1.Previous volumes in this seriesKleihues P., Cavenee W.K. Hamilton S.R., Aaltonen L.A. Jaffe E.S., Harris N.L., SteinFletcher C.D.M., Unni K.K.,(Eds.): (Eds.):H., Vardiman J.V. (Eds.): Mertens F. (Eds.):World Health Organization World Health OrganizationWorld Health Organization World Health OrganizationClassification of Tumours.Classification of Tumours. Classification of Tumours.Classification of Tumours.Pathology and Genetics of Pathology and Genetics ofPathology and Genetics of Pathology and Genetics ofTumours of the NervousTumours of the Digestive Tumours of Haematopoietic Tumours of Soft Tissue andSystem. System.and Lymphoid Tissues. Bone.IARC Press: Lyon 2000 IARC Press: Lyon 2000IARC Press: Lyon 2001 IARC Press: Lyon 2002ISBN 92 83 22409 4ISBN 92 83 22410 8 ISBN 92 83 22411 6ISBN 92 832 2413 2This book and all other volumes of the series can be purchased from:International Agency forIARCPress IARCPressResearch on Cancer (IARC) 150 Cours Albert Thomas 1775 K Street, NW, Suite 48069008 Lyon (France) Washington, DC 20006 (USA)Tel. +33 4 72 73 85 15Toll-free order line: 877 WHO-IARCFax +33 4 72 73 83 02 Fax (202) 223 1782press@iarc.fr iarcpress@who.intWorld Health Organization (WHO) WHO Marketing and Dissemination WHO Publications Center1211 Geneva (Switzerland) Albany, NY 12210 (USA)Tel. +41 22 791 2476Tel. (518) 436 9686Fax +41 22 791 4857 Fax (518) 436 7433bookorders@who.ch qcorp@compuserve.comOxford University Press (OUP) OUP Oxford (UK)Tel. +44 1536 45453424 hr. Hotline:Tel. +44 1 536 74 17 27Fax +44 1 865 26 77 82book.orders@oup.co.ukWHO Blue Books on the web:www.iarc.fr/who-bluebooks

2. World Health Organization Classification of TumoursWHO OMS International Agency for Research on Cancer (IARC) Pathology and Genetics of Tumours of the Breast and Female Genital Organs Edited byFattaneh A. Tavassoli Peter Devilee IARCPress Lyon, 2003 3. World Health Organization Classification of TumoursSeries Editors Paul Kleihues, M.D. Leslie H. Sobin, M.D.Pathology and Genetics of Tumours of the Breast and Female Genital OrgansEditorsFattaneh A. Tavassoli, M.D. Peter Devilee, Ph.D.Coordinating Editors Lawrence M. Roth, M.D. Rosemary Millis, M.D. Editorial AssistantsIsabelle Forcier Christine ZorianLayout Lauren A. Hunter Sibylle Sring Pascale Dia Illustrations Georges Mollon Lauren A. HunterPrinted 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 theInternational 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 indicatedin the List of Contributors on page 365The Working Group on Gynaecological Tumours greatlyappreciates 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, 2003Publications of the World Health Organization enjoy copyright protection inaccordance with the provisions of Protocol 2 of the Universal Copyright Convention.All rights reserved. The International Agency for Research on Cancer welcomesrequests 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 theWorld 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 othersof 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 Neoplasmsgenetics. 2. Breast Neoplasmspathology 3. Genital Neoplasms, Femalegenetics 4. Genital Neoplasms, Femalepathology I. Tavassoli, Fattaneh A. II. Devilee, Peter III. Series ISBN 92 832 2412 4 (NLM Classification W 1) 6. Contents1 Tumours of the breast 93 Tumours of the fallopian tube andInvasive breast carcinoma 13 uterine ligaments203Invasive ductal carcinoma, NOS19 Tumours of the fallopian tube206Invasive lobular carcinoma23 Tumours of the uterine ligaments 212Tubular carcinoma 26Invasive cribriform carcinoma 27 4 Tumours of the uterine corpus217Medullary carcinoma 28 Epithelial tumours and related lesions 221Mucin producing carcinomas30 Endometrial carcinoma221Neuroendocrine tumours32 Endometrial hyperplasia228Invasive papillary carcinoma34 Endometrial polyp230Invasive micropapillary carcinoma 35 Mesenchymal tumours and related lesions233Apocrine carcinoma36 Endometrial stromal and related tumours233 Smooth muscle tumours236Metaplastic carcinomas37 Other mesenchymal tumours242Lipid-rich carcinoma41 Mixed epithelial and mesenchymal tumours 245Secretory carcinoma 42 Gestational trophoblastic disease250Oncocytic carcinoma 43 Sex cord-like, neuroectodermal / neuroendocrine tumours,Adenoid cystic carcinoma44lymphomas and leukaemias255Acinic cell carcinoma 45 Secondary tumours of the uterine corpus257Glycogen-rich clear cell carcinoma46Sebaceous carcinoma 46 5 Tumours of the uterine cervix259Inflammatory carcinoma47 Epithelial tumours 262Bilateral breast carcinoma48 Squamous tumours and precursors266Precursor lesionsGlandular tumours and precursors 272Lobular neoplasia 60 Uncommon carcinomas and neuroendocrine tumours 277Intraductal proliferative lesions 63 Mesenchymal tumours280Microinvasive carcinoma 74 Mixed epithelial and mesenchymal tumours 284Intraductal papillary neoplasms 76 Melanotic, germ cell, lymphoid andBenign epithelial lesions 81secondary tumours of the cervix 287Myoepithelial lesions 86Mesenchymal tumours 89 6 Tumours of the vagina291Fibroepithelial tumours 99 Epithelial tumours 293Tumours of the nipple104 Squamous tumours 293Malignant lymphoma and metastatic tumours107 Glandular tumours297Tumours of the male breast 110 Tumours of skin appendage origin 324 Mesenchymal tumours3022 Tumours of the ovary and peritoneum113 Mixed epithelial and mesenchymal tumours 306 Melanotic, neuroectodermal, lymphoid andSurface epithelial-stromal tumours 117secondary tumours 308Serous tumours 119Mucinous tumours 124 7 Tumours of the vulva 313Endometrioid tumours 130 Epithelial tumours 316Clear cell tumours 137 Squamous tumours 316Transitional cell tumours140 Glandular tumours321Squamous cell lesions143 Mesenchymal tumours326Mixed epithelial tumours 144 Melanocytic tumours331Undifferentiated carcinomas145 Germ cell, neuroectodermal, lymphoid andSex cord-stromal tumours 146secondary tumours 333Granulosa-stromal cell tumours 146 8 Inherited tumour syndromes 335Sertoli-stromal cell tumours 153 Familial aggregation of cancers of the breast andMixed sex cord-stromal tumours 158female genital organs 336Steroid cell tumours 160 BRCA1 syndrome 338Germ cell tumours163 BRCA2 syndrome 346Primitive germ cell tumours163 Li-Fraumeni syndrome 351Biphasic or triphasic teratomas168 Cowden syndrome355Monodermal teratomas 171 Hereditary non-polyposis colon cancer (HNPCC)358Mixed germ cell-sex cord-stromal tumours 176 Ataxia telangiectasia syndrome 361Tumours and related lesions of the rete ovarii 180Miscellaneous tumours and tumour-like lesions182 Contributors 365Lymphomas and leukaemias 191 Source of charts and photographs 370Secondary tumours of the ovary 193 References 372Peritoneal tumours 197 Subject index425 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 tumoursAdenomas Invasive ductal carcinoma, not otherwise specified8500/3 Tubular adenoma8211/0 Mixed type carcinoma Lactating adenoma8204/0 Pleomorphic carcinoma 8022/3 Apocrine adenoma 8401/0 