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Stains

MLH1

Reviewer: Nat Pernick, M.D. (see Reviewers page)
Revised: 27 November 2011, last major update November 2011
Copyright: (c) 2002-2011, PathologyOutlines.com, Inc.

General
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● Mismatch repair gene; mutations associated with Lynch syndrome (hereditary non-polyposis colon cancer) and some cases of sporadic colon cancer

Terminology
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● Also called MutL homolog 1 colon cancer nonpolyposis type 2 (NCBI-Gene), hMLH1

Pathophysiology
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● 90% of cases of Lynch syndrome (hereditary non-polyposis colon cancer) are due to autosomal dominant inheritance of a mutation in MLH1 or MSH2; mutations may also occur in PMS1, PMS2 and MSH3
● MLH1 inactivation causes high levels of microsatellite instability (MSI), which alters the cell’s ability to repair errors normally produced during DNA replication, which is associated with carcinogenesis
● Nongenetic (acquired) inactivation of MLH1 or other mismatch repair genes is associated with 15% of sporadic colorectal carcinomas; acquired promoter hypermethylation often occurs with global hypermethylation of gene promoters known as CpG island methylator phenotype; when CpG sites in promoter regions of both copies of MLH1 are hypermethylated, MLH1 expression is lost and genomic instability occurs (Arch Pathol Lab Med 2011;135:1269)
● MLH1 expression may determine patterns of Kras mutation in colon carcinoma (Hum Mol Genet 2004;13:2303)
● Loss of MLH1 expression commonly associated with serrated intestinal polyps (Am J Surg Pathol 2003;27:65, Am J Surg Pathol 2007;31:1742), colonic medullary carcinoma (Hum Pathol 2009;40:398)
● Loss of MLH1 expression also present in ampullary carcinoma and precursor lesions (occasinally, Am J Surg Pathol 2009;33:691), breast cancer (44%, Hum Pathol 2008;39:672), endometrial and ovarian carcinoma with undifferentiated components (Mod Pathol 2010;23:781), uterine carcinosarcoma (33%, Mod Pathol 2011;24:1368)

Diagrams
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Colorectal carcinoma: mismatch repair (MMR) status (wt-wild type or mut-mutated), and relationship with MLH1 methylation (met) or nonmethylation (unmet) status and KRAS and BRAF mutations

Interpretation
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● Nuclear staining is normal; loss of nuclear staining (with positive internal control) indicates an abnormal result
● Recommended to restrict test to experienced pathologists (Am J Surg Pathol 2008;32:1246), or to have quality assessment programs and classification guidelines (Hum Pathol 2010;41:1387)
● Use molecular testing to follow up indefinite or aberrant staining results

Uses by Pathologists
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● Use immunostaining for MLH1, MSH2, PMS2 and MSH6 to screen for Lynch syndrome; biopsy samples may be as reliable as resections (Am J Surg Pathol 2011;35:447); use of only PMS2 and MSH6 antibodies may be as effective as using all 4 antibodies (Am J Surg Pathol 2009;33:1639, Mod Pathol 2011;24:1004); cases with normal staining due to somatic hypermethylation can occur (Am J Surg Pathol 2011;35:1902)

Micro images
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Various images


Colon and gastric carcinomas and adjacent normal tissue

   
Colon carcinomas with high-level microsatellite instability and hMLH1-negative

   
Well differentiated colon carcinoma with loss (left) and normal (right) MLH1 expression


Comparison of calretinin, CDX2 and MLH1 staining in medullary and poorly differentiated colon adenocarcinoma

   
Hyperplastic polyposis cases: sporadic (left) and hyperplastic polyposis coli syndrome (right)

           
Serrated adenomas and hyperplastic polyps


Solitary rectal ulcer syndrome cases


Normal staining in Warthin's tumor (which is not due to microsatellite instability)

End of Stains > MLH1

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