Pathology in cancer genetics

Pathology in cancer genetics Indirect marker of a genetic profile of tumour. Risk assessment and management. 27/03/2008 22:48:27 Sameer Jhavar.The Institute of Cancer Research, UK 1 Pathology in cancer genetics Genetic cause (Hereditary)/ Sporadic Breast cancer Ovarian cancer Bowel cancer Kidney cancer 27/03/2008 22:48:27 Sameer Jhavar.The Institute of Cancer Research, UK 2 Breast cancer: Medullary histology is significantly more common in BRCA1 associated tumours • INTRADUCT CARCINOMA: PAPILLARY; COMEDO; CRIBRIFORM; • • INFILTRATING DUCTAL CARCINOMA; PAPILLARY; NEUROENDOCRINE (80% of all invasive breast cancers) LOBULAR CARCINOMA IN SITU • • • • • • INFILTRATING LOBULAR CARCINOMA; MUCINOUS; SIGNET RING CELL (10% of all invasive breast cancers) SECRETORY CARCINOMA CARCINOMA IN PREGNANCY SIGNET RING CELL CARCINOMA MUCIN SECRETING CARCINOMA IDC WITH CHONDROID METAPLASIA • • • • • • • • • • • • MEDULLARY CARCINOMA (5-10% of invasive cancers) TUBULAR CARCINOMA CARCINOMA WITH SARCOID REACTION; WITH GRANULOMAS; WITH SQUAMOUS DIFFERENTIATION; SCC WITH PSEUDOSARCOMATOUS STROMA SCC WITH SPINDLE CELL STROMA LEIOMYOSARCOMA NEURILEMMOMMA SARCOMA (MFH) LYMPHOMA LEUKEMIC INFILTRATE SARCOMA (HEMAMGIOPERICYTOMA) ANGIOSARCOMA 27/03/2008 22:48:27 Sameer Jhavar.The Institute of Cancer Research, UK 3 Breast cancer: Medullary histology is significantly more common in BRCA1 associated tumours. • Medullary breast cancers: 13-24% have BRCA1 mutations • Non-medullary histology: 6% had BRCA1 mutations • In BRCA1 carriers—up to 20% breast cancers are of Medullary histology. •In BRCA2 carriers– up to 3% breast cancers are of Medullary histology. Bisinger F et al, Can. Res, 1998, Eisinger F et al, JAMA, 1998 and Malone K et al JAMA,1998 27/03/2008 22:48:27 Sameer Jhavar.The Institute of Cancer Research, UK 4 Breast cancer: Medullary histology is significantly more common in BRCA1 associated tumours a well-circumscribed mass mammographically. young women (younger than 35 years old) with breast cancer. finding of high-grade tumour cells arranged in a syncytial pattern with a pushing border. This pushing border is surrounded by a prominent lymphoplasmacytic infiltrate. If the tumour lacks these features, or has an invasive border or extensive necrosis, it may be better characterized as an atypical medullary carcinoma. 27/03/2008 22:48:27 Sameer Jhavar.The Institute of Cancer Research, UK 5 Breast cancer: Medullary histology is significantly more common in BRCA1 associated tumours 27/03/2008 22:48:27 Sameer Jhavar.The Institute of Cancer Research, UK 6 Breast cancer: Medullary histology is significantly more common in BRCA1 associated tumours 27/03/2008 22:48:27 Sameer Jhavar.The Institute of Cancer Research, UK 7 BRCA1 associated breast tumours: pathology in comparison to sporadic tumours BRCA1 Invasive High grade ER-ve, PR-ve, Her2-ve, p53 +ve, CK5/6, 14, 17 +ve (Derived from basal layer of the mammary epithelium) High mitotic rates Low mitotic rates Non-BRCA1 Less invasive, less extent of pushing margins Low grade Nuclear pleomorphism + Solid sheets of cells Necrosis + Lymphocytic infiltrate ( LI) + Nuclear pleomorphism less Less extent of solid sheets of cells Necrosis Less LI Invasive lobular type more common 27/03/2008 22:48:27 Sameer Jhavar.The Institute of Cancer Research, UK 8 BRCA2 associated breast tumours: pathology in comparison to sporadic tumours & genotypephenotype correlation • • • • More heterogeneous, 999del5 (Icelandinc founder mutation) associated Breast cancer-Less tubule formation, more nuclear pleomorphism, higher mitotic rates. BRCA2 associated breast cancers--: Continuous pushing margins, fewer tubules, lower mitotic counts, Lobular and tubulolobular histology. 