- stage small cell carcinomas respond to difficulty in distinguishing between intra-ization of chromogranin A have been conventional treatment without progres- cystic papillary carcinoma, intracysticidentified by electron microscopy in sion of the disease at a follow up of 33 papillary carcinoma with invasion, andendocrine breast carcinomas {397}. to 48 months {2662}. invasive papillary carcinoma {1827}.A B CFig. 1.35 Invasive papillary carcinoma. A Microfocus magnification image of a papillary carcinoma shows a low density rounded tumour. B Large section histology.C Ultrasonography shows a lobulated, well delineated lesion.34 Tumours of the breast
  • 33. MacroscopyFisher et al. reported that invasive papil-lary carcinoma is grossly circumscribedin two-thirds of cases {879}. Other inva-sive papillary carcinomas are grosslyindistinguishable from invasive breastcancers of no special type.HistopathologyOf the 1,603 breast cancers reviewed in A Bthe NSABP-B04 study, 38 had papillary Fig. 1.36 Papillary carcinoma with invasion. A Overview of an intraductal papillary carcinoma, present atfeatures, and all but 3 of these were the centre, with invasive carcinoma apparent in the upper right side of the lesion. B Higher magnification"pure," without an admixture of other his- shows an infiltrating duct carcinoma pattern by the invasive component of the lesion while the in situ regiontologic types {879}. Microscopically, is clearly papillary.expansile invasive papillary carcinomasare characteristically circumscribed,show delicate or blunt papillae, and show carcinoma {868,871,879}. Among 35 sive micro p a p i l l a ry carcinoma wasfocal solid areas of tumour growth. The patients with this tumour in the NSABP- coined by Siriaunkgul and Tavassolicells typically show amphophillic cyto- B04 trial, after 5 years median follow-up, who first described nine examples ofplasm, but may have apocrine features, there were only 3 treatment failures, this lesion {707}. While quite rare in itsand also may exhibit apical "snouting" of including 1 patient who died fro m pure form, focal micropapillary growthcytoplasm similar to tubular carcinoma. metastatic papillary carcinoma. These has been reported in 3-6% of more com-The nuclei of tumour cells are typically survival data were similar to those mon types of invasive carc i n o m a sintermediate grade, and most tumours reported in patients with pure tubular {1982,2194}. It occurs in the same ageare histologic grade 2 {879}. Tumour stro- and mucinous carcinomas in this study range as invasive ductal carcinoma ofma is not abundant in most cases, and {879}. A later publication updating the no special type.occasional cases show prominent extra- NSABP-B04 results at 15 years revealedcellular mucin production. Calcifications, that patients with "favourable" histology Clinical featuresalthough not usually evident mammo- tumours (including invasive papillary Invasive micropapillary carcinoma usual-graphically, are commonly seen histolog- carcinomas) still had significantly better ly presents as a solid mass. Axillaryically, but usually are present in associat- survival in univariate analysis, but lymph node metastases are present ated DCIS. DCIS is present in more than tumour histology was not an independ- first presentation in 72-77% {707,1715,75% of cases, and usually, but not exclu- ent predictor of survival in multivariate 1982,2194,2229,3049} .sively, has a papillary pattern. In rare analysis {871}. However, node-negativelesions in which both the invasive and in patients with invasive papillary carcino- Macroscopysitu components have papillary features, mas enrolled in the NSABP-B06 trial Pure micropapillary carcinoma has a lob-it may be difficult to determine the relative experienced improved survival after 10 ulated outline due to the expansive modeproportion of each. Lymphatic vessel years follow-up compared to patients of growth.invasion has been noted in one third of with carcinomas of no special type, andcases. Microscopic involvement of skin or tumour histology was an independent Histopathologynipple was present in 8 of 35 cases p redictor of survival in multivariate Micropapillary carcinoma consists of hol-(23%), but Paget disease of the nipple analysis {868}. low aggregates of malignant cells, whichwas not observed {879}. on cross section have the appearance ofEstrogen receptor positivity was ob- tubules with diminished or obliteratedserved in all 5 cases of invasive papillary Invasive micropapillary lumens rarely containing pyknotic nuclei.carcinoma examined in one study, and carcinoma These tumour cell cluster lie within arti-progesterone receptor positivity in 4 of 5 factual stromal spaces caused by shrink-(80%) {2351}. In a review of cytogenetic Definition age of the surrounding tissue. The stro-findings in 5 examples of invasive papil- A carcinoma composed of small clusters mal spaces lack an endothelial lining andlary carcinoma, 60% exhibited relatively of tumour cells lying within clear stromal may be part of a speculated "missingsimple cytogenetic abnormalities {40}. In spaces resembling dilated vascular lymphatic labyrinth" in mammary stromaaddition, none of the 4 examples of pap- channels. {1152}. Nuclear pleomorphism is mode-illary carcinomas examined in two recent rate, mitotic activity low, and there is nei -reports were associated with either TP53 ICD-O code 8507/3 ther necrosis nor lymphocytic reaction. Inprotein accumulation or ERBB2 oncopro- non-pure tumours, gradual or abrupttein overexpression {2440,2750}. Epidemiology transitions from typical invasive ductal Carcinomas with a dominant micropapil- carcinoma to the micropapillary compo-Clinical course and prognosis lary growth pattern account for less than nents are found. Peritumoural angioinva-There are only limited data on the prog- 2% of all invasive breast cancers {707, sion may be present in up to 60% ofnostic significance of invasive papillary 1715,1982,2194,2229}. The term inva- cases. Intravascular tumour emboli, Invasive breast cancer 35
  • 34. predominantly of apocrine cells consti- tute at the most 4% of all invasive carci- nomas; focal apocrine cells diagnosed either by histology, immunohistoche- mistry or genetic techniques are fre- quent and occur in at least 30% of "ordi- nary" invasive carcinomas {1700}. Clinical features There is no difference between the clin- ical or mammographic features, size and site of carcinomas among apocrine and non-apocrine lesions. Bilaterality is rare in apocrine carcinomas. Histopathology Any type and grade of breast carcinoma can display apocrine diff e re n t i a t i o n including ordinary invasive duct carci- nomas, tubular, medullary, papillary, m i c ro p a p i l l a ry and neuro e n d o c r i n eFig. 1.37 Invasive micropapillary carcinoma. Tumour cell clusters with irregular central spaces proliferate types {17,569,809,1700}, as well aswithin empty stromal spaces. Some clusters have reversed polarity with an “inside out” morphology. classical and pleomorphic invasive lob- ular carcinomas {802,808}. However, recognition of apocrine carcinoma atlymph node metastases and malignant ICD-O code 8401/3 present has no practical importancecells in pleural fluids all show the same and is only of academic value.arrangement found in the primary Epidemiology Apocrine lobular in situ neoplasiastumour. The reported incidence of apocrine car- {802,2534}, and apocrine ductal in situ cinoma depends on the method of carcinomas (ADCIS) are also well rec-Prognostic and predictive features detection. Based on light microscopy ognized {17,1605,2887}. Apocrine car-This unusual growth pattern is correlat- alone it is only 0.3-4% {149,910}. An cinomas, whatever their origin, are usu-ed with the presence of vascular inva- ultrastructural study found a frequency ally composed by two types of cells var-sion and axillary lymph node metas- of 0.4% for apocrine carcinomas in a iously intermingled {804}. Type A celltases. In multivariate analyses, however, prospective series {1926}. recognized first by most authors hasa micropapillary growth pattern has no Immunohistochemical studies using abundant granular intenselyindependent significance for survival anti GCDFP-15, a putative marker of eosinophilic cytoplasm. The granules{1982,2194}. apocrine diff e rentiation {1800} gave are periodic acid-Schiff positive after conflicting data with an incidence rang- diastase digestion. Their nuclei varyApocrine carcinoma ing from 12% {809} to 72% {3113}. from globoid with prominent nucleoli to Twenty seven per cent of cases were hyperchromatic. Some tumours, whenDefinition positive with an in situ hybridization constituted by a pure proliferation ofA carcinoma showing cytological and method using a mRNA probe against type A cells, superficially mimic granu-immunohistochemical features of apoc- the sequence of the GCDFP-15 {1700}. lar cell tumours. This type of apocrinerine cells in >90% of the tumour cells. In conclusion, carcinomas composed carcinoma has sometimes been referredA B CFig. 1.38 Invasive micropapillary carcinoma. A Note the prominent vascular invasion and occasional pyknotic nuclei within the central spaces. B Lymph node metas-tasis. C EMAstaining of of the peripheral cell membranes suggestive of an ‘inside out’ morphology.36 Tumours of the breast
  • 35. Fig. 1.39 Apocrine carcinoma. Note abundant Fig. 1.40 Apocrine carcinoma, surperficially resem- Fig. 1.41 Apocrine carcinoma. Immunostaining showseosinophilic cytoplasm and vesicular nuclei. bling a granular cell tumour. intense positivity for as myoblastomatoid {806}. Type B Genetics Most patients present with a well circum-cell shows abundant cytoplasm in which Molecular studies in benign, hyperplas- scribed palpable mass, with a medianfine empty vacuoles are seen. These lat- tic and neoplastic apocrine lesions par- size of 3-4 cm, in some reports moreter result in foamy appearance so that allel those seen in non apocrine than half of these tumours measure overthe cells may resemble histiocytes and tumours {1357,1673}. 5 cm, with some massive lesions (>20sebaceous cells. Nuclei are similar to cm) which may displace the nipple andthose in type A cells. These same cells Prognosis and predictive factors ulcerate through the skin.have been designated as sebocrine Survival analysis of 72 cases of invasive On mammography, most metaplastic{2876}. (See also Sebaceous carcino- apocrine duct carcinoma compared with carcinomas appear as well delineatedma, page 46). Carcinomas composed non apocrine duct carcinoma revealed mass densities. Microcalcifications arepurely of foamy apocrine cells may no statistical difference {17,809}. not a common feature, but may be pres-surperfically resemble a histiocytic pro- ent in the adenocarcinomatous areas;liferation or even an inflammatory reac- ossification, when present, is, of course,tion {806}. In difficult cases, both granu- Metaplastic carcinomas apparent on mammography.lar cell tumours and histiocytic prolifera-tions can be easily distinguished by Definition Macroscopystaining the tumours with keratin anti- Metaplastic carcinoma is a general The tumours are firm, well delineatedbodies that are positive only in apocrine t e rm referring to a hetero g e n e o u s and often solid on cut surface. Squa-carcinomas. group of neoplasms generally charac- mous or chondroid differentiation is terized by an intimate admixture of ade- reflected as pearly white to firm gliste-Immunoprofile nocarcinoma with dominant areas of ning areas on the cut surface. One largeApocrine carcinomas are typically spindle cell, squamous, and/or mes- and/or multiple small cysts may beGCDFP-15 positive and BCL2 protein enchymal differentiation; the metaplas- apparent on the cut surface of largernegative. Expression of GCDFP-15 is a tic spindle cell and squamous cell car- squamous tumours.feature common to many variants of cinomas may present in a pure formbreast carcinoma, however, and has without any admixture with a recogniza-been used to support breast origin in ble adenocarcinoma. Metaplastic carci- Table 1.08metastatic carcinomas of unknown pri- nomas can be classified into broad Classification of metaplastic carcinomas.mary site. Estrogen and progesterone subtypes according to the phenotypicreceptors are usually negative in apoc- appearance of the tumour. Purely epithelialrine carcinoma by immonuhistochemi- Squamouscal assessment. Interestingly, many ER-, ICD-O code 8575/3 Large cell keratinizingPR- apocrine carcinomas do have theERmRNA, but fail to produce the protein Synonyms Spindle cell{336}. The expression of other biologi- Matrix producing carcinoma, carcino- Acantholyticcal markers is in general similar to that sarcoma, spindle cell carcinoma. Adenocarcinoma with spindle cell differentiationof other carcinomas {177,1605,2425}. Adenosquamous, including mucoepidermoidAndrogen receptors have been report- Epidemiologyed as positive in 97% of ADCIS in one Metaplastic carcinomas account forseries {1605} and 81% in another less than 1% of all invasive mammary Mixed epithelial and Mesenchymal{2624}. Sixty-two percent of invasive carcinomas {1273}. The average age at (specify components)duct carcinomas were positive in the presentation is 55. Carcinoma with chondroid metaplasialatter series {2624} and in 22% of cases Carcinoma with osseous metaplasiain another study {1874}. The signifi- Clinical features Carcinosarcoma (specify components)cance of AR in apocrine carcinomas is Clinical presentation is not different fromuncertain. that of infiltrating duct NOS carcinoma. Invasive breast cancer 37
  • 36. Squamous cell carcinoma graded based mainly on nuclear fea- tures and, to a lesser degree, cytoplas- A breast carcinoma entirely composed mic differentiation. of metaplastic squamous cells that may be keratinizing, non-keratinizing or spin- Immunoprofile dled; they are neither derived from the The spindle cell and acantholytic vari- overlying skin nor represent metastases ants require immunohistochemical con- from other sites. firmation of their epithelial nature. The epithelial tumour cell components are ICD-O codes positive for broad spectrum and high Squamous cell carcinoma 8070/3 molecular weight cytokeratins (CK5 Large cell keratinizing variant 8071/3 and CK34betaE12), but negative forFig. 1.42 Squamous cell carcinoma. A well cir- Spindle cell variant 8074/3 vascular endothelial markers. Nearly allcumscribed mass shows numerous irregularly Acantholytic variant 8075/3 squamous cell carcinomas are nega-shaped depressions on cut surface. tive for both estrogen (ER) and proges- Histopathology terone receptors (PR) {3059,3061}. Squamous cell carcinomas assume several phenotypes including large Adenocarcinoma with spindle cell cell keratinizing, non-keratinizing, and metaplasia less frequently spindle cell and acan- tholytic types; some show a combina- Definition tion of these patterns {752,987,1022, An invasive adenocarcinoma with abun- 1928,2520,2932,3061}. The most bland dant spindle cell transformation. The appearing and well differentiated cells spindle cells are neither squamous, nor often line cystic spaces; as the tumour mesenchymal, but rather glandular in cells emanate out to infiltrate the sur- nature. rounding stroma, they become spindle shaped and lose their squamous fea- ICD-O code 8572/3 tures. A pronounced stromal reaction is often admixed with the spindled Clinical featuresFig. 1.43 Squamous cell carcinoma, acan- squamous carcinoma. The squamous This tumour occurs mainly in post-tholytic variant, which is often mistaken for differentiation is retained in metastatic menopausal women and presents as aangiosarcoma. foci. Squamous cell carcinoma can be discrete mass. Pathologic features Macroscopically, a well circumscribed, solid mass, the tumour is composed of tubules of adenocarcinoma admixed with neoplastic spindle cells. The spindle cells immunoreact with epi- thelial markers including CK7, but not with CK5,6 or other markers of squamous/myoepithelial differentiation. At the ultrastructural level, the spindleA BC DFig. 1.44 Squamous cell carcinoma of the breast. A Macroscopically, there are often central cystic areas. Fig. 1.45 Adenocarcinoma with spindle cell meta-B Variously shaped spaces lined by squamous epithelium are characteristic of the more common mammary plasia. The spindle cells are neither squamous norsquamous cell carcinoma. C Higher magnification showing a range of squamous cell differentiation with the most mesenchymal, but rather glandular, intermixeddifferentiated at the right. D Immunostain for cytokeratins 5, 6 is positive as expected for squamous epithelium. with glands.38 Tumours of the breast
  • 37. cells contain intracytoplasmic lumensconfirming a glandular cell population.Adenosquamous carcinomaDefinitionAn invasive carcinoma with areas of welldeveloped tubule/gland formation inti-mately admixed with often widely dis-persed solid nests of squamous diffe-rentiation.ICD-O code 8560/3HistopathologyWhile focal squamous differentiationhas been observed in 3.7% of infiltra-ting duct carcinomas {878}, a promi-nent admixture of invasive ductal andsquamous cell carcinoma is rarely ob-served. The squamous component is Fig. 1.46 Adenosquamous carcinoma. Both glandular and squamous differentiation coexist in this carcinoma.often keratinizing, but ranges from verywell differentiated keratinizing areas topoorly diff e rentiated non-keratinizingfoci.Eight tumours described as examples oflow grade mucoepidermoid carcinoma,comparable to those occuring in thesalivary glands, have been reportedin the breast; these behave as lowgrade carcinomas {1130,1156,1515,1629,1709,2191,2234}.ImmunoprofileThe squamous component is negativefor both ER and PR, while the positivityof the ductal carcinoma componentfor ER and PR depends on its degree ofdifferentiation.Low grade adenosquamouscarcinomaLow grade adenosquamous carcinoma Fig. 1.47 Low grade adenosquamous carcinoma / infiltrating syringomatous adenoma. A highly infiltrative{2431} is a variant of metaplastic carci- growth pattern is responsible for the high frequency of local recurrence associated with many lesions.noma which is morphologically similar toadenosquamous carcinoma of the skinand has been classified by some as Clinical features may contain squamous cells, squamoussyringomatous squamous tumour {2816}. The age range at presentation is wide. pearls or squamous cyst formation. TheThe same lesion has been interpreted as These lesions usually present as a small stroma is typically "fibromatosis-like"an infiltrating syringomatous adenoma palpable mass between 5 and 80 mm in being cellular and composed of blandby others who prefer to avoid designa- size. spindle cells. The stromal componenttion of carcinoma for a group of lesions can, however, be collagenous, hyalinizedwhich mainly recur after local excision. Histology or variably cellular, and osteocartilage- These tumours are composed of small nous foci can occur rarely. It has beenICD-O code 8560/1 glandular structure and solid cords of recognized that some low grade epithelial cells haphazardly arranged in adenosquamous carcinomas may beSynonym an infiltrative spindle celled stromal com- found in association with a central scle-Infiltrating syringomatous adenoma. This ponent {2421,2995}. The proportions of rosing proliferation such as a radial scar,entity is also discussed in Tumours of these three components is variable sclerosing papillary lesion or sclerosingthe Nipple. between cases. The solid nests of cells adenosis {672,2421,2995}. The frequen- Invasive breast cancer 39
  • 38. Mixed epithelial / mesenchymal mesenchymal component fails to metaplastic carcinomas immunoreact with any epithelial marker. ICD-O code 8575/3 Differential diagnosis The differential diagnosis varies for the Synonyms different subtypes of metaplastic carci- Carcinoma with osseous metaplasia noma. (8571/3), carcinoma with chondroid Angiosarcoma may be confused with the metaplasia (8571/3), matrix producing acantholytic variant of squamous cell carcinoma, carcinosarcoma (8980/3). carcinoma, but focal areas of squamous differentiation can be found when sam- Histopathology pled thoroughly. A negative immunoreac- This wide variety of tumours, some of tion with vascular endothelial markers which are also regarded as "matrix pro- and a positive reaction with cytokeratins ducing carcinomas" {1414,2953}, show will support the diagnosis of an epithelial infiltrating carcinoma mixed with often neoplasm. heterologous mesenchymal elements Fibromatosis and a variety of spindled ranging from areas of bland chondroid mesenchymal tumours may be confused and osseous differentiation to frank with spindle cell squamous carcinoma; sarcoma (chondrosarcoma, osteosar- these are all generally negative for coma, rhabdomyosarcoma, liposarco- epithelial markers. ma, fibrosarcoma). When the mesen- Myoepithelial carcinoma is the most diffi- chymal component is malignant, the cult lesion to distinguish from spindle cell designation of carcinosarcoma is used. squamous carcinoma. The former oftenFig. 1.48 Mucoepidermoid carcinoma.This low Undifferentiated spindle cell elements has ducts with prominent to hyperplasticgrade invasive carcinoma is morphologically simi- may form part of the tumour. Grading is myoepithelial cells at its periphery, whilelar to its counterpart in the salivary glands. based mainly on nuclear features and, the latter may have clear cut focal squa- to a lesser degree, cytoplasmic differ- mous differentiation. Reactions to a vari-cy of ductal carcinoma in situ in associa- entiation. ety of immunostains may be similar, withtion with adenosquamous carcinomas is the possible exception of those myoepi-variable. These tumours lack estrogen Immunoprofile thelial carcinomas that are diffuselyreceptor expression {672,3142}. The spindle cell elements may show pos- S-100 positive. Electron microscopy may itive reactivity for cytokeratins, albeit be needed to distinguish some of thesePrognosis and predictive factors focally. Chondroid elements are frequent- lesions. Squamous carcinoma cells haveThe majority of case have an excellent ly S-100 positive and may coexpress abundant tonofilaments and well devel-prognosis, but a proportion of cases can cytokeratins, but are negative for actin. oped desmosomes whether spindled orbehave in a locally aggressive manner Many of these tumours are negative for polygonal. Intercellular bridges are{2995}, recurrence appears to be related ER and PR both in the adenocarcinoma abundant in the well differentiated areasto adequacy of local excision. Lymph and the mesenchymal areas, but the In contrast, the spindle cell myoepithelialnode metastatic spread is extremely rare adenocarcinoma component may be ER carcinomas often have pinocytotic vesi-and noted in a single case that was and PR positive if well to moderately dif- cles, myofibrils and basal lamina in addi-3.5 cm {2995}. ferentiated. In carcinosarcomas, the tion to tonofilaments and desmosomes.A B CFig. 1.49 A Metaplastic carcinoma with chondroid differentiation, 77 year old patient, mastectomy. B Carcinoma with mesenchymal (benign osseous and chondroid)differentiation. Typically, these carcinomas have a well delineated pushing margin. Areas of osseous and/or chondroid differentiation are variably scattered in anotherwise typical infiltrating ductal carcinoma. C Carcinoma with mesenchymal (benign osseous and chondroid) differentiation. The adenocarcinoma is admixed,in part, with chondroid matrix containing lacunar spaces and rare chondrocytes.40 Tumours of the breast
  • 39. A BFig. 1.50 Carcinosarcoma. A Two aggregates of carcinoma are separated by abundant sarcoma. B Immunostaining shows absence of reactivity with Kermix in the mes-enchymal component, while the epithelial cells are positive.The squamous and adenosquamous plasia, the five year survival has ranged the AFIP {2876}. A frequency of 0.8%carcinoma should be distinguished from from 28-68% {474,1273,3060}; those with was found in a study using Sudan III onpleomorphic carcinomas that may have spindle or squamous differentiation have frozen sections {3158}.either pattern admixed with a large num- a 63% 5-year survival {1273}. Advanced The age of patients with putative lipidber of bizarre tumour giant cells; this dis- stage and lymph node involvement is rich carcinoma ranges from 33 to 81tinction is important as pleomorphic car- associated with a more aggressive years. All except one were female, thecinomas are far more aggressive than course as anticipated. Among squamous exception being a 55-year-old maneither squamous or adenosquamous cell carcinomas, the acantholytic variant {1803}.carcinoma. may exhibit a more aggressive behaviourAdenocarcinomas with chondroid differ- {807}. Clinical featuresentiation should be distinguished from The carcinosarcomas are very aggres- Most patients have palpable nodules.pleomorphic adenomas. Pleomorphic sive tumours. Some metastasize as One case presented as Paget disease ofadenomas invariably have a myoepithe- mixed epithelial and mesenchymal the nipple {28}.lial cell component (that may be domi- tumours, while only the epithelial or thenant in some tumours) growing around sarcomatous component may metasta- Macroscopyspaces lined by benign epithelial cells. size in others. The tumour size in the cases reportedMyoepithelial cells are not evident in There is not much information available varies from 1.2 to 15 cm {3158}.adenocarcinomas with chondroid differ- on the efficacy of current therapies inentiation. the management of metaplastic carci- Histopathology nomas. Lipid-rich carcinoma should be distin-Prognosis and predictive factors of guished from other carcinomas with vac-metaplastic carcinomas ulated, clear cytoplasm {702}. If histo-Given the tumour size of >3-4 cm in Lipid-rich carcinoma chemical methods are employed onmany cases, metastases to axillary frozen breast carcinomas, up to 75%nodes are relatively uncommon; approxi- Definition contain cytoplasmic lipid droplets, butmately 10-15% of pure squamous cell A breast carcinoma in which approxi- only 6% in large quantities {873}; onlycarcinomas have axillary node metas- mately 90% of neoplastic cells contain these cases should be designated lipid-tases {503,1928}. About 19-25% of those abundant cytoplasmic neutral lipids. rich carcinoma.with chondro-osseous elements have Histology shows a grade III invasive car-axillary node metastases {752,1273, ICD-O code 8314/3 cinoma in most cases. There may be2259}, and 21% have distant metastases associated in situ lobular or ductal carci -{752}. Axillary node metastases were Synonym noma {28,2330}. The neoplastic cellsmore common (56%) among tumours Lipid secreting carcinoma. have large, clear, foamy to vacuolatedwith spindle and squamous metaplasia cytoplasm in which neutral lipids shouldin Huvos’s study {239}, however. When Epidemiology be demonstrable {2876}. The tumourmetaplastic carcinomas metastasize to Using conventional morphological fea- cells are devoid of mucins. Alpha lactal-the axillary nodes or beyond, they retain tures only (i.e. foamy to vacuolated clear bumin and lactoferrin were found in fiveand often manifest their metaplastic cells), incidences of <1-6%, have been cases while fat globule membrane anti-potential. In studies combining carcino- reported {28,2330,2988}. Four cases gen was evident in occasional cells onlymas with chondroid and osseous meta- only were seen within a 12-year period at {3158}. Invasive breast cancer 41
  • 40. Lobular neoplasia F.A. Tavassoli R.R. Millis W. Boecker S.R. LakhaniDefinition tectomy. No mammographic abnormali- cuous nucleoli. The two cell types mayCharacterized by a proliferation of gener- ties are recognized {2128,2273}, except be mixed. When composed of pleomor-ally small and often loosely cohesive in the occasional variant of LN characte- phic cells, the term pleomorphic LN hascells, the term lobular neoplasia (LN) rized by calcification developing within been used. The neoplastic cells eitherrefers to the entire spectrum of atypical central necrosis {2534}. replace or displace the native epithelialepithelial proliferations originating in the cells in the TDLU. The myoepithelial cellsterminal duct-lobular unit (TDLU), with or Macroscopy may remain in their original basal loca-without pagetoid involvement of terminal LN is not associated with any grossly tion or they may be dislodged andducts. In a minority of women after long- recognizable features. admixed with the neoplastic cells. Theterm follow-up, LN constitutes a risk fac- basement membrane is generally intacttor and a nonobligatory precursor for the Histopathology although this is not always visible in allsubsequent development of invasive The lesion is located within the terminal sections. Pagetoid involvement of adja-carcinoma in either breast, of either duc - duct-lobular unit {3091} with pagetoid cent ducts between intact overlying flat-tal or lobular type. involvement of the terminal ducts evident tened epithelium and underlying base- in as many as 75% of cases {86,1096}. ment membrane is frequent and canICD-O code On low power examination, while lobular result in several different patterns includ-Lobular carcinoma in situ (LCIS) 8520/2 architecture is maintained, the acini of ing a ‘clover leaf’ or ‘necklace’ appear- one or more lobules are expanded to ance {1099}. Solid obliteration of aciniSynonyms and historical annotation varying degrees by a monomorphic pro- may occur, sometimes with massive dis-The designations atypical lobular hyper- liferation of loosely cohesive, usually tension and central necrosis. LN mayplasia (ALH) and lobular carcinoma in small cells, with uniform round nuclei, involve a variety of lesions including scle-situ (LCIS) have been widely used for indistinct nucleoli, uniform chromatin rosing adenosis, radial scars, papillaryvariable degrees of the lesion. and rather indistinct cell margins with lesions, fibroadenomas and collagenousTwo series published in 1978 {1100, sparse cytoplasm. Necrosis and calcifica- spherulosis.2438} concluded that the features gene- tion are uncommon and mitoses are infre-rally used to subdivide the lobular quent. Intracytoplasmic lumens are often Immunoprofilechanges into LCIS and ALH were not present but are not specific to LN {89}. In LN is positive for estrogen receptor (ER)of prognostic significance. To avoid some lesions, however, the proliferating in 60-90% of cases and in a slightly lowerovertreatment, Haagensen suggested cells are larger and more pleomorphic or percentage for progesterone receptorthe designation lobular neoplasia (LN) of signet ring type. Apocrine metaplasia (PR) {62,369,1010,2159,2483}. The clas-for these lesions {1100}. To emphasize occurs but the existence of endocrine sical variety of LN is more likely to betheir non-invasive nature, the term lobu- variant of LN {801} is disputed. positive than the pleomorphic variantlar intraepithelial neoplasia (LIN) has Two types of LN have been recognized {223,2683}. Unlike high grade DCIS,been proposed. Based on morphological {1100}: Type A with the more usual mor- however, classic LN rarely expressescriteria and clinical outcome, LIN has phology described above and Type B ERBB2 or TP53 protein {62,2327a,2483,been categorized into three grades composed of larger, more atypical cells 2746}. Positivity is more likely with the{338}. with less uniform chromatin and conspi- pleomorphic variant {1859,2683}. Intra-EpidemiologyThe frequency of LN ranges from lessthan 1% {3106,3107} to 3.8 % {1099} ofall breast carcinomas. It is found in 0.5-4% of otherwise benign breast biopsies{2150}. Women with LN range in agefrom 15 {32} to over 90 years old {2876},but most are premenopausal.Clinical featuresThe lesion is multicentric in as many as A B85% of patients {2446,2876} and bilateral Fig. 1.74 Early lobular neoplasia. A The few neoplastic lobular cells are hardly apparent on a quick examinationin 30% {1096} to 67% {2001} of women of the TDLU. B Double immunostaining with E-cadherin (brown) and CK34BE12 (purple) unmasks the few neoplas-who had been treated by bilateral mas- tic cells (purple) proliferating in this lobule. These early lesions are often missed on H&E stained sections.60 Tumours of the breast
