Unusual Mismatch Repair Immunohistochemical Patterns in Endometrial Carcinoma

Watkins, Jaclyn C; Nucci, Marisa R.; Ritterhouse, Lauren L.; Howitt, Brooke E.; Sholl, Lynette M.

doi:10.1097/pas.0000000000000663

Cited by 77 publications

(85 citation statements)

References 44 publications

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“…Intratumoral heterogeneity of MMR status has been described in some cases of colorectal and endometrial cancer but has so far not been analyzed in pancreatic adenocarcinoma. [26][27][28][29][30] To learn more on MSI heterogeneity in pancreatic cancer, a cohort of 597 operated pancreatic cancers was screened by IHC for loss of the MMR proteins MLH1, PMS2, MSH2, and/or MSH6 on a tissue microarray (TMA). Cases with suspected MSI were further analyzed by PCR and repeated IHC on large sections followed by a thorough analysis of all available cancer-containing tissue blocks for possible intratumoral heterogeneity.…”

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confidence: 99%

MMR Deficiency is Homogeneous in Pancreatic Carcinoma and Associated with High Density of Cd8-Positive Lymphocytes

et al. 2020

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Background. Microsatellite instability (MSI) has emerged as a predictive biomarker for immune checkpoint inhibitor therapy. Cancer heterogeneity represents a potential obstacle for the analysis of predicitive biomarkers. MSI has been reported in pancreatic cancer, but data on the possible extent of intratumoral heterogeneity are lacking. Methods. To study MSI heterogeneity in pancreatic cancer, a tissue microarray (TMA) comprising 597 tumors was screened by immunohistochemistry with antibodies for the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6.

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confidence: 99%

MMR Deficiency is Homogeneous in Pancreatic Carcinoma and Associated with High Density of Cd8-Positive Lymphocytes

et al. 2020

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“…27 Although the majority of the indeterminate staining has been described in CRC, it has also been well documented in EC with more heterogeneity in the staining pattern, and subclonal loss as being the most frequent finding. [28][29][30][31] Indeterminate MMR staining in not unexpected because some gene mutations can be associated with intact protein expression, albeit a dysfunctional one, that can be detected by routine IHC. 8,32 Nontruncating point mutations or mutations in the noncoding region can also result in loss of enzymatic function with preservation of the defective protein that can cause weak staining.…”

Section: Discussionmentioning

confidence: 99%

Screening for Lynch Syndrome by Immunohistochemistry of Mismatch Repair Proteins: Significance of Indeterminate Result and Correlation With Mutational Studies

Sarode

Robinson

2019

Archives of Pathology &Amp; Laboratory Medicine

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Context.— Immunohistochemical expression of mismatch repair (MMR) protein is a well-accepted method for routine screening for Lynch syndrome with relatively high sensitivity and specificity. Occasionally, however, immunohistochemistry (IHC) can yield an equivocal result with poor reproducibility and the potential for misdiagnosis. Objective.— To determine the frequency and significance of indeterminate MMR IHC expression in patients routinely screened for Lynch syndrome and correlation with germline mutation studies. Design.— Semiquantitative scoring of MMR IHC was performed by image analysis in 479 cases, of which 380 were colorectal and 99 endometrial cancer. Scores of 10% or more, less than 10%, and 0% were used as cutoffs for retained, indeterminate, and loss of expression, respectively. Negative and indeterminate IHC results were confirmed by mutational studies. Results.— Four hundred eighteen of 479 cases (87.2%) were reported as retained expression, 45 (9.3%) as loss of expression, and 16 (3.3%) as indeterminate expression. Fifteen of 45 (33.3%) and 8 of 16 (50%) with loss and indeterminate expression, respectively, were found to have Lynch syndrome by germline studies. The overall frequency of Lynch syndrome in our patient population was 4.8% (23 of 479), and 34.7% of these (8 of 23) were associated with indeterminate IHC expression. In the indeterminate group, MLH1 germline mutation was the most frequent (6 of 13; 46.2%), followed by MSH6 (4 of 13; 30.7%). Conclusions.— Our findings provide further evidence that indeterminate IHC should be further investigated for possible MMR germline mutation. Guidelines for interpretation of MMR IHC and the establishment of more objective criteria for defining indeterminate results are important to improve the sensitivity and specificity of the IHC assay.

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“…The few available studies describing MSI in cohorts of NETs are basically limited to pancreatic primaries with reported frequencies between 10% (5/48) and 33% (18/55) by PCR-based methods [7,8]. Intratumoral heterogeneity of MSI-a potential strong confounder for molecular based treatments-has been observed in several cancer types, including colorectal cancer [9][10][11][12][13]. However, intratumoral heterogeneity of MSI in neuroendocrine neoplasms has not been evaluated so far.…”

Section: Introductionmentioning

confidence: 99%

Homogeneous MMR Deficiency Throughout the Entire Tumor Mass Occurs in a Subset of Colorectal Neuroendocrine Carcinomas

et al. 2020

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Neuroendocrine neoplasms comprise a heterogeneous group of tumors, categorized into neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) depending on tumor differentiation. NECs and high-grade NETs (G3) confer a poor prognosis, demanding novel treatment strategies such as immune checkpoint inhibition in tumors with microsatellite instability (MSI). To study any possible intratumoral heterogeneity of MSI, a tissue microarray (TMA) containing 199 NETs and 40 NECs was constructed to screen for MSI using immunohistochemistry (IHC) for the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6. Four cases suspicious for MSI were identified. Validation of MSI by repeated IHC on large sections and polymerase chain reaction (PCR)-based analysis using the "Bethesda Panel" confirmed MSI in 3 cecal NECs. One pancreatic NET G3 with MSI-compatible TMA results was MMR intact on large section IHC and microsatellite stable (MSS). The remaining 235 tumors exhibited intact MMR. Protein loss of MLH1/PMS2 was found in two and MSH6 loss in one cancer with MSI. Large section IHC on all available tumor-containing tissue blocks in NECs with MSI did not identify aberrant tumor areas with intact MMR. Our data indicate that MSI is common in colorectal NECs (3 out of 10) but highly infrequent in neuroendocrine neoplasms from many other sites. The lack of intratumoral heterogeneity of MMR deficiency suggests early development of MSI during tumorigenesis in a subset of colorectal NECs and indicates that microsatellite status obtained from small biopsies may be representative for the entire cancer mass.

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Unusual Mismatch Repair Immunohistochemical Patterns in Endometrial Carcinoma

Cited by 77 publications

References 44 publications

MMR Deficiency is Homogeneous in Pancreatic Carcinoma and Associated with High Density of Cd8-Positive Lymphocytes

MMR Deficiency is Homogeneous in Pancreatic Carcinoma and Associated with High Density of Cd8-Positive Lymphocytes

Screening for Lynch Syndrome by Immunohistochemistry of Mismatch Repair Proteins: Significance of Indeterminate Result and Correlation With Mutational Studies

Homogeneous MMR Deficiency Throughout the Entire Tumor Mass Occurs in a Subset of Colorectal Neuroendocrine Carcinomas

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