Immunohistochemical testing of conventional adenomas for loss of expression of mismatch repair proteins in Lynch syndrome mutation carriers: a case series from the Australasian site of the colon cancer family registry

Abstract

Debate continues as to the usefulness of assessing adenomas for loss of mismatch repair protein expression to identify individuals with suspected Lynch syndrome. We tested 109 polyps from 69 proven mutation carriers (35 females and 34 males) belonging to 49 Lynch syndrome families. All polyps were tested by immunohistochemistry for four mismatch repair proteins MLH1, MSH2, MSH6 and PMS2. Detailed pathology review was performed by specialist gastrointestinal pathologists. The majority of polyps (86%) were conventional adenomas (n = 94), with 65 tubular and 28 tubulovillous adenomas and a single villous adenoma. The remaining 15 lesions (14%) were serrated polyps. Overall, loss of mismatch repair expression was noted for 78/109 (72%) of polyps. Loss of mismatch repair expression was seen in 74 of 94 (79%) conventional adenomas, and 4/15 (27%) serrated polyps from mismatch repair gene mutation carriers. In all instances, loss of expression was consistent with the underlying germline mutation. mismatch repair protein expression was lost in 27 of 29 adenomas with a villous component compared with 47 of 65 adenomas without this feature (93% vs 73%; p=0.028). A strong trend was observed for high-grade dysplasia. mismatch repair deficiency was observed in 12 of 12 conventional adenomas with high-grade dysplasia compared with 60 of 79 with low grade dysplasia (100% vs 76%; p=0.065). We were unable to demonstrate a significant association between conventional adenoma size or site and mismatch repair deficiency. All (4/4 or 100%) of the serrated polyps demonstrating mismatch repair deficiency were traditional serrated adenomas from a single family. Diagnostic testing of adenomas in suspected Lynch syndrome families is a useful alternative in cases where cancers are unavailable. The overwhelming majority of conventional adenomas from mutation carriers show loss of mismatch repair protein expression concordant with the underlying germline mutation.

Advanced Colorectal Adenomas in Patients Under 45 Years of Age Are Mostly Sporadic

“…Several prior studies have evaluated the diagnostic utility of IHC in adenomas from patients with known LS and found loss of staining by IHC in 60–80 % of adenomas [31, 33, 34]. Moreover, the presence of MMR deficiency is more prevalent in large adenomas (>8 mm) or those with advanced histologic features (high-grade dysplasia, villous histology); and over 90 % of polyps evaluated in our study met these criteria.…”

“…Moreover, the presence of MMR deficiency is more prevalent in large adenomas (>8 mm) or those with advanced histologic features (high-grade dysplasia, villous histology); and over 90 % of polyps evaluated in our study met these criteria. In those settings, loss of MMR IHC expression exhibits a sensitivity of >90 % in identifying MMR deficiency [25, 31, 33, 34]. That said, the current findings should be interpreted with caution.…”

Evaluation of colorectal cancers for Lynch syndrome: practical molecular diagnostics for surgical pathologists

“…18 Another study found that 80% of Lynch-associated adenomas were mismatch repair deficient by IHC. 19 This study identified a relationship between mismatch repair deficiency and a villous component or high-grade dysplasia, but not with size. At this point the available evidence suggests that mismatch repair deficiency in an adenoma is useful in identifying potential Lynch syndrome mutation carriers, but that the lack of mismatch repair deficiency in an adenoma is not as strong a criterion to exclude Lynch syndrome as the lack of mismatch repair deficiency in a cancer.…”

BRAFV600E Immunohistochemistry Facilitates Universal Screening of Colorectal Cancers for Lynch Syndrome

“…The ACCFR has been previously described, comprising a richly annotated cohort which includes MMR IHC information correlated with molecular data such as MSI status, MMR gene mutation status, MLH1 and CpG island methylator phenotype (CIMP) methylation analysis and BRAFV600E status determined by allele-specific PCR (AS-PCR). [36-38]. For this arm of the study CRC samples demonstrating loss of expression for MSH2 and/or MSH6 or solitary loss of PMS2 protein expression by IHC were excluded because of their very strong association with LS.…”