Mismatch repair deficiency in hematological malignancies with microsatellite instability

ObjectivesFor synchronous endometrial and ovarian cancers, most centers rely on mismatch repair testing of the endometrial cancer to identify Lynch syndrome, and neglect the ovarian tumor site completely. We examined the mismatch repair immunohistochemistry and microsatellite instability results from the endometrium and ovary to assess discordance between the tumor sites and between tests.Methods30 women with newly diagnosed synchronous endometrial and ovarian cancer were prospectively recruited from three cancer centers in Ontario, Canada. Both tumor sites were assessed for mismatch repair deficiency by immunohistochemistry and microsatellite instability test; discordance in results between tumor sites and discordance between test results at each site was examined. Cases with discordant results had tumors sequenced with a targeted panel in order to reconcile the findings. All women underwent mismatch repair gene germline testing.ResultsOf 30 patients, 11 (37%) were mismatch repair deficient or microsatellite instable at either tumor site, with 5 (17%) testing positive for Lynch syndrome. Mismatch repair immunohistochemistry expression was discordant between endometrial and ovarian tumor sites in 2 of 27 patients (7%) while microsatellite instability results were discordant in 2 of 25 patients (8%). Relying on immunohistochemistry or microsatellite instability alone on the endometrial tumor would have missed one and three cases of Lynch syndrome, respectively. One patient with Lynch syndrome with a PMS2 pathogenic variant was not detected by either immunohistochemistry or microsatellite instability testing. The rate of discordance between immunohistochemistry and microsatellite instability test was 3.8% in the ovary and 12% in the endometrium.ConclusionsThere was discordance in immunohistochemistry and microsatellite instability results between tumor sites and between tests within each site. Endometrial tumor testing with mismatch repair immunohistochemistry performed well, but missed one case of Lynch syndrome. Given the high incidence of Lynch syndrome (17%), consideration may be given to germline testing in all patients with synchronous endometrial and ovarian cancers.

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Utility of Discordant Mismatch Repair-Deficiency (MMR)/Microsatellite Instability (MSI) Testing in Screening Uterine Leiomyosarcoma Patient for Lynch/Other Familial Cancer Syndromes

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqaa161.326 ◽

2020 ◽

Vol 154 (Supplement_1) ◽

pp. S149-S150

Author(s):

K S Reddy

Keyword(s):

Microsatellite Instability ◽

Mismatch Repair ◽

Familial Cancer ◽

False Negative ◽

Uterine Leiomyosarcoma ◽

Average Risk ◽

Mismatch Repair Deficiency ◽

Repair Deficiency ◽

Familial Cancer Syndromes ◽

The Impact

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.

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