Carcinoma with osteoclastic giant cells 8035/3 Pleomorphic adenoma8940/0 Carcinoma with choriocarcinomatous featuresDuctal adenoma 8503/0 Carcinoma with melanotic features Invasive lobular carcinoma8520/3 Myoepithelial lesions Tubular carcinoma 8211/3 Myoepitheliosis Invasive cribriform carcinoma 8201/3 Adenomyoepithelial adenosis Medullary carcinoma 8510/3 Adenomyoepithelioma8983/0 Mucinous carcinoma and other tumours with abundant mucin Malignant myoepithelioma 8982/3 Mucinous carcinoma8480/3 Cystadenocarcinoma and columnar cell mucinous carcinoma 8480/3Mesenchymal tumours Signet ring cell carcinoma8490/3Haemangioma 9120/0 Neuroendocrine tumoursAngiomatosis Solid neuroendocrine carcinomaHaemangiopericytoma 9150/1 Atypical carcinoid tumour 8249/3Pseudoangiomatous stromal hyperplasia Small cell / oat cell carcinoma 8041/3Myofibroblastoma8825/0 Large cell neuroendocrine carcinoma 8013/3Fibromatosis (aggressive) 8821/1 Invasive papillary carcinoma8503/3Inflammatory myofibroblastic tumour 8825/1 Invasive micropapillary carcinoma 8507/3Lipoma8850/0 Apocrine carcinoma8401/3 Angiolipoma8861/0 Metaplastic carcinomas8575/3Granular cell tumour9580/0 Pure epithelial metaplastic carcinomas8575/3Neurofibroma9540/0 Squamous cell carcinoma 8070/3Schwannoma9560/0 Adenocarcinoma with spindle cell metaplasia 8572/3Angiosarcoma9120/3 Adenosquamous carcinoma 8560/3Liposarcoma 8850/3 Mucoepidermoid carcinoma8430/3Rhabdomyosarcoma8900/3 Mixed epithelial/mesenchymal metaplastic carcinomas 8575/3Osteosarcoma9180/3 Lipid-rich carcinoma8314/3Leiomyoma 8890/0 Secretory carcinoma 8502/3Leiomyosarcoma8890/3 Oncocytic carcinoma 8290/3 Adenoid cystic carcinoma8200/3Fibroepithelial tumours Acinic cell carcinoma 8550/3Fibroadenoma9010/0 Glycogen-rich clear cell carcinoma8315/3Phyllodes tumour9020/1 Sebaceous carcinoma 8410/3 Benign 9020/0 Inflammatory carcinoma8530/3 Borderline 9020/1 Lobular neoplasiaMalignant9020/3 Lobular carcinoma in situ 8520/2Periductal stromal sarcoma, low grade9020/3 Intraductal proliferative lesions Mammary hamartoma Usual ductal hyperplasia Flat epithelial atypiaTumours of the nipple Atypical ductal hyperplasia Nipple adenoma8506/0 Ductal carcinoma in situ8500/2Syringomatous adenoma 8407/0 Microinvasive carcinoma Paget disease of the nipple 8540/3 Intraductal papillary neoplasms Central papilloma 8503/0Malignant lymphoma Peripheral papilloma8503/0Diffuse large B-cell lymphoma 9680/3 Atypical papillomaBurkitt lymphoma9687/3 Intraductal papillary carcinoma 8503/2Extranodal marginal-zone B-cell lymphoma of MALT type 9699/3 Intracystic papillary carcinoma 8504/2Follicular 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 Invasive8500/3 Radial scar / complex sclerosing lesion In situ 8500/2 __________ 1Morphology code of the International Classification of Diseases for Oncology (ICD-O) {1969}2 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. TNM classification of carcinomas of the breast TNM Clinical Classification 1,2 M Distant Metastasis T Primary TumourMX Distant metastasis cannot be assessed TXPrimary tumour cannot be assessed M0 No distant metastasis T0No 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 situpT Primary Tumour Tis (Paget) Paget disease of the nipple with no tumourThe 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 dimensionNote: When classifying pT the tumour size is a measurement of the invasive compo- T1micMicroinvasion 0.1 cm or less in greatest dimensionanent. If there is a large in situ component (e.g. 4 cm) and a small invasive component T1aMore than 0.1 cm but not more than 0.5 cm in greatest dimension(e.g. 0.5 cm), the tumour is coded pT1a. T1bMore than 0.5 cm but not more than 1 cm in greatest dimension T1cMore than 1 cm but not more than 2 cm in greatest dimensionpN 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 fordimensionstudy or previously removed) T3 Tumour more than 5 cm in greatest dimensionpN0 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 thanonly as described in T4a to T4d2 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** T4aExtension to chest wallpN1aMetastasis in 1-3 axillary lymph node(s), including at least one T4bOedema (including peau dorange), or ulceration of the skin of the larger than 2 mm in greatest dimensionbreast, or satellite skin nodules confined to the same breastpN1bInternal mammary lymph nodes with microscopic metastasis T4cBoth 4a and 4b, abovedetected by sentinel lymph node dissection but not clinically T4dInflammatory carcinomabapparent pN1cMetastasis 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 pN2aMetastasis 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 ofpN2bMetastasis in clinically apparent internal mammary lymph the skin, nipple retraction, or other skin changes, except those in T4b and T4d, maynode(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 3ipsilateral 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 N0No regional lymph node metastasis metastasis in internal mammary lymph nodes; or in ipsilateral N1Metastasis in movable ipsilateral axillary lymph node(s)supraclavicular lymph nodes N2Metastasis in fixed ipsilateral axillary lymph node(s) or inpN3aMetastasis in 10 or more axillary lymph nodes (at least oneclinically apparent* ipsilateral internal mammary lymph node(s) in larger than 2 mm) or metastasis in infraclavicular lymph nodesthe absence of clinically evident axillary lymph node metastasis pN3bMetastasis in clinically apparent internal mammary lymph node(s) N2aMetastasis in axillary lymph node(s) fixed to one another or toin the presence of one or more positive axillary lymph node(s); or other structuresmetastasis in more than 3 axillary lymph nodes and in internal N2b Metastasis only in clinically apparent* internal mammary lymphmammary lymph nodes with microscopic metastasis detectednode(s) and in the absence of clinically evident axillary lymphby sentinel lymph node dissection but not clinically apparentnode metastasispN3cMetastasis in supraclavicular lymph node(s) N3Metastasis 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 typicallyor 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 studiespM Distant Metastasis (excluding lymphoscintigraphy)The pM categories correspond to the M categories.11 10. Stage GroupingStage 0 TisN0M0Stage I T1 N0M0Stage IIA T0 N1M0T1 N1M0T2 N0M0Stage IIB T2 N1M0T3 N0M0Stage IIIAT0 N2M0T1 N2M0T2 N2M0T3 N1, N2M0Stage IIIBT4 N0,N1,N2M0Stage IIICAny TN3M0Stage IVAny TAny N M1_________1 {1969}1. 2A help desk for specific questions about the TNM classification is available at http://tnm.uicc.org.3The 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). 