Punctate <scp>MLH</scp>1 mismatch repair immunostaining in colorectal cancer

Loughrey, Maurice B.; Dunne, Philip D.; Coleman, Helen; McQuaid, Stephen; James, Jacqueline

doi:10.1111/his.13780

Cited by 13 publications

(10 citation statements)

References 6 publications

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“…Similar to our cases, all of them showed complete negativity on repeating MLH1-IHC with ES05-clone, and MLH1 promotor was methylated [11]. Loughrey et al reported a similar aberrant MLH1-IHC pattern with the M1-clone, in 9 of the 16 PMS2-negative CRCs from his cohort, and 4 of these showed somatic BRAF V600E mutation [12]. Loughrey et al therefore suggested that the punctate pattern represents a non-functional MLH1 protein variant with retained antigenicity, generated due to the somatic mutation [12].…”

Section: Discussionsupporting

confidence: 87%

Granular dot-like staining with MLH1 immunohistochemistry is a clone-dependent artefact

Dasgupta

Ewing-Graham

Groenendijk

et al. 2020

Pathology - Research and Practice

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Immunohistochemistry (IHC) for DNA mismatch repair proteins MLH1, PMS2, MSH2, and MSH6 is used for microsatellite instability (MSI) screening in colorectal carcinoma (CRC) and endometrial carcinoma (EC). Loss of PMS2, with retained MLH1 staining occurs in germline mutations of PMS2 gene, and is an indication for genetic testing. We report a pitfall of immunohistochemical interpretation in an EC, initially regarded as MLH1-positive and PMS2-negative. Review of the MLH1-IHC (M1-clone) revealed a granular, dot-like, nuclear staining. On repeating the MLH1-IHC with a different clone (ES05-clone), complete negativity was noted, and on molecular testing, MLH1 promotor methylation was detected. The dot-like pattern was therefore adjudged a clone-dependent artefact. On reviewing the archived MLH1-IHC slides, we observed the same dot-like pattern in two CRCs; in both cases the M1-clone had been used. Awareness of this artefact may prevent reporting errors, and unnecessary referrals for germline mutation testing.

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Section: Discussionsupporting

confidence: 87%

Granular dot-like staining with MLH1 immunohistochemistry is a clone-dependent artefact

Dasgupta

Ewing-Graham

Groenendijk

et al. 2020

Pathology - Research and Practice

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“…All eight cases were MSI‐H and showed complete loss of PMS2 staining. This pattern of abnormality has been described in more detail in another publication relating to this cohort 36 …”

Section: Resultssupporting

confidence: 70%

“…This pattern of abnormality has been described in more detail in another publication relating to this cohort. 36 Seven cases showed unusual combinations of loss of expression as determined with MMR IHC on assessment of triplicate cores: two cases showed loss of MSH6 and PMS2 staining; one case showed loss of MLH1 and MSH6 staining; one case showed loss of MSH6 staining and clonal loss of MSH2 staining; one case showed loss of MLH1, PMS2 and MSH6 staining; and two cases showed loss of staining for all four proteins. All seven cases were MSI-H. Repeat MMR IHC on whole sections confirmed these findings, with two exceptions.…”

Section: U N U S U a L V A R I A N T S O F M M R I H C S T A I N I N Gmentioning

confidence: 91%

“…Much more rarely, but also considered to be abnormal, were cases with markedly weak/abnormal staining in comparison with internal controls (Figure 1E), ‘clonal’ loss of staining, with an abrupt transition from present to absent staining for one or more markers (Figure 1G), or punctate staining, seen uniquely for MLH1, associated with complete loss of PMS2 staining (Figure 1F). These patterns are all now considered to be variants of abnormal MMR IHC staining 14,26,33–36 …”

Section: Methodsmentioning

confidence: 99%

“…These patterns are all now considered to be variants of abnormal MMR IHC staining. 14,26,[33][34][35][36] Cases considered to be abnormal or equivocal for scoring on initial assessment by the primary observer were reviewed by an experienced gastrointestinal pathologist (M.B.L.) with expertise in MMR IHC interpretation.…”

Section: M R I H Cmentioning

confidence: 99%

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Identifying mismatch repair‐deficient colon cancer: near‐perfect concordance between immunohistochemistry and microsatellite instability testing in a large, population‐based series

et al. 2020

Self Cite

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Identifying mismatch repair-deficient colon cancer: near-perfect concordance between immunohistochemistry and microsatellite instability testing in a large, population-based series Aims: Establishing the mismatch repair (MMR) status of colorectal cancers is important to enable the detection of underlying Lynch syndrome and inform prognosis and therapy. Current testing typically involves either polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing or MMR protein immunohistochemistry (IHC). The aim of this study was to compare these two approaches in a large, population-based cohort of stage 2 and 3 colon cancer cases in Northern Ireland. Methods and results: The study used the Promega pentaplex assay to determine MSI status and a four-antibody MMR IHC panel. IHC was applied to tumour tissue microarrays with triplicate tumour sampling, and assessed manually. Of 593 cases with available MSI and MMR IHC results, 136 (22.9%) were MSI-high (MSI-H) and 135 (22.8%) showed abnormal MMR IHC. Concordance was extremely high, with 97.1% of MSI-H cases showing abnormal MMR IHC, and 97.8% of cases with abnormal IHC showing MSI-H status. Under-representation of tumour epithelial cells in samples from heavily inflamed tumours resulted in misclassification of several cases with abnormal MMR IHC as microsatellite-stable. MMR IHC revealed rare cases with unusual patterns of MMR protein expression, unusual combinations of expression loss, or secondary clonal loss of expression, as further illustrated by repeat immunostaining on whole tissue sections. Conclusions: MSI PCR testing and MMR IHC can be considered to be equally proficient tests for establishing MMR/MSI status, when there is awareness of the potential pitfalls of either method. The choice of methodology may depend on available services and expertise.

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Immunohistochemistry for Mismatch Repair Proteins

Sekine

2020

Lynch Syndrome

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Punctate MLH1 mismatch repair immunostaining in colorectal cancer

Cited by 13 publications

References 6 publications

Granular dot-like staining with MLH1 immunohistochemistry is a clone-dependent artefact

Granular dot-like staining with MLH1 immunohistochemistry is a clone-dependent artefact

Identifying mismatch repair‐deficient colon cancer: near‐perfect concordance between immunohistochemistry and microsatellite instability testing in a large, population‐based series

Immunohistochemistry for Mismatch Repair Proteins

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