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Hereditary Ovarian and Breast Cancer Syndrome

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Hereditary Ovarian and Breast Cancer Syndrome Hereditary Ovarian and Breast Cancer Syndrome C. Blake Gilks, MD Dept of Pathology Vancouver General Hospital University of British Columbia [email protected] The USCAP requires that anyone in a position to influenceACCME/Disclosures or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Drs.Gilks declares no conflict(s) of interest Molecular basis of HBOC Mutations in BRCA1 or BRCA2 account for most cases; result in abnormalities in homologous recombination Other genes may also be mutated: BRIP1, RAD51C, RAD51D, PALB2, BARD1, TP53 etc. Risk of Gyne Ca in HBOC Ovarian ca risk (lifetime) approximately 35-45% for BRCA1 and 13-23% for BRCA2, by age 70 Endometrial Ca risk? (apparently not) Ovarian Cancers in BRCA Mutation Carriers CONSISTENT: Epithelial carcinomas, more likely to be advanced stage, and high grade (grade 1 rarely reported). NOT borderline or mucinous VARIABLE: usually serous but proportion of endometrioid and clear cell, while low, varies CIMBA Study Data from ~6900 BRCA1 and BRCA2 mutation carriers Ovarian ca morphology same for BRCA1 and BRCA2 carriers More than 1000 ovarian carcinomas: 67% serous Mavaddat N et al. Cancer Epidemiol Biomarkers Prev 2012;21:134-47. CIMBA Study (con) Mucinous 1% Clear cell 1% Endometrioid 12% Other 19% Risch et al, Am J Hum Genet 2001;68:700 – 93% serous Shaw et al, Int J Gynecol Pathol 2002;21:407 – 100% serous Why this difference? “Careful study of ovarian tumors often reveals two or even three or more cell types.” Sternberg’s Textbook of Pathology (2007) HG serous clear cell mucinous Implications of mixed carcinomas being common ovarian carcinoma subtypes are closely related differences between subtypes are unlikely to be relevant in 2007 ovarian carcinoma subtypes are not reproducibly diagnosable by pathologists Implications of lack of reproducibility patients given different diagnoses in different centers results of studies on natural history provide conflicting results (e.g. clear cell carcinoma in NA/Europe vs Asia) impossible to move forward with good studies on molecular pathology or clinical trials of new treatments in 2016 What has changed? HG serous clear cell mucinous Evolution of ovarian carcinoma diagnosis Table 1 • Histotype diagnosis agreement between 2002 and 2014 (pathologist A): 52% • Histotype diagnosis agreement between pathologist A and B (2014): 98% It is now possible for pathologists to routinely sub- classify ovarian carcinomas into a small number of reproducible, clinically relevant groups Ovarian cancer histotypes Serous – high grade Serous – low grade Clear cell Endometrioid Mucinous Germline BRCA mutations are seen in > 20% of HGS cancers 26 BRCA1/2 germline mutation carriers 131 EOC 103 HGS 5 cases cases 12 9 Summary of Results 26/103 (25%) high grade serous carcinomas had germline BRCA1 or BRCA2 mutations Results from Australian Ovarian Cancer Study Group 1001 patients with non-mucinous ovarian ca 14.1% of patients had germline BRCA1/2 mutations 16.6% of patients with serous ca had germline BRCA mutations 22.6% of patients with high-grade serous ca had germline mutations Current BC recommendation “High-grade serous carcinoma of ovary/fallopianre. HBOCS tube/peritoneum is associated with a BRCA1/2 mutation in over 20% of patients. We recommend that this patient be referred to the BCCA Hereditary Cancer Program.” High-grade Serous Carcinoma -Chromosomal instability/aneuploidy (100%) -p53 mutations (>95%), BRCA loss (30-45%) Cyclin E amplification (20%) Prognosis of HGSC in patients with HBOC syndrome: 10 year overall survival 30% for non-carriers 25% for BRCA1 mutation carriers 35% for BRCA2 mutation carriers Candido-dos-Reis FJ et al. Clin Cancer Res 2015;21:652-7 Prevention Strategies HBOCS: RRBSO reduces deaths due to “ovarian” cancer by 80% (!?!) Case 1 Clinical History 33 year old, 10 cm complex pelvic mass, CA125 = 120 kU/L (norm ≤35) Laparotomy: left ovarian mass, 1 liter of bloody ascites, 3 cm nodule of right pelvic sidewall Frozen section diagnosis: granulosa cell tumor Differential Diagnosis High-grade serous carcinoma (WT1 -) Grade 3 endometrioid carcinoma De-differentiated carcinoma/Undifferentiated carcinoma (ER +, too cohesive/epithelial) Metastatic carcinoma (strong ER +, clinical) Less likely – small cell carcinoma of hypercalcemic type (SMARCA4 +), malignant sex cord-stomal tumor (inhibin and FOXL2 -) Immunohistochemistry 97% of HGSC are WT1 positive and 94% of HGSC are TP53 abnormal by