4The 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 maybe used for pathological classification. If classification is based solely on sentinel node biopsy without subsequent axillary lymph node dissection it should be designated (sn) forsentinel node, e.g. pN1(sn).12 Tumours of the breast 11. Invasive breast carcinomaI.O. Ellis S.J. SchnittC.J. Cornelisse A.J. Sasco X. Sastre-Garau R. Kaaks G. Bussolati P. Pisani F.A. Tavassoli D.E. Goldgar V. EusebiP. Devilee J.L. PeterseM.J. Cleton-Jansen K. Mukai A.L. Brresen-Dale L. TabrL. vant Veer J. JacquemierA. SapinoDefinitionThe 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 andtinues to increase in particular in theerations will maintain their higher risk anda marked tendency to metastasize to dis-developing countries {1969}0. Thereafter, the age-specific curve will approach thattant sites. The vast majority of these tu-in developed countries, the advent ofof 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 alteredvaried 10-fold world wide, indicatingparenchymal epithelium, particularly cellsboth incidence and mortality; the latter important differences in the distributionof the terminal duct lobular unit (TDLU). no longer appropriately reflect trends inof the underlying causes {2850}9.Breast carcinomas exhibit a wide rangethe underlying risk of the disease.Geographical variations, time trends,of morphological phenotypes and specif- Breast cancer incidence, as with mostand studies of populations migratingic histopathological types have particularepithelial 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 thedence rates for three selected popula- risk of the host country in one or two gen-Epidemiologytions representing countries with lowerations {2850}8, 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 beforefactors 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, risingAetiologythe occurrence of cancer in women atsteeply up to menopausal age and lessThe aetiology of breast cancer is multi-any other site {2850}7. The areas of highrapidly or not at all afterwards. The differ-factorial and involves diet, reproductiverisk are the affluent populations of Northent behaviour at older ages is due to afactors, and related hormonal imbal-America, Europe and Australia where 6%cohort effect in the populations of Japanances. 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 {2850}6, 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 KingdomFig. 1.01 Global incidence rates of breast cancer. Age-standardized rates (ASR) per 100,000 population andand the Netherlands {2850}5. year. From Globocan 2000 {2850}4. 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 ofFig. 1.04 Female breast cancer mortality trends.in selected populations 1988-1993. From M. Parkinreproductive life have been consideredSource: WHO/NCHS.et al. {2850}3. to be risk factors for breast cancer in women. Breast cancer occurs more fre-data it has clearly emerged that breastquently among women who have an finding an increased risk for inducedcancer is a disease of affluent societiesearly menarche, remain nulliparous or, if abortion. Similarly, the protective effect ofwhich have acquired the Westernparous, 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 atcumulative breast feeding, preferablyRegions which have featured this menopause also increases the risk exceeding two years {2850}2.lifestyle for a long period of time (North {2850}1.America, Northern Europe, Australia) Most of these factors have also beenExogenous 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 markedthe negative impact of late age at firstThe evidence suggests a small increaseincrease in incidence and mortality. Indelivery, reduced number of pregnan-in the relative risk associated with the useaddition to breast cancer, the Western cies and shorter breast feeding timeof combined oral contraceptives, espe-lifestyle carries a high risk of cancer{2850}0. Recent data indicates that thecially among current and recent users,of the prostate, colon/rectum, and age at any delivery, not just the first iswhich is not related to duration of useendometrium. Specific environmentalassociated with breast cancer risk, withand 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 {1759}9.{1759}8. 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 {1759}7. Epidemiological studies on postmeno- pausal estrogen therapy show a small increase in risk with longer duration of use in current and recent users {1759}6. 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 {1759}5. 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 {1759}4. 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 {1759}3.14 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 {1759}2. 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 {1759}1.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 {1759}0. 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{2850}9. 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 {2850}8. phism {2850}7 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 SmokingBMI and breast cancer is strongerpreventive for vegetables and fruit, orThe evidence on smoking and breast among women who have never usedrisk for fat may have been overstatedcancer remains inconclusive {2850}6. 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 {2850}5. the elevations in endogenous estrogenof exposure to contaminants, either production among heavier women. Adultformed during cooking, such as hetero- Body weightweight gain is a strong and consistentcyclic amines in well-done meat or pesti-It has long been known that the influencepredictor of postmenopausal breast can-cide residues. of weight on breast cancer risk dependscer risk particularly among women who on the menopausal status {2850}4. Morehave never used hormone replacementAlcoholthan 100 studies over nearly 30 years in therapy {2850}3.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 breastbreast cancer, the overall associationed with a mild increase in risk of breastcancer risk among postmenopausal between BMI and breast cancer riskcancer {2850}2. A dose-responsewomen. This is largely independent ofamong premenopausal women is the reproductive and lifestyle risk factors andinverse. The reduction in risk with exces - of the effect of physical activity. Thesive 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 agehowever, the breast cancer mortality rate after menopause. is not lower among heavier pre- The increase in risk with body-massmenopausal women {2850}1. index (BMI) has been somewhat modest in the majority of studies {2850}0. Above a Physical activity BMI of 24 kg/m2, the incidence rateThe association between physical activi- increases among postmenopausal ty and breast cancer risk is independent women. The greatest slope of increases of menopausal status {3024}9. 