27/03/2008 22:48:27 Sameer Jhavar.The Institute of Cancer Research, UK 9 Ovarian cancers • • • • SEROUS CYSTADENOCARCNOMA MUCINOUS CYSTADENOCARCINOMA MESODERMAL MIXED TUMOURS CLEAR CELL OR HYPERNEPHROID CARCINOMA • • • • • • • • • • • • • • • • • • • • • ENDOMETROID CARCINOMA ENDODERMAL SINUS (MESONEPHRIC) TUMOUR/ YOLK SAC TUMOUR---GERM CELL BRENNER TUMOUR; BENIGN AND MALIGNANT DYSGERMINOMA (LIKE SEMINOMA IN MALES)----- GERM CELL BENIGN CYSTIC TERATOMA IMMATURE/ MALIGNANT TERATOMA BENIGN CYSTIC TERATOMA (WITH MALIGNANT TRASNFORMATION) GRANULOSA CELL TUMOUR---SEX CORD STROMAL TUMOUR THECA-GRANULOSA CELL TUMOUR----SEX CORD STROMAL TUMOUR SERTOLI CELL TUMOUR (ARRHENOBLASTOMA; ANDROBLASTOMA)----SEX CORD STROMAL LEYDIG CELL TUMOUR----SEX CORD STROMAL THECOMA FIBROTHECOMA FIBROMA FIBROSARCOMA HILUS CLL TUMOUR BURKITTS LYMPHOMA SECONDARY TCC SECONDARY LEIOMYOSARCOMA KRUKENBERGS SECONDARY CARCINOID 27/03/2008 22:48:27 Sameer Jhavar.The Institute of Cancer Research, UK 10 Ovarian cancers • Serous tumours: resemble epithelium of fallopian tube. (BRCA ASSOCIATED): 30% OF ALL OVARIAN CANCERS • Mucinous tumours: mimic mucosa of the endocervix. (HNPCC ASSOCIATED): (10% OF ALL OVARIAN CANCERS) • Endometrioid carcinoma: similar to glands of the endometrium. (HNPCC ASSOCIATED) (20% OF ALL OVARIAN CANCERS) 27/03/2008 22:48:27 Sameer Jhavar.The Institute of Cancer Research, UK 11 Ovarian cancers NO. (%) POSITIVE FOR MUTATIONS IN HISTOLOGY BRCA1 39 (7.6) 2 (2.1) 0 (0) 0 (0) 0 (0) BRCA2 Either Invasive (n = 515) Serous (n = 341) Endometrioid (n = 94) Mucinous (n = 44) Other (n = 36) Borderline (n = 134) 27/03/2008 22:48:27 21 (4.1) 60 (11.7) 2 (2.1) 0 (0) 0 (0) 0 (0) 4 (4.3) 0 (0) 0 (0) 0 (0) Risch H et al, 2001, Am J Hum Gen. 37 (10.9) 19 (5.6) 56 (16.4) Sameer Jhavar.The Institute of Cancer Research, UK 12 Ovarian cancer: BRCA1 carriers: >90% cancers are of serous cystadenocarcinoma histology. Epithelial ovarian, papillary serous peritoneal primary, fallopian tube cancer: BRCA associated. Mucinous epithelial (could be HNPCC; NOT BRCA associated): ovarian cancer at age <30 years may be more likely to be due to HNPCC mutations (MSH2 and MLH1) and not due to BRCA1/2. Germ cell tumours of the ovary (NOT ASSOCIATED WITH BRCA): Living affected relative many years after a reported diagnosis could be an indication of the more curable non-epithelial ovarian cancer. 27/03/2008 22:48:27 Sameer Jhavar.The Institute of Cancer Research, UK 13 ―stomach‖, ―womb‖, ―abdominal‖, cancers should raise the suspicion of ovarian cancer. Strenuous attempts to confirm the diagnosis of ovarian cancer should be made. Not associated with BRCA1 and BRCA2 mutations mucinous borderline epithelial ovarian cancer papillary serous primary peritoneal cancers fallopian tube cancer very young onset, mucinous or endometroid ovarian cancer . More likelihood of synchronous endometrial cancer. PJ syndrome and testicular feminisation syndrome Associated with Gorlins syndrome sex cord tumours (granulosa cell, theca-granulosa cell, sertoli cell (arrhenoblastoma; androblastoma), leydig cell tumor. ovarian fibromas Associated