Morphological and Molecular Typing of breast Cancer Ian Ellis Molecular Medical Sciences, University of Nottingham Department of Histopathology, Nottingham University Hospitals NHS Trust Histological Type Survival (%) Histological type Tubular Tubular variant Lobular Cribriform Papillary Mucinous Medullary Ductal NST Long term survivors n = 119 8 7 16 13 5 2 9 30 Consecutive series n = 1050 3 5 10 3 1 2 5 67 Short term survivors n = 200 0 0 5 0 0 0 4 83 Dixon et al, Br J Surg 1985; 72: 445-448 Nottingham Tenovus Primary Breast Cancer Study Histological type Excellent (>80% 10 year survival) Tubular, tubulo-lobular, invasive cribriform, mucinous Good (60-80% 10 year survival) Tubular mixed, alveolar lobular, mixed ductal NST & special type Moderate (50-60% 10 year survival) Medullary, atypical medullary, classical lobular, invasive papillary Poor (<50% 10 year survival) Ductal NST, solid lobular, lobular mixed, mixed ductal NST & lobular 1
Infiltrating Lobular Carcinoma Morphological features Composed of small regular cells identical to those seen in LCIS The cells are usually dissociated from each other and form single files and targetoid patterns around normal ducts and acini The following sub-types are recognised: classical, alveolar, solid, tubulo-lobular, mixed, pleomorphic NB 90% of the tumour must be of lobular pattern to be so classified NHS BSP EQA Scheme Subtype of invasive carcinoma Circulation NST Lobular Tubular Medullary Mucinous Mix Other Overall (No. cases) (66) (12) (9) (4) (9) (1) (2) (103) 902,911,912 0.18 0.09 0.24 - - 0.03 0.03 0.15 921,922,931 0.22 0.26 0.36 0.30-0.01 0.03 0.22 932,941,942 0.50 0.68 0.68 0.49 0.98 0.02 0.15 0.60 951,952,961 0.53 0.65 0.64 0.50 0.79 0.19 0.82 0.58 962,971,972 0.64 0.81 0.71 0.54 0.99 0.04 0.16 0.68 981.982,991 0.43 0.74 0.30 0.31 0.59 0.09 0.80 0.49 All 0.50 0.70 0.55 0.48 0.89 0.10 0.56 0.56 NHS BSP EQA Scheme Subtype of invasive carcinoma Circulation NST Lobular Tubular Medullary Mucinous Mix Other Overall (No. cases) (66) (12) (9) (4) (9) (1) (2) (103) 902,911,912 0.18 0.09 0.24 - - 0.03 0.03 0.15 921,922,931 0.22 0.26 0.36 0.30-0.01 0.03 0.22 932,941,942 0.50 0.68 0.68 0.49 0.98 0.02 0.15 0.60 951,952,961 0.53 0.65 0.64 0.50 0.79 0.19 0.82 0.58 962,971,972 0.64 0.81 0.71 0.54 0.99 0.04 0.16 0.68 981.982,991 0.43 0.74 0.30 0.31 0.59 0.09 0.80 0.49 All 0.50 0.70 0.55 0.48 0.89 0.10 0.56 0.56 Medullary Carcinoma Morphological features Sharply circumscribed soft, rounded tumour mass with pushing rather than infiltrating margin Interconnecting sheets of large, bizarre and pleomorphic carcinoma cells forming a syncytial network Stroma contains moderate to large numbers of lympho-plasmacytoid cells which do not intervene extensively between individual tumour cells In situ component insignificant Biological Importance of Tumour Type - Hereditary and Familial Breast Cancer Histopathological and genetic characteristics Invasive carcinomas of medullary type or with medullary features occur more frequently in familial and early-onset (< 35 years) cases - Rosen et al, 1992; Kollias et al, 1997 Medullary-like carcinomas are found significantly more frequently in BRCA-1 carriers than in BRCA-2 carriers and control populations - Marcus et al, 1996; Breast Cancer Linkage Consortium, 1997; Lakhani et al, 1998; Lakhani et al, 1999 2