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 levelsand 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 beingActivity that is sustained throughout life-women 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. Asphism 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 withWhen evaluating tubules and glandulartumour mass without calcifications. The no associated calcifications in 64% of theacini only structures exhibiting clear cen-mammographic histological correlation cases.tral lumina are counted; cut off points ofof 1,168 open surgical biopsies at Falun2) An additional 17% had both calcifica-75% and 10% of glandular/tumour areaCentral Hospital, Sweden, included 866tions and tumour mass.are used to allocate the score.3) Only calcifications without associated Nuclear pleomorphism is assessed byTable 1.03tumour 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 numberStellate and circular64%Grading of invasive carcinoma and size of nucleoli are useful additionalwithout calcificationsInvasive ductal carcinomas and all otherfeatures in allocating scores for pleomor-Stellate and circular17%invasive tumours are routinely graded phism.with calcifications based on an assessment of tubule/glandEvaluation of mitotic figures requires careformation, nuclear pleomorphism and and observers must count only definedCalcifications only19%mitotic counts. mitotic figures; hyperchromatic andMany studies have demonstrated a sig- pyknotic nuclei are ignored since theynificant association between histological are more likely to represent apoptosisTable 1.04grade and survival in invasive breast car-than proliferation. Mitotic counts requireSpectrum of histological diagnosis correspondingcinoma. 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 {1698,2655}1. The totalInvasive ductal carcinoma, NOS 59%included as a component of the minimumnumber of mitoses per 10 high powerdata set for histological reporting offields. Field selection for mitotic scoringMedullary carcinoma 8%breast cancer {1698,2655}0. Assessment of should be from the peripheral leadinghistological grade has become moreedge of the tumour. If there is hetero-Mucinous carcinoma7%objective with modifications of the Patleygeneity, regions exhibiting a higher fre-& Scarff {2850}9 method first by Bloom quency of mitoses should be chosen.Intracystic carcinoma 5%and Richardson {2850}8 and more recentlyField selection is by random meanderby Elston and Ellis {2850}7. through the chosen area. Only fields withTubular carcinoma 4%a representative tumour cell burdenInvasive lobular carcinoma4%Method of grading should be assessed.Three tumour characteristics are evaluat- The three values are added together toOther diagnoses13%ed; tubule formation as an expression ofproduce scores of 3 to 9, to which theglandular 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{2850}6.6-7 pointsFeature ScoreGrade 3 - poorly differentiated: 8-9 points Tubule and gland formationMajority of tumour (>75%)1Invasive ductal carcinoma,Moderate degree (10-75%) 2not otherwise specified (NOS) Little or none (11 >20 >23Synonyms and historical annotationInvasive ductal carcinoma, no specifictype (ductal NST); infiltrating ductal car-cinoma. tion {2850}5. This perpetuates thesingle entity from the point of view of theMany names have been used for thistraditional concept that these tumourssite of origin of most breast carcinomasf o rm of breast carcinoma includingare derived exclusively from mammary{2850}4. Some groups {2850}3scirrhous 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 tothe phrase not otherwise specifiedInfiltrating ductal carcinoma is used byhave arisen from within lobules for which (NOS), whilst others {2850}2 prefer to usethe Armed Forces Institute of Pathology there is no evidence. In addition it hasno specific type (NST) to emphasize{2850}1 and was the nomenclaturebeen 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 increasinglyABCFig. 1.10 Well differentiated infiltrating ductal carcinoma, Grade 1. A First screen. Intramammary lymph node and small (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 asor 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 orcomponent 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 {2850}4. The sis. Lymphovascular invasion is present cellspatients range in age from 28 to 96in 19% of cases.years with a median of 51. MostGenerally 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 ismas are TP53 positive, and one third areThe common denominator of all thesethe first manifestation of disease. TheS-100 protein positive. All are positive forcarcinomas 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 {2850}3.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 cancer21 20. year survival rate is around 70%, similar Carcinoma with to, or better than, patients with ordinarychoriocarcinomatous features infiltrating carcinomas {2850}2. Prognosis is related to the characteristics of thePatients with ductal NOS carcinoma may associated carcinoma and does not have elevated levels of serum human appear to be influenced by the pres-chorionic gonadotrophin (-HCG) ence of stromal giant cells.{2850}1 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 -HCG positive cells {2850}0. body on paraffin sections) {2704}9 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 {2704}8.reported {2704}7. 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, monocytesmorphological similarity to histiocytic A few case reports have describedalong with mononucleated and binucle-cells and osteoclasts {2704}6.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 confirmedmalignant melanoma {2704}5epithelial component or are found within the histiocytic nature of the osteoclasticand 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 {2704}4. 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 {2704}3. and macrophages. Tumour associatedsuggesting an origin from the same neo-The carcinomatous part of the lesion ismacrophages (TAMs) are capable of dif-plastic clone {2704}2.most frequently a well to moderately dif-ferentiating into multinucleated cells, The mere presence of melanin in breastferentiated infiltrating ductal carcinomawhich can affect bone resorption in cancer cells should not be construed asbut all the other histological types havemetastases {2704}1. Osteoclastic giant evidence of melanocytic differentiation,been observed particularly invasivecells in carcinoma are probably alsosince melanin pigmentation of carcinomacribriform carcinoma {2704}0, andrelated to TAMs. Angiogenesis and cells can occur when breast cancersalso tubular, mucinous, papillary {2850}9,chemotactic agents produced by theinvade the skin and involve the dermo-lobular {2850}8, squamous andcarcinoma may be responsible for theepidermal junction {2850}7. In addition,other metaplastic patterns {2850}6. involved by cancer and their ultimate showing melanocytic differentiation fromAbout one-third of the reported casestransformation to osteoclastic giant cellsbreast carcinomas with prominent cyto-had lymph nodes metastasis. The five {2850}5.plasmic lipofuscin deposition {2850}4.ABFig. 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 {2850}3. Primary melanomas mayarise anywhere in the skin of the breast,but an origin in the nipple-areola com-plex is extremely rare {2850}2. 