IHC 10% of EC are WT1 positive and 14% are TP53 abnormal by IHC WT1- WT1+ TP53 normal/wild 286 EC (94%) 31 EC (27%) type 20 HGSC (6%) 84 HGSC (73%) TP53 48 EC (50%) 6 EC (0.5%) abnormal/aberrant 49 HGSC (50%) 1273 HGSC (99.5%) Final Diagnosis Grade 3 endometrioid carcinoma of the left ovary, with metastasis to left pelvic sidewall, cul-de-sac, and right pelvic sidewall Left fallopian tube, bladder peritoneum and omentum negative for malignancy Endometriosis in biopsy from right pelvic sidewall Abnormal MMR – PMS2 deleted Case 2 86 year old with PMB Endometrial Bx: grade 3 carcinoma TAHBSO performed Differential Diagnosis Primary fallopian tube ca metastatic to endometrium Primary endometrial ca metastatic to fallopian tube Independent primary tumors 60 cases of USC with fallopian tubes submitted in toto Fallopian tube mucosal involvement in 16 (27%) Bilateral tubal involvement in 9 of 16 (56%) Final Diagnosis Serous carcinoma of endometrium with secondary involvement of mucosa of right fallopian tube, cervix (with invasion of cervical stroma), deep myometrial invasion, and extensive lymphvascular invasion Conclusions Accurate diagnosis of ovarian carcinoma histotype can allow for histotype-specific referral of patients to the hereditary cancer program; patients with HGSC should be offered testing for HBOC Not all high-grade tubo-ovarian carcinomas are HGSC (but most are!) Fallopian tube mucosal involvement can be secondary/unrelated to HBOC REFERENCES: Hereditary Ovarian and Breast Carcinoma C. Blake Gilks 1. Kurman R, Carcangiu M, Herrington S, Young R, eds. WHO classification of tumors of female reproductive organs, 4th edn. Lyon, France: IARC; 2014. 2. Köbel M, Kalloger SE, Boyd N, et al. Ovarian carcinoma subtypes are different diseases: implications for biomarker studies. PLoS Med 2008; 5(12): e232. 3. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidomiol Biomarkers Prev 2012;21:134-47. 4. Köbel M, Bak J, Bertelsen BI, et al. Ovarian carcinoma histotype determination is highly reproducible, and is improved through the use of immunohistochemistry. Histopathology. 2014;64(7):1004-1013. 5. Schrader KA, Hurlburt J, Kalloger SE et al. Germline BRCA1 and BRCA2 mutations in ovarian cancer: utility of a histology-based referral strategy. Obstet Gynecol 2012;129:235-40. 6. Lu FI, Gilks CB, Mulligan AM, et al. Prevalence of loss of expression of DNA mismatch repair proteins in primary epithelial ovarian tumors. Int J Gynecol Pathol. 2012;31:524-531. 7. Mackenzie R, Talhouk A, Eshragh S, et al. Morphologic and Molecular Characteristics of Mixed Epithelial Ovarian Cancers. Am J Surg Pathol. 2015;39:1548-1557. 8. McAlpine JN, Porter H, Köbel M, et al. BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma. Mod Pathol. 2012;25:740-750. 9. Ali RH, Seidman JD, Luk M, et al. Transitional cell carcinoma of the ovary is related to high-grade serous carcinoma and is distinct from malignant brenner tumor. Int J Gynecol Pathol. 2012;31:499-506. 10. Aysal A, Karnezis A, Medhi I, et al. Ovarian endometrioid adenocarcinoma: incidence and clinical significance of the morphologic and immunohistochemical markers of mismatch repair protein defects and tumor microsatellite instability. Am J Surg Pathol. 2012;36:163-172. 11. Tafe LJ, Garg K, Chew I, et al. Endometrial and ovarian carcinomas with undifferentiated components: clinically aggressive and frequently underrecognized neoplasms. Mod Pathol. 2010;23:781-789. 12. Silva EG, Deavers MT, Bodurka DC, et al. Association of low-grade endometrioid carcinoma of the uterus and ovary with undifferentiated carcinoma: a new type of dedifferentiated carcinoma? Int J Gynecol Pathol. 2006;25:52-58. 13. Köbel M, Reuss A, Bois AD, et al. The biological and clinical value of p53 expression in pelvic high-grade serous carcinomas. J Pathol. 2010;222:191-198. 14. Lee S, Piskorz AM, Le Page C, et al. Calibration and Optimization of p53, WT1, and Napsin A Immunohistochemistry Ancillary Tests for Histotyping of Ovarian Carcinoma: Canadian Immunohistochemistry Quality Control (CIQC) Experience. Int J Gynecol Pathol. 2015. 15. Candido-dos-Reis FJ, Song H, Goode EL et al. Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer. Clin Cancer Res 2015;21:652-7. 16. Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol 2012;30:2654-63. 17. Etemadmoghadam D, Weir BA, Au-Yeung G et al. Synthetic lethality between CCNE1 amplification and loss of BRCA1. PNAS 2013;110:19489-94. 18. Norquist BM, Harrell MI, Brady ME et al. Inherited mutations in women with ovarian carcinomas. JAMA Oncol 2015; Dec 30 epub ahead of print. .
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