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WHO classification of breast tumours 2019

Dr Puay Hoon Tan Singapore General Hospital Singapore Email: [email protected]

Hong Kong Division of the International Academy of Pathology (IAP) 30th Anniversary Scientific Congress Published, November 2019

Online version https://tumourclassification.iarc.who.int/

2 WHO Classification of Tumours - ONLINE

Now available at: tumourclassification.iarc.who.int

Instant access to the following books:

5th edition 4th edition Digestive Tumours Eye Tumours Breast Tumours Skin Tumours and Bone Endocrine Tumours Head and Neck Tumours Central Nervous System - update

Special subscription rate of 100 Euros This new, easy to use resource provides: ▪ Interactive database ▪ Access to whole slide images ▪ Ability to search for information through all the books ▪ Easy access to reference information ▪ Quick access to many, soon to be all, of the books in the series WHO Classification of Tumours ~ ‘Blue Books’ • Essential tool for standardising diagnostic practice. • Allows translation of research into clinical utility. • Diagnostic criteria and standards are underpinned by evidence evaluated and debated by experts in the field. • About 200 authors and editors participate in each book.

Foreword, Dr Ian Cree, Breast blue book 2019 WHO Classification of Tumours ~ ‘Blue Books’ ▪ Localisation • Tumour types common to ▪ Clinical features multiple systems are ▪ Epidemiology described together ~ ▪ Aetiology haematolymphoid, ▪ Pathogenesis mesenchymal tumours, ▪ Macroscopic appearance genetic tumour syndromes. ▪ Histopathology • Benign to malignant lesions. ▪ Cytology ▪ Diagnostic molecular • Systematic approach with pathology tumours described in a ▪ Essential and desirable uniform manner. diagnostic criteria • Standardised modular ▪ Staging arrangement. ▪ Prognosis & prediction

Foreword, Dr Ian Cree, Breast blue book 2019 WHO Classification of Breast Tumours 2019 • 2nd volume of the WHO 5th series of tumour classifications • Led by Dr Ian Cree, Head WHO Classification of Tumours Group, IARC • Standing Editorial Board • Expert Editorial Board • Includes surgeon, radiologist • Contributors ~ 154 • Website ~ https://tumourclassification.iarc.who.int Countries No. of Contributors Australia 9 Austria 2 Belgium 6 Brazil 4 Canada 6 China 6 France 3 Germany 5 Hungary 2 Italy 5 Japan 14 Lebanon 1 Netherlands 8 Portugal 2 Qatar 1 Republic of Korea 1 Singapore 5 Spain 3 Switzerland 2 United Kingdom 14 USA 55 Total: 154 Houston Texas USA WHO breast tumour classification 2019 ~ table of contents I ▪ Introduction to tumours of the breast ▪ Epithelial tumours of the breast • Benign epithelial proliferations and precursors • Usual ductal hyperplasia • Columnar cell lesions including flat epithelial atypia • Atypical ductal hyperplasia • Adenosis and benign sclerosing lesions • Sclerosing adenosis • adenosis and • Microglandular adenosis • Radial scar/complex sclerosing lesion • • Tubular adenoma • Lactating adenoma • Ductal adenoma • Epithelial-myoepithelial tumours • Pleomorphic adenoma • Adenomyoepithelioma • Malignant adenomyoepithelioma WHO breast tumour classification 2019 ~ table of contents II ▪ Epithelial tumours of the breast (continued) • Papillary • Intraductal • Papillary ductal in situ • Encapsulated papillary carcinoma • Solid papillary carcinoma (in situ and invasive) • Invasive papillary carcinoma ▪ Invasive breast carcinoma NST • Non-invasive lobular neoplasia ▪ Microinvasive carcinoma • Atypical lobular hyperplasia ▪ Invasive ▪ Tubular carcinoma • Lobular carcinoma in situ ▪ Cribriform carcinoma • in situ ▪ Mucinous carcinoma • Invasive breast carcinoma ▪ Mucinous ▪ Invasive micropapillary carcinoma ▪ Carcinoma with apocrine differentiation ▪ Metaplastic carcinoma WHO breast tumour classification 2019 ~ table of contents III

▪ Epithelial tumours of the breast (continued) • Rare and salivary -type tumours ▪ ▪ ▪ Secretory carcinoma ▪ ▪ Polymorphous ▪ Tall cell carcinoma with reversed polarity