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 {2850}1. 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 highgrade carcinoma.GeneticsThe genetic variation seen in breast can-cer as a whole is similarly reflected inApproximately 70-80% of ductal NOS radiological {2850}0 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 geneticcases ERBB2 positive. The management also been reported {2060}9, repre-alterations seen with increasing gradeof 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 {2060}8. However, no significant dif-of a linear progression model in this typeas 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 {2060}7. At mammography, architec-groups that specific genetic lesion orInvasive lobular carcinoma tural distortion is more commonlyregions of alteration are associated withobserved 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 {2060}6.does not support this view. It implies that ted with lobular carcinoma in situ is com-breast cancer of ductal NOS typeposed of non-cohesive cells individually Macroscopyincludes a number of tumours of unrelat-dispersed or arranged in single-file linearILC frequently present as irregular anded genetic evolutionary pathways {2060}5pattern 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 code8520/3 because of the diffuse growth pattern ofspecial type tumours including lobular the cell infiltrate {2060}4. The mean diam-{2060}3 and tubular carcinoma {2060}2.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 {2060}1.NOS tumours can be classified in to sub-{2060}0. Duringtypes on the basis of expression patterns the last 20 years, a steady increase in itsHistopathology{2060}9.incidence has been reported in women The classical pattern of ILC {2060}8, which might be attributa-1780,3066} is characterized by a prolife-Prognosis and predictive factorsble to the increased use of hormoneration of small cells, which lack cohesionDuctal NOS carcinoma forms the bulk replacement therapy {2060}7.(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) {2060}6.35-50% 10 year survival {2060}5 comparedto breast cancer as a whole with around Clinical featuresa 55% 10 year survival. Prognosis isThe majority of women present with ainfluenced profoundly by the classicalpalpable mass that may involve any partprognostic variables of histologicalof 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 {2060}4. A high rate of multicentrictors at the end of this chapter) and by tumours has been reported by somepredictors of therapeutic response such {2060}3 but this has not been found inFig. 1.18 Macroscopy of an invasive lobular carci-as estrogen receptor and ERBB2 status.other series based on clinical {2060}2 or noma displays an ill defined lesion. Invasive breast cancer 23 22. ABFig. 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 atThe admixture of tubular growth patternthrough a fibrous connective tissue orleast 20 cells {2060}1, 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. Pleomorphicnoma (TLC) (ICD-O 8524/3) {2060}0. LCIScords frequently present a concentric lobular carcinoma retains the distinctiveis observed in about one third of TLC.pattern around normal ducts. There is growth pattern of lobular carcinoma butComparison of the clinico-pathologicaloften little host reaction or disturbance ofexhibits 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 {2072}9. Intra-lobulartases were more common in TLC (43%)nuclei and a thin rim of cytoplasm with anlesions composed of signet ring cells or than in TC (12%) {2072}8. A high rate ofoccasional intracytoplasmic lumen pleomorphic cells are features frequentlyestrogen receptor (ER) positivity has also{2072}7 often harbouring a central mucoidassociated with it. Pleomorphic lobularbeen reported in TLC {2072}6. Furtherinclusion. Mitoses are typically infre- carcinoma may show apocrine {2072}5 or analysis of TLC, especially regarding E-quent. This classical form of ILC is asso-histiocytoid {2072}4 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 casesshowing an admixture of the classicalas a variant of tubular or of lobular{2072}3. type with one or more of these patternstumours. Without this data these tumoursIn addition to this common form, variant{2072}2. In about 5% of invasive breastare best classified as a variant of lobularpatterns of ILC have been described.cancers, both ductal and lobular featurescarcinoma.The solid pattern is characterized by of differentiation are present {2072}1 (seesheets of uniform small cells of lobularMixed type carcinoma, page 21).Immunoprofilemorphology {2072}0. The cells lack cell toAnalysis of E-cadherin expression mayAbout 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 oftal and lobular tumours but the80% observed in IDC {989,2060}9.mitoses than the classical type. In the immunophenotype remains ambiguousProgesterone receptor (PR) positivity isalveolar variant , tumour cells are mainlyin a minority of cases {989,2060}8. 60-70% in either tumour type {989,2060}7. ER was found to be expressed inimmunostaining can be related to the ranging from 3-10% {989,2060}6,presence of protein truncation mutations 2696,2935}. Metastatic involvement bybut the rate of positivity was higher {989,2060}5, together with the inacti- scattered isolated cells may simulate(100%) in alveolar {989,2060}4 and lower vation of the wild type allele. Alternativesinusoidal histiocytes and re q u i re(10%) in pleomorphic ILC {989,2060}3 than in mechanisms may also be involved in immunohistochemical detection.the classical type. The proliferation ratethe alteration of E-cadherin {989,2060}2The metastatic pattern of ILC differs fromin ILC is generally low {989,2060}1. With theand/or of E-cadherin-associated proteins that of IDC. A higher frequency of tumourexception of pleomorphic lobular carci- {989,2060}0.extension to bone, gastro-intestinal tract,noma ERBB2 overexpression in ILCAnalysis of neoplastic lesions correspon-uterus, meninges, ovary and diffuse{2060}9, is lower than reportedding to early steps of tumour develop- serosal involvement is observed in ILCin IDC {2060}8.ment has shown that both loss of het-while extension to lung is more frequenterozygosity of the 16q chromosomal in IDC {2060}7.Geneticsregion {2060}6 and of E-cadherin expres- IHC using antibodies raised againstUsing flow cytometry, ILCs were found sion {2060}5 were also observed inGCDFP-15, cytokeratin 7, ER, andnear diploid in about 50% of the casesLCIS and in mixed ductal-lobular carcino-E-cadherin may help establish a female{2060}4. This fits with the finding that chro-ma {2060}3. Inactivation of the E-cadheringenital tract tumour as a metastatic ILC.mosomal abnormalities, assessed bygene may thus represent an early event inSeveral studies have reported a morecytogenetical {2060}2 or comparativeoncogenesis and this biological trait indi-favourable disease outcome for ILC thangenomic hybridization (CGH) analysiscates that LCIS is a potential precursor offor IDC {2060}1 where-{2060}0, are less numerous in ILC than inILC. However, other molecular events as others found no significant differencesIDC. In ILC, the most common geneticmust be involved in the transition from{2060}9 or a worse prog-alteration, found in 63-87% of the casesin situ to invasive lobular tumours. nosis for ILC {2060}8.