  • 41. A B CFig. 1.75 Lobular neoplasia. A Aggregates of loosely cohesive neoplastic cells proliferate beneath the native epithelial cell lining (pagetoid growth pattern).B Typically, the neoplastic cells are E-cadherin negative. C Immunostain for CK34BE12 shows a polarized positive reaction in the cytoplasm.cytoplasmic immunoreactivity for casein to the lobule without unfolding it (so the site of the E-cadherin gene, washas also been reported {1994,2149}. called lobular cancerization). The pres- found in approximately 30%. LOH wasE-cadherin, commonly identified in duc- ence of secondary lumina or a rosette- identified in LN associated with invasivetal lesions, is generally absent from both like arrangement of cells indicates a duc- carcinoma and in pure LN, suggestingLN and invasive lobular carc i n o m a tal lesion. In problematic cases, the that it may be a direct precursor of in-{1892,2336}. immunoprofile may be helpful. LN is typi- vasive lobular cancer. Further support cally E-cadherin and CK 5,6 negative, but for this hypothesis has come from aGrading HMW CK34BE12 positive {337}. DCIS, on report that showed LOH in 50% of LNA three tiered grading system has been the other hand, is typically E-cadherin associated with invasive carcinoma atsuggested, based on the extent and positive, but CK34BE12 negative. Occa- markers on chromosome 11q13 {1988}.degree of proliferation and/or cytologi- sional lesions are negative or positive for LOH was seen in 10% of ALH and 41%cal features. Those lesions with marked- both HMWCK34BE12 and E-cadherin of invasive lobular carcinomas. Usingly distended acini, often with central markers. Since, at present, it is uncertain comparative genomic hybridizationnecrosis, and those composed of either how these morphologically and immuno- (CGH), loss of chromosomal materials e v e rely pleomorphic cells or pure histochemically hybrid lesions with ductal from 16p, 16q, 17p and 22q and gainsignet ring cells with or without acinar and lobular features would behave, it is of material to 6q was identified indistension, were designated LIN 3; they important that they are recognized so that equal frequency in 14 ALH and 31 LCIShave been reported to be often associ- more can be learned about their nature inated with invasive carcinoma {2876}. the future {337}.This grading system requires validation When LN involves sclerosing adenosis orby other centres and is not endorsed at other sclerosing lesions, it can be con-this time. fused with an invasive carcinoma. The presence of a myoepithelial cell layerDifferential diagnosis around the neoplastic cell clustersPoor tissue preservation may give a false excludes the possibility of an invasiveimpression of loosely cohesive cells carcinoma; immunostaining for actin canleading to over-diagnosis of LN. unmask the myoepithelial cells, thusDistinction from a solid DCIS can be diffi- facilitating the distinction.cult on morphological grounds alone, Presence of isolated cells invading the Aparticularly when DCIS remains confined stroma around a focus of LN can cause diagnostic problems. Absence of myoepithelial cells around the individual cells and their haphazard distribution accentuated by any of the epithelial markers (optimally with double immunos- taining techniques) can help establish the presence of stromal invasion by indi- vidual or small clusters of neoplastic cells. B Fig. 1.77 Lobular neoplasia. A The acini are filled Molecular genetics and moderately distended by neoplastic cells; the Loss of heterozygosity (LOH) at loci fre- acinar outlines are retained. B Clover-leaf pattern.Fig. 1.76 Lobular neoplasia. CK5/6 immunohisto- quently observed in invasive carcinoma This is one of the classic patterns of LN, with thechemistry demonstrating the pagetoid spread of has also been reported in LN, ranging acini distended by neoplastic cells pulling awaytumour cells infiltrating the positively stained original from 8% on chromosome 17p to 50% on from the intralobular segment of the terminal duct,epithelium, leading to a reticulated staining pattern. 17q {1569}. LOH on chromosome 16q, creating a clover-leaf or necklace appearance. Lobular neoplasia 61
  • 42. lesions {1707}, suggesting that both areneoplastic and at a similar stage ofgenetic evolution.The most direct evidence for a precursorrole of LN comes from mutational analy-sis of the E-cadherin gene {259,260}. Inone study {261}, 27 of 48 (56%) invasivelobular carcinomas had mutation in theE-cadherin gene, while none of 50 breastcancers of other types showed any alter-ation. It was subsequently demonstratedthat truncating mutations identified ininvasive lobular carcinoma were alsopresent in the adjacent LN, providingdirect proof that LN was a precursorlesion {3034}.Prognosis and predictive factorsThe relative risk (RR) for subsequentdevelopment of invasive carcinoma Fig. 1.78 Lobular neoplasia. Loosely cohesive neoplastic cells are proliferating in this lobule, but they haveamong patients with LN ranges from 6.9 not distended the about 12 times that expected inwomen without LN {87,88,1100}.Amongst 1174 women in 18 separate ret-rospective studies, diagnosed as havingLN and treated by biopsy alone, 181(15.4%) eventually developed invasivecarcinoma {88,1096,1100,2150,2428,2438}. Of these, 102 (8.7%) developed inthe ipsilateral breast, and 79 (6.7%) inthe contralateral breast, demonstratingan almost equal risk for either breast.However, in a prospective study of 100 A Bcases of LN with 10 years of follow-up,11 of 13 invasive recurrences were ipsi-lateral {2127}.With extended follow-up, the risk ofdevelopment of invasive cancer contin-ues to increase to 35% for those womenwho survive 35 years after their initialdiagnosis of LN. Furthermore, the RRincreases substantially from 4.9 (95% CI:3.7–6.4) after one biopsy with LN to 16.1(95% CI:6.9–31.8) after a second biopsy C Dwith LN {298}. Fig. 1.79 Lobular neoplasia. A Necrotic type with massive distention of the acini. B Note the loosely cohe-Early studies suggested that among LN sive cells and the necrosis. C Lobular neoplasia, pleomorphic type. Even though there is not a significant dis- tention of the involved TDLU, the neoplastic cells are highly pleomorphic and loosely cohesive. This is thelesions, there are no clinical or pathologi- intraepithelial counterpart of pleomorphic invasive lobular carcinoma. D LN involving sclerosing features associated with increased The lobulated configuration of the sclerosing adenosis is apparent at low magnification. The ductules inrisk of subsequent invasive carcinoma part of the lesion are filled and expanded by proliferation of a monotonous neoplastic cell population. This{2150,2438}. However, a more recent setting may be confused with invasive carcinoma, particularly when the sections are using the three tiered grading sys-tem, but with a comparatively short fol-low-up of 5 years, found that LIN 3 and, to Management of LN has evolved with long-term follow-up. The current recom-a lesser extent LIN 2, were associated increased understanding of the disease mended management for LN is, there-with an increased risk {869}, but LIN 1 {1082}. The current consensus is that LN fore, life long follow-up with or withoutwas not. In another study, 86% of inva- constitutes a risk factor and a non obli- tamoxifen treatment. Re-excision shouldsive carcinomas associated with LIN 3 gate precursor for subsequent develop- be considered in cases of massive aci-were lobular in type, in contrast to 47% of ment of invasive carcinoma in either nar distension, and when pleomorphic,those associated with LIN 2 and only 11% breast, of either ductal or lobular type, signet ring or necrotic variants are identi-of those associated with LIN 1 {338}. but only in a minority of women after fied at or close to the margin.62 Tumours of the breast
  • 43. F.A. Tavassoli S.J. SchnittIntraductal proliferative lesions H. Hoefler W. Boecker J. Rosai S.H. Heywang-Köbrunner R. Holland F. Moinfar I.O. Ellis S.R. LakhaniDefinition alone, particularly with standardization of epithelial neoplasias which in the WHOIntraductal proliferative lesions are a histopathological criteria. However, even classification of tumours of the digestivegroup of cytologically and architecturally then, the distinction between some of the system have been defined as ‘lesionsdiverse proliferations, typically originating lesions (particularly between ADH and characterized by morphological changesfrom the terminal duct-lobular unit and some low grade forms of DCIS) remains that include altered architecture andconfined to the mammary duct lobular problematic. In addition, population- abnormalities in cytology and differentia-system. They are associated with an based mammography screening has tion; they result from clonal alterations inincreased risk, albeit of greatly different resulted in increased detection of lesions genes and carry a predisposition, albeitmagnitudes, for the subsequent develop- that show cytological atypia with or with- of variable magnitude, for invasion andment of invasive carcinoma. out intraluminal proliferation but do not metastasis’ {1114}. The WHO Working fulfil the diagnostic criteria for any of the Group felt that UDH is not a significantICD-O codes existing categories. Those lesions lack- risk factor and that at the time of theIn the ICD-O classification, /2 is used ing intraluminal projection have been meeting, there was insufficient geneticfor in situ carcinomas. The code 8500/2 described in the past as clinging carci- evidence to classify it as a precursorcovers all grades of ductal carcinoma in noma and more recently referred to lesion. However, a recent CGH studysitu and ductal intraepithelial neoplasia, under a variety of names including flat suggests that a subset of UDH can be agrade 3. epithelial atypia, atypical cystic lobules, precursor of ADH {1037}. atypical columnar alteration with promi-Site of origin and route of lesion nent apical snouts and secretions. Classification and gradingprogression These emerging genetic data and theA vast majority of intraductal proliferative Progression to invasive breast cancer increasingly frequent detection of ADHlesions originate in the terminal duct-lob - Clinical follow-up studies have indicated and low grade DCIS by mammographyular unit (TDLU) {3091}. A substantially that these intraductal proliferative lesions have raised important questions aboutsmaller proportion originates in larger are associated with different levels of risk the manner in which intraductal prolifera-and lactiferous ducts. for subsequent development of invasive tive lesions are currently classified.Segmentally distributed, ductal carcino- breast cancer, that ranges from approxi- Although used by pathology laboratoriesma in situ (DCIS) progression within the mately 1.5 times that of the reference worldwide, the traditional classificationduct system is from its origin in a TDLU population for UDH, to 4-5-fold (range, system suffers from high interobservertoward the nipple and into adjacent 2.4-13.0-fold) for ADH, and 8-10-fold for variability, in particular, in distinguishingbranches of a given segment of the duct DCIS {886}. Recent immunophenotypic between atypical ductal hyperplasiasystem. The rare lesions that develop and molecular genetic studies have pro- (ADH) and some types of low grade duc-within the lactiferous ducts may progress vided new insights into these lesions indi- tal carcinoma in situ (DCIS). Some mem -toward the nipple resulting in Paget dis- cating that the long-held notion of a linear bers of the Working Group proposed thatease or to the adjacent branches of a progression from normal epithelium the traditional terminology be replacedreference duct {2089,2090,2093}. through hyperplasia, atypical hyperplasia by ductal intraepithelial neoplasia (DIN), and carcinoma in situ to invasive cancer reserving the term carcinoma for invasiveTerminology is overly simplistic; the inter-relationship tumours. This would help to avoid theIntraductal proliferative lesions of the between these various intraductal prolif- possibility of overtreatment, particularlybreast have traditionally been divided erative lesions and invasive breast cancer in the framework of population-basedinto three categories: usual ductal hyper- is far more complex. In brief, these data mammography screening programmes.plasia (UDH), atypical ductal hyperplasia have suggested that: (1) UDH shares few In several other organ sites, the shift in(ADH) and ductal carcinoma in situ similarities with most ADH, DCIS or inva- terminology has already occurred e.g.(DCIS). It should be noted, however, that sive cancer; (2) ADH shares many simi- cervix (CIN), prostate (PIN) and in thethe term "DCIS" encompasses a highly larities with low grade DCIS; (3) low grade recent WHO classification of tumours ofheterogeneous group of lesions that dif- DCIS and high grade DCIS appear to rep- the digestive system {1114}.fer with regard to their mode of presenta- resent genetically distinct disorders lead- The majority of participants in the WHOtion, histopathological features, biologi- ing to distinct forms of invasive breast Working Group was in favour of maintain-cal markers, and risk for progression to carcinoma, further emphasizing their het- ing the traditional terminology which ininvasive cancer. In most cases, the erogeneity; and (4) at least some lesions Table 1.11 is shown next to the corre-histopathological distinction between dif- with flat epithelial atypia are neoplastic. sponding terms of the DIN classification.ferent types of intraductal proliferation These data support the notion that ADH For purposes of clinical managementcan be made on morphological grounds and all forms of DCIS represent intra- and tumour registry coding, when the Intraductal proliferative lesions 63
  • 44. DIN terminology is used, the traditional Table 1.11terminology should be mentioned as Classification of intraductal proliferative lesions.well. The classification of intraductal pro- Traditional terminology Ductal intraepithelial neoplasia (DIN)liferative lesions should be viewed as an terminologyevolving concept that may be modifiedas additional molecular genetic data Usual ductal hyperplasia (UDH) Usual ductal hyperplasia (UDH)become available. Flat epithelial atypia Ductal intraepithelial neoplasia,Diagnostic reproducibility grade 1A (DIN 1A)Multiple studies have assessed repro- Atypical ductal hyperplasia (ADH) Ductal intraepithelial neoplasia,ducibility in diagnosing the range of intra- grade 1B (DIN 1B)ductal proliferative lesions, some withemphasis on the borderline lesions {299, Ductal carcinoma in situ, Ductal intraepithelial neoplasia,503,2155,2157,2411,2571,2723,2724}. low grade (DCIS grade 1) grade1C (DIN 1C)These studies have clearly indicated thatinterobserver agreement is poor when no Ductal carcinoma in situ, Ductal intraepithelial neoplasia,standardized criteria are used {2411}. intermediate grade (DCIS grade 2) grade 2 (DIN 2)Although diagnostic reproducibility isimproved with the use of standardized cri- Ductal carcinoma in situ, Ductal intraepithelial neoplasia,teria {2571} discrepancies in diagnosis high grade (DCIS grade 3) grade 3 (DIN 3)persist in some cases, particularly in thedistinction between ADH and limited formsof low grade DCIS. In one study, consis- (FISH) analysis {1949}. Further evidence to 8 decades post adolescence. Alltency in diagnosis and classification did for genetic heterogeneity comes from these lesions are extremely rare prior tonot change significantly when interpreta- comparative genomic hybridization puberty; when they do occur amongtion was confined to specific images as (CGH) data of microdissected tissue in infants and children, they are generally acompared with assessment of the entire usual ductal hyperplasia (UDH), atypical reflection of exogenous or abnormaltissue section on a slide, reflecting incon- ductal hyperplasia (ADH) {135} and endogenous hormonal stimulation. Thesistencies secondary to differences in DCIS {134,366}. mean age for DCIS is between 50-59morphological interpretation {780}. While There has been a tendency to interpret years. Though most often unilateral,clinical follow-up studies have generally loss of heterozygosity as evidence for about 22% of women with DCIS in onedemonstrated increasing levels of breast clonal evolution and neoplastic transfor- breast develop either in situ or invasivecancer risk associated with UDH, ADH mation. However, histologically normal carcinoma in the contralateral breastand DCIS respectively, concerns about ductal epithelium closely adjacent to inva- {3055}.diagnostic reproducibility have led some sive ductal carcinoma may share an LOHto question the practice of utilizing these pattern with the carcinoma, while normal Macroscopyrisk estimates at the individual level {299}. ducts further away in the breast do not A vast majority of intraductal prolifera- {671}. LOH has been reported in normal tive lesions, particularly those detectedAetiology epithelial tissues of the breast, in associa- mammographically, are not evident onIn general, the factors that are associated tion with carcinoma and in reduction macroscopic inspection of the speci-with the development of invasive breast mammoplasties, however, the significance men. A small proportion of high gradecarcinoma are also associated with of these finding remains to be evaluated DCIS may be extensive enough andincreased risk for the development {671,1586,1945}. LOH has also been with such an abundance of intraluminalof intraductal proliferative lesions {1439a, identified in the stromal component of necrosis or associated stromal reaction1551a,2536a}. (See section on epidemio- in situ {1889} and invasive breast carcino- that it would present as multiple areas oflogy of breast carcinoma). ma {1545,1889}, in non-neoplastic tissue round, pale comedo necrosis or a firm, from reduction mammoplasty specimens gritty mass.Genetics of precursor lesions {1568}, and in normal-appearing breastTo date, several genetic analyses have ducts {1586}. The biological significancebeen performed on potential precursor of these alterations are still poorly under- Usual ductal hyperplasia (UDH)lesions of carcinoma of the breast. The stood, but the available data suggest thatsometimes contradictory results (see genetic alterations may occur very early in Definitionbelow) may be due to: (i) small number of breast tumorigenesis prior to detectable A benign ductal proliferative lesion typi-cases analysed, (ii) the use of different morphological changes and that epithe- cally characterized by secondaryhistological classification criteria, (iii) his- lial/stromal interactions play a role in pro- lumens, and streaming of the central pro-tomorphological heterogeneity of both the gression of mammary carcinoma. liferating cells. Although not considerednormal and neoplastic breast tissue and a precursor lesion, long-term follow-up of(iv) genetic heterogeneity, as identified by Clinical features patients with UDH suggests a slightlyeither conventional cytogenetics {1175} The age range of women with intraductal elevated risk for the subsequent devel-or by fluorescence in situ hybridization proliferative lesions is wide, spanning 7 opment of invasive carcinoma.64 Tumours of the breast
  • 45. absence of either microcalcifications or necrosis does not impact the diagnosis. UDH with necrosis, a rare event, may be mistaken for DCIS; the diagnosis should be based on the cytological features and not the presence of necrotic debris. UDH generally displays either diffuse or a mosaic pattern of positivity with high molecular weight cytokeratins {1963,A B 2126} such as CK5, CK1/5/10/14 (clone CK34betaE12 or clone D5/16 B4); it is also positive for E-cadherin. In UDH, the percentage of ER-positive cells was found slightly increased compared to the normal breast {2667}. Increased levels of cyclin D1 expression were recently described in 11-19% of UDH cases {1172,3264}. Genetic alterations Approximately 7% of UDH show someC D degree of aneuploidy. Loss of heterozy-Fig. 1.80 Usual ductal hyperplasia. A Florid type. The peripheral distribution of irregularly sized spaces is a gosity (LOH) for at least one locus, hascharacteristic of UDH readily apparent at low magnification. B The proliferating cells may form epithelial been noted in one-third of UDH {2071}.bridges, but the bridges are delicate and formed by spindled stretched cells. C Intensive, predominantly On chromosome 11p, LOH was presentsolid intraductal proliferation of a heterogeneous cell population. Note spindling of the cells. Several irreg- in 10-20% of UDH cases {72,2071}.ular peripheral luminal spaces. D Intraluminal proliferation with many CK5-positive and occasional CK5- Losses on 16q and 17p were identified innegative cells. UDH lesions without evidence of adjacent carcinoma {1037} whereas no alterationsSynonyms In some cases, the proliferation has a were reported by others {301}. In UDHIntraductal hyperplasia, hyperplasia of solid pattern and no secondary lumens adjacent to carcinoma, polysomy of chro-the usual type, epitheliosis, ordinary are evident. Cytologically, the lesion is mosome 1 as well as increased signal fre-intraductal hyperplasia. composed of cells with indistinct cell mar- quencies for the 20q13 region (typically gins, variation in the tinctorial features of present in DCIS) were identified by FISHMammography the cytoplasm and variation in shape and {593,3100}. By CGH, UDH lesions adja-UDH does not have a mammographic size of nuclei. Admixture of epithelial, cent to carcinoma showed gain on chro-presentation, except in rare cases with myoepithelial or metaplastic apocrine mosome 20q and loss on 13q in 4 of 5microcalcification. cells is not uncommon. The presence or cases {136}, although no alteration was reported in another study {301}. SomeRisk of progression Table 1.12 recent CGH studies suggest that a pro-Long-term follow up of patients with UDH Usual ductal hyperplasia. portion of UDH lesions is monoclonalin one study showed that 2.6% develop {1037,1358}, and that a subset showssubsequent invasive carcinoma after an Architectural features alterations similar to those observed inaverage interval of over 14 years, com- 1. Irregular fenestrations ADH {1037}; however, the frequency ofpared to 8.3 years for those with ADH 2. Peripheral fenestrations genetic alterations seen in UDH using{2886}. In another study, the absolute risk 3. Stretched or twisted epithelial bridges LOH and CGH is much lower than inof a woman with UDH developing breast 4. Streaming ADH. TP53 protein expression has not 5. Uneven distribution of nuclei and overlappedcancer within 15 years was 4% {732}. been demonstrated in UDH or in any nucleiThe Cancer Committee of the College of other benign proliferative lesions {1567}.American Pathologists has assigned Mutations of the TP53 gene are also Cellular featuresUDH a slightly increased risk (RR of 1.5- absent, except as inherited mutations in 1. Multiple cell types2.0) for subsequent development of inva- 2. Variation in appearance of epithelial cells Li-Fraumeni patients {72}.sive carcinoma {885}. 3. Indistinct cell margins and deviation from a round contourHistopathology 4. Variation in the appearance of nuclei Flat epithelial atypiaUDH is characterized by irregularlyshaped and sized secondary lumens, One of the most important indicators of UDH is Definitionoften peripherally distributed, and stream- the presence of an admixture of two or more A presumably neoplastic intraductaling of the central bolus of proliferating cell types (epithelial, myoepithelial and/or alteration characterized by replacementcells. Epithelial bridges are thin and metaplastic apocrine cells). of the native epithelial cells by a single orstretched; nuclei are unevenly distributed. 3-5 layers of mildly atypical cells. Intraductal proliferative lesions 65
  • 46. Synonyms Risk of progressionDuctal intraepithelial neoplasia 1A (DIN The Cancer Committee of the College of1A); clinging carcinoma, monomorphous American Pathologists has assignedtype; atypical cystic lobules; atypical lob- ADH a moderately increased risk (RR ofules, type A; atypical columnar change. 4.0-5.0) for subsequent development of invasive breast cancer {885}. FollowingRisk of progression a breast biopsy diagnosis of ADH, 3.7-Some cases of flat epithelial atypia may 22% of the women develop invasiveprogress to invasive breast cancer but carcinomas {299,733,1520,2886}. Onno quantitative epidemiological data are the other hand, ADH has also beencurrently available for risk estimation. present in 2.2% {2158} to 10.5% {1688} Fig. 1.82 Flat epithelial atypia. Immunostain for of controls who did not develop subse- CK34βE12 shows no staining in the neoplastic cellsHistopathology quent carcinoma. The average interval lining the ductules, but the residual luminal epithe-A flat type of epithelial atypia, this lial cells adherent along the luminal surface show to the subsequent development of inva-change is characterized by replacement intense staining. sive carcinoma is 8.3 years comparedof the native epithelial cells by a single to 14.3 years for women with UDHlayer of mildly atypical cells often with {2886}.apical snouts, or proliferation of a mono- while among seven flat atypias associ- However, drastically different relative risktonous atypical cell population in the ated with infiltrating carcinomas, the fre- (RR) estimations have been reported forform of stratification of uniform, cuboidal quency of LOH on 11q (D11S1311) was ADH, ranging from a low of 2.4 to a highto columnar cells generally up to 3-5 cell 57% {1889}. of 13 {412,732,1688,1775,1830,2155,layers with occasional mounding. 2158}. The upper values are even higherArcades and micropapillary formations than the RR of 8-11 suggested for DCISare absent or very rare. The TDLUs Atypical ductal hyperplasia {732,885}. On the other hand, the RR ofinvolved are variably distended and may (ADH) 2.4 for ADH reported in one study {1775}contain secretory or floccular material is much closer to the RR of 1.9 associa-that often contains microcalcifications. Definition ted with UDH. A neoplastic intraductal lesion character-Genetic alterations ized by proliferation of evenly distributed, HistopathologyData on genetic alterations in flat monomorphic cells and associated with The most distinctive feature of this lesionepithelial atypia are limited. LOH has a moderately elevated risk for progres- is the proliferation of evenly distributed,been found in at least one locus in 70% sion to invasive breast cancer. monomorphic cells with generally ovoidof cases in a study evaluating eight loci to rounded nuclei. The cells may grow inin thirteen lesions {1889}. LOH on 11q Synonyms micropapillae, tufts, fronds, arcades,(D11S1311) was the most commonly Ductal intraepithelial neoplasia 1B (DIN rigid bridges, solid and cribriform pat-noted in 50% of the pure flat atypia, 1B), atypical intraductal hyperplasia. terns. Cytologically, ADH corresponds to low grade DCIS. ADH is diagnosed when characteristic cells coexist with patterns of UDH, and/or there is partial involvement of TDLU by classic morphology. There is currently no general agreement on whether quantitative criteria should be applied to separate ADH from low grade DCIS. Some define the upper limit of ADH as one or more completely involved duct/ductular cross sections measuring ≤2 mm in aggregate, while others require that the characteristic cytology and architecture be present completely in two spaces. Microcalcifications may be absent, focal or extensive within the lumen of involved ducts; its presence does not impact diagnosis. Immunoprofile ERBB2 protein overexpression is rare in ADH {72,1172}, in contrast to high ampli-Fig. 1.81 Flat epithelial atypia. A terminal duct-lobular unit with distended acini and a floccular secretory fication rates in high grade DCIS, sug-luminal content. The spaces are lined by one to three layers of monotonous atypical cells. gesting that ERBB2 alterations are either66 Tumours of the breast
  • 47. vative treatment (complete local eradica- tion) is usually curative (see below). Epidemiology A striking increase in the detection of DCIS has been noted with the introduc- tion of widespread screening mammogra- phy and increasing awareness of breast cancer in the general population since 1983. The average annual increase in theFig. 1.83 Atypical ductal hyperplasia. Several Fig. 1.84 Atypical ductal hyperplasia. A terminal incidence rate of DCIS in the decade ofrounded calcifications, possibly including 1-2 “tea duct-lobular unit with dilated ductules that are 1973 to 1983 was 3.9% compared tocup” shaped calcifications are seen. Usually such partly filled with a CK5/6 negative ductal prolifera- 17.5% annually in the decade betweencalcifications indicate benign changes. However, tion which on H&E had the characteristics of a low 1983 to 1992, increasing from 2.4 perthe calcifications appear to follow two ducts. grade DCIS. Note on the left side some cytokeratinFurthermore, a faint group of very fine microcalcifi- positive ductules. 100,000 women in 1973 to 15.8 percations can barely be perceived. 100,000 in 1992 for women of all races, an overall increase of 557% {794}. In the US, data from the National Cancernot an early event in malignant transfor- Ductal carcinoma in situ (DCIS) Institute’s Surveillance, Epidemiology andmation or that they are largely restricted End Results (SEER) program noted thatto high grade DCIS. Increased levels of the proportion of breast carcinomas diag-cyclin D1 expression were recently Definition nosed as DCIS increased from 2.8% indescribed in 27-57% of ADH {1172, A neoplastic intraductal lesion character- 1973 to 14.4% in 1995 {794}. While close3264}. Nuclear accumulation of the TP53 ized by increased epithelial proliferation, to 90% of pre-mammography DCIS wereprotein is absent in ADH and low grade subtle to marked cellular atypia and an of the high grade comedo type, nearlyDCIS {1567}. Nearly 90% of ADH are inherent but not necessarily obligate ten- 60% of mammographically detectednegative for high molecular weight cytok- dency for progression to invasive breast lesions are non-comedo and this percen-eratins 1/5/10/14 (clones CK34BetaE12 cancer. tage is increasing.and D5/16 B4), an important feature in Interestingly, despite the more limitedseparating ADH from UDH {1963,2126}. ICD-O code 8500/2 surgical excisions, mortality from "DCIS" has declined. Of women with DCISGenetic alterations Synonyms diagnosed between 1978 and 1983Fifty percent of ADH cases share their Intraductal carcinoma, ductal intraepi- (pre-mammographic era), 3.4% diedLOH patterns with invasive carcinomas thelial neoplasia (DIN 1C to DIN 3). of breast cancer at 10 years, despitefrom the same breast, strongly support- having been treated by mastectomy ining a precursor relationship between Risk of progression the vast majority of cases. On the otherthese lesions {1567}. LOH has been DCIS is considered a precursor lesion hand, only 1.9% of women diagnosedidentified frequently on chromosomes (obligate or non-obligate), with a relative with DCIS between 1984 and 1989 died16q, 17p, and 11q13 {1567,1570}. TP53 risk (RR) of 8-11 for the development of breast cancer at 10 years, despite themutations are restricted to affected mem- of invasive breast cancer {732,885}. increasing trend toward lumpectomybers of Li-Fraumeni families. However, there is evidence that conser- {794}. Judging from the 10-year follow-A BFig. 1.85 Atypical ductal hyperplasia. A Two adjacent ducts showing partial cribriform involvement in a background of flat epithelial atypia. B Partial involvementof a duct by a cribriform proliferation of uniform, rounded cells in the setting of a flat epithelial atypia. Microcalcification is also present. Intraductal proliferative lesions 67
  • 48. up period currently available for thesewomen, it appears as if "DCIS per se isnot a life threatening disease" {794}. Thedeaths that do occur are related to anundetected invasive carcinoma presentat the time of the initial diagnosis ofDCIS, progression of residual incom-pletely excised DCIS to invasive carcino-ma, or development of a de novo inva-sive carcinoma elsewhere in the breast A B{794}.Clinical featuresIn countries where population screen-ing is performed, the vast majority ofDCIS (>85%) are detected by imagingalone. Only approximately 10% of DCISare associated with some clinical find-ings and up to 5% is detected inciden-tally in surgical specimens, obtained forother reasons. Clinical findings, which C Dmay be associated with DCIS include (i) Fig. 1.86 Ductal carcinoma in situ images. A This galactogram was performed because of pathologic dis-palpable abnormality, (ii) pathological charge from a single duct. On the galactogram multiple filling defects and truncation of the duct (approx. 4 cmnipple discharge and (iii) nipple alter- behind the nipple) are demonstrated. B Low grade cribriform DCIS. In this patient, an ill circumscribed nodu-ations associated with Paget disease. lar nonpalpable (8 mm) low grade cribriform DCIS was detected by ultrasound. C MRI of an intermediate grade papillary DCIS. A strongly enhancing somewhat ill circumscribed lesion is visualized at 6 o’clock in the patient’s right breast (coronal plane). D High grade comedo-type DCIS. Highly suspicious coarse granular andImaging pleomorphic microcalcifications are shown, which follow the ductal course indicating presence of a DCIS.Mammography constitutes by far themost important method for the detectionof DCIS. In current screening programs,10-30% of all detected ‘malignancies’are DCIS {810,1280}. In the majority ofcases, mammographic detection isbased on the presence of significantmicrocalcifications that are associatedwith most of these lesions {1206,1231,2796}.Calcifications associated with well dif-ferentiated DCIS are usually of the lami-nated, crystalline type re s e m b l i n gpsammoma bodies. They often developas pearl-like particles in the luminalspaces within the secretion of thetumour and appear on the mammogramas multiple clusters of granular micro-calcifications that are usually fine. Thesemultiple clusters reflect the frequent lob-ular arrangement of this type of DCIS.Calcifications associated with poorlydifferentiated DCIS, are, histologically, A Balmost exclusively of the amorphous Fig. 1.87 A High grade DCIS with solid growth pattern is usually associated with fragmented, branching, cast-type developing in the necrotic areas ing type calcifications. Microfocus magnification, detail image. The rod-like, “casting-type” calcifications areof the tumour. They appear on the mam- characterisitc for Grade 3 DCIS. B High grade DCIS with micropapillary growth pattern is usually associatedmogram as either linear, often bran- with dotted casting type calcifications.ching, or as coarse, granular micro-calcifications. About 17% of the lesions lack histologic Size, extent and distributionCalcifications associated with the inter- evidence of microcalcifications; they are Size/extent is an important factor in themediately differentiated DCIS may be either mammographically occult or mani- management of DCIS. The assessment ofof either the amorphous or the lamina- fest as an architectural distortion, a nodu- extent of DCIS is complex and needs inted type. lar mass or nonspecific density {1206}. optimal conditions the correlation of the68 Tumours of the breast