Hereditary and Familial Breast Cancer Histopathological, immunohistochemical and genetic characteristics Breast cancers in patients with BRCA1 germline mutations are more often negative for ER, PgR and HER-2 and positive for p53 protein The combined morphologic and immunohistochemical data can be used to predict the risk of a young patient harbouring a germline mutation in BRCA1 Round 2002 2 Case NST Tubular Mucinous Lobular 16 ST 429 22 0 0 MIX 22 22 0 0 17 ST 21 0 0 425 MIX 18 9 0 27 20 ST 6 0 287 0 MIX 207 0 207 0 Classification of Histological Type Revised system with emphasis on concordance of recognition Pure Special Type: A classical example showing the hall mark histological features You would be confident that other pathologists would recognise this case as a pure special type The definitions used are as in the UK Guidelines and require 90% purity. Medullary Carcinoma: Worse concordance in EQA scheme BRCA 1 emerging data Medullary Like Carcinoma: Syncytial interconnecting masses Grade III Large vescicular nuclei, prominent nucleoli Lymphoid cell rich stroma Pushing/well defined margins In situ uncommon 3
NST with special type features (mixed): No Special Type: A tumour showing no or less than 50% special type characteristics A tumour heterogeneous in morphology with some special type characteristics (>50%, <90%) e.g. tubular differentiation. The special type should be identified as an additional feature Or have one or more characteristics of a special type but lack the full combination of features required for pure special type designation, for example a distinctive lobular infiltrative growth pattern with pleomorphic non lobular cell morphology. Rare Tumour Type: A tumour showing the features (Pure >90%) of a recognised but unusual tumour type Apocrine Invasive micropapillary Adenoid cystic Metaplastic Tubular carcinoma is known to have a favourable prognosis, but does this subtype represents a distinct type of breast carcinoma and does it behave like other low-grade luminal A type breast carcinomas? Rakha et al. J Clin Oncol 28:99-104 Assessed the clinicopathologic and molecular features and prognostic value of TC compared with grade 1 ductal carcinomas of the breast. Large well-characterized series of breast cancers 2,608 invasive carcinoma, unselected consecutive cases 212 Grade 1 ductal carcinomas 102 Tubular carcinomas TC more likely to be detected on mammographic screening, had smaller median size, and less frequently showed lymphovascular invasion. Compared with grade 1 ductal carcinoma, TC was associated with longer disease-free survival (213.25, P 0.001) and breast cancer specific survival (28.8, P 0.003). None of the patients with TC developed distant metastasis or died from the disease without an intervening recurrence as invasive carcinoma of different histologic type Rakha et al. J Clin Oncol 28:99-104 Rakha et al. J Clin Oncol 28:99-104 4
Conclusion The biologic behaviour of TC is excellent and is more favourable than that of grade 1 ductal carcinoma. Patients with TC may be at risk of developing second primary carcinomas in the contralateral breast, which may be of higher grade and poorer potential prognostic outcome. Patients with TC have a close to normal life expectancy, and as a consequence, adjuvant systemic therapy may not be justified in their routine management. Allele Loss in Breast Carcinoma 1p 1q 3p 6q 7q 8p 11p 11q 13q 16q 17p 17q 18q Rakha et al. J Clin Oncol 28:99-104 Allele Loss in Tubular Carcinoma E Cadherin Lobular Carcinoma High LOH: 3p 11q 13q 16q FHIT ATM? Man et al Cancer Research 1996, 56: 5484?Common Precursor LOH 16q C-erbB-2 & p53 Low Grade Carcinoma High Grade Carcinoma Other candidates: BRCA 1 17q Medullary BRCA 2 13q Tub & Lob 1q 3p 11q 13q 17q Tubular?Common Precursor E Cadherin LOH 16q Lobular Carcinoma Lobular Ductal Low Grade Carcinoma?Common Precursor E Cadherin 16q LOH 16q Lobular Carcinoma Low Grade Carcinoma C-erbB-2 & p53 High Grade Carcinoma C-erbB-2 & p53 High Grade Carcinoma 17q 5