• Neuroendocrine neoplasms ▪ Neuroendocrine tumour ▪ Neuroendocrine carcinoma WHO breast tumour classification 2019 ~ table of contents IV

▪ Fibroepithelial tumours and hamartomas of the breast • Hamartoma • • Phyllodes tumour ▪ Tumours of the • Syringomatous tumour • Nipple adenoma • Paget disease of the breast WHO breast tumour classification 2019 ~ table of contents V Mesenchymal tumours of the breast

▪ Vascular tumours ▪ Peripheral nerve sheath tumours • Haemangioma • Schwannoma • Angiomatosis • Neurofibroma • Atypical vascular lesions • Granular cell tumour ▪ • Postradiation angiosarcoma tumours • of the breast • • Primary angiosarcoma of the ▪ Adipocytic tumours breast • ▪ Fibroblastic and • Angiolipoma myofibroblastic tumours • • ▪ Other mesenchymal tumours and • Myofibroblastoma tumour-like conditions • Pseudoangiomatous stromal • Desmoid hyperplasia • Inflammatory myofibroblastic tumour WHO breast tumour classification 2019 ~ table of contents VI

▪ Haematolymphoid tumours of the breast • Lymphoma • Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) • Follicular lymphoma • Diffuse large B-cell lymphoma • Burkitt lymphoma • Breast implant-associated anaplastic large cell lymphoma ▪ Tumours of the male breast • Gynaecomastia • Carcinoma in situ • Invasive carcinoma ▪ Metastases to the breast WHO breast tumour classification 2019 ~ table of contents VII ▪ Genetic tumour syndromes of the breast • BRCA1/2-associated hereditary breast and ovarian cancer syndrome • Cowden syndrome • Ataxia-telangiectasia • Li-Fraumeni syndrome, TP53-associated • Li-Fraumeni syndrome, CHEK2-associated • CDH1-associated • PALB2-associated • Peutz-Jeghers syndrome • Neurofibromatosis type 1 • Polygenic component of breast cancer susceptibility Scope ▪ Invasive carcinoma • Mitotic count per mm2 • Carcinoma with medullary features • Invasive carcinoma NST with basal-like and medullary features • Stromal response & tumour microenvironment • Rare cancers re-allocated ▪ Neuroendocrine tumours ▪ Fibroepithelial tumours ▪ New entities Invasive carcinoma Microscope field diameter and corresponding field area for mitotic count scores Mitotic count

• Conversion of mitotic count from the traditional denominator of 10 high-power fields to a defined area expressed in mm2. • This serves to standardize the true area over which mitoses are enumerated, because different microscopes have high-power fields of different sizes. • Also helpful for reporting using digital systems. • Facilitates future AI models of mitotic counting. Mitotic count • Challenges in conversion! • x mitoses/10hpf ≠ x mitoses/mm2. • If the microscope field diameter (HPF) is 0.5mm ~ • If the microscope field diameter (HPF) is 0.6mm ~

Field diameter Field area Area of 10 HPF Mitotic count Mitotic count of HPF (mm) (mm2) (mm2) /10HPF /mm2 0.5 0.196 1.96 7 3.57

0.6 0.283 2.83 10 3.53 “”

▪ Well circumscribed tumour. ▪ Histologic criteria: • Syncytial growth pattern (> 75%). • Absence of glandular structures. • Diffuse lymphoplasmacytic infiltrate, moderate to marked. • Nuclear pleomorphism, moderate to marked. • Complete histological circumscription. (syncytial growth pattern plus 2 or 3 other criteria: atypical medullary carcinoma) Poor interobserver reproducibility Carcinoma with medullary features ~ WHO 2019 approach ▪ 2012 ~ medullary carcinoma, atypical medullary carcinoma and invasive carcinoma no special type (NST) with medullary features were grouped together under ‘ with medullary features’, in recognition of their common characteristics of an immune enriched microenvironment, basal-like expression and occasional association with BRCA1 mutations. ▪ 2019 ~ these tumours are subsumed as a combined morphologic subset under ‘invasive carcinoma NST with medullary pattern’, regarding them as part of the spectrum of TIL-rich breast cancers with basal-like molecular profiles. Invasive carcinoma NST with medullary pattern Invasive carcinoma NST with medullary pattern Stromal microenvironment ~ response patterns ▪ Cellular fibroblastic proliferation. ▪ Scant . ▪ Marked hyalinization. ▪ Foci of elastosis. ▪ Fibrotic focus ~ • Area of exaggerated reactive stromal formation larger than 1mm within the tumour with or without coagulative necrosis • More aggressive behaviour ▪ Tumour infiltrating lymphocytes (TILs). ▪ Immune infiltrate in tumours – mononuclear lymphoid cells infiltrating the tumour and its stroma, reflecting the host immune response against tumour cells. ▪ High numberTumour of TILsinfiltrating associated with improved lymphocytesoutcome. ~ ▪ High number of TILs associated with better response to neoadjuvant therapy in triple negative and HER2 positive breast cancer.