  • 49. dimensional studies appears to be con- Table 1.13 tinuous rather than discontinuous {831}. Features of DCIS to be documented for the surgical More specifically, whereas poorly differ- pathology report. entiated DCIS shows a predominantly Major lesion characteristics continuous growth, the well differentiated 1. Nuclear grade DCIS, in contrast, may present a more 2. Necrosis discontinuous (multifocal) distribution. 3. Architectural patterns These results have a direct implication on the reliability of the margin assessment of Associated features surgical specimens. In cases of poorly 1. MarginsA If positive, note focal or diffuse involvement. differentiated DCIS, margin assessment Distance from any margin to the nearest should, theoretically, be more reliable focus of DCIS. than well differentiated DCIS. In a multifo- 2. Size (either extent or distribution) cal process with discontinuous growth, 3. Microcalcifications (specify within DCIS or the surgical margin may lie between the elsewhere) tumour foci, giving the false impression of 4. Correlate morphological findings with speci- a free margin. men imaging and mammographic findings The distribution of DCIS in the breast is typically not multicentric, defined as tumour involvement in two or more remote calcification, DCIS is generally dividedB areas separated by uninvolved glandular into three grades; the first two featuresFig. 1.88 Large excision biopsy of a high grade duc- tissue of 5 cm. On the contrary, DCIS is constitute the major criteria in the majori-tal carcinoma in situ. A Note the sharp demarcation typically ‘segmental’ in distribution ty of grading systems. It is not uncom-between DCIS, comedo type (left), and adjacent {1230}. In practical terms, this implies that mon to find admixture of various gradesfibrous stroma. B Mammography showing a large two apparently separate areas of "malig- of DCIS as well as various cytologicalarea with highly polymorphic microcalcifications. nant" mammographic microcalcifications variants of DCIS within the same biopsy usually do not represent separate fields of or even within the same ductal space.mammogram, the specimen X-ray and DCIS but rather a larger tumour in which When more than one grade of DCIS isthe histologic slides. Since the majority of the two mammographically identified present, the proportion (percentage) ofDCIS is non palpable, the mammograph- fields are connected by DCIS, which is various grades should be noted in theic estimate is the sole guide for resection. mammographically invisible due to the diagnosis {2876}. It is important to noteTherefore, data on the mammographic lack of detectable size of microcalcifica- that a three tiered grading system doespathological correlation of the tumour size tions. One should be aware that single not necessarily imply progression fromare essential for guiding the extent of sur- microscopic calcium particles smaller grade 1 or well differentiated to grade 3gery. The mammographic extent of a than about 80µ cannot be seen on con- or poorly differentiated DCIS.DCIS is defined as the greatest distance ventional mammograms.between the most peripherally located Histopathologyclusters of suspicious microcalcifications, Grading Low grade DCISand the histologic extent as the greatest Although there is currently no universal Low grade DCIS is composed of small,distance between the most peripherally agreement on classification of DCIS, there monomorphic cells, growing in arcades,located, histologically verified, DCIS foci. has been a move away from traditional micropapillae, cribriform or solid pat-Histologic evaluation supported by corre- architectural classification. Most modern terns. The nuclei are of uniform size andlation with the X-ray of the sliced speci- systems use cytonuclear grade alone or have a regular chromatin pattern withmen allows a precise and reproducible in combination with necrosis and or cell inconspicuous nucleoli; mitotic figuresassessment of the extent of any DCIS polarization. Recent international consen-present. Whole organ studies have shown sus conferences held on this subjectthat mammography, on the basis of sig- endorsed this change and recommended Table 1.14 Minimal criteria for low grade DCIS.nificant microcalcifications, generally that, until more data emerges on clinicalunderestimates the histologic or "real" outcome related to pathology variables, Cytological featuressize of DCIS by an average of 1-2 cm. In grading of DCIS should form the basis of 1. Monotonous, uniform rounded cella series of DCIS cases with mammo- classification and that grading should be populationgraphic sizes up to 3 cm, the size differ- based primarily on cytonuclear features 2. Subtle increase in nuclear-cytoplasmic ratioence was less than 2 cm in more than {6,7,1565,2346}. 3. Equidistant or highly organized nuclear80% of the cases {1231}. Pathologists are encouraged to include distributionDCIS may appear as a multifocal process additional information on necrosis, architec- 4. Round nuclei 5. Hyperchromasia may or may not be presentdue to the presence of multiple tumour ture, polarization, margin status, size andfoci on two-dimensional plane sections. calcification in their reports. Architectural featuresHowever, these tumour spots may not Depending primarily on the degree of Arcades, cribriform, solid and/ornecessarily represent separate foci. nuclear atypia, intraluminal necrosis and, micropapillary patternIntraductal tumour growth on three- to a lesser extent, on mitotic activity and Intraductal proliferative lesions 69
  • 50. are rare. Some require complete involve- similar to those of low grade DCIS, form- with irregular contour and distribution,ment of a single duct cross section by ing solid, cribriform or micropapillary coarse, clumped chromatin and promi-characteristic cells and architecture, patterns, but with some ducts contain- nent nucleoli. Mitotic figures are usuallywhile others require either involvement of ing intraluminal necrosis. Others display common but their presence is nottwo spaces or one or more duct cross nuclei of intermediate grade with occa- required. Characteristic is the comedosections exceeding 2 mm in diameter. sional nucleoli and coarse chromatin; necrosis with abundant necrotic debris inMicrocalcifications are generally of the necrosis may or may not be present. duct lumens surrounded by a generallypsammomatous type. There may be The distribution of amorphous or lami- solid proliferation of large pleomorphicoccasional desquamated cells within the nated microcalcifications is generally tumour cells. However, intraluminal necro-ductal lumen but the presence of necro- similar to that of low grade DCIS or it sis is not obligatory. Even a single layer ofsis and comedo histology are unaccept- may display characteristics of both low highly anaplastic cells lining the duct in aable within low grade DCIS. grade and high grade patterns of micro- flat fashion is sufficient. AmorphousDCIS with micropapillary pattern may be calcification. microcalcifications are common.associated with a more extensive distri-bution in multiple quadrants of the High grade DCIS Unusual variantsbreast compared to other variants High grade DCIS is usually larger than A minority of the DCIS lesions is com-{2584}. The working group’s minimal cri- 5 mm but even a single <1 mm ductule posed of spindled {827}, apocrineteria for diagnosis of low grade DCIS are with the typical morphological features is {2887}, signet ring, neuroendocrine,shown in Table 1.14. sufficient for diagnosis. It is composed of squamous or clear cells. There is no con- highly atypical cells proliferating as one sensus or uniform approach to gradingIntermediate grade DCIS layer, forming micropapillae, cribriform or of these unusual variants. Some believeIntermediate grade DCIS lesions are solid patterns. Nuclei are high grade, assessment of nuclear features andoften composed of cells cytologically markedly pleomorphic, poorly polarized, necrosis can be applied to grading of theA BC DFig. 1.89 Low grade ductal carcinoma in situ. A Micropapillary type showing the longitudinal segment of a duct with numerous micropapillae characteristic of thisvariant. B Micropapillary type. The micropapillae lack a fibrovascular core and are composed of a piling of uniform cells with rounded nuclei. C Cribriform type.Multiple adjacent ducts are distended by a sieve-like proliferation of monotonous uniform cells. The multiple spaces are rounded and distributed in an organizedfashion. D Cribriform type. A highly uniform population of cells with round nuclei distributed equidistant from one another grow in a cribriform pattern.70 Tumours of the breast
  • 51. unusual variants as well. Using this in DCIS {412}. With the Ki67 antibody, theapproach many apocrine DCIS lesions highest proliferating index (PI) of 13%qualify as high grade, while a minority has been noted among the comedowould qualify as intermediate or, rarely, DCIS, while the PI for low grade DCIS,high grade DCIS. The clear and spindle cribriform type is 4.5% and for micropap-cell DCIS are sometimes found coexis- illary type, it is 0% {61}.tent and continuous with typical low DNA Ploidy: Aneuploidy has been foundgrade DCIS, but often the nuclei are in 7% of UDH, 13-36% of ADH, and 30-moderately atypical qualifying the 72% of low to high grade DCIS respec-lesions as intermediate grade DCIS. tively {408,579,792}.High nuclear grade spindle or clear cell Fig. 1.91 DCIS, intermediate grade (DCIS grade 2).DCIS is extremely rare. A vast majority of Hormone receptor expression This typical and most common intermediate gradeapocrine carcinomas are ER, PR and Estrogen plays a central role in regulating DCIS is characterized by a cribriform growth pat-BCL2 negative, but androgen receptor the growth and differentiation of breast tern and intraluminal necrosis.positive {2888}. epithelium as well as in the expression of other genes including the progesterone studies have evaluated estrogen receptorProliferation receptor (PR) {72}. The presence and (ER) in intraductal proliferative breastIn vivo labelling with bromodeoxyuridine concentration of the two receptors are lesions. Among DCIS, about 75% of the(BrdU) has found no significant differ- used, not only as a clinical index of cases show ER expression {72,1399},ences between proliferating cell fraction potential therapeutic response, but also and an association between ER positivityamong UDH and ADH, but the proliferat- as markers of prognosis for invasive and the degree of differentiation hasing cell fraction is significantly increased breast carcinomas {196}. Only a few been described {1399}. There is agree- ment that nearly all examples of ADH express high levels of ER in nearly all the cells {72,1301,2667}. The relationship between ER positive cell numbers and patient age, as found in normal breast epithelium, is lost in these ADH lesions, indicating autonomy of ER expression or of the cells expressing the receptor {2667}.A B Differential diagnosis The solid variant of low grade DCIS may be misinterpreted as lobular neo- plasia (LN). Immunohistochemistry for E-cadherin and CK1/5/10/14 (clone CK34BetaE12) are helpful in separa- ting the two. Low grade DCIS is E-cad- herin positive in 100% of cases {337, 1090,3034} and CK34BetaE12 negative in 92% of cases {337,1890}, whereasC D lobular neoplasia (LN) is E-cadherin negative {337,1033} and CK34BetaE12 positive in nearly all cases {337}. The presence of individual or clusters of cells invading the stroma (microinvasion) around a duct with DCIS is a frequent source of diagnostic problems. The diffi- culty is compounded by the frequent presence of dense lymphoplasmacytic infiltrate around the involved ducts.E F Immunostains for an epithelial and myo- epithelial marker are helpful optimally inFig. 1.90 Intermediate grade ductal carcinoma in situ. A Micropapillary type. The micropapillae are varied inshape and composed of cells with moderately atypical, pleomorphic nuclei. A few apoptotic cells are present in the form of double immunostaining; thethe lumen. B Flat type, approaching high grade DCIS. Two adjacent ductal spaces are lined by atypical cells, rare epithelial cell marker can unmask themitotic figures and a few apoptotic nuclei. C, D Duct/part of a duct with micropapillary atypical epithelial prolif- haphazard distribution of the cells, whileeration. Note secretory material in the lumen that should not be mixed up with comedo-type necrosis. E Clear the absence of a myoepithelial cell layercell type. The neoplastic cells have clear cytoplasm with moderate nuclear pleomorphism. F Apocrine type with would generally ascertain the invasivemoderate nuclear size variation. The abundant pink, granular cytoplasm suggests an apocrine cell type. nature of the cells in question. Despite all Intraductal proliferative lesions 71
  • 52. these added studies, the distinction canremain impossible in some cases.An unknown, but relatively small, pro-p o rtion of intraepithelial neoplasiascannot be easily separated into ductalor lobular subtypes on the basis of pureH&E morphology. Using immunostainsfor E-cadherin and CK34βE12, some ofthese will qualify as ductal (E-cad-herin+, CK34BetaE12-), some as lobu- 1 cmlar (E-cadherin-, CK34βE12+), while Fig. 1.92 High grade ductal carcinoma in situ form- Fig. 1.93 High grade ductal carcinoma in situ. Lowothers are either negative for both ing a tumour mass. Large section, H&E. power view shows extensive DCIS with calcification.markers (negative hybrid) or positive forboth (positive hybrid) {337}. This impor-tant group requires further evaluation asit may reflect a neoplasm of mammarystem cells or the immediate post-stemcells with plasticity and potential toevolve into either ductal or lobularlesions {338}.Expression profilingGene expression profiling has become apowerful tool in the molecular classifica- A Btion of cancer. Recently, the feasibilityand reproducibility of array technology inDCIS was demonstrated {1721}. Morethan 100 changes in gene expression inDCIS were identified in comparison withcontrol transcripts. Several genes, previ-ously implicated in human breast cancerprogression, demonstrated differentialexpression in DCIS versus non-malignantbreast epithelium, e.g. up-regulation of C Dlactoferrin (a marker of estrogen stimula-tion), PS2 (an estrogen-responsive mark-er), and SIX1 (a homeobox protein fre-quently up-regulated in metastatic breastcancer), and down-regulation of oxytocinreceptor {3148}.Genetic alterationsMost studies on somatic gene alterationsin premalignant breast lesions are based E Fon small sample numbers and have not Fig. 1.94 High grade ductal carcinoma in situ. A Multiple duct spaces with amorphous microcalcificationsbeen validated by larger series {72}, with and peripheral epithelial proliferations. B Comedo type. The proliferating cells show significant nuclear atyp-the exceptions of the TP53 tumour sup - ia, mitotic figures and there is intraluminal necrosis. C Flat type. Significantly atypical cells have replacedpressor gene and the oncogenes ERBB2 the native, normal mammary epithelium. D Flat type. A highly anaplastic cell population has replaced theand CCND1 {72,196}. Other genes, not native epithelial cell layer. E Flat type with significant nuclear pleomorphism. F Flat type. A highly anaplasticdiscussed here (e.g. oncogenes c-myc, cell population has replaced the native epithelial layer, but there is no significant intraluminal proliferation.fes, c-met, and tumour suppresser geneRB1) may also play an important role inbreast carcinogenesis (for review see carcinoma, abnormalities of chromo- Chromosomal imbalance{3048}). somes 1 and 16 have been identified in CGH studies of DCIS have demonstra- DCIS {1146,1567}. FISH-analyses using ted a large number of chromosomalCytogenetics DNA probes to centromeric sequences alterations including frequent gains onConventional cytogenetic analysis of of almost all chromosomes frequently 1q, 6q, 8q, 17q, 19q, 20q, and Xq, andpremalignant lesions of the breast has identified polysomy of chromosome 3, losses on 8p, 13q, 16q, 17p, and 22qbeen carried out in only a small number 10, and 17 and loss of chromosome 1, {134,301,365,366,1333,1548,3045}.of cases, and, as with invasive ductal 16, and 18 in DCIS {1949}. Most of these chromosomal imbalances72 Tumours of the breast
  • 53. resemble those identified in invasive generally associated with aggressiveductal carcinoma, adding weight to the biological features and poor clinicaltheory that DCIS is a direct precursor. outcome. Most TP53 mutations are mis- sense point mutations resulting in anLOH inactivated protein that accumulates inIn DCIS, loss of heterozygosity (LOH) the cell nucleus {72,712}. In DCIS, TP53was frequently identified at several loci mutations were found with different fre-on chromosomes 1 {1942}, 3p21 {1743}, quency among the three histologicaland chromosomes 8p, 13q, 16q, 17p, grades, ranging from rare in low grade17q, and 18q {924,2317,3036}. The DCIS, 5% in intermediate-grade, andhighest reported rates of LOH in DCIS A common (40%) in high grade DCISare between 50% and 80% and involve {712,3048}.loci on chromosomes 16q, 17p, and17q, suggesting that altered genes in Prognosis and predictive factorsthese regions may be important in the The most important factor influencingdevelopment of DCIS {72,924,3036}. the possibility of recurrence is persist-Among more than 100 genetic loci stud- ence of neoplastic cells post-excision;ied so far on chromosome 17, nearly all primary and recurrent DCIS generallyDCIS lesions showed at least one LOH have the same LOH pattern, with acqui-{72,301,924,1942,2071,2317,2475}. By sition of additional alterations in the latterCGH and FISH, low and some intermedi- {1670} The significance of margins isate grade DCIS and invasive tubular car- B mainly to ascertain complete excision. Incinoma (G1) show loss of 16q, harbour- Fig. 1.95 Unusual intraductal proliferation. randomized clinical trials, comedoing one of the cadherin gene clusters, A The lesion shows a uniform cell population pro- necrosis was found to be an importantwhereas some intermediate grade and liferating in a solid pagetoid pattern similar to lob- predictor of local recurrence in thehigh grade DCIS and nearly all G2 and ular neoplasia, but the cells appear more adhe- NSABP-B17 trial {2843}, while solid andG3 invasive ductal carcinomas show no rent than in typical lobular neoplasia (LN). cribriform growth patterns along withloss of genetic material on this locus but B Double immunostain is positive for both involved margin of excision were foundhave alterations of other chromosomes CK34βE12 (purple) and E-cadherin (brown), quali- to be predictive of local recurrence in(-13q, +17p, +20q). Based upon this fying the lesion as a hybrid positive type that may EORTC-10853 trial {270,271}. In retro- suggest the diagnosis of, a genetic progression model was spective trials, on the other hand, highproposed {301}. nuclear grade, larger lesion size, come- do necrosis and involved margins ofERBB2 (CCND1) is considered a potential onco- excision were all found to be predictiveThe ERBB2 (Her2/neu) oncogene has gene, but in clinical studies of invasive of local recurrence following breast con-received attention because of its associ- breast cancer, overexpression of cyclin servative treatment for DCIS.ation with lymph node metastases, short D1 was found to be associated with Although mastectomy has long been therelapse free time, poor survival, and estrogen receptor expression and low traditional treatment for this disease, itdecreased response to endocrine and histological grade, both markers of good likely represents over-treatment for manychemotherapy in breast cancer patients prognosis {1007}. Amplification of patients, particularly those with small,{72,1567}. Studies of ERB B2 have used CCND1 occurs in about 20% of DCIS mammographically detected lesions.mainly FISH technique to identify ampli- and is more commonly found in high Careful mammographic and pathologicfication and immunohistochemistry (IHC) grade than in low grade DCIS (32% ver- evaluation are essential to help assessto detect over expression of the onco- sus 8%) {2700}. The cyclin D1 protein patient suitability for breast conservinggene, which are highly correlated {72}. was detected in 50% of cases, and high treatment.Amplification and/or over expression levels were more likely in low grade than While excision and radiation therapy ofwas observed on average in 30% of in the intermediate and high grade DCIS DCIS (with or without Tamoxifen) haveDCIS, correlating directly with differenti- {2700}. Although so far no oncogene has significantly reduced the chances ofation {72}; it was detected in a high pro- been identified on chromosome 20q13, recurrence {866,870}, some patientsportion of DCIS of high nuclear grade amplification of this region was frequent- with small, low grade lesions appear to(60-80%) but was not common in low ly found in DCIS {134,856}. be adequately treated with excisionnuclear grade DCIS {196}. Patients with alone, whereas those with extensiveERBB2 positive tumours may benefit TP53 mutations lesions may be better served by mas-from adjuvant treatment with monoclonal The TP53 protein is a transcription fac- tectomy. Better prognostic markers areantibody (Herceptin). tor involved in the control of cell prolif- needed to help determine which DCIS eration, response to DNA damage, lesions are likely to recur or to progressCyclin D1 apoptosis and several other signaling to invasive cancer following breast con-This protein plays an important part in pathways. It is the most commonly serving treatment. The optimal manage-regulating the progress of the cell during mutated tumour suppressor gene in ment is evolving as data accumulatesthe G1 phase of the cell cycle. The gene sporadic breast cancer {196} and this is from a variety of prospective studies. Intraductal proliferative lesions 73
  • 54. I.O. EllisMicroinvasive carcinoma F.A. TavassoliDefinition exceeding 1 mm in maximum dimension. unlimited number of clearly separateA tumour in which the dominant lesion is Some studies have provided no maxi- foci of infiltration into the stroma withnon-invasive, but in which there are one mum size {2579,3140} or criteria {1467, none exceeding 1 mm in diameter {80},or more clearly separate small, micro- 2703}. Others have defined the micro- 1 or 2 foci of microinvasion with nonescopic foci of infiltration into non-spe- invasive component as a percentage of exceeding 1 mm {2695}, a single focuscialized interlobular stroma. If there is the surface of the histologic sections not exceeding 2 mm or three foci, nonedoubt about the presence of invasion, {2583}. Some have described subtypes exceeding 2 mm in maximum diameterthe case should be classified as an in separating those purely composed of {2680}.situ carcinoma. single cells and those also containing Some authors propose that the defini- cell clusters and/or tubules of non-grad- tion of microinvasive carcinoma requiresICD-O code able tumour without providing informa- extension of the invasive tumour cellsMicroinvasive carcinoma is not generally tion about maximum size, extent, or beyond the specialized lobular stromaaccepted as a tumour entity and does number of microinvasive foci {656}. {774,2905} despite the definitive pres-not have an ICD-O code. M o re precise definitions accept an ence of vascular channels both withinEpidemiologyMicroinvasive carcinomas are rare andoccur mostly in association with an in situcarcinoma. They account for far less than1% of breast carcinomas even in pureconsultation practices where the largestnumber of microinvasive carcinoma isreviewed {2680}.Clinical featuresThere are no specific clinical featuresassociated with microinvasive carcino-ma. These lesions are typically associat-ed with ductal carcinoma in situ which isoften extensive. The features associatedwith the associated in situ componentare responsible for detection as a mass Alesion, mammographic calcification or anipple discharge. (See clinical featuresof ductal and lobular carcinoma in situ).HistopathologyThere is no generally accepted agree-ment on the definition of microinvasivecarcinoma. This is particularly true for themaximum diameter compatible with thediagnosis of microinvasive carcinoma.Size limitsMicroinvasive carcinoma has beendefined as having a size limit of 1 mm{1984,2425,2739,2905}. Consequently,diagnosis of microinvasive carcinoma israre in routine practice, in contrast to Blarger (>1 mm) foci of invasion. Fig. 1.96 Microinvasive carcinoma. A A small focus of invasive carcinoma barely 0.8 mm in maximum extentAlternatively, it has also been defined as is present adjacent to an aggregate of ducts displaying mainly flat epithelial atypia. B Immunostain for actina single focus no larger than 2 mm in shows no evidence of a myoepithelial (ME) cell layer around the invasive tubules, in contrast to persistence ofmaximum dimension or 2-3 foci, none a distinct ME cell layer around the adjacent tubules with flat epithelial atypia.74 Tumours of the breast
  • 55. A B CFig. 1.97 Microinvasive carcinoma. A Two ducts are filled by DCIS, while small clusters of carcinoma cells invade the stroma (upper right quadrant of the field)admixed with a dense lymphocytic infiltrate. B Higher magnification shows small invasive cell clusters within stromal spaces distributed over a 0.7 mm area andsurrounded by a dense lymphocytic infiltrate. C Immunostain for actin decorates the vessel walls, while absence of myoepithelial cells around the tumour cell clus-ters confirms their invasive nature.the specialized lobular stroma and type and is distinct from the patterns ciated with a finite number of invasiveimmediately surrounding the basement seen with cancerization of lobules. foci <1 mm in maximum dimension or amembrane that invests the ducts. single invasive focus <2 mm {2680, Differential diagnosis 2695}. Others have shown a small per-Associated lesions When there is doubt about the presence centage (up to 5%) with axillary nodeTy p i c a l l y, microinvasive carc i n o m a of invasion and particularly, if uncertainty metastases {2453,2744} or haveoccur in larger areas of high grade DCIS persists even after recuts and immuno- described up to 20% axillary nodein which the tumour cell population stains for detection of myoepithelial cells, metastases {656,1472,2282,2579,2583}.extends to involve lobular units or areas the case should be diagnosed as an in Of 38 women who had undergone mas-of benign disease. situ carcinoma. Similarly, suspicious tectomy for their minimally invasive carci-Microinvasion occurs in association not lesions which disappear on deeper lev- nomas (a single focus <2 mm or up to 3only with all grades of DCIS, including els should be regarded as unproven, invasive foci, none exceeding 1 mm, withpapillary DCIS, but also with other pre- with no definite evidence of established no axillary node metastases), developedcursor lesions of invasive breast cancer, invasion. recurrences or metastases {2680}. Thee.g. lobular neoplasia (LN) {1226,1249, Invasion is associated with a loss of few other studies with comparable, but1993}, indicating that at least some immunoreactivity to myoepithelial cells. A not exactly the same definition, and fol-forms of lobular neoplasia behave as variety of markers is available for the low-up data support the excellent prog-true precursors of invasive lesions. identification of myoepithelial cells nosis for these tumours within the short {3181}. The most helpful include smooth periods of available follow-up {2453,Stromal reaction muscle actin, calponin, and smooth mus- 2695,3140}.Microinvasion is most often present in cle myosin (heavy chain); the latter in In practice, it may be impossible fora background of significant periductal / particular shows the least cross-reactivi- pathologists to routinely examine anperilobular lymphocytic infiltrate or an ty with myofibroblasts that may mimic a entire sample exhaustively. Therefore, italtered desmoplastic stroma, features myoepithelial cell layer when apposed to is quite possible that small foci of inva-often present in cases of comedo DCIS. the invasive cells. sive carcinoma may be missed, particu-Angulation of mesenchymal structures larly in the setting of extensive in situ car-may be emphasized by the plane of Prognosis and predictive factors cinoma. For this reason, it may be appro-sectioning and can produce features In true microinvasive carcinomas of the priate to sample the lowest axillary lymphreminiscent of invasive carc i n o m a . breast, the incidence of metastatic dis- nodes, or sentinel node as a matter ofBasement membrane structures in such ease in axillary lymph nodes is very low routine, when treating patients by mas-foci may be discontinuous but it is and the condition is generally managed tectomy for extensive DCIS with or with-unusual to lose the entire basement clinically as a form of DCIS. out accompanying microinvasive carci-membrane around such a lesion. However, given the lack of a generally noma {1472}. The pathology reportSimilarly myoepithelial cells may be accepted standardized definition of should provide the size of the largestscarce but are rarely totally absent in microinvasive carcinoma, there is little focus along with the number of foci ofsuch areas. evidence on the behaviour of microinva- invasion, noting any special studies uti- sive carcinoma. A recent detailed review lized to arrive at the diagnosis, ie. 1.3 mm,Change in morphology of the literature {2425} concluded that a 2 foci, immunocytochemistry.When true invasion extends into non- variety of different diagnostic criteria and Until there is a generally accepted defini-specialized stroma, the islands of definitions have been used and as a con- tion with reliable follow-up data, microin-tumour cells frequently adopt a different sequence it is difficult to draw any defin- vasive carcinoma of the breast remainsmorphological character which is more itive conclusions. an evolving concept that has nottypical of well established invasive There are studies that have found no evi- reached the status of a WHO-endorsedmammary carcinoma of ductal NOS dence of axillary node metastases asso- disease entity. Microinvasive carcinoma 75