{2060}7, is a loss of the long arm ofFurthermore, 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 {2060}6,classical type than for variants {2060}5. This strongly705,725}. However, alveolar ILC hastissues {2060}4, 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{2060}3, whereas a poor prognosis of{2060}2. A correlation has been foundtumour suppressive properties, may bepleomorphic ILC has been reported inbetween deletion of 16q and the loss of involved in breast oncogenesis.some series {2060}1. No difference inE-cadherin expression {2060}0. Immu- A combination of mutation analysis and the outcome of different subtypes hasnohistochemical analysis has shownE-cadherin protein expression may offerbeen observed in other series {2072}9.complete loss of E-cadherin expressiona method for identification of lobular Furthermore, a large extent of lymphin 80-100% of ILC {2072}8. This contrasts with theincrease significantly the risk of localm e re decrease in staining intensity Prognosis and predictive factors relapse {2072}7. A link between lack ofobserved in 30-60% of IDC.A lower frequency of axillary nodalE-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-cadherinreported in several series, the difference reported {2072}6. Invasive breast cancer25 24. Treatment of ILC should depend on the epithelial atypia {2072}5. In addition,stage of the tumour and parallel that ofan association with radial scar has beenIDC. Conservative treatment has beenproposed {2072}4.shown to be appropriate for ILC {2072}3.MacroscopyThere is no specific macroscopical fea-ture which distinguishes tubular carcino-Tubular carcinoma ma from the more common ductal nospecial type (NOS) or mixed types, otherDefinitionthan small tumour size. Tubular carcino-A special type of breast carcinoma with a mas usually measure between 0.2 cmFig. 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 {2072}2.lar structures with open lumina lined by aTwo morphological subtypes have beenA secondary, but important feature issingle layer of epithelial cells. described, the pure type which has athe cellular desmoplastic stroma, whichpronounced stellate configuration withaccompanies the tubular structures.ICD-O code8211/3radiating arms and central yellow flecksCalcification may be present in the inva-due to stromal elastosis and the sclero-sive tubular, associated in situ or theEpidemiologysing type characterized by a more dif-stromal components.Pure tubular carcinoma accounts for fuse, ill defined structure {2072}1. 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 Histopathologyis 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 tubulesOccasionally, the in situ component isoften readily detectable mammographi- composed of a single layer of epitheliallobular in type. More recently an associ-cally because of their spiculate nature cells enclosing a clear lumen. Theseation has been described with flat epithe-and associated cellular stroma and aretubules are generally oval or rounded and,lial atypia and associated micropapillaryseen at higher frequencies of 9-19%, in typically, a proportion appears angu- DCIS {2072}0.mammographic screening series {989}9. regular with little nuclear pleomorphismthe 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 forWHO Classification {989}8 and ain older patients, be smaller in size and diagnosis of pure tubular carcinoma,number of published studies {989}7 no specific cut-off point is indicatedment {989}6. architecture. Apical snouts are seen in asalthough there is an assumption that allThese tumours are recognized to occur many as a third of the cases {989}5, butthe tumour is of a tubular configuration.in association with some epithelial prolif- are not pathognomonic. MyoepithelialSome authors have applied a strict 100%erative lesions including well differentiat-cells are absent but some tubules may rule for tubular structures {989}4,ed/low grade types of ductal carcinomahave an incomplete surrounding layer of some set the proportion of tubular struc-in situ (DCIS), lobular neoplasia and flatbasement membrane components. tures at 75% {989}3, andABFig. 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% {989}2. 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 ofareas 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, whichICD-O code8201/3the tubules. However, the tubules of MA implies that tubular carcinoma of theare more rounded and regular and oftenbreast is genetically distinct. Epidemiologycontain colloid-like secretory material, at Invasive cribriform carcinoma (ICC)least focally, compared to the often angu-Prognosis and predictive factorsaccounts 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 {989}1.brane is present around tubules of MA.1829,2081,2224} which in some series isComplex sclerosing lesions/radial scars similar to age matched women withoutClinical featureshave a typical architecture with centralbreast cancer {989}0. 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 {2060}9. Multi-tures show varying degrees of dilatationniques. Following breast conservation,focality is observed in 20% of the casesand ductal epithelial hyperplasia.the risk of local recurrence is so low that {2060}8.some centres consider adjuvant radio-Immunophenotype therapy unnecessary. Axillary nodeHistopathologyTubular carcinoma is nearly alwaysmetastases occur infrequently, and when The pure ICC consists almost entirelyestrogen and progesterone receptorobserved rarely involve more than one (>90%) of an invasive cribriform pat-positive, has a low growth fraction, andlow axillary lymph node. There is littletern. The tumour is arranged as inva-is ERBB2 and EGFR negative {2060}7. lar carcinoma {2060}6 and the use of well defined spaces are formed bysystemic adjuvant therapy and axillaryarches of cells (a sieve-like or cribri-Geneticsnode dissection are considered un-form pattern). Apical snouts are a reg-Tubular carcinomas of the breast have a necessary by some groups {2060}5.ular feature. The tumour cells are smalllow frequency of genetic alterationsand show a low or moderate degree ofwhen compared to other types of breastnuclear 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 16qDefinitionICC. 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 locusprognosis that grows in a cribriform pat- many as 80% of cases {2060}4. Axillary{2060}3. Of particular tern similar to that seen in intraductallymph node metastases occur in 14.3%interest is the observation that othercribriform carcinoma; a minor ( Absence of glandular structuresence of medullary features was found in35% {1174}2 to 60% {1174}1 of tumours aris- > Diffuse lymphoplasmacytic infiltrate, moderate to markeding in BRCA1 carriers. Reciprocally, in apopulation of MC, germ line mutations of > Nuclear pleomorphism, moderate to markedBRCA1 was observed in 11% of theFig. 