Scoring of TILs in invasive breast cancer • Use H&E sections, with evaluation at 200x (20x ocular, 10x eyepiece) or 400x (40x ocular, 10x eyepiece) microscope magnification. • Score TILs in the stroma between areas of carcinoma. • All mononuclear cells (lymphocytes and plasma cells) are scored. • Stromal TILs scored as a % of stromal areas alone. • Peri-tumoural follicular aggregates and tertiary lymphoid structures should not be included in the assessment. • If TILs are heterogeneously distributed, an average (avoid hotspots) is reported. WHO 2019 Rare cancers classified under invasive breast carcinoma NST • Medullary • Oncocytic • Lipid-rich Tumours considered morphological • Glycogen-rich patterns of IBC-NST, 90% purity rule • Clear cell does not apply • Sebaceous • Neuroendocrine differentiation • Carcinoma with osteoclast-like stromal giant cells • Pleomorphic • Choriocarcinomatous • Melanocytic Oncocytic carcinoma

WHO 2012

Lipid rich carcinoma

Glycogen rich carcinoma

PAS

3 PASD 3 Sebaceous carcinoma

WHO 2012

Carcinoma with osteoclast-like stromal cells

Pleomorphic carcinoma Choriocarcinomatous carcinoma

Melanotic carcinoma (S100, SOX10, melanA, HMB45 positive) Neuroendocrine neoplasms Neuroendocrine neoplasms

▪ Proposal by IARC and WHO to adopt the term ‘neuroendocrine ’ to encompass all tumour classes with predominant neuroendocrine differentiation, including both well-differentiated and poorly differentiated forms. Mod Pathol 2018;12:1770-86 ▪ Morphology & neuroendocrine expression are key features. ▪ Acknowledgment that true primary NEN of the breast are rare and poorly defined, apart from uncommon cases of small cell carcinoma. ▪ Neuroendocrine tumours in the breast are malignant by definition. Neuroendocrine neoplasms

▪ Definitions in the breast vary. ▪ Significant overlap between NEN and other breast carcinomas showing NE differentiation. ▪ Solid papillary carcinoma, hypercellular mucinous carcinoma ~ distinct breast neoplasms that express NE markers ~ not classified as NET/NEN. ▪ Invasive carcinoma NST with NE differentiation diagnosed if NE histological features and NE marker expression are not distinct or uniform enough to classify the tumour as NEN. Tumours with Comments neuroendocrine expression, terminology (WHO/IARC) Neuroendocrine tumour, well ▪ Resembles grade 1 (-like) and grade 2 differentiated (atypical carcinoid-like) tumours, regarded as carcinoma in the breast ▪ Need to exclude metastasis Neuroendocrine tumour, poorly ▪ Small cell neuroendocrine carcinoma differentiated ▪ Large cell neuroendocrine carcinoma

Distinct breast cancer types with ▪ Solid papillary carcinoma (in situ and invasive) frequent neuroendocrine ▪ Mucinous carcinoma (hypercellular) differentiation Invasive breast carcinoma with ▪ Classify based on morphology of the breast variable neuroendocrine carcinoma, rather than as a neuroendocrine differentiation tumour ▪ Do not routinely perform neuroendocrine stains Small cell carcinoma of the breast

4 0 Small cell carcinoma of the breast ~ synaptophysin

4 1 Fibroepithelial tumours Fibroepithelial tumours

• Pathogenesis ~ • MED12 mutations in about 60% of (codon 44 of exon 2). • MED12, TERT promoter, RARA, FLNA, SETD2, TP53, Rb1, EGFR, IGF1R mutations in phyllodes tumours. A proposed model of the genomic progression of breast fibroepithelial tumours