  • 56. G. MacGroganIntraductal papillary neoplasms F. Moinfar U. RajuDefinition EpidemiologyPapillary neoplasms are characterized The incidence of the various forms ofby epithelial proliferations supported by intraductal papillary lesions is uncertainfibrovascular stalks with or without an due to the lack of consistent terminolo-intervening myoepithelial cell layer. gy. Overall, less than 10% of benignThey may occur anywhere within the breast neoplasms correspond to papil-ductal system from the nipple to the ter- lomas {413,1098}. Central papillomasminal ductal lobular unit (TDLU) and can occur at any age, but the majoritymay be benign (intraductal papilloma), p resent during the fourth and fifthatypical, or malignant (intraductal papil- decades {1098,1945}.lary carcinoma). Clinical features Unilateral sanguineous, or sero-Intraductal papilloma sanguineous, nipple discharge is the most frequent clinical sign, and isA proliferation of epithelial and myoep- observed in 64-88% of patients {3148}. Aithelial cells overlying fibrovascular stalks palpable mass is less frequent.creating an arborescent structure within Mammographic abnormalities include a Fig. 1.98 Distribution of papillomas in breast.the lumen of a duct. circumscribed retro-areolar mass ofIntraductal papilloma of the breast is benign appearance, a solitary retro-areo-broadly divided into central (large duct) lar dilated duct and, rarely, microcalcifi- rograde flow of contrast material.papilloma, usually located in the subare- cations {401,3148}. Small papillomas Galactography may be useful to theolar region, and peripheral papilloma may be mammographically occult breast surgeon in identifying and local-arising in the TDLU {2092}. The confus- because of their location in the central izing the discharging duct, prior to ducting term "papillomatosis" should be dense breast and usually lack of calcifi- excision {3148}.avoided as it has been used for usual cation. Typical sonographic featuresductal hyperplasia as well as for multiple include a well defined smooth-walled, Macroscopypapillomas. solid, hypoechoic nodule or a lobulated, Palpable lesions may form well circum- smooth-walled, cystic lesion with solid scribed round tumours with a cauliflower-ICD-O code 8503/0 components. Duct dilatation with visible like mass attached by one or more pedi- solid intraluminal echoes is common cles to the wall of a dilated duct contain-Central papilloma {3176}. ing serous and/or sanguineous fluid. The Galactography shows an intraluminal size of central papillomas varies consid-Synonyms smooth or irregular filling defect asso- erably from a few millimetres to 3-4 cm orLarge duct papilloma, major duct pa- ciated with obstructed or dilated ducts, larger and they can extend along thepilloma. or a complete duct obstruction with ret- duct for several centimetres.A BFig. 1.99 Central papilloma. A Smooth intraluminal filling defect associated with duct dilatation. B Well Fig. 1.100 Papilloma, gross. Nodular mass in adefined smooth wall cystic lesion with a solid component. cystic duct.76 Tumours of the breast
  • 57. Papilloma may be subject to morpho- logical changes such as inflammation, necrosis, myoepithelial hyperplasia, apocrine, squamous, sebaceous, muci- nous, osseous and chondroid metaplasia as well as usual intraductal hyperplasia {148,893,1350,1945,2327,2420,2873}. A pseudo-infiltrative pattern may be ob- served at the periphery of these lesions particularly in the sclerosing variant. The myoepithelial cell layer may have an uneven distribution both in areas of UDH, ADH, and DCIS {2325}. The entire range of ductal intraepithelial proliferations may arise within, or sec- ondarily involve, a central papilloma. TheA clinical implications of such lesions have not at this time been fully established and should be considered in the context of the surrounding breast tissue. Peripheral papilloma Synonym Microscopic papilloma. Epidemiology The average age at presentation of peripheral papillomas is similar to that of central papillomas or slightly younger {401,1097,1945}.B Clinical features Peripheral papillomas are often clinically occult. They rarely present as a mass and nipple discharge is far less frequent in this group {401}. They are also usually mammographically occult, but they may manifest as peripherally situated micro- calcifications, nodular prominent ducts or multiple small peripheral well circum- scribed masses {401}. Microcalcifications may be located in the peripheral papillo- mas or in adjacent non-papillary intra- ductal proliferative lesions, e.g. ADH. Macroscopy Unless they are associated with other changes, peripheral papillomas are usu-C ally a microscopic finding.Fig. 1.101 A Typical morphology of a papilloma of the breast. B Cytokeratin (34 βE12) staining decoratesmyoepithelial and some epithelial cells. C Papilloma with atypical ductal hyperplasia (ADH). Note HHF-35 Histopathologyimmunoreactive myoepithelial cells at the periphery of ADH. Peripheral papillomas are usually multi- ple. They originate within the TDLUs fromHistopathology ductal patterns coexist. When the ductal where they may extend into the largerPapillomas are characterized by an pattern predominates and is associated ducts {2092}. The histological featuresarborescent structure composed of with marked sclerosis, the term scle- are basically the same as for centralfibrovascular stalks covered by a layer of rosing papilloma may be used. Ductal papillomas. Compared to central papillo-myoepithelial cells with overlying epithe- adenoma is considered by some as a mas, however, peripheral papillomas arelial cells. In some lesions papillary and variant of generally sclerosing papilloma. more frequently observed in association Intraductal papillary neoplasms 77
  • 58. Table 1.15Differential diagnosis of benign papilloma and intraductal papillary carcinoma. Feature Papilloma Papillary intraductal carcinoma Cell types covering fibrovascular stalks Epithelial and myoepithelial Epithelial (myoepithelial cells may be seen at periphery of duct wall)* Nuclei Normochromatic vesicular chromatin; May be hyperchromatic, with diffuse variable in size and shape chromatin: relatively uniform in size and shape Apocrine metaplasia Frequent Absent Fibrovascular stalks Usually broad and present throughout lesion; Often fine and may be absent in some areas; may show sclerosis sclerosis uncommon Immunohistochemical markers for myoepithelial Positive Negative* cells (e.g. smooth muscle actin, HMW-CK [such as CK 5/6]) * Myoepithelial cells may be present in some papillary carcinomas–see text for explanation.with concomitant usual ductal hyperpla- with peripheral papilloma may be higher Intraductal papillary carcinomasia, atypical intraductal hyperplasia, compared to central papilloma. However,ductal carcinoma in situ or invasive car- this risk also depends on the concurrent ICD-O code 8503/2cinoma as well as with sclerosing adeno- presence of other forms of proliferativesis or radial scar {1097,1945,2091,2092}. disease and as yet no study has been SynonymThe term micropapilloma has been designed to specifically answer this Papillary carcinoma, non-invasive.applied to the smallest type of peripheral question {2151}. There is disagreementpapillomas corresponding to multiple as to whether the risk of subsequent Definitionmicroscopic papillomas that grow in foci invasive breast carcinoma applies only to This lesion is located within a variablyof adenosis. Collagenous spherulosis, the same site in the ipsilateral breast or distended duct and may extend into itsconsisting of round eosinophilic applies to both breasts {2151,2326}. The branches. It is characterized by prolif-spherules of basement membrane (type significance of atypia within a papilloma eration of fibrovascular stalks and itsIV collagen), edged by myoepithelial is still not clear and is obscured by the diagnosis requires that 90% or more ofcells may be seen in some peripheral frequent concurrent presence of atypiapapillomas. within the surrounding breast parenchy- ma. It appears that if epithelial atypia isAtypical papilloma confined to the papilloma without sur- rounding proliferation or atypia the risk ofAtypical intraductal papillomas are char- subsequent invasive breast carcinoma isacterized by the presence of a focal similar to that of non-atypical papilloma.atypical epithelial proliferation with low As expected, epithelial atypia whengrade nuclei. Such intraepithelial prolifer- present simultaneously both within andations may occasionally resemble atypi- outside a papilloma is associated with acal ductal hyperplasia (ADH) or small moderate to highly increased relative riskfoci of low grade DCIS. {2151}; this is not a reflection of the risk A associated with pure atypical papilloma,Prognosis and predictive features however.of benign and atypical papillomas The standard treatment for papillomas has been complete excision with micro-The risk of subsequent invasive carcino- scopic assessment of surroundingma associated with papillomas or atypi- breast tissue. Because of potential vari-cal papillomas should be appreciated in ability within a papillary lesion, completethe context of the surrounding breast tis- excision is prudent, regardless of thesue. A benign papilloma without sur- findings in a previous core biopsy.rounding changes is associated with a The differential diagnosis of benign andslightly increased relative risk of subse- malignant papillary lesions on frozen Bquent invasive breast carcinoma, similar section can be extremely difficult and a Fig. 1.102 Central papilloma. A An arborescentto that of moderate or florid usual ductal definitive diagnosis should always be structure composed of papillary fronds within ahyperplasia in the breast proper made only after examination of paraffin dilated duct. B Myoepithelial hyperplasia with SMA{885,2151}. The relative risk associated embedded material. positive “myoid” transformation.78 Tumours of the breast
  • 59. A BC DFig. 1.103 Papillary intraductal carcinoma. A Cystically dilated duct with arborescent papillary tumour. B Papillary structure lined by epithelial columnar cells.C Two papillary structures lined by atypical cylindrical cells with formation of arcades. D Papillary structures are devoid of myoepithelial cells. Smooth muscle actin(SMA) immunostaining highlights vascular structures in papillary fronds. Epithelial cells lining the papillary fronds are CK 5/6 negative (not shown).the papillary processes are totally ICD-O code 8504/2 (mean 2 cm, range 0.4-10 cm) locateddevoid of a myoepithelial cell layer within a large cystic duct characterizedregardless of presence or absence of Synonyms by thin fibrovascular stalks devoid ofnotable epithelial proliferation, and/or Intracystic papillary carcinoma, non- a myoepithelial cell layer and a neo-that any of the recognized patterns of invasive; papillary intraductal carcinoma; plastic epithelial cell population usuallylow grade DCIS occupies 90% or more papillary ductal carcinoma in situ; presenting characteristics of low gradeof the lesion. encysted papillary carcinoma. DCIS. These cells are arranged in eitherThese neoplasms can be either solitary solid, cribriform, micropapillary or strati-and central in location corresponding to Epidemiology fied spindle cell patterns {413,1618,intracystic papillary carcinoma, or mul- Less than 2% of breast carcinomas cor- 1945}. Some may show a dimorphic celltifocal within the TDLU and correspond respond to intraductal papillary carcino-to the papillary type of DCIS. mas {413,1945}. The average age of occurrence is around 65 (range, 34-92 years) {413,1618}.Intracystic papillary carcinoma Clinical and macroscopic featuresDefinition On the basis of clinical presentation andThis lesion is a variant of intraductal macroscopy, there are no distinctive fea-papillary carcinoma, located within a tures that can separate papilloma fromlarge cystic duct and characterized by papillary carcinoma, nonetheless, intracys-thin fibrovascular stalks devoid of a tic papillary carcinomas tend to be larger.myoepithelial cell layer and of a neo- Fig. 1.104 Gross appearance of an intracystic pap-plastic epithelial cell population with Histopathology illary breast carcinoma. Macroscopically, the dis-histopathological features characteristic Intraductal papillary carcinoma is a tinction between papilloma and papillary carcino-of low grade DCIS. papillary lesion usually of large size ma may be difficult. Intraductal papillary neoplasms 79
  • 60. population (featuring epithelial and myo-epithelial differentiation) which may bemistaken for two cell types {1618}. Lessfrequently, the epithelial cell componentpresents the characteristics of intermedi-ate or high grade DCIS. ConcomitantDCIS may be present in the surroundingbreast tissue. A complete absence of themyoepithelial cell layer in the papillaryprocesses indicates a carcinoma; thepresence of myoepithelial cells does not Binvariably exclude the diagnosis of intra-ductal papillary carcinoma, however. Amyoepithelial cell layer is usually presentin the lining of the duct wall into which thepapillary carcinoma proliferates.Solid and transitional cell variants havebeen described {1752,1905}. The distinc-tive features of the former are productionof extracellular and intracellular mucin,association with mucinous carcinomaand often a spindle cell population.Argyrophilia and neuroendocrine features A Chave been noted in a large number of the Fig. 1.105 Intracystic papillary carcinoma. A Left breast, medio-lateral oblique projection showing a 3x3 cm,solid cases {694,1752,2955}. The transi- solitary, high density circular mass in the lower half of the breast. B Breast ultrasound demonstrates intra-tional cell variant is characterized by pro- cystic growth. C Intracystic papillary carcinoma in situ. Large section histology.liferation of sheets of transitional typecells overlying the fibrovascular cores.As with benign papillomas entrapment ofepithelial structures within the wall canresult in a pseudoinvasive pattern. Adefinitive diagnosis of invasive carcino-ma associated with intracystic papillarycarcinoma should only be consideredwhen neoplastic epithelial structures infil-trate the breast tissue beyond the fibrouswall and have one of the recognized pat- A Bterns of invasive carcinoma. Following aneedle biopsy (fine needle aspiration orcore biopsy), epithelial displacement intothe needle tract, scar tissue or lymphaticspaces can mimic invasion {3231}.Genetic alterationsGenetic alterations in the form of intersti-tial deletions {701}, LOH {1671}, numeri-cal and structural alterations at chromo-somes 16q and 1q with fusion of chro- C Dmosomes 16 and 1 [der(1;16)] {2961} Fig. 1.106 Ductal intracystic papillary carcinoma. A Typical papillary pattern. B Cribriform pattern.have been described, but the signifi- C Stratified columnar cells, in the absence of myoepithelial cells. D Transitional cell-type pattern.cance of these alterations are as yet,unclear. DCIS or invasive carcinoma in the sur- of the lesion and surrounding breast tis-Prognosis and predictive factors rounding breast tissue are associated sue is mandatory for treatment andIntraductal papillary carcinoma in the with an increase in frequency of local appreciation of subsequent breast can-absence of concomitant DCIS or invasive recurrence (in situ or invasive) in the for- cer risk.carcinoma in the surrounding breast tis- mer, and an increase in local and Prognosis and management of papillarysue has a very favourable prognosis with metastatic rates in the latter {413}. type of DCIS is similar to that of commonno reported lymph node metastases or Complete excision of intraductal papil- DCIS and is dealt with in the correspon-disease-related deaths. The presence of lary carcinoma with adequate sampling ding chapter.80 Tumours of the breast
  • 61. colour measuring from 0.5 to 12 cm. Larger tumours occur in older patients. Histopathology Microscopically SC is generally circum- scribed, but areas of invasion of the adi- pose tissue are frequent. Sclerotic tissue in the centre of the lesion may be observed. The lesions are structurallyA B composed of 3 patterns present in vary- ing combinations:Fig. 1.51 Lipid rich carcinoma. A The cells have abundant eosinopohilic or microvacuolated cytoplasm withround nuclei displaying prominent nucleoli. B Oil red O stain shows abundant intracytoplasmic lipids with- 1. A microcystic (honeycombed) patternin every cell. composed of small cysts often merge into larger spaces closely simulate thy- roid follicles {2722},Immunoprofile (37%) were aged less than 20 years, 21 2. A compact more solid, andThere is limited data in hormone receptor (31%) older than 30 years and the 3. A tubular pattern consisting of nume-expression but all tumours from one remaining 21 in between. Therefore, the rous tubular spaces containing secre-series were negative {3158}. term secretory carcinoma is preferred tions {1519}. {2080}. Mucoid carcinoma, invasive lob- The neoplastic cells have been subdi-Ultrastructure ular carcinoma and signet ring cell carci- vided into two types {2881} with all pos-Well developed Golgi apparatus and noma are "secretory" carcinomas "in sible combinations. One has a largelipid droplets of different sizes are recog- sensu strictu", but are all well defined dis- amount of pale staining granular cyto-nized in the cytoplasm {1546}. tinct entities and therefore it is preferred plasm, which on occasions can appear to restrict the use of the term secretory foamy. The nuclei are ovoid and have aPrognosis and predictive factors carcinoma to this rare tumour type small nucleolus. Intracytoplasmic lumi-Despite the positive correlation of lipid {2080}. na (ICL) are numerous and vary fromcontent with high histological grade small to "enormous" {1579}. Fusion of{873} and extensive lymph node metas- Clinical features ICL generates the microcystic struc-tases in 11 of 12 patients {2330}, at the The tumours manifest as indolent, mobile tures. The secretion located within thepresent it is not possible to establish with lumps, located near the areola in about ICL or in the extracytoplasmic compart-certainty that lipid rich carcinomas are half of the cases, this being especially so ment is intensely eosinophilic and PASaggressive tumours. The reported series in men and children. positive after diastase digestion in mostinclude very heterogeneous lesions and of the cases; Alcian blue positive mate-have very short follow up. Macroscopy rial is also seen. The two types of muco- SC usually presents as circumscribed substances are usually independently nodules, greyish-white or yellow to tan in produced and a combination of the twoSecretory carcinomaDefinitionA rare, low grade carcinoma with a solid,microcystic (honeycomb) and tubulararchitecture, composed of cells that pr o-duce abundant intracellular and extra-cellular secretory (milk-like) material.ICD-O code 8502/3SynonymJuvenile carcinoma.EpidemiologyThis is a rare tumour, with a frequencybelow 0.15% of all breast cancers{323,1579}. The tumour usually occurs infemales, but has also been seen in malesincluding a 3-year-old boy {1401}.It occurs in children {1831} as well asadults {1519,2080}. A recent report{2430} disclosed 67 patients. Twenty-five Fig. 1.52 Secretory carcinoma. The tumour cells have abundant pink eosinophilic cytoplasm.42 Tumours of the breast
  • 62. mitochondrial antibody, found 70-90% of the neoplastic cells packed massively with immunoreactive granules. Epidemiology Only occasional cases have been described {566,616}. However, the inci- dence in the breast is probably underes- timated as oncocytes are easily over- looked or misdiagnosed as apocrine ele- ments {615}. All described patients haveFig. 1.53 Secretory carcinoma. The tumour cells Fig. 1.54 Secretory carcinoma. Abundant secretory been over 60 years old. There is nohave abundant pink eosinophilic cytoplasm. material is evident. predilection for site. One case occurred in a man {566}.as seen in the "tagetoid pattern" of ICL ICD-O code 8290/3 Macroscopydescribed by Gad and Azzopardi {943} The largest tumour measured 2.8 cmis rarely evident. Historical annotation {616}.Mitoses and necrotic areas are rare. Oncocyte (a Greek derived word )Ductal in situ carcinoma of either the means "swollen cell", in this case due to Histopathologysecretory or low grade type may be an accumulation of mitochondria. The The tumours are all similar with defined,present, either at the margins or within term oncocyte is used when mitochon- circumscribed borders and vary fromthe tumour {2430}. dria occupy 60% of the cytoplasm glandular to solid. The cells have abun- {990}. Oncocytic tumours can be seen dant cytoplasm filled with smallImmunoprofile in various organs and tissues {2271, eosinophilic granules. Nuclei are monot-EMA, alpha lactalbumin and S-100 pro- 2405}. onous and round to ovoid with a con-tein are frequently expressed in SC In oncocytes, mitochondria are diffusely spicuous nucleolus. Mitoses are not fre-{323,1579,2430}. Estrogen re c e p t o r s dispersed throughout the cytoplasm quent. In situ carcinomas with a papil-are mostly undetectable. while in mitochondrion-rich cells they lary appearance have been described are grouped to one cell pole {2948}. {616}.Prognosis and predictive factors The proportion of oncocytes presentSC has an extremely favourable progno- within a tumour required to call it onco- Differential diagnosissis in children and adolescents but cytic has been arbitrarily proposed by Oncocytic carcinomas can be distin-seems slightly more aggressive in older various authors and varies from organ to guished from apocrine, neuroendocrinepatients {2881}. Isolated recurrences in organ. In a small series of breast onco- carcinomas and oncocytic myoepithelialchildren are exceptional {52}, but the cytic carcinomas, Damiani et al. {616}, lesions {615,945,2013} by their immu-risk of nodal involvement is similar in using immunohistochemistry with an anti nophenotype.young and older patients {2430}.Axillary lymph node metastases arefound in approximately 15% of patients{2814} but metastases are confined to 4lymph nodes at the most {52}.Tumours less than 2 cm in size areunlikely to pro g ress {2881}. Simplemastectomy, as opposed to excision ofthe tumour, has led to a cure, with theexception of the case reported by Meis{1860}. Recurrence of the tumour mayappear after 20 years {1519}, and pro-longed follow up is advocated. Fatalcases are the exception {1519,2881}and have never been reported in chil-dren.Oncocytic carcinomaDefinitionA breast carcinoma composed of morethan 70% oncocytic cells. Fig. 1.55 Oncocytic carcinoma. Note well circumscribed nodule and cells with abundant eosinophilic cytoplasm. Invasive breast carcinoma 43
  • 63. Immunoprofile Three basic patterns are seen: trabecu- t o ry glandular structures (glandularThe cases studied by Damiani et al. {616} lar-tubular, cribriform and solid. The 3 space) which contain eosinophilic gran-showed diffuse and strong immunoreac- patterns have been used by Ro et al. ular secretion of neutral mucosub-tivity with an anti mitochondrial antibody. {2381} to develop their grading system. stances, and are periodic acid-SchiffEpithelial membrane antigen outlined the The cribriform pattern is the most char- positive after diastase digestion {152}.luminal borders of neoplastic glands acteristic as the neoplastic areas are The dual structural pattern reflects awhen these were present. GCDFP-15 was perforated by small apertures like a dual cell component. The basaloid cellabsent in 3 cases and ER was observed sieve. The "apertures" are of two types: has scanty cytoplasm, a round to ovoidin 90% of the cells in one {616}. The first, also referred to as pseudolu- nucleus and one to two nucleoli {1581}. mens {1406}, results from intratumoral It constitutes the bulk of the lesion andPrognosis and predictive factors invaginations of the stroma (stromal also lines the cribriform stromal spaces.The follow up and number of reported space). Accordingly, this type of space The second type of cell lines the truecases is too small to allow meaningful is of varying shape, mostly round, and glandular lumina, and has eosinophilicdiscussion of prognosis. contains myxoid acidic stromal muco- cytoplasm and round nuclei similar to substances which stain with Alcian blue those of the basaloid cells. A third type {152} or straps of collagen with small of cell seen in 14% of cases byAdenoid cystic carcinoma capillaries. Sometimes the stro m a l Tavassoli and Norris {2885} consists of spaces are filled by hyaline collagen sebaceous elements that can occasion-Definition and the smallest are constituted by ally be numerous.A carcinoma of low aggressive potential, small spherules or cylinders of hyaline ACC contains a central core of neoplas-histologically similar to the salivary gland material which has been shown ultra- tic cells, surrounded by areas of inva-counterpart. structurally and immunohistochemically sion; ductal carcinoma in situ is absent to be basal lamina {463}. With immuno- at the periphery. The stroma varies fromICD-O code 8200/3 histochemistry a rim of laminin and col- tissue very similar to that seen in the lagen IV positive material outlines the normal breast to desmoplastic, myxoidSynonyms stromal spaces. The second type of or even extensively adipose.Carcinoma adenoides cysticum, adeno- space is more difficult to see as it is less ACC has been seen in association withcystic basal cell carcinoma, cylindroma- numerous and usually composed of adenomyoepithelioma {2994} and lowtous carcinoma. small lumina. These are genuine secre- grade syringomatous (adenosquamous) carcinoma {2419} which suggests aEpidemiology close relationship among these com-Adenoid cystic carcinoma (ACC) repre- bined epithelial and myoepithelialsent about 0.1% of breast carcinomas tumours.{149,1581}. It is important that stringentcriteria are adopted to avoid misclassi- Differential diagnosisfied lesions as found in about 50% of the ACC must be distinguished from benigncases recorded by the Connecticut collagenous spherulosis {519} and fromTumor Registry {2815}. The age distribu- cribriform carcinoma, which more close-tion, is similar to that seen in infiltrating ly simulates ACC. Cribriform carcinomaduct carcinomas in general {2419}. is characterized by proliferation of one type of neoplastic cell only, and oneClinical features type of mucosubstance. In addition,The lesions are equally distributed Fig. 1.56 Adenoid cystic carcinoma. The typical estrogen and progesterone receptorsbetween the two breasts and about 50% fenestrated nests composed of two cell types (dom- are abundant in cribriform carcinomasare found in the sub-periareolar region inant basaloid and few eosinophilic) are shown. and absent from virtually all cases of{149}. They may be painful or tender and ACC {2381}.unexpectedly cystic. A discrete nodule isthe most common presentation. Immunoprofile and ultrastructure The two main cell types are different atMacroscopy both ultrastructural and immunohisto-The size varies from 0.7 to 12 cm, with an chemical levels.average amongst most reported cases of Ultrastructurally, the basaloid cells have3 cm. Tumours are usually circumscribed, myoepithelial features particularly whenand microcysts are evident. They are located at the interstitial surface thatpink, tan or grey in appearance {2309, lines the pseudoglandular spaces2419}. {3244}. They show thin cytoplasmic fila- ments with points of focal condensationHistopathology {3094}. These cells have been shown toACC of the breast is very similar to that of Fig. 1.57 Adenoid cystic carcioma. In this case, be positive for actomyosin {105} andthe salivary gland, lung and cervix {1838}. there is a predominant tubular architecture. similar to myoepithelial cells are posi-44 Tumours of the breast
  • 64. is keratin 7 positive, while the ade- Clinical features nosquamous cell is both keratin 7 and ACCA presents as a palpable nodule 14 positive {902}. These cells can ranging from 2 to 5 cm size. One case undergo squamous metaplasia as seen was discovered at mammography {619}. in two of the cases re p o rted by Lamovec et al. {1581}. Squamous Histopathology metaplasia is more common in breast The tumours show a combination of ACC, but is virtually never seen in sali- solid, microcystic and microglandular vary gland ACC. areas. One case {619} was mostly solid, and another {2404} had comedo-likeA Prognosis and predictive factors areas with a peripheral rim of microg- ACC is a low grade malignant tumour landular structures. generally cured by simple mastectomy. Cytologically, the cells have abundant, Like its analogue in the salivary gland, it usually granular, amphophilic to eosi- rarely spreads via the lymphatic stream. nophilic cytoplasm. The granules may Local recurrence is related to incom- be coarse and, bright red, reminiscent plete excision, but patients have been of those in Paneth cells or amphophilic. reported to survive 16 years after the However, clear "hypernephroid" cyto- excision of the recurrence {2223}. Only plasm is not unusual. The nuclei are two cases of axillary node metastases irregular, round to ovoid, with a single have been re p o rted {2381,3094}. nucleolus. The mitotic count varies andB Distant metastases occur in about 10% can be as high as 15 mitoses/10 highFig. 1.58 Adenoid cystic carcinoma. Immunostain of cases {544} and the lungs are fre- power fields {619}.for laminin (A) decorates the basement mem- quently involved.branes, while cytoplasmic immunoreaction with Immunoprofileactin (B) unmasks the neoplastic myopithelial cell Most of the cells stain intensely withcomponent of the tumour. Acinic cell carcinoma anti-amylase, lysozyme chymotrypsin, EMA and S-100 protein antisera {619}. Definition GCDFP-15, the mucoapocrine marker,tive for smooth muscle actin and Acinic cell carcinoma (ACCA) is the may also be focally positive.calponin {902} as well as keratin 14. breast counterpart of similar tumoursNevertheless, most basaloid cells are that occur in the parotid gland and Ultrastructurenondescript elements showing at elec- show acinic cell (serous) differentia- Three cases published were composedtron microscopy level few filaments and tion. of cells with cytoplasm filled by zymo-organelles without specific feature s gen-like granules measuring from 0.08{1507,2885}. ICD-O code 8550/3 to 0.9 µm {619,2404,2561}.The cells that line the glandular luminaare cuboidal to spindle-shaped. When Epidemiology Prognosis and predictive factorscuboidal, they have blunt micro v i l l i ACCA is a rare tumour. Seven cases None of the 7 reported cases has diedalong the luminal margins (secretory have been recorded {619,2561}. Other of the tumour, although follow up wastype). When spindle-shaped, they carcinomas showing serous secretion, limited (maximum 5 years). In two casesshow abundant tonofilaments along probably related to ACCA, have also axillary lymph nodes contained metas-with microvillous cytoplasmic process- been reported {1287,1483}. It affects tases. Treatments varied from neoadju-es such as to merit the design {2885}. women between 35 and 80 years (mean vant chemotherapy with radical mas-Accordingly, the secretory type of cell 56 years) {619}. tectomy to lumpectomy alone.Fig. 1.59 Acinic cell carcinoma showing aggre- Fig. 1.60 Acinic cell carcinoma. Note the absence Fig. 1.61 Acinic cell carcinoma, immunostain isgates of cells with granular cytoplasm. of nuclear atypia. positive for lysozyme. Invasive breast carcinoma 45
  • 65. Glycogen–rich, clear cell been observed without significant clear {2313,2754}. The incidence of axillarycarcinoma (GRCC) cell in 58% of breast carcinoma {880}. lymph node invasion is significantly high- The lesions usually have the structural er than in the other non-GRCC formsDefinition features of intraductal and infiltrating {1264}. The histologic grade is intermedi-A carcinoma in which more than 90% ductal neoplasms but rarely those of lob- ate to high with a paucity of grade Iof the neoplastic cells have abundant ular, medullary or tubular types have tumours {1165}.clear cytoplasm containing glycogen. been noted. GRCCs has either circum- Although follow up studies confirm that scribed or infiltrative borders {880,165, disease free and overall survival is signif-ICD-O code 8315/3 2754,2870}. icantly worse in GRCC, due to the low The in situ component, either in the incidence, there are no multiparametricSynonyms pure form or in association with most analyses to compare GRCC stage byClear cell carcinoma 8310/3 invasive cases has a compact solid, stage with the other histological types ofGlycogen-rich carcinoma 8315/3 comedo or papillary growth pattern. breast carcinoma. The invasive tumour is generally com-Epidemiology posed of solid nests, rarely of tubular orThe frequency is from 1-3% of breast car- papillary structures. Sebaceous carcinomacinomas {880,1264}, with an age range The tumour cells tend to have sharplyof 41-78 years, median 57 years {2870}. defined borders and polygonal contours. Definition The clear or finely granular cytoplasm A primary breast carcinoma of the skinClinical features contains PAS positive diastase labile adnexal type with sebaceous differentia-These tumours show similar presentation glycogen. The nuclei are hyperchromatic, tion. There should be no evidence of der-features to ductal NOS carcinoma. with clumped chromatin and prominent ivation from cuteneous adnexal seba- nucleoli. ceous glands.MacroscopyThe clear cell glycogen-rich carcinoma Differential diagnosis ICD-O code 8410/3does not differ grossly from that of usual To differentiate this tumour from otherinvasive or intraductal carcinoma {1165}. clear cell tumours, including lipid rich EpidemiologyThe neoplasm ranges from 1 to 8 cm in carcinoma, histiocytoid carcinoma, ade- Only 4 examples of this rare mammarysize {2422,2754,2870}. nomyoepithelioma, clear cell hidradeno- tumour have been observed {2876}. The ma and metastatic clear cell carcinoma women, three of whom were white, wereHistopathology (particularly of renal origin), enzyme aged 45-62 years {2876,3006}.A strict definition for clear cell glycogen- cytochemistry and immunohistochem-rich is necessary for two reasons. istry are useful {702,1165,1549,2754}. Clinical featuresCarcinomas in the breast with a clear cell All the patients presented with a palpa-appearance are uncommon and are due Immunoprofile ble an artefact produced by extraction of Hormone receptor status is similar tointracytoplasmic substances during tis- ductal NOS {880}. Macroscopysue processing. However, as the sub- The tumours range in size from 7.5-20stances that are extracted differ, they may Prognosis and predictive factors cm. The margins are sharply delineated,be of different biological significance. In Most reports suggest that GRCC is more and the cut surface is solid and brightaddition, intracytoplasmic glycogen has aggressive than typical ductal carcinoma yellow.A BFig. 1.62 Glycogen-rich carcinoma. A Cells with abundant clear cytoplasm and relatively uniform round nuclei grow in a solid pattern supported by branchingvessels. B Note transition from typical ductal epithelial cells to clear cells in a duct adjacent to the invasive carcinoma.46 Tumours of the breast
