Abstract
Casestudy
Lynch Syndrome (LS) is primarily linked to colorectal and endometrial cancers. Occasional sarcomas, including leiomyosarcoma, have been recognized within the spectrum of LS demonstrating mismatch repair-deficiency (MMR)/microsatellite instability (MSI) in this context.
Results
A 67-year-old female of bilineal Ashkenazi Jewish descent was recently diagnosed with uterine leiomyosarcoma in addition to metastatic papillary thyroid carcinoma at age 58. She met NCCN criteria for LS and BRCA1/2 (brother with renal cancer at age 64, father with colon cancer at age 60, paternal half-sister with rectal cancer at age 50 and maternal aunt with breast cancer).
Studies have shown that immunohistochemistry (IHC) for MMR proteins and PCR-based MSI have comparable sensitivity and specificity with high concordance, but neither test alone is sufficient to capture all defective MMR tumors. Screening strategies vary depending on the level of clinical suspicion for LS. When high, a normal result by one method warrants testing via a second method or concurrent IHC plus PCR testing to minimize the impact of rare false normal results. Rarely, this strategy can yield discordant results, as in our case wherein MSI by PCR was stable (MSS) but IHC for MLH-1 and PMS-2 showed heterogeneous (patchy/focal) nuclear loss of protein expression. The latter is not always due to artefact but can correspond to MMR status differences within the tumor, requiring recognition to prevent false-positive/false-negative evaluations. Heterogenous MLH1 and/or PMS2 expression, may be suggestive of variable MLH1 methylation/second hit mutations, variable epitope expression or expression related to variable differentiation.
Conclusion
The clinical significance of this pattern was unclear in our patient whose initial genetic screen (including MLH1, PMS2, MSH2, MSH6, EPCAM) was negative. However, as studies have indicated that patients with indeterminate IHC findings can have MLH1 hypermethylation or germline mutations, she had justification to undergo extended genetic screening. A heterozygous pathogenic variant in BLM 2207_2212delinsTAGATTC (p.Tyr736Leufs*5) associated with autosomal recessive Bloom Syndrome (BS) was identified. Carriers of BS do not show symptoms of the disease, but they are at a greater than average risk of developing cancers.
A sensitive and scalable microsatellite instability assay to diagnose constitutional mismatch repair deficiency by sequencing of peripheral blood leukocytes
