Microsatellite Instability-High (MSI-H) Left-Sided Colorectal Carcinoma Is Frequently Associated with Lynch Syndrome: Implications for Lynch Syndrome Screening and Detection
Huankai Hu, Douglas J Hartman, Randall E Brand, Nathan Bahary, Beth Dudley, Simon I Chiosea, Marina N Nikiforova, Reetesh K Pai. University of Pittsburgh, Pittsburgh, PA
Background: Some institutions perform universal microsatellite instability (MSI) testing of CRCs to identify patients with Lynch syndrome (LS). Others triage CRCs for MSI testing based clinicopathologic variables within published predictive models for identifying MSI-H CRCs. We analyzed the clinicopathologic features of sporadic and LS-associated MSI-H CRCs and assessed the utility of predictive pathology models in identifying LS-associated CRCs.
Design: 149 MSI-H CRCs were identified between 2009 to June 2012 by MSI PCR (88 cases), mismatch repair (MMR) protein immunohistochemistry (IHC) (16 cases), or both PCR and IHC (45 cases). CRCs were analyzed for grade, location, tumor-infiltrating lymphocytes (TILs), Crohn's-like lymphocytic reaction, mucinous/signet ring cell histology, medullary growth, and histologic heterogeneity. MSI-H CRCs were divided into sporadic and LS-associated groups based on BRAF mutation, MLH1 promoter hypermethylation, family and personal cancer history, and germline MMR gene mutation. The utility of two predictive pathology models for MSI-H CRCs (PREDICT, Hyde A, et al. Am J Surg Pathol 2010 and MSPath, Jenkins MA, et al. Gastroenterology 2007) were evaluated.
Results: Left-sided MSI-H CRCs were frequently associated with LS compared with right-sided MSI-H CRC (12/21, 57% vs. 16/127, 16%, p=0.0001). 10/32 (31%) LS-associated CRCs were diagnosed in patients >60 years. There was no significant difference in tumor histology between LS-associated and sporadic MSI-H CRC. However, left-sided LS-associated CRC less frequently demonstrated TILs compared with right-sided LS-associated CRC (5/12, 42% vs. 15/20, 75%), although this was not statistically significant (p=0.13). Neither the PREDICT or MSPath models identified all LS-associated CRCs (PREDICT: 27/32, 84%; MSPath: 29/32, 91%); however, both models identified a significantly higher proportion of sporadic MSI-H CRCs (PREDICT: 111/117, 96%, p=0.038; MSPath, 117/117, 100%, p=0.009).
Conclusions: 57% of left-sided MSI-H CRCs are LS-associated compared with 16% of right-sided MSI-H CRCs. Published models of predicting MSI-H fail to identify LS-associated CRC given their reliance on right-sided location. 31% of LS-associated CRC are identified in patients >60 years. These results support universal testing for MSI in CRC and indicate that finding MSI-H in left-sided CRC should heighten suspicion for LS.
Wednesday, March 6, 2013 9:30 AM
Poster Session V # 92, Wednesday Morning