  • 66. Table 1.09Glycogen-rich (GRCC) and non glycogen-rich clear cell tumours of the breast. GRCC Lipid rich Histiocytoid Apocrine Hidradenoma Secretory Adenomyo- Metastatic clear carcinoma lobular carcinoma carcinoma carcinoma epithelioma cell carcinoma from the kidney Cell type One One One One Two One Two One Cytoplasm Empty Foamy Foamy Foamy Empty Foamy/empty/ Empty granular Nuclei High grade High grade Low grade Low grade Low grade Low grade Low grade Low grade PAS + - - + + + + + PAS diastase - - - + + - +/- - Mucicarmine - - + + - + - - Oil red-O - + - - - - - - Smooth actin - - - - - - + - Vimentin + S100 - - - - + + + - GCDFP-15 +/- - + + - - + (apocrine) -Histopathology Neither has the smaller second cell pop- Inflammatory carcinomaThe tumour is characterized by a lobula- ulation or the squamous metaplasia thatted or nested proliferation of a varying may be present in sebaceous carcinoma. Definitionadmixture of sebaceous cells with abun- A particular form of mammary carcinomadant finely vacuolated cytoplasm sur- Prognosis and predictive factors with a distinct clinical presentation {1607}rounded by smaller ovoid to spindle cells Not much is known about the behaviour believed to be due to lymphatic obstruc-with a small amount of eosinophilic cyto- of these tumours. The 7.5 cm tumour was tion from an underlying invasive ade-plasm and without any vacuolization. The treated by radical mastectomy, but none nocarcinoma; the vast majority of casesnuclei in both cell types are irregularly of the 20 axillary nodes was positive have a prominent dermal lymphatic infil-shaped to rounded, vesicular with 0 to 2 {2876}. Another recently reported case tration by tumour. Inflammatory carcino-nucleoli. Mitotic figures are sparse, but was associated with extensive metas- ma is a form of advanced breast carcino-may be focally abundant. Focal squa- tases with sebaceous differentiation evi- ma classified as T4d {51, 2976}. Dermalmous morules may be present focally. dent at the distant sites {3006}. lymphatic invasion without the character-Sebocrine cells with features of bothapocrine and sebaceous cells and notedin a variety of apocrine lesions have notbeen a notable feature of sebaceous car-cinomas.ImmunoprofileThe tumour cells stain positively with pan-cytokeratin (AE1/AE3/LP34). In the threecases assessed, immunostains for prog-esterone receptor (PR) were positive inall, two were estrogen receptor (ER) pos-itive, and one was ER negative.Differential diagnosisApocrine carcinoma with a large popula-tion of sebocrine cells and lipid rich car-cinomas enter the differential diagnosis.The former invariably has typical apoc-rine cells admixed and the latter formscords and irregular cell clusters with a Fig. 1.63 Sebaceous carcinoma. The cells have abundant finely vacuolated cytoplasm and form roundedmore subtle vacuolization of the cells. aggregates with a few amphophilic cells present in the periphery. Invasive breast carcinoma 47
  • 67. Differential diagnosis There may be a discrepancy between clinical presentation with inflammatory features and presence of dermal lym- phatic emboli. Dermal vascular emboli may not be present in a biopsy taken from erythematous or oedematous area, or may be present in skin beyond the clinical skin changes. The skin biopsy will usually also show dermal lymphatic dilatation. The clinical features of inflam- matory carcinoma are generally regard- ed as specific but underlyng true inflam- matory conditions should be excluded if histological confirmation is not achieved. Prognosis and predictive factors Prior to the introduction of systemic therapy the prognosis of inflammatory carcinoma even when treated by mas-Fig. 1.64 Sebaceous carcinoma. Cells with moderate amounts of eosinophilic or abundant microvacuolat- tectomy, was very poor with 5 year sur-ed cytoplasm and variably compressed nuclei resembling lipoblasts are admixed. vival under 5% {1052,2384}. Use of sys- temic chemotherapy has produced anistic clinical picture is insufficient to qual- is not an inflammatory condition. The improvement in survival figures reportedify as inflammatory carcinoma. cutaneous signs are produced as a con- as 25 to 50% at 5 years {406,828,1805, sequence of lymphatic obstruction and 1907,2154}. In cases treated with neoad-ICD-O code 8530/3 consequent oedema, which produce juvant chemotherapy or radiotherapy, signs mimicking an inflammatory process. residual tumour, including intravascularEpidemiology Inflammatory signs can be the primary emboli, are usually present in the mas-The age distribution is similar to ductal clinical presenting abnormality (primary tectomy specimen even when a clinicalNOS carcinoma and breast carcinoma in inflammatory carcinoma) or develop as a response has been observed {2427}.general {1095,2384}. There is no recog- consequence of tumour recurrence (sec- Mastectomy and radiotherapy are con-nized specific association with younger ondary inflammatory carcinoma). sidered beneficial for initial local controlage and pregnancy but the phenomenon Histologically the underlying invasive and palliation of symptoms {406,582,of peritumoural lymphatic vascular inva- carcinoma is not regarded as having 2243}. There are no consistent findingssion is found more frequently in younger specific histological features, the majori- with respect to influence of additionalwomen {1095,2795}. The reported fre- ty of tumours have ductal NOS and are of clinical features such as presence ofquency of an inflammatory presentation of grade 3 morphology {1708,1851}. These a clinical mass or findings in skin biopsyprimary breast carcinoma varies between tumours often have an associated lym- on survival. However, response to che-1 and 10%, being influenced by the diag- phoid infiltrate usually of mature lympho- motherapy and radiotherapy, and patho -nostic criteria (clinical or pathological) cytes and plasma cells, a low frequency logical response have been shown to beand the nature of the reporting centre of estrogen receptor positivity {445,1490} associated with improved disease free(local population clinical centre versus and ERBB2 overexpression {1074}. The survival {473,828,841,1826}.tertiary referral centre) {769,1641,2517}. skin often shows co-existing features associated with lymphatic obstructionClinical features including separation of collagen fibres Bilateral breast carcinomaThe clinical findings include diffuse ery- with broadening of the reticular dermalthema, oedema, peau d’orange, tender- layer due to oedema. Involved dermal Definitionness, induration, warmth, enlargement lymphatics may have an associated A synchronous breast cancer is oneand in some cases a palpable ill defined lymphoplasmacytic infiltrate {2427}. detected within two months of the initialmass. The diagnosis is based on clinical Secondary or recurrent inflammatory car- primary tumour.features and should be confirmed by cinoma has been shown to be associat- Approximately 5-10% of women treatedbiopsy. Dermal lymphatic tumour emboli ed more with ductal NOS and apocrine for breast cancer will have either syn-are not always found in small diagnostic histological types of breast carcinoma chronous bilateral cancers or will deve-skin biopsy samples {724,2384}. and is rare following presentation with lop a subsequent contralateral breast other types, papillary, medullary and cancer (CBC) {448,872,1219,1491,Histopathology mucinous {2384}. The skin may also 2383}. The prevalence of synchronousDespite the name, inflammatory carcino- show stromal metastatic deposits of bilateral breast cancer is approximatelyma is not associated with any significant tumour particularly in secondary or 1% of all breast cancers {448,648,872,degree of inflammatory cell infiltration and recurrent inflammatory carcinoma. 1491,1936}. An increase in the detection48 Tumours of the breast
  • 68. of synchronous cancers has been re- appears to have a worse prognosis cal examination of the resected primaryported following the introduction of bi- than unilateral cohorts or women with tumour, regional lymph nodes, and/orlateral mammography for the investiga- metachronous CBC {164,1092,1233}. more distant metastases, when relevant.tion of symptomatic breast disease and Others have failed to demonstrate any The staging system currently in mostfor population based breast screening survival difference between women with widespread use is the TNM Classification{751,872,1491,1492}. unilateral and those with synchronous {51,2976}. The most recent edition is pro-It is well recognized that a previous his- CBC {911,1053,2555}. vided at the beginning of this chapter.tory of breast cancer increases the risk of The pathological tumour status ("pT") is asubsequent breast cancer in the con- measurement only of the invasive com-tralateral breast. The reported annual Tumour spread and staging ponent. The extent of the associatedhazard rates of between 0.5-1% per year intraductal component should not be{448,872,1491,2383,2798} appear rela- Tumour spread taken into consideration. In cases oftively constant up to 15 years {1491} giv- Breast cancer may spread via lymphatic microinvasive carcinoma (T1mic) ining a cumulative incidence rate for sur- and haematogenous routes and by direct which multiple foci of microinvasion arevivors of around 5% at 10 years and 10% extension to adjacent structures. Spread present, multiplicity should be noted butat 15 years. via the lymphatic route is most frequently the size of only the largest focus is used,Family history {253,448,1219} and early to the ipsilateral axillary lymph nodes, i.e. the size of the individual foci shouldage of onset {35,1168,2798} have been but spread to internal mammary nodes not be added together. The pathologicalreported to increase the risk of CBC and to other regional nodal groups may node status ("pN") is based on informa-development in some studies but others also occur. Although breast cancer may tion derived from histological examina-have found no such associations with metastasize to any site, the most com- tion of routine haematoxylin and eosin-either early age of onset {252,253,872} or mon are bone, lung, and liver. Unusual stained sections. Cases with only isolat-family history {35,872}. One study has sites of metastasis (e.g. peritoneal sur- ed tumour cells are classified as pNOreported that family history, early age of faces, retroperitoneum, gastrointestinal (see relevant footnote in the TNM Tableonset and lobular histology are independ- tract, and reproductive organs) and which also indicates how to designateent predictors of metachronous contralat- unusual presentations of metastatic dis- sentinel lymph node findings). A sub-eral breast cancer development {1492}. ease are more often seen with invasive classification of isolated tumour cells isThese characteristics suggest a possible lobular carcinomas than with other histo- provided in TNM publications {51,1195,genetic predisposition. Women with a logical types {319,704,1142,1578}. 2976}.strong family history who develop breast Several models have been proposed tocancer at an early age are at consider- explain the spread of breast cancer. The Measurement of tumour sizeable risk of contralateral breast cancer Halsted model, assumes a spread from The microscopic invasive tumour size (I)as a first event of recurrence particularly the breast to regional lymph nodes and is used for TNM Classification (pT). Theif the first primary is of lobular histology from there to distant sites. This hypothe- dominant (largest) invasive tumour focusor is of favourable prognostic type {1491, sis provided the rationale for radical en is measured, except in multifocal1492}. bloc resection of the breast and regional tumours where no such large singlePatients with metachronous CBC are lymph nodes. Others suggest a systemic focus is apparent. In these cases theyounger at the age of onset of the origi- disease from inception, which implies whole tumour size (w) is used.nal primary. Many, but not all, series that survival is unaffected by local treat-report that a higher percentage of the ment. However, clinical behaviour sug- Somatic genetics of invasivetumours are of lobular type {35,252,872, gests that metastases occur as a func- breast cancer1219,1241,1492,2383}. This observation tion of tumour growth and progressiondoes not imply that tumours of lobular {1181}. This concept is supported by the As in other organ sites, it has become evi-type, in isolation from other risk factors results of axillary sentinel lymph nodes, dent that breast cancers develop throughsuch as young age and family history, which show that metastatic axillary lymph a sequential accumulation of geneticshould be considered to have a higher node involvement is a progressive alterations, including activation of onco-risk of bilateral breast involvement process. genes (e.g. by gene amplification), and{1491}. A greater frequency of multicen- inactivation of tumour suppressor genes,tricity in one or both breast tumours has Tumour staging e.g. by gene mutations and deletions.also been reported {355}. There does not Both clinical and pathological staging isappear to be any association with histo- used in breast carcinoma. Clinical stag- Cytogeneticslogical grade, other tumour types or the ing is based on information gathered As yet no karyotypic hallmarks of breaststage of the disease {355,1491,1492}. prior to first definitive treatment, includ- cancer have been identified, such as ing data derived from physical examina- the t(8;14) in chronic myelogenousPrognosis and predictive features tion, imaging studies, biopsy, surgical leukaemia (CML), or the i(12p) in testicu-Theoretically women with synchronous exploration, and other relevant findings. lar cancer. There is not even a cytoge-CBC have a higher tumour burden than Pathological staging is based on data netic marker for any of the histologicalwomen with unilateral disease which used for clinical staging supplemented subtypes of breast cancer. One reasonmay jeopardize their survival prospects or modified by evidence obtained during for this is certainly the technical difficulty{1035}. Indeed, synchronous CBC surgery, particularly from the pathologi- of obtaining sufficient numbers of good Invasive breast carcinoma 49
  • 69. quality metaphase spreads from an indi- somes and homogeneously staining CGH and gene expression analysis.vidual tumour. However, it may also relate regions, are a frequent occurrence in Oncogenic activation by point-mutationto the genetic complexity of this tumour. breast cancer. These regions were later seems to be rare in breast tumours.Nonetheless, several hundred primary shown to contain amplified oncogenes Listed by chromosome region, the follow-tumours have been karyotyped to date, (see below). Comparative genomic ing (onco)gene amplifications seem toallowing some general patterns to be hybridization (CGH) has identified over be involved in the progression of breastdiscerned {1879}. An increased modal 20 chromosomal subregions with cancer.chromosome number is the most con- increased DNA-sequence copy-number,spicuous characteristic in many tumours, including 1q31-q32, 8q24, 11q13, 1p13-21: DAM1 has been found ampli-in keeping with the finding that approxi- 16p13, 17q12, 17q22-q24 and 20q13. fied in two breast cancer cell lines, but itmately two-thirds of all breast cancers For many of these regions, the critically is not certain whether this gene is drivinghave a hyperploid DNA-content in flow- amplified genes are not precisely known. the amplification {1962}.cytometric analysis. Unbalanced translo- Chromosomal regions with increased 7p13: The epidermal growth factorcations are most often seen as recurrent copy-number often span tens of receptor gene (EGFR), encoding a cellchanges, with the i(1)(q10) and the megabases, suggesting the involvement membrane localized growth factorder(1;16)(q10;p10) the most prominent. of more than one gene. Loss of chromo- receptor, is amplified in less than 3% ofFor the latter, it is not clear whether loss somal material is also detected by CGH, breast carcinomas.of 16q or gain of 1q is the selective and this pattern is largely, though not 8p12: The fibroblast growth factor recep-change, or whether both are. Other con- completely, in agreement with loss of het- tor 1 gene (FGFR1; formerly called FLG)spicuous changes are i(8)(q10), and erozygosity data (see below). encoding a cell membrane locatedsubchromosomal deletions on chromo- receptor for fibroblast growth factor, issomes 1 (bands p13, p22, q12, q42), 3 Oncogenes amplified in approximately 10% of breast(p12-p14), and 6 (q21). No specific A number of known oncogenes were ini- carcinomas {41}.genes have been associated with any of tially found to be amplified in subsets of 8q24: MYC encodes a nuclear proteinthese changes. breast cancer by Southern blot analyses involved in regulation of growth and and fluorescent in situ hybridization. apoptosis. MYC amplification is found inDNA amplification Subsequently, a number of genes have approximately 20% of breast {250,596}.Classic cytogenetic analysis had already been identified as critical targets for The MYC protein has a very short half-indicated that double minute chromo- DNA amplifications by a combination of life, precluding the assessment of proteinFig. 1.65 Invasive ductal carcinoma. Summary of comparative genome hybridization analysis of 80 cases. The chromosome numbers are in black. The red curvesdepict the average ratio profiles between tumour-derived and normal-derived fluorescence signals. Of the three lines to the right of each chromosome, the middlerepresents a ratio of 1.0; deviations of the curve to the left or right indicate loss or gain of chromosomal material, respectively. Average ratios were computed from"n" single chromosomes from different metaphases. Data were retrieved from the Online CGH Tumour Database ( For details on methodology see F. Richard et al. {2366}.50 Tumours of the breast
  • 70. A B CFig. 1.66 Poorly differentiated DCIS. A Immunohistochemical staining and bright field in situ hybridization (BRISH) of cyclin D1 in the same case of DCIS. Strongstaining of poorly differentiated DCIS. B Immunohistochemical staining and BRISH of cyclin D1 in the same case of DCIS. BRISH with a chromosome 11-specific(peri)centromeric probe. C BRISH with the cyclin D1 specific cosmid. Immunohistochemical staining and BRISH of cyclin D1 in the same case of DCIS. BRISH withthe cyclin D1 specific cosmid. Reprinted with permission from C.B. Vos et al. {3035}.overexpression as a substitute for the ERBB2 protein, but not all tumours with cell proliferation {346}. NCOA3 geneanalysis of gene amplification. Ampli- overexpression have amplified 17q12. encodes a co-activator of the estrogenfication of subregions of 8q can be Overexpression is found in approximate- receptor {109}, and its amplification hascomplex. There appears to be at least ly 20-30% of human breast carcinomas been found to be associated with estro-one additional oncogene mapping to {2962}. In breast cancers with normal gen receptor positivity. High resolutionchromosome 8q12-22, which has not ERBB2 copy number, expression of mapping of the amplified domains hasbeen identified yet. ERBB2 may be variable but is very rarely suggested that a putative oncogene,10q26: The fibroblast growth factor as high as that in tumours with ERBB2 ZNF217, and CYP24 (encoding vitamin Dreceptor 2 (FGFR2; formerly: BEK) gene amplification (usually 10-fold to 100-fold 24 hydroxylase), whose overexpressionencodes a cell membrane located higher and equivalent to millions of is likely to lead to abrogation of growthreceptor for fibroblast growth factor. This monomers). Numerous studies have control mediated by vitamin D, may begene is amplified in approximately 12% investigated the relationship between targets for the amplification {60}.of breast carcinomas {41}. ERBB2 status and clinicopathological The STK15 gene (also known as BTAK11q13: Amplification of the cyclin D1 characteristics in breast cancer {2962}. and Aurora-A) is amplified in appro-gene (CCND1), encoding a nuclear pro- 17q22-q24: At least three genes ximately 12% of primary breast tumours,tein involved in cell cycle regulation, has (RPS6KB1, PAT1, and TBX2) have been as well as in breast, ovarian, colon,been found in 15-20% of breast tumours, found to be co-amplified and overex- prostate, neuroblastoma, and cervicalin association with estrogen receptor pressed in ~10% of breast cancers {181}. cancer cell lines {3259}. S T K 1 5positivity. Cyclin D1 can also bind to the Further analysis identified RPS6KB1, encodes a centrosome-associatedestrogen receptor, resulting in ligand- MUL, APPBP2, TRAP240 and one serine-threonine kinase, and may alsoindependent activation of the receptor unknown gene to be consistently overex- be overexpressed in tumours without{3273}. Immunohistochemically, cyclin pressed in two commonly amplified sub- amplification of 20q13 {1885}. Centro-D1 appears to be overexpressed in 80% regions {1896}. The ribosomal protein S6 somes appear to maintain genomic sta-of invasive lobular carcinomas, but is not kinase (RPS6KB1) is a serine-threonine bility through the establishment of bipo-always accompanied by CCND1 gene kinase whose activation is thought to reg- lar spindles during cell division, en-amplification {2133}. ulate a wide array of cellular processes suring equal segregation of replicated17q12: The human epidermal growth involved in the mitogenic response c h romosomes to daughter cells.factor receptor-2 (ERBB2) proto-onco- including protein synthesis, translation of Deregulated duplication and distributiongene (also known as HER2, and equiva - specific mRNA species, and cell cycle of centrosomes are implicated in chro-lent to the rodent neu gene) encodes a progression from G1 to S phase. mosome segregation abnorm a l i t i e s ,185-kD transmembrane glycoprotein 20q13: It is presently unknown whether leading to aneuploidy seen in manywith intrinsic tyrosine kinase activity. A the CSE1L/CAS gene, the NCOA3 gene cancer cell types. Elevated S T K 1 5ligand for ERBB2 has not been identified or any other gene in this region serves as expression induces centrosome amplifi-but it is hypothesized that ERBB2 ampli- the target for the amplification, which is cation and overrides the checkpointfies the signal provided by other recep- found in approximately 15% of breast mechanism that monitors mitotic spindletors of this family by heterodimerizing carcinomas. Three independent regions a s s e m b l y, leading to chro m o s o m a lwith them. Ligand-dependent activation of amplification have been identified instability {83,1885,3259}.of ERBB1, ERBB3, and ERBB4 by EGF or and their co-amplification is common.heregulin results in heterodimerization Cellular apoptosis susceptibility (CAS) Loss of heterozygosity (LOH)and, thereby, ERBB2 activation. ERBB2 encodes a protein, which may have a Loss of heterozygosity (LOH) has beenamplification results in overexpression of function in the control of apoptosis and found to affect all chromosome arms Invasive breast carcinoma 51
  • 71. genic RAS {621}. In breast tumour cell lines, the promoter of RASSF1A is highly methylated and its expression is down- regulated {622}. In primary tumours, the proportion with promotor-hypermethyla- tion is lower, and so is the effect on expression down-regulation {42}. No inactivating mutations in the coding regions have been detected, and the relationship between LOH and promotor- methylation status is presently unclear {1368}. To avoid these difficulties in inter- preting the available data, we shall restrict ourselves here to those genes for which acquired inactivating mutations in the coding region have been demon- strated in a proportion of primary breast cancers or breast cancer cell lines. Using these criteria, very few tumour suppressor genes have been identifiedFig. 1.67 Lobular carcinoma of breast. Immunohistochemical staining of a lobular breast carcinoma with a in breast cancer. Listed by chromosomalmutated CDH1 gene. Normal duct epithelium shows positive staining for membrane associated E-cadherin, site, they are:which is lacking in tumour cells. 6q26: IGF2R. The M6P/IGF2R gene, encoding the insulin-like growth factor IIin breast cancer to varying degrees a tumour suppressor gene more accu- (IGF-II)/mannose 6-phosphate receptor,{265,680}. Unfortunately, collation of rately, aiding its identification. is frequently inactivated during carcino-LOH data into a coherent map has been genesis. IGF2R is postulated to be a tu-complicated enormously by the use of Tumour suppressor genes mour suppressor due to its ability to binddifferent terminology and technology in Several chromosome regions showing and degrade the mitogen IGF-II, promotethis area {679}. A tumour specific loss of frequent LOH have been extensively activation of the growth inhibitor TGFβ,an allele, but also an imbalance in allele investigated because of the presence and regulate the targeting of lysosomalintensities (allelic imbalance) are both of appealing candidate tumour suppres- enzymes. Several missense mutations incalled LOH. LOH is often equated with sor genes. Many of these regions are M6P/IGF2R disrupt the ligand bindingdeletion although it may also be supported by CGH and cytogenetic functions of the intact IGF2R. Missensecaused by somatic re c o m b i n a t i o n . analyses. They include 1p32-36, 3p14- mutations have been found in about 6%Complete loss of an allele can only be 21, 6q25, 7q31, 8p12-21, 9p21, 13q12- of primary breast tumours {1125}.reliably and unequivocally measured in q14, 16q22, 16q24, 17p13, 18q21. 7q31: ST7 (for suppression of tumouri-tumour DNA samples with very low lev- Several interesting candidate tumour genicity 7) is a gene with unknown cellu-els of contamination from non-malignant suppressor genes lie in these regions lar function. Transfection of ST7 into thecells (i.e. <25%). Without microdissec- (for example, FANCA in 16q24, HIC1 in prostate-cancer-derived cell line PC3,tion or flow sorting of tumour cells, this 17p13, PDGFRL in 8p21, FHIT in 3p14, abrogated its tumourigenicity in vivo.cannot be obtained from many primary CDKN2A in 9p21, TP73 in 1p36), but Three breast tumour cell lines harbouredbreast cancer tissues. In addition, allel- their role in breast cancer remains to be frame shifting mutations in ST7, whichic imbalance can also be caused by established. was accompanied by LOH in at least onec h romosomal aneuploidy (trisomies By definition, a tumour suppressor gene of them. A role of ST7 in primary breastetc), or low-copy amplification of certain is a gene whose normal function inhibits cancer has been questioned {358,2912}.chromosome regions, which is funda- the initiation or progression of tumour 8q11: RB1CC1. The RB1CC1 protein is amentally different from classical LOH. growth. This can be demonstrated by key regulator of the tumour suppressorThese factors impede meta-analysis of cell biological, biochemical or genetic gene RB1. It is localized in the nucleuspublished allelic imbalance/LOH data in evidence, which are not always in full and has been proposed to be a tran-breast cancer, although it is clear that agreement. For example, transfection of scription factor because of its leucinethere are chromosome arms where LOH the retinoblastoma gene RB1 into some zipper motif and coiled-coil structure.occurs at very high rates. breast cancer cell lines reverts their Seven of 35 (20%) primary breast can-LOH is interpreted in the light of tumourigenic phenotype in vitro, yet no cers examined contained mutations inKnudsons two-hit model for the inacti- inactivating RB1 mutations have been RB1CC1, including 9 large interstitialvation of a tumour suppressor gene reported in primary breast tumours. deletions predicted to yield markedly{679}. Numerous studies have attempt- RASSF1A is located in the region 3p21, truncated RB1CC1 proteins {440}. In all 7ed to map common regions of LOH on which is frequently deleted in breast can- cases, both RB1CC1 alleles were inacti -chromosome arms with frequent LOH. cer. It might serve as a Ras effector, vated, and in each case both mutationsSuch a region could flag the position of mediating the apoptotic effects of onco- were acquired somatically.52 Tumours of the breast
  • 72. 16q22: CDH1. The cell-cell adhesion genes have not yet been detected in strong expression of the estrogen recep-molecule E-cadherin acts as a strong breast cancer. tor cluster of genes. The tumours of theinvasion suppressor in experimental other groups were mainly ER-negative.tumour cell systems. Frequent inactivat- Gene expression patterns The basal-like group is characterizeding mutations have been identified in Expression profiling is expression-analy- by high expression of keratins 5/6 andCDH1 in over 60% of infiltrating lobular sis of thousands of genes simultaneous- 17 and laminin. The ERBB2-group alsobreast cancers, but not in ductal carcino- ly using microarrays {69,1072,1171, expresses several other genes in themas {261}. Most mutations cause transla- 2218,2756,3104}. Tumours show great ERBB2 amplicon, such as GRB7. Thetional frame shifting, and are predicted to multidimensional variation in gene ex- normal breast-like group shows a highyield secreted truncated E-cadherin frag- pression, with many different sets of expression of genes characteristic ofments. Most mutations occur in combina- genes showing independent patterns of adipose tissue and other non-epithelialtion with LOH, so that no E-cadherin variation. These sets of genes relate to cell types. Cluster analyses of 2 pub-expression is detectable immunohisto- biological processes such as prolifera- lished, independent data sets represent-chemically. This offers a molecular expla- tion or cell signalling. Despite this varia- ing different patient cohorts from differentnation for the typical scattered tumour tion, there are also striking similarities laboratories, uncovered the same breastcell growth in infiltrative lobular breast between tumours, providing new oppor- cancer subtypes {2757}.cancer. Lobular carcinoma in situ (LCIS) tunities for tumour classification. ER-pos-has also been found to contain CDH1 itive and ER-negative cancers show dis- Somatic genetics of breast cancermutations {3034}. tinct expression profiles {1072,2986, metastases17p13: TP53 encodes a nuclear protein 3104}. Breast cancers arising in women According to the present view, metasta-of 53 kD, which binds to DNA as a carrying a BRCA1 mutation could be dis- sis marks the end in a sequence oftetramer and is involved in the regulation tinguished from sporadic cases, and genomic changes underlying the pro-of transcription and DNA replication. from those that developed in BRCA2 car- gression of an epithelial cell to a lethalNormal p53 may induce cell cycle arrest riers {1171,2986}. Although this field is cancer. Not surprisingly, therefore, lymphor apoptosis, depending on the cellular still in its infancy, 5 distinct gene expres- node metastases and distant metastasesenvironment {3147}. Mutations, which sion patterns were discerned among 115 in general contain more genomic aberra-inactivate or alter either one of these tumours {2218,2756,2757}, one basal- tions than their cognate primary tumoursfunctions, are found in approximately like, one ERBB2-overexpressing, two {1117,2028}. Flow cytometric DNA con-20% of breast carcinomas {2237}. Most luminal-like, and one normal breast tis- tent measurements have demonstratedof these are missense changes in the sue-like subgroup. Approximately 25% of extensive DNA ploidy heterogeneity inDNA-binding domain of the protein; a the tumours did not fit any of these clas- primary breast carcinomas, with the con-small proportion (~20%) are frame shift- sifications. The luminal-like tumours current presence of diploid and multipleing. The large majority of these mutations express keratins 8 and 18, and show aneuploid DNA stemlines. Identical het-are accompanied by loss of the wildtypeallele (LOH). Missense mutations in TP53can be detected immunohistochemicallybecause mutated p53 fails to activateexpression of MDM2. The MDM2 proteinnormally targets p53 for ubiquitin-medi-ated degradation, constituting a feed-back loop to maintain low levels of p53protein in the cell.Microsatellite instabilityMicrosatellite instability (MSI) is a genet-ic defect caused by mutations in mis-match repair genes (MLH1, MSH2,MSH6, PMS1, and PMS2), reflected bythe presence of multiple alleles at lociconsisting of small tandem repeats ormononucleotide runs. MSI in breast can-cer is negligible, with the possibleexception of breast cancer arising in thecontext of the HNPCC inherited coloncancer syndrome. The most convincingstudy is probably that of Anbazhagan etal., who have analysed 267 breast carci-nomas at 104 microsatellite loci {85}; not Fig. 1.68 Allelotyping of breast cancer. The percentage LOH is calculated as the ratio between the numberone single case of MSI was detected. of tumours with loss of an allele at a given chromosome arm and the total number of cases informative (i.e.Somatic mutations in the mismatch repair heterozygous) for the analysis. Red bars: p-arm; green bars: q-arm. Invasive breast carcinoma 53
