Previous volumes in this seriesKleihues P., Cavenee W.K.       Hamilton S.R., Aaltonen L.A.   Jaffe E.S., Harris N.L., Ste...
World Health Organization Classification of Tumours                    WHO                           OMS           Interna...
World Health Organization Classification of Tumours                          Series Editors     Paul Kleihues, M.D.       ...
This volume was produced in collaboration with the                  International Academy of Pathology (IAP)The WHO Classi...
Published by IARC Press, International Agency for Research on Cancer,                                             150 cour...
Contents1   Tumours of the breast                             9    3 Tumours of the fallopian tube and    Invasive breast ...
CHAPTER 1             Tumours of the BreastCancer of the breast is one of the most common human neo-plasms, accounting for...
WHO histological classification of tumours of the breast Epithelial tumours                                               ...
TNM classification of carcinomas of the breast TNM Clinical Classification 1,2                                            ...
Stage Grouping                                            Stage 0                                 Tis                     ...
Invasive breast carcinoma                                                                            I.O. Ellis           ...
More than most other human neoplasms,                                                       breast cancer often shows fami...
Rapid growth and greater adult height,reflecting in part, the total food intake inearly years, are associated with anincre...
similar effects within different popula-tions. Although lifetime physical activityis desirable, beginning recreationalphys...
tives, administrative and clerical jobs{387}. A recent hypothesis deals with cir-cadian disruption through night work,with...
A                                                      B                                                      CFig. 1.09 M...
Grade 1 - well differentiated: 3-5 points             Table 1.05Grade 2 - moderately differentiated:                  Semi...
mixed category, preferring to include                      Classically, ductal NOS carcinomas are                         ...
ent and this is occasionally extensive. Ina minority of cases a distinct lympho-plasmacytoid infiltrate can be identified....
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  1. 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 press@iarc.fr 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 bookorders@who.ch 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 book.orders@oup.co.ukWHO Blue Books on the web: www.iarc.fr/who-bluebooks
  2. 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. 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. 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. 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. 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. 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. 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 (http://snomed.org). 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. 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. 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 http://tnm.uicc.org. 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. 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. 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 trends.in selected populations 1988-1993. From M. Parkin reproductive life have been considered Source: WHO/NCHS.et 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. 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. 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. 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. 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. 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. 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. 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

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