TERT Well differentiated liposarcoma in phyllodes tumour ▪ Previously considered as a malignant heterologous element indicating malignant grade. ▪ WHO 2019 ~ consensus that well differentiated liposarcoma in the breast has no metastatic potential and hence insufficient as a sole criterion to warrant malignant grade. ▪ Abnormal adipocytes lack MDM2 or CDK4 amplifications in contrast to extramammary well differentiated liposarcoma. ▪ Need to evaluate other stromal parameters for grading. New entities ~ ▪ Mucinous cystadenocarcinoma ▪ Tall cell carcinoma with reversed polarity

4 6 Mucinous cystadenocarcinoma

• Invasive breast carcinoma characterized by cystic structures lined by tall columnar cells with abundant intracytoplasmic mucin, resembling pacreatobiliary or ovarian mucinous cystadenocarcinoma. • Asian, postmenopausal. • Well circumscribed cystic mass with gelatinous contents. • No myoepithelial cells; DCIS may be present in surrounding tissue. • Usually triple negative or occasionally HER2 positive; CK7 positive, CK20, CDX2 negative. • Prognosis is usually good, with no reported distant metastases.

47 Tan PH, Sahin AA. Atlas of Differential Diagnosis in Breast Pathology, Springer 2017 WHO 2019 Tall cell carcinoma with reversed polarity: Old terminology ~ Solid papillary breast carcinoma resembling the tall cell variant of papillary thyroid carcinoma; Solid papillary carcinoma with reverse polarity

• Unrelated to papillary thyroid carcinoma. • Low grade triple negative invasive disease. • IDH2 mutations described in more than 75% of cases. • Specific antibody IDH1/2 can highlight the mutation (Mod Pathol 2018; 31:1367-80). • Favourable prognosis. Alsadoun et al. Modern Pathology (2018) 31:1367–1380

51 Courtesy of Dr Wentao Yang Topic Status WHO 2012 Change in WHO 2019 *Mitotic counts Expressed per 10 HPF Given per mm2 *Carcinoma with medullary Separate entity Now regarded as TIL-rich IBC- features NST *Oncocytic, lipid-rich, Separate entities Now regarded as rare variants glycogen-rich, clear cell, of IBC-NST sebaceous, pleomorphic, melanotic, choriocarcinomatous carcinomas, carcinoma with osteoclast-like giant cells Inflammatory, bilateral and Separate entities Now recognised as distinct non-synchronous breast clinical presentations rather carcinomas than special subtypes Lobular carcinoma in situ Classic, pleomorphic, Classic, pleomorphic, florid apocrine types types *Neuroendocrine neoplasms True primary neuroendocrine neoplasms are typed as NET, SCNEC, LCNEC

Summary of major changes within the new classification of tumours of the breast, Histopathology 2020;77:181-185 Topic Status WHO 2012 Change in WHO 2019 *Invasive breast carcinoma Overridden by morphological with neuroendocrine tumour type (NST, mucinous, differentiation solid papillary) *Well-differentiated Histological criterion of No longer a histological liposarcoma in phyllodes malignancy by itself criterion of malignancy by tumours itself *Mucinous Not recognised Recognised as new entity cystadenocarcinoma *Breast tumour resembling Not mentioned Now grouped as tall cell the tall cell variant of carcinoma with reversed papillary thyroid carcinoma polarity with reverse polarity Periductal stromal tumour Separate fibroepithelial Variant of phyllodes tumour entity Mesenchymal tumours, Covered in dedicated chapters haematolymphoid tumours and genetic tumour syndromes

Summary of major changes within the new classification of tumours of the breast, Histopathology 2020;77:181-185

Summary • Key changes in 2019 WHO classification of breast tumours. • Aim to improve and standardise histological criteria for diagnosis. • New information included since the 4th series (2012). • Website contains whole slide images. • Blue books available since November 2019. • International collaboration on (breast) cancer reporting (ICCR) ongoing (DCIS, invasive cancer, lymph node, post- neoadjuvant chemotherapy datasets). Buddha Tooth Relic Boat Quay Temple

Singapore

Little India Gardens by the Bay Invasive cribriform carcinoma with osteoclastic giant cells

Tan PH, Sahin AA. Atlas of Differential Diagnosis in Breast Pathology. Springer 2017 Pleomorphic carcinoma

SGH Breast Pathology Course 2019 Case 6