  • 73. mary tumour, these data suggest that breast tumour cells may disseminate in a far less progressed genomic state than previously thought, and that they acquire genomic aberrations typical of metasta- tic cells thereafter. These findings have two major clinical implications. First, all adjuvant therapies that do not target genetic or epigenetic events occurring early during tumourigenesis are unlikely to eradicate minimal residual disease, because disseminated cancer cells may not uniformly share mutations that are acquired later on. Second, because dis- seminated cells progress independently from the primary tumour, a simple extrap- olation from primary tumour data to dis- seminated cancer cells is impossible. Genetic susceptibility: familial risk of breast cancerFig. 1.69 Hierarchical clustering of 115 tumour tissues and 7 nonmalignant tissues using gene expres- Introductionsion profiling. Experimental dendrogram showing the clustering of the tumours into five subgroups (toppanel). Gene clusters associated with the ERBB2 oncogene, luminal subtype B, basal subtype, normal Breast cancer has been recognized forbreast-like group, luminal subtype A with high estrogen receptor expression. Scale bar represents fold over 100 years as having a familial com-change for any given gene relative to the median level of expression across all samples. From T. Sorlie ponent {349}. Epidemiological investiga-et al. {2757}. tions have attempted to quantify the risks associated with a positive family history and to examine whether the pattern oferogeneity is often present in their cog- detectable distant metastasis displayed related individuals is consistent with thenate lymph node metastases, suggest- significantly fewer chromosomal aberra- effects of a single gene of large effect,ing that the generation of DNA ploidy tions than primary tumours or cells from shared environmental effects, manydiversity has taken place prior to metas- patients with manifest metastasis, and genes acting in an additive manner, ortasis {197}. LOH analysis of these DNA their aberrations appeared to be ran- most likely, a combination of two or moreploidy stemlines showed that all allelic domly generated {2560}. In contrast, pri- of these. In addition a number of specificimbalances observed in the diploid mary tumours and disseminated cancer genes have been identified as playing aclones recurred in the cognate aneuploid cells from patients with manifest metasta- role. The most important ones areclones, but were, in the latter, accompa- sis harboured different and characteristic BRCA1 and BRCA2 which are discussednied by additional allelic imbalances at chromosomal imbalances. Thus, con- in Chapter 8. However, these two genesother loci and/or chromosome arms trary to the widely held view that the pre- account for only about a fifth of overall{313}. This indicates that the majority of cursors of metastasis are derived from familial breast cancer {107,592,2230}allelic imbalances in breast carcinomas the most advanced clone within the pri- and explain less than half of all high risk,are established during generation of site-specific breast cancer families {898,DNA ploidy diversity. Identical allelic 2631}.imbalances in both the diploid and aneu-ploid clones of a tumour suggests linear Familial risk of breast cancertumour progression. But the simultane- Virtually every study has found signifi-ous presence of early diploid and cantly elevated relative risks of breastadvanced aneuploid clones in both pri- cancer for female relatives of breastmary and metastatic tumour sites sug- cancer patients. However, the magni-gested that acquisition of metastatic tude has varied according to the num-propensity can be an early event in the ber and type of affected relatives, age atgenetic progression of breast cancer. diagnosis of the proband(s), laterality,Intriguingly, single disseminated cancer and the overall study design. Most stud-cells have been detected in the bone ies have found relative risks betweenmarrow of 36% of breast cancer patients 2 and 3 for first-degree relatives selec-{339}. Using single-cell CGH, it was Fig. 1.70 Axillary lymph node. The nodal architec- ted without regard to age at diagnosisdemonstrated that disseminated cells ture is destroyed by massive metastatic ductal or laterality. A comprehensive study,from patients without a clinically carcinoma. using the Utah Population Database, of54 Tumours of the breast
  • 74. first-degree relatives of breast cancer Table 1.10probands diagnosed before age 80 esti- Estimates of relative risks for breast cancer.mated a relative risk of 1.8 in the relatives{1029}. When the breast cancer was of Relative affected, status of proband Estimate of relative risk {Reference} (Study Type)early onset (diagnosed before age 50),the relative risk among first-degree rela- Mother 3.0 {1321a} (a)tives increased to 2.6 and the risk for Sister 3.0 {1321a} (a)early-onset breast cancer among these Mother 2.0 {2214} (a)relatives was 3.7 (95% CI. 2.8—4.6). Therisk to subsequent relatives in families Sister 3.0 {2214} (a)with two affected sisters was increased Sister, premenopausal proband 5.0 {92a} (b)to 2.7 with a particularly high risk of 4.9 Sister, postmenopausal proband 2.0 {92a} (b)of early onset breast cancer. A second First-degree relative (FDR) 2.0 {346a} (c)registry-based study in Sweden found Sister, bilateral proband 6.0 {2129} (c)essentially identical results to the Utah Sister 2.0 {412a} (d)study {715}. Mother 2.0 {412a} (d)Perhaps the largest population-based First-degree relative (FDR) 2.0 {2556a} (a)study (the Cancer and Steroid Hormone(CASH) case-control study) of pro- FDR<45, proband<45 3.0 {2556a} (a)bands with breast cancer diagnosed FDR>45, proband>45 1.5 {2556a} (a)between the ages of 20 and 54 estima- First degree relative 2.1 {501} (c)ted the risk of breast cancer in first- First degree relative, proband <55 2.3 {1246} (a)degree relatives compared with con- First degree relative, proband >55 1.6 {1246} (a)trols was 2.1 {501}. FDR, bilateral proband 6.4 {1246} (a)A study of cancer at a number of sites First degree relative 2.3 {2720a} (c)in a large set of twins in Scandinavia{1658}, estimated the proportion of va- Second degree relative 1.8 {2720a} (c)riance due to genetic (heritability), First degree relative 1.8 {896} (a)shared environment, and random (in- FDR<50, proband<50 3.7 {896} (a)dividual-specific) environmental effects FDR, 2 affected probands 2.7 {896} (a)for each cancer site. Based on this Mother 1.9 {715} (a)data, the authors calculated a co-twin Sister 2.0 {715} (a)relative risk of 2.8 in DZ and 5.2 in MZtwins, and estimated that 27% of breastcancer is due to inherited cause while (a) Ratio of observed frequencies in cancer families to expected frequencies in the general population;only 6% could be attributed to shared (b) Ratio of observed rate of cancer in relatives of cases to observed rate of cancer in relatives of cases to observed rate of cancer in relatives of selected controls;environment. (c) Odds ratio from case-control study with non-cancer controlsThe role of other factors with respect to (d) Relative risk from prospective history has been examined.Larger familial effects among relatives ofyoung bilateral probands compared withyoung probands with unilateral breast the Utah Population Database, when tions detected in these population stud-cancer have been found {93,1246,2129}. risks to all other sites among such ies is due to the BRCA1 gene, known toThe relationship of histology to familial probands were examined statistically be involved in a large proportion ofbreast cancer is less clear {500,2989}. significant familial associations were extended kindreds with clearly inheritedAnother feature, which conveys strong found between breast cancer and can- susceptibility to breast and ovarian can-familial risk of breast cancer, is the cers of the prostate (relative risk = 1.2, cer. It is likely that some of the discrep-occurrence of breast cancer in a male. It P<0.0001), colon (1.35, P<0.0001), thy- ancies in results are linked to the fre-has been estimated that female relatives roid (1.7, P<0.001) and non-Hodgkin quency of BRCA1 deleterious alleles inof probands with male breast cancer lymphoma (1.4, P<0.001) {1029}. The the respective datasets.have a two-fold to three-fold increased Swedish registry study also found a sig-risk of breast cancer {94,2449}. nificant familial relationship between Possible models to explain the familial breast and prostate cancer of similar risk of breast cancerFamilial associations of breast and other magnitude. BRCA1 and BRCA2 explain only a minor-cancers Other studies have also shown relation- ity (about 20%) of the overall familial riskA number of studies have found in- ships between breast cancer and ovari- of breast cancer although they may con-creased risks for other cancers among an, colon and uterine cancers, although tribute much more substantially to therelatives of breast cancer probands. The the results have not been consistent four-fold increased risk at younger ages.most commonly reported are ovarian, across studies {95,1992,2172,2918}. Assuming an overall two-fold increaseduterine, prostate and colon cancers. In Undoubtedly, the majority of the associa- risk among first-degree female relatives Invasive breast carcinoma 55
  • 75. detected at a late stage as small tumours are not felt in the pregnant or lactating breast {91,311,1079}. Preg- nancy in women who have been treated for breast cancer does not appear to affect prognosis {119}. Morphological factors The traditional pathological factors of lymph node status, tumour size, histo- logical type, and histological grade are the most useful prognostic factors in b reast cancer patients {886,1763}, although this is now challenged by gene expression profiling. Lymph node status The status of the axillary lymph nodes is the most important single prognostic factor for patients with breast cancer. Numerous studies have shown that dis-Fig. 1.71 Lymphatic vessel invasion. Several tumour cell nests are present in endothelial lined spaces. e a s e - f ree and overall survival rates decrease as the number of positiveof breast cancer cases and that, as is the weakness of the effects). Only until nodes increases {886}. The clinical sig-likely, these genes act in an additive more of these loci are identified, and nificance of micrometastases and iso-manner with the other loci involved in their interaction with known epidemio- lated tumour cells in the nodes, particu-familial aggregation, then we are left with logical risk factors assessed, will we be larly those identified exclusively bya residual familial risk of 1.8 to be able to untangle the underlying causes immunohistochemistry, remains a mat-explained by other genes and/or corre- of the observed familial risk. ter of debate {71,1655} although virtual-lated family environment. There could be ly all studies with more than 100several genes similar in action to BRCA1 Prognosis and predictive factors patients have shown that micrometas-and BRCA2, with lower breast cancer tases are associated with a small butrisks, or a set of more common polymor- Clinical features significant decrease in disease-fre ephisms in biologically relevant genes, Age and/or overall survival {1655}.each associated with only a small The prognostic significance of age and Approximately 10-20% of patients con-increased risk, or something in-between. menopausal status in patients with breast sidered to be node-negative by routineGenes are not the only factor which c a rcinoma is controversial. Yo u n g e r pathological examination have identifi-could cause the observed familial patients have been found to have a poor able tumour cells as determined by se-correlation. Shared lifestyle or environ- prognosis {59,2029}, a favourable out- rial sectioning, immunohistochemicalmental risk factors would also cause come {2500} or no correlation has been staining for epithelial markers, or both.some degree of familial clustering, found with age at all {1207}. These dis- However, at present, it appears prema-however it can be demonstrated that crepancies may be due to differences in ture to recommend the routine use ofthe known environmental risk factors patient selection, age grouping, and step sections and/or immunohistoche-for breast cancer are unlkely to con- other factors, including high grade, vas- mistry to evaluate sentinel or non-sen-tribute significantly to the overall famil- cular invasion, extensive in situ compo- tinel lymph nodes {71}.ial risk {1238}. nent, steroid receptor negativity, highBased on a model of the contribution of proliferation, TP53 abnormalities. An Tumour sizegenetic variation to the overall familial increased incidence of node positivity Tumour size is an important prognosticrisk, it can be estimated that variation in was found in two large studies of patients factor. Even among patients with breastas few as 70 of the 30,000 genes in the under 35 years. cancers 1 cm and smaller (T1a andhuman genome may contribute to T1b), size is an important prognosticbreast cancer susceptibility. Of course, Pregnancy factor for axillary lymph node involve-this model is based on a number of Breast cancer developing during preg- ment and outcome {461}. However, theunverifiable assumptions and does not nancy is generally considered to have manner in which the pathologicalinclude potential gene-gene and gene- an unfavourable prognosis. There is, tumour size is reported varies. Someenvironment interactions, so should be however, conflicting data as to whether pathologists report the macroscopici n t e r p reted cautiously. However, it this is an independent factor. It may be size, some a microscopic size thatseems clear that there are not going to partly, or entirely, due to the poor prog- includes both the invasive and in sitube hundreds of loci involved (or if there nosis associated with young age and components, and others re p o rt theare, they will be impossible to find given also the fact that the cancer is often microscopic size of the invasive compo-56 Tumours of the breast
  • 76. nent only. There is often poor correlation Lymphatic and blood vessel invasionbetween the tumour size determined by Lymphatic vessel invasion has be e ngross pathological examination and the shown to be an important and in-size of the invasive component as deter- dependent prognostic factor, part i c u-mined by histological measure m e n t larly in patients with T1, node-nega-{27}. The size of the invasive component tive breast cancers {461,1606,1623,is clinically significant, and so the 2433,2445,2452}. Its major value ispathological tumour size for classifica- in identifying patients at increasedtion (pT) is a measurement of only the risk of axillary lymph node involve-invasive component {51}. There f o re , ment {627,839,1592,2253,2415} andwhen there is a discrepancy between adverse outcome {186a,627,1623,the gross and the microscopic size of Fig. 1.72 Carcinoma with central fibrosis. There is 2415,2434}. As with histological grade,the invasive component, the microscop- extensive central fibrosis with only a rim of inva- the ability of pathologists to repro-ic size takes precedence, and should sive carcinoma left around the fibrotic area. ducibly identify lymphatic vessel inva-be indicated in the pathology report and sion has been challenged {998} butused for pathological staging. can be improved if stringent criteria mours, independent of lymph node a re employed {627,2109,2253,2415,Histological type status and tumour size {550,777,836, 2452}. Lymphatic vessel invasionSome special histological types of 868,886,1031,1763,2030,2434}. Tu- must be distinguished from tumourbreast cancer are associated with a mour grading has prognostic value cell nests within artifactual tissueparticularly favourable clinical outcome even in breast cancers 1 cm and small- spaces created by shrinkage or{771,2433}. These include tubular, inva- er {461}. The optimal grading method retraction of the stroma during tissuesive cribriform, mucinous, and adenoid {777} has been detailed earlier in this p rocessing.cystic carcinomas. Some authors also chapter. The combination of histological Blood vessel invasion has been report-include tubulolobular and papillary car- type and grade provides a more accu- ed to have an adverse effect on clinicalcinomas. The 20-year recurrence-free rate assessment of prognosis than does outcome. However, there is a broadsurvival of special type tumours 1.1 to histological type alone {2216}. range in the reported incidence, from3.0 cm in size is similar to that of inva- Histological grade may also provide under 5% to almost 50% {1470,1592,sive ductal carcinomas of no special useful information with re g a rd to 2444,2445,2452, 3083}. This is due totype 1 cm and smaller (87% and 86%, response to chemotherapy and, there- a variety of factors including therespectively) {2433}. The prognostic fore, be a predictive factor as well as a patient population, the criteria andsignificance of medullary carcinoma prognostic indicator. Several studies methodology used, and difficulty inremains controvertial and is discussed have suggested that high histological identifying blood vessels.elsewhere (see medullary carcinoma). grade is associated with a better response to certain chemotherapy regi- Perineural invasionHistological grade mens than low histological grade Perineural invasion is sometimes ob-Grading is recommended for all inva- {2254}. However, additional studies are served in invasive breast cancers, but itsive carcinomas of the breast, regard- required to define this relationship more has not been shown to be an indepen-less of morphological type {1984, clearly {612}. dent prognostic factor {2426}.2216,2905}. This practice has been crit-icized by some pathologists who feel Tumour cell proliferation Tumour necrosisthat grading is not appropriate for the Markers of proliferation have been In most studies {2452}, the presence ofspecial histological types such as pure extensively investigated to evaluate n e c rosis has been associated withtubular, invasive cribriform, mucinous, prognosis {886,1304}. Mitotic count is an adverse effect on clinical outcomemedullary and infiltrating lobular carci- p a rt of histological grading. Other {414, 877,999,2175}, although in one,nomas. For example, most infiltrating methods include DNA flow cytometry necrosis was associated with a worselobular carcinomas, especially those of measurement of S-phase fraction (SPF). prognosis only within the first two yearsclassical subtype, are assessed as Many studies indicate that high SPF is after diagnosis {999}.grade 2 and the overall survival curve of associated with inferior outcome.lobular carcinoma overlies that of all Ki-67/MIB-1 is a labile, non-histone nu- Inflammatory cell infiltratesother types of grade 2 carcinoma. In clear protein detected in the G1 through The presence of a prominent mononu-mucinous carcinoma and in carcinoma M phases of the cell cycle, but not in clear cell infiltrate has been correlatedof mixed morphological type, grading resting cells and is therefore a direct indi- in some studies with high histologicalprovides a more appropriate estimate of cator of the growth fraction. The percent- grade {2030}. However, the prognosticprognosis than type alone {2216}. In age of Ki-67 positive cells can be used to significance of this finding is contro-m e d u l l a ry carcinoma no additional stratify patients into good and poor sur- versial, with some studies noting anprognostic value has been found. vivors. Quantitative RT-PCR in detecting adverse effect on clinical outcomeHigher rates of distant metastasis and the mRNA level has also been intro- {67,286,2785} and others observingpoorer survival are seen in patients with duced as well as array based quantifica- either no significant effect or a benefi-higher grade (poorly differentiated) tu- tion of proliferation (see below). cial effect {635,1601,2445,2785}. Invasive breast carcinoma 57
  • 77. Extent of ductal carcinoma in situ ER-positive tumours were associated p redictor for response to alkylatingThe presence of an extensive intraductal with an improved prognosis, but studies agents and a moderately positive pre-component is a prognostic factor for with long-term follow-up have suggested dictive factor for response to anthracy-local recurrence in patients treated with that ER-positive tumours, despite having clines. There was insufficient data toconservative surgery and radiation thera- a slower growth rate, do not have a lower draw conclusions on the response topy, when the status of the excision mar- metastatic potential. Nonetheless, ER taxanes or radiotherapy. In an adjuvantgins is unknown. However, this is not an status remains very useful in predicting setting, ERBB2 status should not beindependent predictor when the micro- the response to adjuvant tamoxifen {4, used to select adjuvant systemicscopic margin status is taken into con- 368,1304,1833,2120}. Measurement of chemotherapy or endocrine therapy.sideration {2569}. Its relationship with both ER and PR has been clinical prac- Conversely, when adjuvant chemothe-metastatic spread and patient survival tice for more than 20 years. PR is a rapy is recommended, anthracycline-remains unclear {2176,2437,2689}. surrogate marker of a functional ER. In based therapy should be pre f e r red estrogen target tissues, estrogen treat- for ERBB2 positive patients. A human-Tumour stroma ment induces PR. Both can be detec- ized anti-ERBB2 monoclonal antibody,Prominent stromal elastosis has variously ted by ligand binding assay, or more trastuzumab (Herceptin), has beenbeen reported to be associated with a commonly nowadays, by immunohis- developed as a novel anti-cancer drugfavourable prognosis {2664,2858}, an tochemical (IHC) analysis using mo- targeting overexpressed ERBB2 {529}.unfavourable prognosis {84,1016}, and noclonal antibodies. ER/PR-positive This has been shown to be effective into have no prognostic significance {626, tumours have a 60-70% response rate 20% of patients with ERBB2 amplified1266,2393}. The presence of a fibrotic compared to less than 10% for ER/PR- tumours.focus in the centre of an invasive carci- negative tumours. ER-positive/PR-nega-noma has also been reported to be an tive tumours have an intermediate re- TP53 mutationsindependent adverse prognostic indica- sponse of approximately 40%. Hormone Approximately 25% of breast cancerstor {545,1153} receptor status is the only recommend- have mutations in the tumour suppres- ed molecular marker to be used in treat- sor gene TP53, most of which are mis-Combined morphologic prognostic factors ment decision {9,886, 1030}. The impact sense mutations leading to the accumu-The best way to integrate histological of hormone receptor status on prognosis lation of a stable, but inactive protein inprognostic factors is an unresolved and treatment outcome prediction is the tumour cells {1196,2759,2761}.issue {1833}. The Nottingham Prognostic complex. The finding, in cell lines, that Both DNA sequencing and IHC haveIndex takes into consideration tumour tamoxifen can interact with the recently been used to assess TP53-status in thesize, lymph node status and histological identifed ERβ receptor (ERB) may pro- tumour. However, some 20% of thegrade, and stratifies patients into good, vide new clues towards improvement of mutations do not yield a stable proteinmoderate and poor prognostic groups predicting tamoxifen responsiveness and are thus not detected by IHC, whilewith annual mortality rates of 3%, 7%, {1526,1925,3269}. normal (wildtype) protein may accumu-and 30%, respectively {954}. Another Epidermal growth factor receptor (EGFR) late in response to DNA damage or cel-proposal for a prognostic index includes and transforming growth factor alpha lular stress signals. Studies using DNAtumour size, lymph node status and (TGFα), antiapoptotic protein bcl-2, sequencing all showed a strong asso-mitotic index (morphometric prognostic cyclin dependent kinase inhibitor p27 ciation with survival whereas thoseindex) {2993}. are other potential prognostic markers using only IHC did not, or did so only that look promising. Elevated expression weakly {5,886,1304,2237,2760}. GivenMolecular markers and gene of EGFR, in the absence of gene amplifi- the diverse cellular functions of the p53expression cation, has been associated with estro- protein and the location and type ofA large number of genetic alterations gen receptor negativity {2509}. alteration within the gene, specifichave been identified in invasive breast mutations might conceivably be associ-c a rcinomas, many of which are of The ERBB2 / HER2 oncogene ated with a particularly poor prognosis.potential prognostic or predictive value. The prognostic value of ERBB2 over- Patients with mutations in their tumoursSome provide treatment-independent e x p ression, first re p o rted in 1987 affecting the L2/L3 domain of the p53information on patient survival, others {2719}, has been extensively studied protein, which is important for DNApredict the likelihood that a patient will {2962,3173}. ERBB2 over-expression is binding, have a particularly poor sur-benefit from a certain therapy. Some a weak to moderately independent pre- vival {251,317,976,1523}.alterations may have both prognostic dictor of survival, at least for node-pos- The role of p53 in the control of the celland predictive value. itive patients. Gene amplification or cycle, DNA damage repair, and apopto- over-expression of the ERBB2 protein sis, provides a strong biological ration-Steroid hormone receptors can be measured by Southern blot ale for investigating whether mutations(Estrogen receptor (ER) and analysis, FISH, differential PCR, IHC are predictors of response to DNA dam-Progesterone receptor PR) and ELISA {2958}. Studies of the pre- aging agents. Several studies usingEstrogen is an important mitogen exer- dictive value of ERBB2-status have not DNA sequencing of the entire geneting its activity by binding to its receptor been consistent. A recent review {3173} have addressed this in relation to differ-(ER). Approximately 60% of breast carci- concluded that ERBB2 seems to be a ent chemotherapy and radiotherapynomas express the ER protein. Initially, weak to moderately strong negative regimes {16,241,249,976}. A stro n g58 Tumours of the breast
  • 78. cated that gene expression patterns can be identified that associate with lymph node or distant metastasis, and that are capable of predicting disease course in individual patients with high accuracies (circa 90%). In the largest study to date {2990}, analysing 295 tumours, the expression profile was a strong independent factor and outcom- peted lymph node status as a predictor of outcome. These findings suggest that some primary tumours express a "metastasis signature", which is difficult to reconcile with the classic tumour pro- gression model in which a rare subpop- ulation of tumour cells have accumulat- ed the numerous alterations required for metastasis to occur. Interestingly, some of the genes in the signature seem to be derived from non-epithelial components of the tumour {2328}, sug- gesting that stromal elements represent an important contributing factor to the metastatic phenotype. Survival differ-Fig. 1.73 A Supervised classification on prognosis signatures, using a set of prognostic reporter genes ences were also noted between the dif-to identify optimally two types of disease outcome from 78 sporadic breast tumours into a poor progno- ferent subtypes of breast tumours assis and good prognosis group. B Each row represents a tumour and each column a gene. Genes are defined by expression patterns {2756,ordered according to their correlation coefficient with the two prognostic groups. Tumours are ordered 2757}. The patients with basal-like andby the correlation to the average profile of the good prognosis group. Solid line, prognostic classifier withoptimal accuracy; dashed line, with optimized sensitivity. Above the dashed line patients have a good ERBB2+ subtypes were associated withprognosis signature, below the dashed line the prognosis signature is poor. The metastasis status for the shortest survival, while a differenceeach patient is shown in the right panel: white indicates patients who developed distant metastases in the outcome for tumours classified aswithin 5 years after the primary diagnosis; black indicates patients who continued to be disease-free for luminal A versus luminal B was also evi-at least 5 years. From L.J. van’t Veer et al. {2986}. dent. The luminal subtype B may repre- sent a class of ER-positive tumours with poor outcome, possibly not respondingassociation between specific mutations fication of the FGFR1 gene on 8p12 has to tamoxifen. This strongly supports theand short survival and poor response to been correlated with reduced disease- idea that many of these breast tumourtreatment was seen, emphasizing the free survival, especially if the gene is subtypes represent biologically distinctimportance of DNA sequence analysis amplified together with the cyclin D1 disease entities with different clinicalof the entire coding region of TP53 gene {596}. The MYC gene on 8q24 is outcome.when evaluating its prognostic and pre- amplified in approximately 20% of breast A remarkable feature of the expressiondictive value. carcinomas, which is associated with signatures identified in these studies is estrogen receptor negativity {596}, local- that they usually involve fewer than 100Loss of heterozygosity (LOH) ly advanced disease and poor prognosis genes {257,2986}, in one instance evenLOH at the TP53 gene has been shown {250}. On 11q13, cyclin D1 (CCND1) is only 17 genes {2328}. However, some-to be a marker for prognosis and pre- amplified in 15-20% of breast tumours. In what confusing is that the overlapdictor of response to certain therapies ER-positive tumours, CCND1 amplifica- between the different sets of genes thus(see above). Other regions with LOH tion is associated with a relatively poor defined is incomplete {1257,2757}.that appear to correlate to short survival prognosis {596,2582}, and is more fre- F u rther comparative studies areinclude 11q23 and several regions on quent in lobular carcinomas compared to required to elucidate the critical compo-3p {1216,1552}. Deletion of 9q13 is also ductal carcinomas. nents of the poor prognosis signature,associated with shorter survival. The while the clinical utility of this new diag-target gene(s) in these areas have still Expression profiling nostic tool must now be demonstratedto be identified {1326}. Much recent work has been focused in a prospective trial setting. At a more on the potential of gene expression fundamental level, it will be interestingDNA amplification profiles to predict the clinical outcome to establish whether the observed asso-Conventional as well as array-based of breast cancer {257,1257,2328,2757, ciation between expression signaturesCGH have identified a number of ampli- 2986,2990}. These studies, although and survival reflects an intrinsic biolog-fied regions containing putative onco- heterogeneous in patient selection and ical behaviour of breast tumour cells orgenes with prognostic potential. Ampli- numbers of tumours analysed, have indi- a differential response to therapy. Invasive breast carcinoma 59