Class 1?Common Precursor E Cadherin 16q LOH 16q Lobular Carcinoma Low Grade Carcinoma Class 2 C-erbB-2 & p53 17q High Grade Carcinoma Genome plots of the previous case FEA Cyclin D1 DCIS Cyclin D1 Cyclin D1 LN 6
Conclusion ER neg ER pos Luminal Type A lesions Luminal ck ER rich HER2 neg 16q del ADH/ Low Grade DCIS CCLs ALH/ LCIS Sorlie, et al. PNAS 2001 LOW GRADE NEOPLASIA FAMILY Cribriform TUBULAR G1 IDC TUBULOLOBULAR ILC Basal-like/ TN vs special types Mucinous Neuroendocrine Micropapillary Papillary Do special types of breast cancer have distinct molecular subtypes? Medullary Metaplastic Secretory Adenoid cystic Apocrine Pleomorphic lobular Acinic Reis-Filho et al., Histopathology 2006; Rakha E, Reis-Filho JS, Ellis IO. JCO, 2008; Lae et al. Mod Pathol 2008; Weiget et al., J Pathol 2008; Weigelt et al., Breast Cancer Res Treat 2009; Weigelt et al. Nat Rev Clin Oncol 2009 Special types of breast cancer are more homogeneous at the transcriptome level Luminal Basal-like Mol apocrine N=113 (11 special types of breast cancer) Operon arrays 24,650 genes TMAs 22 markers Mucinous A Classic ILC/ Tubular Mucinous B Neuroendocrine Micropapillary Adenoid cystic Medullary Metaplastic Pleomorphic ILC Apocrine Weigelt et al. J Pathol 2008 7
Special types vs molecular subtypes IDC Osteoclastic Luminal Neuroendocrine Mucinous Tubular HER2 Classic ILC Micropapillary Apocrine Molecular apocrine Pleomorphic ILC Adenoid cystic Basal-like Medullary Claudin low? Metaplastic Reis-Filho et al., Histopathology 2006; Rakha, Reis-Filho & Ellis. JCO, 2008; Weiget et al., J Pathol 2008; Weigelt et al., Breast Cancer Res Treat 2009; Weigelt et al. Mod Pathol 2009; Weigelt et al. Nat Rev Clin Oncol 2009; Weigelt et al. J Pathol 2010 Take home messages Each special type of breast cancer is more homogeneous at the molecular level Luminal phenotype: Tubular, classic lobular, neuroendocrine and mucinous Basal-like phenotype: Medullary, metaplastic, secretory and adenoid cystic Molecular apocrine and HER2 phenotype: Apocrine and pleomorphic lobular carcinomas The integrative subgroups have distinct copy number profiles The integrative subgroups have distinct clinical outcomes 8
The integrative subgroups have distinct clinical outcomes IntClust 2 ER positive, poor prognosis 11q13/14 cis-acting tumours CCND1 (11q13.3), EMSY (11q113.5), PAK1 (11q14.1), RSF1 (11q14.1) 11q13/14 amplicon(s) IntClust 3 Low genetic instability Luminal A predominant Good prognoses types (tubular, lobular) Conclusions Breast cancer classification system with clinical relevance will be based on: morphology phenotype molecular genetics Routine provision of prognostic and predictive information Gene profiles can provide prognostic and predictive information and some are validated for clinical use Gene profile methods can be translated to alternative simpler methods which appear equally effective Conclusions Next generation molecular methods are likely to provide greater insight Translation of research techniques / methods to routine clinical practice are to be expected Robust validated & standardised routine methods Quality assurance integrated into service provision Pathology has a central role - analytical & coordination Decision making support systems will be essential 9
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