1.28 Medullary carcinoma. Note multinucleatedcases {1174}0. 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 {546}9. 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, butAC 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 {546}8mucinous 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 SynonymsThe descriptive term cellular mucinousA variety of carcinomas in the breast areColloid carcinoma, mucoid carcinoma,carcinoma has been used by somecharacterized by production of abundantgelatinous carcinoma. {546}7 to differentiate the endocrine vari-extracellular and/or intracellular mucin.ant of mucinous carcinoma from the non-Among these are mucinous (colloid) car-Epidemiologyendocrine one; presence of intracyto-cinoma, mucinous cystadenocarcinoma, Pure mucinous carcinoma accounts forplasmic neuroendocrine granules doescolumnar cell mucinous carcinoma and about 2% of all breast carcinomas not always correlate with the degree ofsignet ring cell carcinoma.{546}6. It occurs in a wide cellularity, however. age range, but the mean and medianTraditionally, pure and mixed variantsMucinous carcinoma age of patients with mucinous carcinoma of mucinous carcinoma have been in some studies is somewhat higher than described {546}5. 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 {546}4.carcinoma. The pure mucinous carcino-small and uniform cells floating in largemas 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 tomucin and argyrophilic granules. As that of breast carcinomas in general. soon as another pattern becomes evi- Mammographically, mucinous carcinomadent as a component of the tumour appears as a well defined, lobulatedmass, the lesions qualifies as a mixed lesion. On magnification or compression tumour (the proportion of the different views {546}3, a less defined margincomponents 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- Macroscopyfused 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 {546}2. The presence of com-tumour excision. and a soft consistency make the lesionpressed spaces lined by epithelial and30 Tumours of the breast 29. myoepithelial cells in fibroadenomas,{546}1. In general, pure mucinousmucin that appears either cystic (muci-along with mast cells within the myxoidcarcinomas have a favourable prognosisnous cystadenocarcinoma) or solidstroma, helps in its recognition.{546}0. The ten-year survival(columnar cell mucinous carcinoma) toIn mucocoele-like lesions, the presenceranges from 80% {199,2922}9 to 100%the naked eye.of myoepithelial cells adhering to the {199,2922}8. Pure mucinous carcinomasstrips of cells floating in the lakes of have a far better prognosis than theICD-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 inence in survival rates noted in severalmucinous carcinoma are purely epithe-studies {199,2922}7. About 10% ofEpidemiologylial. 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 tocancer compared to 29% of those withtadenocarcinoma and two of the solida mucocoele is another helpful clue in the mixed type {199,2922}6. A similar dif-columnar cell type have been reporteddistinguishing mucocoele-like lesionsference also exists in the incidence of {199,2922}5. 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 {199,2922}4, while less {199,2922}3. Late distant metastases tadenocarcinomas are similar to com-than 70% {199,2922}2 are progesterone recep- may occur {199,2922}1.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 {199,2922}0.infarction due to mucin embolism to the The tumours vary in size from 0.8 to 19 cerebral arteries {1518,2378}9. 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 toand columnar cell mucinoustumour.pure mucinous carcinomas. Tumour cel-carcinomalularity has also been implicated in thatHistopathologycellular tumours are associated with a DefinitionMicroscopically, both of these variants,worse prognosis {1518,2378}8. The presence or A carcinoma composed of generally tall, are composed of tall columnar muci-absence of argyrophilic granules had nocolumnar cells with basally located bland nous cells with abundant intracyto-prognostic significance in two studies nuclei and abundant intracytoplasmicplasmic mucin and basal nuclei. In theAABBCDFig. 1.31 Mucinous carcinoma. A HypercellularFig. 1.32 A Mucinous cystadenocarcinoma. Papillary processes lined by mucinous columnar cells protudevariant with large clusters of densely packedinto cystic spaces. B Mucinous cystadenocarcinoma. Many of the invasive cells are immunoreactive tomalignant cells. B Hypocellular variant. Lakes ofCK34E12. 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 1.07Endocrine hormone related syndromesCriteria for the differential diagnosis of mucin producing carcinomas.are exceptionally rare. Of interest is theHistological type Location of mucin Growth patternIn situ component increase in the blood of neuroendocrinemarkers such as chromogranin A.Mucinous (colloid)Extracellular Clusters of cellsDuctalcarcinoma in mucus lakesMacroscopyNE breast carcinomas can grow as infil-MucinousIntracellular and Large cysts, columnarDuctal trating or expansile tumours. The consis-cystadenocarcinomaextracellular cells, epithelial tency of tumours with mucin productionstratification, papillae,is soft and gelatinous.solid areasColumnar mucinous Intracellular Round and convoluted Ductal Histopathologycarcinoma glands lined by a singleMost NE breast carcinomas form alveolarlayer of columnar cells structures or solid sheets of cells with atendency to produce peripheral palisad-Signet ring cell carcinomaIntracellular Isolated cells, cords, Mainly ing. However, they may present as differ-clusters lobularent subtypes, depending on the celltype, grade, degree of differentiation andpresence 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 {1518,2378}7.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 DCISSolid neuroendocrine carcinomadominantly bland appearing, columnar{1518,2378}6.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 polarityNeuroendocrine tumoursthat vary from spindle to plasmacytoidand eosinophilic cellular transformationand large clear cells {1518,2378}5 separatedis invariably present, as is invasion ofDefinitionby delicate fibrovascular stroma. Insurrounding stroma by most often thePrimary neuroendocrine (NE) carcino-some tumours, the nests are packedeosinophilic cells. Axillary node metas-mas of the breast are a group, whichinto a solitary, well defined to lobulatedtases occur in a quarter of mucinousexhibits 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 ofneuroendocrine markers in more than carcinoid tumour.round and convoluted glands lined by a50% 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 bynomas. 