  • 79. Benign epithelial proliferations G. Bussolati F.A. Tavassoli B.B. Nielsen I.O. Ellis G. MacGroganLocalization Frequently it is a small and microscopicThere is little data on location or lateral- change, but it may be widespread. Inity of most benign breast lesions. As some instances, it may form a palpablewith carcinoma, the majority arise within mass and has been called nodularthe terminal duct lobular unit (TDLU). A adenosis or adenosis tumour. Severalmajor exception is the benign solitary histological types have been described,intraductal papilloma, appro x i m a t e l y but there is not complete agreement on90% of which occurs in the large ducts their designation. Only the most frequentin the central region of the bre a s t variants are discussed.{1098}. Other benign lesions specific to Radial scar/complex sclerosing lesionthe nipple areolar complex include nip- which incorporates a combination ofple adenoma and syringoma and are benign changes including adenosis is Fig. 1.107 Sclerosing adenosis. Typical organicdiscussed in the chapter on nipple. also included in this section. configuration of the lesion.Clinical features EpidemiologyThe predominant presenting symptoms This lesion occurs most frequently inin women attending a breast clinic are women in their third and fourth decade.described in the section on InvasiveCarcinoma, where signs and symptoms Macroscopymost likely to be associated with a low Adenosis may be non-distinctive, show-risk of malignancy are described. The ing unremarkable fibrous or cysticfrequency of benign conditions varies breast tissue. A few cases assume theconsiderably with the age of the patient. appearance of a firm rubbery greyF i b roadenoma is most frequent in mass.younger patients, other localized benignlesions and cysts occur most frequently Histopathology Fig. 1.108 Sclerosing adenosis. The myoepithelialin women between the ages of 30 and Adenosis in its simplest form is charac- cells are prominent with immunostain for smooth50. This contrasts with carc i n o m a , terized by a usually loosely structured muscle actin.which is rare below the age of 40. proliferation of acinar or tubular struc-The mammographic appearances of tures, composed of an epithelial andbenign epithelial lesions are varied but myoepithelial cell layer and surrounded the glands. Areas of apocrine metapla-common lesions such as cysts are typi- by a basement membrane. sia are also common. Rarely neuralcally seen as well defined or lobulated invasion is encountered and vascularmass lesions. Calcification is also a invasion has been re p o rted {149}.common feature of fibrocystic change Sclerosing adenosis Lesions which form a mass showand sclerosing adenosis. Other benign adenosis with a mixture of growth pat-lesions such as radial scar, complex Sclerosing adenosis (SA) is character- terns {2015}, the most frequent of whichsclerosing lesion and fat necrosis can ized by a compact proliferation of acini is sclerosing adenosis.produce ill defined or spiculate mass with preservation of the luminal epithe- In rare cases sclerosing adenosis maylesions, which are indistinguishable lial and the peripheral myoepithelial be involved by DCIS or LIN {1046,from some forms of breast carcinoma. (ME) cell layers along with a surround- 1275a,1846a,2015,2336a,3104a}. ing basement membrane. These ele- ments can easily be demonstrated by Differential diagnosisAdenosis immunohistochemical staining for ker- Sclerosing adenosis can mimic invasive atin, smooth-muscle actin and laminin, carcinoma. The overall lobulated archi-Definition respectively. Although compression or tecture, persistence of ME cells, andA frequent, benign, proliferative process attenuation of the acini by surrounding lack of epithelial atypia help to excludethat affects mainly the lobular (acinar) f i b rosis may be marked, sclero s i n g carcinoma {321,1046}. In cases involvedcomponent of the breast parenchyma. adenosis nearly always retains an by in situ carcinoma, the immunohisto-It can be accompanied by fibro s i s organic or lobulated configuration often chemical demonstration of persistentcausing considerable distortion of the best observed at low power view. myoepithelial cells is crucial in exclu-glands simulating an invasive process. Microcalcifications are common within ding invasion. Benign epithelial proliferations 81
  • 80. A B CFig. 1.109 A Apocrine adenosis/sclerosing adenosis with apocrine metaplasia and focal atypia. B Immunostain for actin demonstrating myoepithelial cells aroundthe tubules. C Typical apocrine metaplasia in sclerosing adenosis, characterized by a three-fold nuclear size variation.Apocrine adenosis Blunt duct adenosis Adenomyoepithelial adenosisSynonym The term blunt duct adenosis (BDA) has Adenomyoepithelial adenosis (AMEA)Adenosis with apocrine metaplasia. been used for an organoid microscopic is an extremely rare type of adenosis, form of adenosis with variable disten- which seems to be associated withApocrine adenosis (AA) is an ambigu- sion of lumens showing columnar cell adenomyoepithelioma {803,805,1454}ous term, as it has been used for sever- metaplasia {2015}. (see section on adenomyoepithelialal different lesions {805,2698,2699}. In lesions).this context, it is used for adenosis, par-ticularly sclerosing adenosis, with wide- Microglandular adenosis Prognosis and predictive factors ofspread apocrine metaplasia constitut- adenosising at least 50% of the adenotic area Microglandular adenosis (MGA) is a Most types of adenosis are not associat-{3093}. The apocrine epithelium may r a re lesion, characterized by a diff u s e ed with increased risk of subsequent car-exhibit cytological atypia, so that the h a p h a z a rd proliferation of small ro u n d cinoma. However, there are exceptions,histological appearance mimics inva- glands {507,692,2413,2884}. These as nearly one third of cases of MGA har-sive carcinoma {2621,2698,2699}. may be clustered, but without sclerosis bour an invasive carcinoma {803,1454}, or compression {507,3081}. The sur- and apocrine adenosis has been found rounding collagenous stroma may to be monoclonal and perhaps a putative be hypocellular or hyalinized. There is precancerous lesion {3093}. no elastosis. The glands have a round lumen, which frequently contains pe- riodic acid-Schiff (PAS) positive, eo- Radial scar / sinophilic secretory material. The epi- Complex sclerosing lesion thelium is cuboid and without snouts. The cytoplasm may be clear or eosi- Definition nophilic and granular. There is no A benign lesion that on imaging, grossly nuclear atypia. There are no myo- and at low power microscopy resembles epithelial cells {184,321,797,2884}, b u t invasive carcinoma because the lobularA a surrounding basement membrane, architecture is distorted by the sclerosing not always recognizable without process. The term radial scar (RS) has immunohistochemical staining for la- been applied to small lesions and com- minin or collagen IV {692,2884, 3081}, is present. Electron microscopy shows a multilayered basment membrane s u r rounding the tubules of MGA {2884}. The epithelium of MGA is positive for S-100 in addition to cytokeratin {1372}.B When carcinoma arises in association with MGA it may retain an alveolar pat-Fig. 1.110 A Nodular sclerosing adenosis. Note thewell delineated margins. B High power view of the tern {1331} or be of ductal or one of thelesion in A, showing distorted and compressed special types {2016}; the vast majoritytubular structures and intervening hyaline stroma. of these invasive carcinomas retainSuch lesions may pose difficulties in the differen- S-100 immunoreactivity regardless oftial diagnosis to invasive lobular carcinoma. their subtype {1484}. Fig. 1.111 Blunt duct adenosis, typical morphology.82 Tumours of the breast
  • 81. Fig. 1.112 Microglandular adenosis. An extensive Fig. 1.113 Microglandular adenosis with diffusely Fig. 1.114 Microglandular adenosis. The tubuleslesion that presented as a palpable mass; the char- arranged small uniform glands, separated by a are lined by a single layer of attenuated to cuboidalacteristic open lumens of the tubules and the col- densely collagenous background. epithelial cells with vacuolated cytoplasm; colloid-loid-like secretory material are apparent, providing like secretory material is present within the lumen.clues to the nature of the process.Fig. 1.115 Microglandular adenosis. Immunostain Fig. 1.116 Microglandular adenosis with atypia. Fig. 1.117 Ductal carcinoma in situ arising infor smooth muscle actin confirms absence of a There is diminished intraluminal colloid-like secre- microglandular adenosis. Note the significantmyoepithelial cell layer in MGA; the adjacent tion, enlarged cells displaying mild to moderate atypia of the cells proliferating within the oblite-TDLUs show actin-positive myoepithelial cells. nuclear pleomorphism and mitotic figures. rated tubules.plex sclerosing lesion (CSL) to larger ones reflecting the elastotic stroma. The Differential diagnosisthat contain a variety of ductal epithelial appearance may be indistinguishable Distinction from carcinoma depends onhyperplasia along with sclerosis. from that of a carcinoma. the characteristic architecture of a CSL, the lack of cytological atypia, the pres-Synonyms Histopathology ence of a myoepithelial layer (in mostRadial scar, sclerosing papillary lesion, RSs are composed of a mixture of benign cases) and basement membrane aroundradial sclerosing lesion, scleroelastotic changes of which adenosis forms a the tubular structures (demonstration byscar, stellate scar, benign sclerosing major part. They have a stellate outline immunohistochemistry may be neces-ductal proliferation, non-encapsulated with central dense hyalinized collagen sary), the presence of a dense hyalinizedsclerosing lesion, infiltrating epitheliosis. and sometimes marked elastosis. stroma and lack of a reactive fibroblastic Entrapped in the scar are small irregular stroma.Epidemiology tubules. The two cell layer is usuallyThe reported incidence varies depend- retained although this may not always being on the mode of detection and how visible on haematoxylin and eosin stain-detected by mammography when the ing and the myoepithelial layer is occa-appearance mimics that of an infiltrating sionally inapparent. The tubules some-carcinoma producing an irregular stellate times contain eosinophilic secretions.density. Very occasionally they are of suf- Around the periphery of the lesion thereficient size to produce a palpable mass are various degrees of ductal dilatation,{2725}. They are often multiple and fre- ductal epithelial hyperplasia, apocrinequently bilateral. metaplasia and hyperplasia. In the more complex larger CSLs, several of theseMacroscopy lesions appear to combine and then con-These lesions may be undetected on verge with prominent areas of sclerosing Fig. 1.118 Radial scar. Centre of a radial scar withgross examination or may be of sufficient adenosis, and small, frequently scleros- two tubular structures, surrounded by hyalinizedsize to produce an irregular area of firm- ing, peripheral papillomas and various and elastotic tissue. Note the atrophic myoepithe-ness which can exhibit yellow streaks patterns of intraepithelial proliferation. lial layer. Benign epithelial proliferations 83
  • 82. Clinical features The clinical and imaging features are usually those of fibroadenoma. Macroscopy The tumours are firm, well circumscribed and homogeneous with a uniform, yel- lowish, cut surface. Histopathology The lesion is composed entirely of small,Fig. 1.119 Sclerosing adenosis with a radial scar. Fig. 1.120 Radial scar. A central fibrous scar is round tubules with little intervening stro- surrounded by epithelial proliferation. ma. The latter may contain a few lympho- cytes. The epithelial cells are uniform, Mitotic activity is usually low. The tubularPrognosis and predictive factors Tubular adenoma lumen is small and often empty, butIt has been suggested that these eosinophilic proteinaceous material canlesions are pre-neoplastic or even rep- Definition be present. Occasional larger tubulesresent early invasive carc i n o m a s Benign, usually round, nodules formed by give rise to thin branches. Combined{1668} and also that they may repre- a compact proliferation of tubular struc- tubular adenoma and fibroadenoma hassent a marker of risk for the subsequent tures composed of the typical epithelial been described {1202,2874}. Rare casesdevelopment of carcinoma. Follow up and myoepithelial cell layers. The epithe- have been described of in situ and/orstudies, however, have been few and lial cells are similar to those of the normal invasive carcinoma involving adenomasc o n t r a d i c t o ry {843,1320} suggesting resting breast, but adenoma variants (tubular or lactating) {561,1202,1211,that an apparent risk is related to the have been described where these show 2442}, a phenomenon also known tovarious patterns of associated intra- apocrine or lactating features. occur in fibroadenomas.ductal hyperplasia. It is doubtful that,without epithelial proliferation, there is ICD-O code 8211/0a risk of the subsequent development Lactating adenomaof invasive carcinoma. In larger lesions Epidemiologythe risk may be slightly higher as the Tubular adenomas occur mainly in young ICD-O code 8204/0increase in size is usually due to vari- females {1202,1211,1919,2074}. Theyous forms of epithelial hyperplasia. A rarely occur before menarche or after During pregnancy and lactation, thehigh incidence of atypical hyperplasia menopause {1600,2025}. They reported- epithelial cells of a tubular type adeno-and carcinoma (both in situ and inva- ly account for 0.13 to 1.7% of benign ma may show extensive secre t o rysive) has been re p o rted in CSLs breast lesions {1202,1211,2874}. Pa- changes warranting a designation ofdetected by mammography, particu- tients with lactating adenomas are nurs- lactating adenoma {1332,2074}. It haslarly in lesions measuring over 0.6 cm, ing mothers who have noted an area of been suggested that such lesions repre-and in women over 50 years old increased firmness, either during lacta- sent focal accumulation of hyperplastic{719,2725}. tion or, earlier, during pregnancy. lobules.A BFig. 1.121 Tubular adenoma. A The fibrous capsule is present in the left upper corner. B Higher magnification displays epithelial and myoepithelial cell lining of the tubules.84 Tumours of the breast
  • 83. A BFig. 1.122 Lactating adenoma. Epithelial cells show extensive secretory changes (A, B). Fig. 1.123 Pleomorphic adenoma. Nests of clear myoepithelial cells proliferate around few, barely apparent darker epithelial cells; abundant cartilageApocrine adenoma salivary glands Some authors {2442, is present on the right. 2730,2753} consider pleomorphic ade-ICD-O code 8401/0 noma to be a form of intraductal papillo- ma with extensive cartilaginous meta-Synonym plasia. Because of the presence of aNodular adenosis with apocrine metaplasia. chondroid stromal component, pleomor- phic adenomas pose a difficult differen-Sometimes the epithelial cells of nodular tial diagnosis from metaplastic carcino-adenosis show extensive apocrine meta- mas with a mesenchymal componentplasia; these lesions may be termed and primary sarcomas of the breast.apocrine adenoma {561,1713,2442}. The presence of foci of intraductal or invasive carcinoma points to the diag-Immunoprofile nosis of metaplastic carcinoma, whileThe immunophenotype of adenomas is extensive cellular anaplasia character-similar to normal breast and reflects the izes sarcomas.various metaplastic and or secretorychanges affecting them. Ductal adenomaDifferential diagnosisDifferentiation of adenomas from Definitionfibroadenomas is based on the promi- A well circumscribed benign glandularnent proliferating stromal component and proliferation located, at least in part, with-the often elongated and compressed in a duct lumen {151}.epithelial elements in the intracanalicularvariant of the latter. ICD-O code 8503/0 Synonym Fig. 1.124 Ductal adenoma, characterized by aPleomorphic adenoma Sclerosing papilloma. “polypoid “ protrusion into a distended duct; a few papillary projections are evident (arrow).Definition EpidemiologyA rare lesion morphologically similar to These lesions occur over a wide agepleomorphic adenoma (benign mixed range but are most frequent in women proliferating tubules, compressed ortumour) of the salivary glands. over 40 years {151,1577}. It is debatable slightly dilated, and surrounded by whether these lesions represent the fibrosis may impart a pseudoinfiltrativeICD-O code 8940/0 s c l e rotic evolution of an intraductal appearance. Epithelial and stro m a l papilloma or are a distinct entity. changes similar to those observed inEpidemiology intraductal papillomas can occur; apoc-These lesions have been reported in Clinical features rine metaplasia is frequent. {1577}.patients (mainly females) over a wide They may present as a mass or rarely as P a p i l l a ry fronds are not alwaysrange of age {172,454}. Multiple tumours a nipple discharge. Imaging shows a detectable in a given plane of section.have been described {454,2874}. Calci- density which can mimic a carcinoma.fication is common and gives a diagnos- Prognosis and predictive factors oftically important sign on mammography. Histopathology mammary adenomas Arranged mainly at the periphery are All adenomas of the breast are benignHistopathology glandular structures with typical dual lesions that do not recur if adequatelyThe histological picture is the same as cell layer while in the centre there is excised and do not predispose to car-that seen in pleomorphic adenomas of dense scar-like fibrosis. The compact cinoma. Benign epithelial proliferations 85
  • 84. F.A. TavassoliMyoepithelial lesions J. SoaresDefinition HistopathologyLesions either derived from, or com- The intraductal proliferating spindle The periductal variant of myoepithelio-posed of, a dominant to pure population cells may develop a prominent palisa- sis is often associated with sclerosisof myoepithelial (ME) cells. They include ding pattern. The cuboidal cells may and is considered by some to be aadenoid cystic carcinoma, pleomorphic have longitudinal nuclear grooves re- variant of sclerosing adenosis; the cellsadenoma, myoepitheliosis, adenomy- sembling transitional cells. Rarely atypia have varied phenotypes.oepithelial adenosis, adenomyoepithe- and mitotic activity appear, warranting a When completely excised, recurrenceslioma (benign or malignant) and malig- designation of atypical myoepitheliosis. do not develop.nant myoepithelioma (myoepithelial car-cinoma). The first two lesions are dis-cussed elsewhere. In this section, thefocus will be on the others.Immunohistochemical profile ofmyoepithelial cellsMyoepithelial cells show positive immu-noreaction with alpha smooth muscleactin, calponin, caldesmon, smooth mus-cle myosin heavy chain (SMM-HC)maspin S-100 protein and high MW A Bcytokeratins 34betaE12, CK5 and CK14. Fig. 1.125 Myoepitheliosis, periductal type. A The myoepithelial cells with abundant eosinophilic cytoplasmNuclear immunoreactivity with p63 is also proliferate around the epithelial cells compressing the ductular lumens. This change is often multifocal. B Immunostain for actin is positive in the myoepithelial cells, but negative in the epithelial-lined compresseda feature of ME cells. Rarely there is ductular spaces.staining with glial fibrillary acidic protein(GFAP). Myoepithelial cells are negativefor low MW cytokeratins (CK 8/18), estro-gen receptor (ER), progesterone recep-tor (PR), and desmin {191,1516,1573,1741,2418,2702,2738,2953,3099}.EpidemiologyPatients range in age from 22 to 87 years{2418,2868,2875,3192}.Clinical features A BApart from myoepitheliosis, which is rarely Fig. 1.126 Adenomyoepithelial adenosis. A Prominent clear myoepithelial (ME) cells are evident aroundpalpable, these lesions usually present as several ductules. B Both the clear and normal ME cells are intensely imunoreactive for S-100 protein.a palpable tumour and/or mammographicdensity without distinctive features.MyoepitheliosisDefinitionA multifocal, often microscopic, prolifera-tion of spindle to cuboidal myoepithelialcells growing into and/or around smallducts and ductules. A B Fig. 1.127 Adenomyoepithelioma, lobulated type. A The lobulated nature of the tumour is apparent with mas-Macroscopy sive central infarction in the two adjacent nodules. The lighter cells reflect the proliferating ME cells, whileMyoepitheliosis generally appears as a the darker cells represent the epithelial cells. B Adenomyoepithelioma. In this case, the proliferating MEfirm irregular area. cells have a clear cell phenotype and surround a few spaces lined by darker epithelial cells.86 Tumours of the breast
  • 85. A B CFig. 1.128 Adenomyoepithelioma, spindle cell type. A There is a solid proliferation of spindled myoepithelial cells surrounding irregular epithelial lined spaces. B The epithe-lial spaces may show apocrine metaplasia. C Immunostain for S-100 protein shows positivity in the proliferating myoepithelial cells, while the epithelial cells fail to react.Adenomyoepithelial adenosis ICD-O codes give rise to a carcinoma while the back- Benign 8983/0 ground lesion retains its adenomyoepi-Definition Malignant 8983/3 theliomatous appearance {793,900,903,An extremely rare type of adenosis asso- 1695,2868,2953}. The aggressive myo-ciated with adenomyoepithelioma {803, Macroscopy epithelial component may assume a spin-805,1454}. Well delineated, benign adenomyoepi- dle configuration and develop into nod- theliomas are rounded nodules with a ules resembling myofibroblastic lesions.Histopathology median size of 2.5 cm. A variety of epithelial derived carcino-Adenomyoepithelial adenosis (AMEA) mas, sarcomas and carcinosarcomasconsists of a diffuse proliferation of Histopathology occur in this setting (Table1.16) {2868}.round or irregular tubular structures Histologically, AMEs they are character- Rarely, both components develop intolined by a cuboidal to columnar epitheli- ized by a proliferation of layers or either separate malignancies or a singleum, which may show apocrine metapla- sheaths of ME cells around epithelial malignant infiltrative process composedsia. There is a prominent, focally hyper- lined spaces. The tumour may display a of angulated tubules lined by bothplastic myoepithelial cell layer with strik- spindle cell, a tubular, or, most often, a epithelial and myoepithelial cells.ingly clear cytoplasm. There is no signi- lobulated growth pattern. Fibrous septaeficant nuclear atypia or mitotic activity, with central hyalinization or infarction are Differential diagnosisbut most described cases blend with common in the lobulated lesions. The ME The tubular variant of AME should beor surround an adenomyoepithelioma cell phenotype is most variable in the distinguished from a tubular adenoma;{803,805,1454}. lobulated pattern ranging from clear to the latter may have prominent ME cells, eosinophilic and hyaline (plasmacytoid) but lacks the myoepithelial proliferation types. Satellite nodules, seen adjacent to typical of an AME. Furthermore, tubularAdenomyoepithelioma the lobulated variant in some cases adenoma is sharply circumscribed un- reflect an intraductal extension of the like the ill defined tubular AME.Definition lesion. The tubular variant has an ill The lobulated and spindle cell variantsComposed of a predominantly and usually defined margin. Mitotic activity of the of AME should be distinguished fromsolid proliferation of phenotypically vari- proliferating myoepithelial cells in benignable myoepithelial cells around small epi- lesions is generally in the range of 1- Table 1.16thelial lined spaces, in rare instances, the 2/10, always ≤2/10 high power field (hpf). Classification of myoepithelial lesions.epithelial, the myoepithelial or both compo- Either the epithelial, the myoepithelial ornents of an adenomyoepithelioma (AME) both components of an adenomyoepi- 1.Myoepitheliosis a. Intraductalmay become malignant (malignant AME). thelioma may become malignant and b. Periductal 2. Adenomyoepithelial adenosis 3.Adenomyoepithelioma a.Benign b. With malignant change (specify the subtype) – Myoepithelial carcinoma arising in an ade- nomyoepithelioma – Epithelial carcinoma arising in an adenomy- oepithelioma – Malignant epithelial and myoepithelial com- ponents – Sarcoma arising in adenomyoepitheliomaA B – Carcinosarcoma arising in adenomyoepi-Fig. 1.129 Adenomyoepithelioma, adenosis type. A At least focally well delineated, these tumours superfi- theliomacially resemble a tubular adenoma. B Higher magnification shows proliferation of ME cells in the tubules 4. Malignant myoepithelioma (ME carcinoma)beyond the normal single layer. Myoepithelial lesions 87
  • 86. Table 1.17Immunoprofile of various spindle cell tumours of the breast. Tumour Smooth muscle Calponin S-100 Kermix* CAM5.2** ER Desmin CD34 HMB45 actin Myoepithelioma + + + + – – – – – Spindle cell carcinoma – – – ++ + +/– – – – Smooth muscle cell tumours + +/– – +/– +/– +/– + – – Myofibroblastic lesions + +/– +/– – – – –* + – Melanoma – – + – – – – – – ________ * Kermix a cocktail of AE1/AE3 (cytokeratin 1-19), and LP34 (CK5,6 & 18) **Cam 5.2 (CK8 & 18)pleomorphic adenoma; the latter gener- significant atypia. Mitotic activity may irregular and shallow infiltration at theally has prominent areas of chondroid not exceed 3-4 mf/10hpf. The spindled margins is helpful in distinguishing thisand/or osseous differentiation. tumour cells appear to emanate from lesion from fibromatosis and myofibrob- the myoepithelial cells of ductules lastic tumours. ImmunohistochemistryPrognosis and predictive factors entrapped in the periphery of the lesion. is, and, rarely, electron microscopy mayThe majority of AME are benign {1573, Aggregates of collagen and prominent be, required to confirm the myoepithelial1695,2418,2581,2868}. Lesions that central hyalinization may be evident. nature of the neoplastic cells.contain malignant areas, those withhigh mitotic rate, or infiltrating margins Differential diagnosis Prognosis and predictive factorshave a potential for recurrence and The differential diagnosis includes spin- Local recurrence or distant metastasesmetastases. Local recurrence {1440, dle cell carcinomas, fibromatosis and a have rarely been documented {1573,2868,3192} as well as distant metasta- variety of myofibroblastic lesions. The 2581,2875}. Complete excision with un-sis {2875} have been described, mainly presence of a dominant nodule with involved margins is recommended.among those with agressive features.Malignant myoepitheliomaDefinitionAn infiltrating tumour composed purely ofmyoepithelial cells (predominantly spin-dled) with identifiable mitotic activity.SynonymsInfiltrating myoepithelioma, myoepithelial A Bcarcinoma. Fig. 1.130 Malignant myoepithelioma (myoepithelial carcinoma). A The lesion is composed of spindle cells lacking significant atypia or mitotic activity. B At the periphery of the same lesion, often a more epithelioidICD-O code 8982/3 or plump cell population is evident emanating from the myoepithelial cell layer of the entrapped ductules.MacroscopyRanging from 1.0 to 21 cm in size, thesetumours are generally well defined withfocal marginal irre g u l a r i t y, althoughsome are stellate. There may be foci ofnecrosis and haemorrhage on the firmrubbery cut surface in larger tumoursand sometimes nodular areas of hyali-nization even in smaller tumours. A BHistopathology Fig. 1.131 Malignant myoepithelioma. A Immunostain for smooth muscle actin is positive in the neoplastic spin-Histologically, there is an infiltrating pro- dle cells. B Immunostain for kermix (AE1/AE3/LP34) shows intense staining of the entrapped normal ductules; aliferation of spindle cells often lacking less intense immunoreaction is evident in the neoplastic spindle cells.88 Tumours of the breast
  • 87. M. Drijkoningen J.P. BellocqMesenchymal tumours F.A. Tavassoli S. Lanzafame G. Magro G. MacGrogan V. Eusebi J.L. Peterse M. Devouassoux-ShisheboranDefinition benign breast biopsies {2443} and 11% growth pattern. Venous haemangiomasBenign and malignant mesenchymal in a series of post mortem cases (age consist of thick walled vascular channelstumours morphologically similar to those range 29–82 years) {1633}. with smooth muscle walls of varyingoccurring in the soft tissues as well as thickness {2435}.those occurring predominantly in the Macroscopy In perilobular haemangiomas, the lobu-breast. Rarely palpable, the lesions are well cir- lated collections of thin-walled, wide vas- cumscribed and vary from 0.5-2 cm with cular channels are seen within the a reddish-brown spongy appearance. intralobular stroma. Expansion into the Benign vascular tumours extralobular stroma and adjacent adi- Histopathology pose tissue is often present. The vascu-Haemangioma Symptomatic haemangiomas may be of lar channels are lined by flattened cavernous, capillary or venous subtypes endothelium without a surrounding mus-Definition {2435,2611}. Cavernous haemangioma cle layer {1373}. Occasional cases withA benign tumour or malformation of is the most common type; it consists of prominent hyperchromatic endothelialmature vessels. dilated thin walled vessels lined by flat- nuclei have been described and desig- tened endothelium and congested with nated atypical haemangiomas {1225}.ICD-O code 9120/0 blood. Thrombosis may be present An anastomosing growth pattern, papil- with papillary endothelial hyperplasia lary endothelial proliferations andEpidemiology (Masson’s phenomenon) {1946}. Dys- mitoses are absent and their presenceHaemangiomas of the breast have been trophic calcification may be found in or- should arouse suspicion and carefuldescribed in both male and female ganizing thrombi as well as in the stroma exclusion of an angiosarcoma.patients from 18 months to 82 years old between the vascular channels. Capillary{1373,2874}. They rarely present as pal- haemangiomas are composed of nod- Prognosis and predictive factorspable lesions but an increasing number ules of small vessels with a lobular Recurrence, even after incomplete exci-of non-palpable mammary haeman- arrangement around a larger feeding sion, has not been reported. Carefulgiomas are nowadays detected by vessel. The intervening stroma is fibrous. evaluation of the whole lesion to excludebreast imaging {3077}. Incidental "per- The endothelial lining cells may have a well differentiated angiosarcoma isilobular" haemangiomas are found in prominent hyperchromatic nuclei but indicated in all symptomatic vascular1.2% of mastectomies and 4.5% of without tufting or a solid spindle cell breast lesions. Angiomatosis Definition A diffuse excessive proliferation of well formed vascular channels affecting a large area in a contiguous fashion. Synonym Diffuse angioma. Epidemiology This very rare benign vascular lesion may be congenital. Most cases have been described in women between 19 and 61 years old {1921,2416}. One case was in a male. Clinical features Angiomatosis presents as a breast mass.Fig. 1.132 Perilobular haemangioma. Thin walled vessels lined by flattened endothelium are seen within the Rapid increase in size has been des-intralobular stroma. cribed in a woman during pregnancy {76}. Mesenchymal tumours 89
