The Whys OAP Annual Meeting CCO Symposium September 20. Immunohistochemical Assessment Dr. Terence Colgan Mount Sinai Hospital, Toronto

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1 Immunohistochemical Assessment of Mismatch Repair Proteins in Endometrial Cancer: The Whys and How Terence J. Colgan, MD Head of Gynaecological Pathology, Mount Sinai Hospital, University of Toronto, Toronto. Objectives and Disclosures.. Objectives: Describe the value of performing IHC analysis of mismatch repair proteins (IHC-MMR) in endometrial cancer, Evaluate, interpret, and report a panel of IHC- MMR. I have no conflict of interest with this event. Mount Sinai Hospital Employee, LifeLabs Consultant, Honorarium from the American Cancer Society, Cancer(Cytopathology), College of American Pathologists, Committee Chair The Whys Why are mismatch repair proteins important in endometrial cancer? Why assess mismatch repair proteins in endometrial cancer? 1

2 DNA Mismatch Repair Genes & Cancer Mismatch repair gene proteins correct replication error and maintain fidelity of DNA during replication, MMR malfunction results in microsatellite instability (MSI), that is the expansion or contraction of microsatellites which promotes carcinogensis, MSI is a marker for abnormalities of MMR, The MSI phenomenon is found in tumor DNA and compared to non-neoplastic tissue (FFPE). MMR proteins act as functional pairs heterodimers, MLH1 & PMS2 MSH2 & MSH6 Lynch Syndrome (LS) formerly a.k.a. Hereditary Non-polyposis Colon Cancer (HNPCC) Syndrome attributable to mutations in the DNA mismatch repair (MMR) genes an autosomal dominant, variably penetrant cancer predisposition syndrome the most common hereditary cancer syndrome. 2 5 % of all colonic cancers Lynch HT et al Clin Genet. 2009; 76:

3 Mismatch Repair and Endometrial Carcinoma MSI occurs via two pathways MSI may occur through the acquired/sporadic pathway via epigenetic gene silencing via hypermethylation of promoter, usually endometrioid in type, almost always MLH1 MSI may also occur through the inheritance of gene mutation(s) the pathway for MSH2, MSH6, PMS2 for MLH1 only sometimes So, MSI endometrial cancer includes both sporadic and familial cases. LS and Endometrial Carcinoma MSI is present in 15 25% of endometrial carcinomas LS constitutes about 3% of all endometrial cancers 50% of LS first present with endometrial cancer, i.e. sentinel cancer. Lack usual clinical risk factors (e.g. obesity, hypertension, diabetes, PCO) Prevalence of MMR gene mutations in LS Endometrial carcinoma MSH2 50 to 66% MLH1 24 to 40% (these proportions are similar to colon cancer) MSH6 10 to 13% (closely associated with endometrial cancer) PMS2 - < 5% Bonadona et al JAMA 2011; 305:

4 Cancer risks differ among the 3 MMR gene mutations Cumulative endometrial cancer risk to age 70 for all MMR mutations to 33% MLH1 54%, MSH2 21%, MSH6 16% 1 Risk continues to rise after age 70 for MSH6 2, so highest risk of all genes 1. Bonadona et al JAMA 2011; 305: Baglietto et al JNCI 2010; 102: 193. Why detect LS in endometrial cancer patients? For the individual woman to initiate screening for colon cancer. For her relatives colonic surveillance is effective in reducing the risk of colorectal cancer* *EGAPP working group in Gen Med 2009; 11: 35. Can we screen for gynecologic cancers in LS? No consensus on the initiation, type, or frequency of screening for endometrial or ovarian carcinomas No effective screening method to prevent these 2 cancers is available Vasen HF et al J Med Genet 2007; 44: 353. Lindor NM et al JAMA 2006; 296:

5 Prophylactic gynecologic surgery in LS works! Retrospective study of mutation positive LS patients 1 :108 women underwent prophylactic surgery (61 Hyst, 47 BSO) NO CA s vs.control groups in which 33% developed endometrial cancer (mean age = 46), and 5% developed ovarian cancer (mean age = 42) Prophylactic surgery is cost-effective vs surveillance 2,3. 1. Schmeler et al NEJM 2006; 354: Yang KY et al Fam Cancer 2011; 10: Kwon JS et al Cancer 2008; 113; 326. So, we know that detecting Lynch Syndrome in endometrial cancer patients is effective can we rely on?: Clinical criteria (revised Bethesda, Amsterdam II, SGO) Uterine location of tumour, Histologic type of cancer or histologic characteristics. Young age NO!!!! Reflex MMR IHC in endometrial carcinoma: an emerging standard of care MMR IHC has a 96+% sensitivity for MSI-H tumors 1-3 BUT in tact expression does not exclude LS since about 5% have a missense, but antigenic, non-functional protein 4,5 1. Vasen et al Gut 2013; 62: Beamer LC et al JCO 2012; 30: Boland CR et al Gastroent 2010; 138: Bartley A et al APLM 2013; 138: Ferguson SE et al Cancer 2014; 120:

6 The Hows - Interpretation of MMR IHC [1] Terminology use intact or deficient OR normal expression or lack of expression ; avoid negative/positive Interpretation Need an internal control (e.g. lymphocytes, stromal cells, or benign epithelium), Nuclear staining (may be patchy), Consider weak staining deficient, Equivocal staining (e.g. MLH1), repeat on a different block Bartley A et al APLM 2014; 138: 166 IHC MLH1 in tact staining IHC MLH1 In tact staining Atrophic Endometrium EmCa 6

7 The Hows - Interpretation of MMR IHC [2] MLH1 is associated with concomitant loss of PMS2 MSH2 is associated with concomitant loss of MSH6 Loss of PMS2/MSH6 occurs & is only independently meaningful if MLH1 and MSH2 (respectively) is intact Bartley A et al APLM 2014; 138: 166. MLH1 PMS2 MSH2 MSH6 MLH1 PMS2 MSH2 MSH6 7

8 The Hows - Interpretation of MMR IHC [3] CAP on reporting IHC MMR proteins* : For each of the 4 proteins state: Intact nuclear expression, or Loss of nuclear expression, or Cannot be determined (explain), and then choose an interpretation e.g. No loss of nuclear expression of MMR proteins low probability of MSI-H. * Bartley et al, APLM 2014; 13*: 166. The Hows An e.g. of a MSH Clinical Guidance Note, May 2014, for in tact MMR IHC IHC interpretation These findings indicate that it is very unlikely that this carcinoma is associated with Lynch Syndrome (LS). However, while tumours in patients with LS typically show abnormal mismatch repair protein expression, the immunohistochemical findings cannot entirely exclude the possibility of LS. Clinical Guidance - If there is a clinical suspicion of LS based on personal or family history referral to a genetic counsellor is suggested. Features associated with Lynch syndrome include young age of onset (age < 50), strong family history of certain cancer types (including colorectal, small bowel, endometrial, ureter and renal pelvis and ovarian cancer) and multiple primary LS cancers in one individual. The Hows - Interpretation of MMR IHC [4] The MSH6 gene contains microsatellites which can be affected in MSI Consequently, MLH1 and PMS2 deficient tumours may occasionally also show MSH6 deficiency (!all three!) MSH6 deficiency may show negative MSI testing, since MSH2 provides sufficient function.. 8

9 In summary Detection of LS endometrial cancers benefits the woman & her family, IHC for MMR proteins in endometrial cancers is the most effective screening method for LS, The reporting and interpretation of MMR IHC should conform to guidelines. 9

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