with BRCA1 and BRCA2 mutations Associated with HNPCC 27/03/2008 22:48:27 Sameer Jhavar.The Institute of Cancer Research, UK 14 Bowel cancer: inherited syndromes predisposing to CRC Disease FAP HNPCC Juvenile polyposis Cowdens disease PJS Hereditary mixed polyposis syndrome Hereditary colorectal adenoma and carcinoma sequence Hyperplastic polyposis MYH polyposis Colorectal lesion polyps (>100); CRC polyps (few); CRC Polyps; CRC polyps polyps; CRC Polyps; CRC Pathology of polyp adenomatous adenomatous hamatomatous hamatomatous hamatomatous Uvenile polyps, hyperplastic polyps, adenomatous polyps, mixed polyps Adenomatous polyps, serrated adenoma, Gene involved APC MLH1, MSH2, MSH3, PMS1 BMP2R, SMAD4, PTEN STK11 LOCALISED TO UNKNOWN 6q CRAC1 Polyps; CRC polpys Serrated adenomas, hyperplastic polyps, mixed polyp UNKNOWN Similar picture to classical FAP MYH 27/03/2008 22:48:27 Sameer Jhavar.The Institute of Cancer Research, UK 15 Hamartomatous polyps JPS (BMP2R, SMAD4) Unilobulated, smooth Gross infiltration of the lamina propria by chronic inflammatory cells Cystic dilatation of glandular type structures lined by normal appearing columnar epithelium is pathognomonic PJS (STK11) Inflammatory response not seen. Cystic dilatation not seen Hypertrophy or hyperplasia of the smooth muscle layer occurs extending in a tree like fashion into the superficial epithelial layer. 27/03/2008 22:48:27 Sameer Jhavar.The Institute of Cancer Research, UK 16 Life time risk of other cancers in HNPCC Cancer Colorectal cancer (men) Lifetime risk (%) 65-80 Colorectal cancer (women) Endometrial Ovarian Gastric Urinary tract Renal cell Bile duct/gall bladder Small bowel 30-70 40-60 4-12 2-13 4-6 3 2 4-7 27/03/2008 22:48:27 Sameer Jhavar.The Institute of Cancer Research, UK 17 Pathology of other cancers in HNPCC Cancer Colorectal cancer (men) Lifetime risk (%) 65-80 Histology in HNPCC Right sided, Mucinous, poorly diff, solid cribriform growth, signet ring cell type cancer, necrosis, marked lymphocytic infiltration, lymphoid aggregation at tumour margins. MLH1 associated = can be any including Endometrioid type MSH2 associated = nonendometrioid type Papilary epithelial, Serous, mucinous, endometrioid Intestinal type TCC TCC Histology in other genetic condition Colorectal cancer (women) Endometrial 30-70 40-60 Classical endometrioid ―undiffereniated‖ Ovarian Gastric Urinary tract Renal cell Bile duct/gall bladder Small bowel 4-12 2-13 4-6 3 2 4-7 serous Clear cell cancer: VHL Papillary tpe 1: HPRC Underlined features form part of the Bethesda criteria for MSI testing 27/03/2008 22:48:27 Sameer Jhavar.The Institute of Cancer Research, UK 18 Kidney cancers: Clear cell (hereditary and sporadic), papillary (hereditary and sporadic) Inherited mutations in MET oncogene are nearly always associated with papillary renal cell cancer. Inherited mutation in VHL tumour suppressor gene with clear cell renal cancer. Hereditary Papillary renal cell cancer (AD, multiple bilateral Type 1 papillary renal tumours): c-met oncogene mutations and 95% duplication of chromosome 7q Sporadic Papillary renal cell cancer: 13% have c-met oncogene mutations and 75% with duplication of 7q VHL disease associated with mutations in VHL gene Familial clear cell renal cancer: chromosome 3p translocation Sporadic clear cell renal cancers: 57% VHL mutations and 98% LOH 27/03/2008 22:48:27 Sameer Jhavar.The Institute of Cancer Research, UK 19