  • 88. Pseudoangiomatous stromal hyperplasia Definition A benign lesion consisting of complex anastomosing slit-like pseudovascular spaces, that are either acellular or lined by slender spindle-shaped stromal cells. Epidemiology The clinicopathological spectrum of mam- mary pseudoangiomatous stromal hyper- plasia (PASH) extends from insignificant microscopic changes, often associated with either benign or malignant breast dis- ease, to diffuse involvement of the breast or cases where a localized palpable or non-palpable breast mass is produced (nodular PASH) {1275,2270,3037}. The latter is uncommon and reported to occurFig. 1.133 Pseudoangiomatous stromal hyperplasia (PASH). Interanastomosing, empty, slit-like spaces in 0.4% of breast biopsies {2270}. Focal orwithin breast stroma are typical. multifocal PASH without mass formation has been reported in 23% of breast biop-Pathology Clinical features sies, usually as an incidental finding.Macroscopic and histopathological Patients usually present with a mass that PASH has been reported in at least 25%appearances are similar to angiomatosis appears as a well circumscribed area of of cases of gynaecomastia {157,1865}.at other sites. The haemorrhagic spongy density on mammography.lesions are composed of usually thin Aetiologywalled large blood or lymphatic vessels Macroscopy The immunophenotype of the proliferat-diffusely extending throughout the The tumours are round to oval, well cir- ing cells confirms that PASH is of myofi-parenchyma of the breast. cumscribed and range in size from 1 to broblastic origin {1113,2279,2510,3249}. 19 cm {118,1415,2855,2889}. They are The pseudoangiomatous spaces arePrognosis and predictive factors firm with a solid, yellow-tan to grey-white also discernible in frozen sections, indi-Recurrence after incomplete excision cut surface. Myxoid areas alternate with cating that they are not a fixation artefacthas been reported, and may occur after small cysts filled with watery fluid. {157,3037}.a long disease-free interval {2416}. In Haemorrhage and necrosis are evidentmany cases, complete excision requires in some larger tumours. Clinical featuresa mastectomy. Nodular PASH usually present as a Histopathology painless, well circumscribed, mobile The histological and immunophenotype palpable mass, clinically indistinguish-Haemangiopericytoma appearances are similar to haemangio- able from fibroadenoma {532,1275, pericytomas described elsewhere {2889}. 2270,2279,3037,3249}. Smaller lesionsDefinition They are composed of a compact prolife- may be detected by mammographyA circumscribed area of bland ovoid to ration of plump ovoid to spindle cells with {532, 2270}. On imaging, nodular PASHspindled cells proliferating around indistinct cell margins arranged around is indistinguishable from fibroadenomabranching and “stag-horn” vessels. an abundance of usually thin-walled, {2270}. Diffuse lesions are an incidental irregularly branching vascular channels. finding {1275}. Bilateral lesions mayICD-O codes Some of the branching vessels assume occur {157}. Rapid growth has beenBenign 9150/0 a “stag-horn” configuration. Mammary reported {532,2270,2765,3026}.NOS 9150/1 ducts and ductules are often trappedMalignant 9150/3 focally in the periphery of the lesion. Macroscopy Macroscopically, nodular PASH is usual -Epidemiology Prognosis and predictive factors ly indistinguishable from fibroadenomaThis is a rare mesenchymal tumour. Most cases of mammary haemangio- ranging in size from 1 to 17 cm. The cutAround 20 primary haemangiopericy- pericytoma have been benign. There is surface is pale tan-pink to yellow {92,tomas have been reported in the breast. no well documented example of metasta- 1275,2279,2622,3037}.The patients are mostly women aged tic disease or even recurrence {118,22–67, but a few cases have been 1415,2855,2889}. Wide local excision Histopathologyreported in children (5 and 7 years old) rather than mastectomy is often sufficient PASH may be present in normal breastand in men {118,2889}. for complete tumour excision. tissue or in various benign lesions {867,90 Tumours of the breast
  • 89. 1113,1275}. There is a complex pattern ofinteranastomosing empty slit-like spaces,present within and between breast lob-ules with a perilobular concentric arrange-ment {1275,2279}. In gynaecomastia, aperiductal pattern is found {157}. Thespaces are formed by separation of col-lagen fibres and are either acellular orlined by spindle cells, simulating endo-thelial cells. Mitoses, tufting, atypia andpleomorphism are absent {92,1275,2279,3037,3249}. There is no destruction ofnormal breast tissue, no necrosis, norinvasion of fat {1275} and collagen IVcannot identify a basement membranearound the spaces {867}. The interveningstroma often consists of dense, hyali-nized collagen and spindle cells withnuclei displaying pointed ends {1275,2510}. In rare more proliferative lesions, a Fig. 1.134 Myofibroblastoma. An expansile tumour composed of spindle to oval cells arranged in intersectingfascicular pattern is found: the stroma is fascicles interrupted by thick bands of collagen. Some adipose tissue is present in the right upper corner.composed of bundles of plump spindlecells that may obscure the underlyingpseudoangiomatous architecture {2279}.At low power, PASH may resemble low-grade angiosarcoma but can be distin-guished by its growth pattern and cyto-logical features. The immunohistochemi-cal characteristics are also different.ImmunoprofileThe spindle cells adjacent to the clefts arepositive for CD34, vimentin, actin, calponin,but negative for the endothelial cell mar-kers Factor VIII protein, Ulex europaeusagglutinin-1 and CD31. They are also neg-ative for S100, low and high MW cyto-keratins, EMA and CD68. Desmin is usu-ally negative, but may be positive in fasci-cular lesions {157,928,1865,2279,3037}.Prognosis and predictive factors Fig. 1.135 Myofibroblastoma. A more epithelioid cell population may develop focally.PASH is not malignant but local recurrencehas been rarely reported possibly attribu- between 40 and 87 years {1023,1735}. In Histopathologytable to growth after incomplete excision, a few cases, an association with gynae- An expansile tumour with pushing bor-or the presence of multiple lesions that comastia has been documented. ders, myofibroblastroma is composed ofwere not all excised {2270,2279,3037}. spindle to oval cells arranged in short, Clinical features haphazardly intersecting fascicles inter- MFB presents as a solitary slowly grow- rupted by thick bands of brightly eosi-Myofibroblastoma ing nodule. Synchronous bilaterality and nophilic collagen. The cells have relative- unilateral multicentricity is rarely ly abundant, ill defined, pale to deeplyDefinition observed {1113}. Imaging shows a well eosinophilic cytoplasm with a round toA benign spindle cell tumour of the mam- circumscribed, homogeneously solid oval nucleus containing 1 or 2 smallmary stroma composed of myofibroblasts. and hypoechoic mass devoid of micro- nucleoli. Necrosis is usually absent and calcifications {1113,1374,2252}. mitoses are only rarely observed (up to 2ICD-O code 8825/0 mitoses x 10 high power fields). There is Macroscopy no entrapment of mammary ducts or lob-Epidemiology MFB is usually a well circumscribed ules within the tumour. Variable numbersMyofibroblastoma (MFB) occurs in the encapsulated tumour raging in size from of scattered mast cells may be seen inbreast of both women and men aged 0.9 to 10 cm. the stroma but otherwise inflammatory Mesenchymal tumours 91
  • 90. lesion reveals characteristic infiltrating fin- ger-like projections entrapping mammary ducts and lobules {3063}. Fibromatosis must be distinguished from several entities in the breast. Fibrosarcomas are richly cellular, with nuclear atypia and a much higher mitotic rate than fibromatosis. Spindle cell carci- nomas disclose more typical areas of car- cinoma and, in contrast to fibromatosis, the cells are immunoreactive for both epithelial markers and vimentin {1022}. Myoepithelial carcinomas are actin and/or S-100 protein positive. While CAM 5.2 positivity may be weak, pancytokeratin (Kermix) is strongly expressed in at least some tumour cells, and there is diffuse staining with CK34Beta E12 and CK 5,6. Lipomatous myofibroblastomas show aFig. 1.136 Fibromatosis. Fascicles of spindle myofibroblast invade the adipose tissue and extend between finger-like infiltrating growth pattern, remi-lobules (on the left). niscent of fibromatosis {1736}. However, the cells are estrogen (ER), progesteronecells are absent. Variations include the ICD-O code 8821/1 (PR) and androgen receptor (AR) positiveoccurrence of infiltrating margins, a in 70% of cases, while fibromatosis doesprominent epithelioid cell component, Synonym not stain with these antibodies.mono- or multinucleated giant cells with Desmoid tumour. Nodular fasciitis is also composed ofa mild to severe degree of nuclear pleo- immature appearing fibroblasts but tendsmorphism and extensive myxoid or hya- Epidemiology to be more circumscribed, and has aline change in the stroma. Occasionally, Fibromatosis accounts for less than 0.2% higher mitotic rate. The prominent inflam-lipomatous, smooth muscle, cartilagi- of all breast lesions {390,681,1083, matory infiltrate is scattered throughoutnous or osseous components form addi- 2432,3063}. It is seen in women from 13 the lesion and is not limited to the peri-tional integral parts of the tumour {934, to 80 years (average 46 and median 40) phery as in fibromatosis.1734-1736}. MFB should be distin- and is more common in the childbearing Reactive spindle cell nodules and scarsguished from nodular fasciitis, inflamma- age than in perimenopausal or post- at the site of a prior trauma or surgery de-tory myofibroblastic tumour, fibromatosis, menopausal patients {681}. A few cases monstrate areas of fat necrosis, calcifica-benign peripheral nerve sheath tumours, have been reported in men {378,2482}. tions and foreign body granulomas, fea-haemangiopericytomas and leiomyo- tures that are not common in fibromatosis.mas {1736}. The differential diagnosis is Clinical featuresbased on immunophenotype but even so The lesion presents as a solitary, pain- Immunoprofilemay be difficult in some cases. less, firm or hard palpable mass. Bilateral The spindle cells are vimentin positive tumours are rare {681,2432,3063}. Skin or and a small proportion of them are alsoImmunoprofile nipple retraction may be observed {294} actin positive, while they are invariablyThe neoplastic cells react positively for and rarely nipple discharge {3063}. negative for cytokeratin and S-100 pro-vimentin, desmin, α-smooth muscle actin Mammographically, fibromatosis is indis- tein. In contrast to one-third of extra-and variably for CD34, bcl-2 protein, tinguishable from a carcinoma {681}. mammary desmoid tumours {1662,1888,CD99 and sex steroid hormone recep- 2353}, fibromatoses in the breast are ER,tors (estrogen, progesterone and andro- Macroscopy PR, AR, and pS2 (assessed as a measuregen receptors) {1023,1733,1913}. The poorly demarcated tumour measures of functional ER) negative {681,2335}. from 0.5 to 10 cm (average 2.5 cm) {681,2432,3063} with a firm, white-grey Prognosis and predictive factorsFibromatosis cut surface. Mammary fibromatoses display a low propensity for local recurrence, with aDefinition Histopathology reported frequency of 21% {1083}, 23%This uncommon, locally aggressive, Mammary fibromatoses are histologically {3063}, and 27% {2432} of cases com-lesion without metastatic potential origi- similar to those arising from the fascia or pared with that of 57% {790} for extra-nates from fibroblasts and myofibrob- aponeuroses of muscles elsewhere in the mammary lesions. When it does occur,lasts within the breast parenchyma, body with the same immunophenotype. one or more generally develop within twoexcluding mammary involvement by Proliferating spindled fibroblasts and to three years of initial surgery {1083,extension of a fibromatosis arising from myofibroblasts form sweeping and inter- 3063}, but local recurrence may developthe pectoral fascia. lacing fascicles; the periphery of the after a 6-year interval {3063}.92 Tumours of the breast
  • 91. A B CFig. 1.137 A Lipoma. Intraparenchymal well circumscribed mature fat tissue. B Angiolipoma. Well circumscribed mature fat tissue separated by a network of smallvessels. C Cellular angiolipoma. Patches of solid, spindle cell proliferation are typically present.Inflammatory Histopathology Clinical featuresmyofibroblastic tumour The lesion consists of a proliferation of Lipomas usually present as a slow grow- spindle cells with the morphological and ing solitary mass with a soft doughy con-Definition immunohistochemical features of myofi- sistency.A tumour composed of differentiated broblasts, arranged in interlacing fasci-myofibroblastic spindle cells accompa- cles or in a haphazard fashion, and vari- Macroscopynied by numerous inflammatory cells. ably admixed with an inflammatory com- Lipomas are well circumscribed, thinly ponent of lymphocytes, plasma cells and encapsulated round or discoid masses;ICD-O code 8825/1 histiocytes. usually less than 5 cm in diameter. IMT should be distinguished from otherSynonyms benign and malignant spindle cell HistopathologyInflammatory pseudotumour, plasma cell lesions occurring in the breast. The hall- Lipomas differ little from the surroundinggranuloma. mark of IMT is the significant inflammato- fat. They may be altered by fibrous tissue, ry cell component. often hyalinized or show myxoid changes.Epidemiology Secondary alterations like lipogranulomas,Inflammatory myofibroblastic tumour Prognosis and predictive factors lipid cysts, calcifications, may occur as a(IMT) is a heterogeneous clinicopatholog- Although the clinical behaviour of IMT result of impaired blood supply or trauma.ical entity {1845} that may occur at any cannot be predicted on the basis of his-anatomical location. There is uncertainty tological features, in the breast most Variants of lipomaas to whether IMT is reactive or neoplas- reported cases have followed a benign These include angiolipoma {1268,2876,tic in nature. Some authors regard IMT as clinical course after complete surgical 3232} which, unlike angiolipomas ata low grade sarcoma {1845}. Only rare excision {276,467,2235}, with the excep- other sites, in the breast are notoriouslycases of IMT have been reported in the tion of a bilateral case with local recur- painless. Microscopy reveals mature fatbreast {276,467,2235,3183}. rence in both breasts after 5 months cells separated by a branching network {3183}. Additional cases with longer fol- of small vessels that is more pronouncedClinical features low-up are needed to define the exact in the sub capsular areas.IMT usually presents as a palpable cir- clinical behaviour. Characteristically, thrombi are found incumscribed firm mass. some vascular channels. Some lesions rich in vessels are called cellular angio-Macroscopy Lipoma lipomas.Gross examination usually shows a well Other variants which have been des-circumscribed firm white to grey mass. Definition cribed in the breast include spindle cell A tumour composed of mature fat cells without atypia. ICD-O code 8850/0 Epidemiology Although adipose tissue is quantitati- vely an important component of the nor- mal breast tissue, pathologists rarely en- counter intramammary lipomas. Sub- cutaneous lipomas are more often resected. Most common lipomas be-Fig. 1.138 Lipoma. Well circumscribed, lobulated come apparent in patients 40-60 years Fig. 1.139 Adenolipoma. Well circumscribedmass of 11 cm. of age. mature fat containing organoid glandular tissue. Mesenchymal tumours 93
  • 92. lipoma {1645}, hibernoma {2425} and Histopathology ICD-O codeschondrolipoma {1774a}. Adenomas con- The histology is identical to that seen in Schwannoma 9560/0taining glandular breast tissue such as GCT at other sites of the body. There is Neurofibroma 9540/0adenolipoma are considered as hamar- an infiltrating growth pattern, even intomas by some and variants of lipoma by lesions, which appear circumscribed on Epidemiologyothers. gross examination. The cellular compo- The breast is only rarely the primary site nent is composed of solid nests, clus- of BPNST. There are only a few case ters or cords of round to polygonal cells reports of schwannomas {881,953,1081}Granular cell tumour with coarsely granular, eosinophilic peri- and neurofibromas {1223,1675,2645}, odic acid-Schiff (PAS) positive (diastase but to our knowledge primary perineuro-Definition resistant) cytoplasm. due to the pres- ma of the breast has not been recorded.A tumour of putative schwannian origin ence of abundant intracytoplasmic Since neurofibromas may be part of neu-consisting of cells with eosinophlic gran- lysosomes. Awareness that GCT can rofibromatosis type I (NF1), follow-up isular cytoplasm. occur in the breast is essential. needed because of the potential for Immunoreactivity with S-100 is impor- malignant degeneration. The occurrenceICD-O code 9580/0 tant in confirming the diagnosis of GCT; of breast cancer in the context of breast lack of positivity for cytokeratins neurofibromas has been reported {1948}.Epidemiology excludes breast carcinoma. The age of patients at diagnosis is wide,Granular cell tumour (GCT) can occur in ranging from 15 to 80 years with a preva-any site of the body. It is relatively uncom- Prognosis and predictive factors lence of females.mon in the breast {2114}. It occurs more The clinical behaviour of GCT is usuallyoften in females than in males {430} with benign following complete surgical Clinical featuresa wide age range from 17-75 years {325, excision. Rarely, lymph node metas- The lesions present as a painless nodule617,668,3090} GCT is a potential mimick- tases have been reported {668}. In con- and the pathology and immunopheno-er of breast cancer, clinically, radiologi- trast, a malignant course should be type is identical to their counterparts atcally and grossly {608,617,995,2549}. expected in the extremely rare malig- other sites of the body. nant mammary GCTs which showClinical features nuclear pleomorphism, mitoses andGCT generally presents as a single, firm, necrosis {468}. Angiosarcomapainless mass in the breast parenchymabut may be superficial causing skin Definitionretraction and even nipple inversion, Benign peripheral A malignant tumour composed of neo-whereas location deep in the breast nerve sheath tumours plastic elements with the morphologicalparenchyma may lead to secondary properties of endothelial cells.involvement of the pectoralis fascia. DefinitionRarely, patients have simultaneous GCTs Benign peripheral nerve sheath ICD-O code 9120/3occurring at multiple sites in the body, tumours (BPNST) include three distinctincluding the breast {1920,1922}. lesions usually occurring in the periph- SynonymsImaging typically shows a dense mass eral nerves or soft tissues: schwan- These tumours include lesions whichwith stellate margin. nomas composed of diff e re n t i a t e d were formerly termed haemangiosarco- Schwann cells; neurofibromas consis- ma, haemangioblastoma, lymphan-Macroscopy ting of a mixture of Schwann cells, giosarcoma and metastasizing haeman-GCT appears as a well circumscribed or perineurial like cells and fibroblasts and gioma. Lymphangiosarcomas probablyinfiltrative firm mass of 2–3 cm or less perineuromas composed of perineural exist as a specific sarcoma of lymphaticwith a white to yellow or tan cut surface. cells. endothelium but, at present, there is noA B CFig. 1.140 Primary mammary angiosarcoma. A, B Grade I (well differentiated) angiosarcoma showing interanastomosing channels containing red blood cells. Theendothelial nuclei are prominent and hyperchromatic, but mitotic figures are absent. C High grade (poorly differentiated) angiosarcoma. Solid aggregates of pleo-morphic endothelial cells surround vascular channels.94 Tumours of the breast
  • 93. radiotherapy; 4) Secondary in the skin or Macroscopy breast parenchyma or both following Angiosarcomas vary in size from 1 to 20 conservation treatment and radiotherapy . cm, averaging 5 cm {2425}, have a Angiosarcomas, as with other sarcomas spongy appearance and a rim of vascu- of the breast, are rare and their incidence lar engorgement which corresponds to a is about 0.05% of all primary malignan- zone of well differentiated tumour. Poorly cies of the organ {2876}. While the inci- differentiated tumours appear as an ill dence of primary breast angiosarcomas defined indurated fibrous lesion similar to has remained constant, the incidence of that of any other poorly differentiated sar- secondary forms has changed. S-T syn- coma. Angiosarcomas must be sampled drome has dramatically declined in extensively to look for poorly differentiat-Fig. 1.141 Angiosarcoma after breast conservingtreatment. The spongy, haemorrhagic mass con- recent years in institutions in which more ed areas that on occasion constitute thetains occasional solid areas. In this case, the neo- conservation surgical treatments have minority of a tumour.plasm involves the breast parenchyma as well as been adopted, while angiosarcomas ofthe skin. the breast developing after conserving Histopathology surgery with supplementary radiation Two systems have been used to grade therapy have been diagnosed since the angiosarcomas of the breast {717,1847}.reliable criterion upon which to make a late 1980s {570}. Although very similar, the one proposedhistological distinction between tumours by Donnell et al. {717} has gained widederived from endothelia of blood and Primary (de novo) angiosarcoma of impact as it was tested in a large numberlymphatic vessels. breast parenchyma of patients with adequate follow up In patients with primary angiosarcoma, {2436}.Epidemiology the age ranges from 17 to 70 years Grade I (well differentiated) angiosarco-Mammary angiosarcoma can be subdi- (median 38 years) with no prevalence of mas consist of interanastomosing vascu-vided into 1) Primary (de novo) forms in laterality {2436}. The tumours are deeply lar channels that dissect the interlobularthe breast parenchyma; 2) Secondary in located in the breast tissue {2784}. stroma. The neoplastic vessels have verythe skin and soft tissues of the arm fol- Approximately 12% of patients present wide lumina filled with red blood cells.lowing ipsilateral radical mastectomy with diffuse breast enlargement {2876}. The nuclei of the endothelium lining theand subsequent lymphoedema - the When the tumour involves the overlying neoplastic vessels are prominent andStewart Treves (S-T) syndrome; 3) skin a bluish-red discoloration may hyperchromatic. Care must be taken toSecondary in the skin and chest wall fol- ensue. Imaging is of little help {1656, differentiate grade I angiosarcoma fromlowing radical mastectomy and local 2564,3118}. benign vascular tumours. Grade III (poorly differentiated) angiosar- comas are easy to diagnose as inter- anastomosing vascular channels are intermingled with solid endothelial or spindle cell areas that show necrotic foci and numerous mitoses. In a grade III angiosarcoma, more than 50% of the total neoplastic area is composed of solid and spindle cell components with- out evident vascular channels {2425}. A tumour qualifies as grade II (intermedi- ately differentiated) angiosarcoma when at least 75% of the bulk of the tumour is formed by the well differentiated pattern seen in grade I, but in addition there are solid cellular foci scattered throughout the tumour. Clinical feature The average age of patients with grade I angiosarcomas is 43 years while 34 and 29 years are the respective figures for grade II and III angiosarcomas {717}.A B ImmunoprofileFig. 1.142 Angiosarcoma after breast conserving treatment. A As in the majority of cases, this is a poorly dif- Factor VIII, CD34 and CD31 are the mostferentiated angiosarcoma in which vascular channels are hard to see. B Immunostaining for the endothelial widely used antibodies that characterizemarker CD31 clearly demonstrates the solid areas of endothelial cells with occasional vascular channels. endothelial differentiation. While present Mesenchymal tumours 95
  • 94. in all grade I and most grade II angiosar- following mastectomy {2752,3149}. Macroscopycomas these markers may be lost in S-T syndrome is a lethal disease with a Liposarcomas are often well circum-more poorly differentiated tumours or median survival of 19 months {3149}. scribed or encapsulated, about one-thirdareas of tumour. Lungs are the most frequent site of have infiltrative margin. With a median metastasis. size of 8 cm, liposarcomas may becomePrognosis and predictive factors enormous exceeding 15 cm {116,138}.If well differentiated angiosarcomas Post-radiotherapy angiosarcoma Necrosis and haemorrhage may be pres-(Grade I) were excluded, this breast ent on the cut surface of larger tumours.tumour is usually lethal {457}. Angiosarcoma can manifest itself afterGrading systems highlight the relative radiotherapy in two separate settings. Histopathologybenignity of well differentiated angiosar- 1) In the chest wall when radiotherapy The histopathology and immunopheno-comas. The survival probability for grade has been administered after mastecto- type is identical to that of liposarcoma atI tumours was estimated as 91% at 5 my for invasive breast carcinoma with a other sites. The presence of lipoblastsyears and 81% at 10 years. For grade III latency time ranging from 30 to 156 establishes the diagnosis. Practicallytumours the survival probability was 31% months (mean 70 months). The age is every variant of soft tissue liposarcomaat 2 years and 14% at 5 and 10 years. more advanced than that of de novo has been reported in the breast, includ-Grade II lesions had a survival of 68% at angiosarcoma ranging from 61 to 78 ing the pleomorphic, dedifferentiated and5 and 10 years. Recurrence free survival years {2223}. In these cases the neo- myxoid variants. Despite the well delin-at 5 years was 76% for grade I, 70% for plastic endothelial proliferation is neces- eated gross appearance, many mamma-grade II and 15% for grade III angiosar- sarily confined to the skin {392}. ry liposarcomas have at least partial infil-comas {2436}. Metastases are mainly to 2) In the breast after conservation treat- trative margins on histological examina-lungs, skin bone and liver. Very rarely ment for breast carcinoma. Fifty two tion. Atypia is often present at least focal-axillary lymph nodes show metastases at cases had been reported as of ly. The well differentiated and myxoidpresentation {457}. The grade can vary December 1997. The first case was variants have a delicate arborizing vas-between the primary tumour and its described in 1987 {1764}. This type of cular network and few lipoblasts. Thesemetastases {2876}. Radio and angiosarcoma involves only the skin in may assume a signet-ring appearance inchemotherapy are ineffective. more than half the cases, while exclusive the myxoid variant. The pleomorphic vari- involvement of breast parenchyma is ant is composed of highly pleomorphicAngiosarcoma of the skin of the very rare. Most tumours (81%) are multi- cells and bears significant resemblancearm after radical mastectomy focal and a large majority of patients har- to malignant fibrous histiocytoma; thefollowed by lymphoedema bour grade II to III angiosarcomas. presence of lipoblasts identifies the Radiotherapy and chemotherapy are lesion as a liposarcoma. Mitotic figuresStewart and Treves in 1949 gave a lucid ineffective {2876}. are readily identifiable in this variant.description of a condition subsequentlynamed S-T syndrome {2793}. They Differential diagnosisreported six patients who had: 1) under- Liposarcoma Vacuolated cells in a variety of lesionsgone mastectomy for breast cancer may be confused with lipoblasts. Typicalincluding axillary dissection; 2) devel- Definition lipoblasts have scalloped irregular nucleioped an “immediate postmastectomy A variably cellular or myxoid tumour con- with sharply defined vacuoles that con-oedema” in the ipsilateral arm; 3) taining at least a few lipoblasts. tain lipid rather than glycogen or mucin.received irradiation to the breast area Clear nuclear pseudo-inclusions are atogether with the axilla; 4) developed ICD-O code 8850/3 characteristic of the bizarre large cells inoedema which started in the arm and atypical lipomatous tumours and helpextended to the forearm and finally the Epidemiology distinguish these atypical cells from truedorsum of the hands and digits. Primary liposarcoma should be distin- lipoblasts that are diagnostic of a liposar-The patients ranged in age from 37-60 guished from liposarcomatous diffe- coma.years, with a mean age of 64 years {3149}. rentiation in a phyllodes tumour. It occursThe angiosarcomatous nature of S-T predominantly in women ranging in agesyndrome has been conclusively proved from 19-76 years (median, 47 years) {116,by ultrastructure and immunohistochem- 138}. The tumour only rarely occurs in theistry in most of the cases studied {1049, male breast {3027}. Liposarcoma follow-1462,1862,2690}. ing radiation therapy for breast carcinomaThe oedema is preceded by radical mas- has been reported.tectomy for breast carcinoma includingaxillary dissection {275} and develops Clinical featureswithin 12 months. Nearly 65% of patients Patients present most often with a slowlyalso had irradiation of the chest wall and enlarging, painful mass. In general, skinaxilla {2425}. The interval to tumour ap- changes and axillary node enlargementpearance varies from 1-49 years {2425}, are absent. Rarely the tumour is bilateral Fig. 1.143 Liposarcoma. Note the highly pleomor-but most become evident about 10 years {3027}. phic nuclei and multiple lipoblasts.96 Tumours of the breast
  • 95. A BFig. 1.144 Mammary osteosarcoma. A The sectioned surface shows a well delineated, solid mass with focal haemorrhage. B The spindle cell component of thetumour invades the adipose tissue and is admixed with abundant bony frabeculae.Prognosis and predictive factors nant phyllodes tumour or a metaplastic nating in phyllodes tumours or carci-Both the myxoid and pleomorphic vari- carcinoma. nosarcomas. Absence of connection toants of liposarcoma can recur and the skeleton, which should be confirmedmetastasize. Axillary node metastases Pathology by imaging studies, is required for aa re exceptionally rare. Recurre n c e s Primary rhabdomyosarcoma has been diagnosis of a primary mammarygenerally develop within the first year reported in adolescents {773,1166,1198, osteosarcomas.and patients who die from their disease 2402}, when it is predominantly of the Osteosarcomas occur mainly in olderusually do so within a year of the diag- alveolar subtype; the pleomorphic sub- women with a median age of 64.5 years;nosis. Because of the high frequency of type has been reported in older women the age range is 27–89 years {2681}.marginal irregularity, complete excision over forty {2871}. The vast majority of patients are womenwith tumour free margins is necessary. Metastatic rhabdomyosarcoma to the who are predominantly Caucasian. AL i p o s a rcomas behave part i c u l a r l y breast is again predominantly of the alve- prior history of radiation therapy or trau-a g g ressively when associated with olar subtype {1166,1248}. The primary ma has been noted in some womenpregnancy. lesion is usually located on the extremi- {331}. ties, in the nasopharynx/paranasal sinus- es or on the trunk {1166}. A metastasis Clinical featuresRhabdomyosarcoma from an embryonal rhabdomyosarcoma The tumour presents as an enlarging to the breast is less frequent {1166, mass which is associated with pain inDefinition 2531}. one-fifth of cases. Bloody nipple dis-A tumour composed of cells showing Metastatic breast tumours may occur as charge or nipple retraction occurs invarying degrees of skeletal muscle dif- part of disseminated disease or as an 12% of the women. Mammographically,ferentiation. isolated lesion. osteosarcomas present as a well cir- cumscribed mass with focal to extensiveICD-O codes coarse calcification. Because of theirRhabdomyosarcoma 8900/3 Mammary osteosarcoma predominantly circumscribed nature,Alveolar type 8920/3 they may be misinterpreted as a benignPleomorphic type 8901/3 Definition lesion {3072}. A malignant tumour composed of spindleEpidemiology cells that produce osteoid and/or bone MacroscopyP u re primary rhabdomyosarcoma of together with cartilage in some cases. Osteosarcomas vary in size from 1.4 tothe breast is very uncommon, and, 13 cm; most are about 5 cm in size andalthough primary mammary rhabdo- ICD-O code 9180/3 are sharply delineated. The consistencym y o s a rcoma has been described, varies from firm to stony hard dependingit usually represents a metastasis from Synonym on the proportion of osseous differentia-a soft tissue rhabdomyosarcoma Mammary osteogenic sarcoma. tion. Cavitation and necrosis are seen inoccuring in children, young females larger tumours.or males {2402}. More frequently, rhab- Epidemiologydomyosarcomatous differentiation may Accounting for about 12% of all mam- Histopathologybe observed in older women as an mary sarcomas, pure osteosarcomas The histopathological appearance andheterologous component of a malig- must be distinguished from those origi- immunophenotype are similar to that of Mesenchymal tumours 97
  • 96. A BFig. 1.145 Leiomyoma. A The well circumscribed margin (left) is apparent. B The bland smooth muscle cells proliferate in whorls and fascicles.extraosseous osteosarcoma at other Leiomyoma and lobulated cut surface. Their size rangessites of the body. Despite the predomi- leiomyosarcoma from 0.5 to 15 cm {770,2000}.nantly circumscribed margins, charac-teristically, at least focal infiltration is Definition Histopathologypresent. The tumour is composed of a Benign and malignant tumours com- The histopathology and immunopheno-spindle to oval cell population with vari- posed of intersecting bundles of smooth type are identical to that seen in smoothable amounts of osteoid or osseous tis- muscle which is mature in benign lesions. muscle tumours elsewhere in the body.sue; cartilage is present in over a third Malignant lesions are larger in size and These neoplasms may be well circum-of the cases {2681} but no other differ- show more mitotic activity in the neoplas- scribed {1981} or show irregular infiltra-entiated tissues. tic cells. tive borders {2000}. Both are composedThe appearance of the tumours varies of spindle cells arranged in interlacingdepending on the cellular composition ICD-O codes fascicles.(fibroblastic, osteoblastic, osteoclastic) Leiomyoma 8890/0 In leiomyomas, these cells have elongat-as well as the type and amount of matrix Leiomyosarcoma 8890/3 ed cigar-shaped nuclei and eosinophilic(osteoid, osseous, chondroid). cytoplasm without evidence of atypia.The osteoclastic giant cells are immu- Epidemiology Mitoses are sparse and typically fewernoreactive with the macrophage marker Benign and malignant smooth muscle