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 factorsis 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. Thetumour cells contain NE granules.Signet ring cell carcinomaEpidemiologyNE breast carcinomas represent aboutSmall cell / oat cell carcinomaICD-O code 8490/3 2-5% of breast carcinomas. Most patientsare in the 6th or 7th decades of life {1518,2378}4. ICD-O codesSignet ring cell carcinomas are of twoN e u roendocrine diff e rentiation alsoSmall cell carcinoma8041/3types. One type is related to lobular car-occurs in male breast carcinoma {1518,2378}3. Oat cell carcinoma8042/3cinoma and is characterized by largeintracytoplasmic lumina which com-Clinical features This is morphologically indistingui-press the nuclei towards one pole of theThere are no notable or specific diffe- shable from its counterpart in the lungcell {1518,2378}2. Their invasive component rences in presentation from other tumouron the basis of histological andhas the targetoid pattern of classicaltypes. Patients often present with a pal- immunohistochemical features {1518,2378}1.lobular carcinoma. The other type ispable nodule, which usually appears asThe 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 carcinomagrowth 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 chromogranin.be present. Areas of tumour necrosisapocrine 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 breast10-18% of breast carcinomas of thefact and nuclear streaming occur, but carcinomas {1518,2378}0, 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 areMammary small cell carcinoma can bespecial prognostic or therapeutic signif-frequently encountered. confused histologically with lobular car-icance {2060}9.cinoma. The negative immunoreactionLarge cell neuroendocrine for E-cadherin in lobular carcinomas, in Immunoprofilecarcinoma contrast to a positive reaction in 100%Argyrophilia demonstrated by Grimeliusof small cell carcinomas, is useful in the silver precipitation is a feature of neu-ICD-O code 8013/3 differential diagnosis {2060}8. roendocrine breast carcinomas. OnlyIt is also important to differentiate neu- darkly granulated cells should be con-These poorly differentiated tumours are roendocrine breast carcinomas from sidered as argyrophilic {2060}7.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 {2060}6. 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{2060}5. 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 {2060}4. 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 theinvading a dense collagenous stroma.Invasive breast cancer 33 32. evidence of neuroendocrine differentia- The presence of clear vesicles of pre- Invasive papillary carcinomation {2060}3. 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, inmucinous carcinomas {2060}2.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 scarcinomas of the breast probably in-nique {2060}1. About 50% of well orhave 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 {2060}0. In this{989}9. 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 basalinvasive papillary carcinomas will bealso been used and is expressed inmyoepithelial and the luminal epithelial reviewed. Invasive papillary carcinomas100% of small cell carcinomas of thecells, have been demonstrated in histo-comprise less than 1-2% of invasivebreast {989}8, whereas chromogranin A logically normal breast tissue surround- breast cancers, and are characterized byand synaptophysin are expressed ining infiltrating and in situ neuro e n-a relatively good prognosis {989}7.about 50% of such cases. In addition, docrine breast carcinomas {989}6.ICD-O code8503/3express thyroid transcription factor-1(TTF-1) {989}5. Prognosis and predictive factors Clinical featuresImmunodetection of pan-endocrineHistological grading is one of the mostInvasive 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. {989}4 noted a dis-not retain the specific antigen in theusing 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 {989}3, and in more than differentiated, 40% are moderately dif-invasive papillary carcinoma exhibit axil-50% of small cell carcinomas {989}2.ferentiated, and only 15% are poorly dif-lary lymphadenopathy suggestive ofExpression of somatostatin receptorsferentiated. Small cell NE carcinomasmetastatic 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 {989}1.reactive changes {989}0.has been demonstrated in endocrineMucinous differentiation is a favourable Mammographically, invasive papillarybreast carcinomas as well {2389}9. prognostic factor {2389}8.carcinoma is usually characterized byThe prognosis of primary small cell car- nodular densities which may be multiple,Ultrastructurecinomas of the breast depends on the and are frequently lobulated {2389}7.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 {2389}6. 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 insion of the disease at a follow up of 33 papillary carcinoma with invasion, andendocrine breast carcinomas {2389}5.to 48 months {2389}4. invasive papillary carcinoma {2389}3.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 {2389}2. Other inva-sive papillary carcinomas are grosslyindistinguishable from invasive breastcancers of no special type.HistopathologyOf the 1,603 breast cancers reviewed in ABthe NSABP-B04 study, 38 had papillaryFig. 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 {2389}1. Microscopically, is clearly papillary.expansile invasive papillary carcinomasare characteristically circumscribed,show delicate or blunt papillae, and show carcinoma {2389}0. 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 {564}9. While quite rare in itsand also may exhibit apical "snouting" of including 1 patient who died fro mpure 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 typicallysurvival data were similar to those mon types of invasive carc i n o m a sintermediate grade, and most tumoursreported in patients with pure tubular{564}8. It occurs in the same ageare histologic grade 2 {564}7. Tumour stro-and mucinous carcinomas in this study range as invasive ductal carcinoma ofma is not abundant in most cases, and {564}6. 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 betterly presents as a solid mass. Axillaryically, but usually are present in associat-survival in univariate analysis, butlymph node metastases are present ated DCIS. DCIS is present in more than tumour histology was not an independ- first presentation in 72-77% {564}5 .sively, has a papillary pattern. In rareanalysis {564}4. 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 10ulated outline due to the expansive modeproportion of each. Lymphatic vesselyears follow-up compared to patientsof 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 multivariateMicropapillary carcinoma consists of hol-(23%), but Paget disease of the nippleanalysis {564}3. low aggregates of malignant cells, whichwas not observed {564}2. 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 conta