Pathology Outlines

Stains & molecular markers
MLH1

Authors: Maryam Abdelghani, M.D., Brian Quigley, M.D.

Topic Completed: 1 January 2014

Minor changes: 9 November 2020

Copyright: 2002-2021, PathologyOutlines.com, Inc.

PubMed Search: MLH1 [title]

Page views in 2020: 5,617

Page views in 2021 to date: 240

Table of Contents

Cite this page: Abdelghani M. MLH1. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainsmlh1.html. Accessed January 19th, 2021.

Definition / general

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

Terminology

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

Pathophysiology

90% of cases of Lynch syndrome (hereditary non-polyposis colon cancer) are due to autosomal dominant inheritance of a mutation in MLH1 (50%) or MSH2 (40%)
Mutations may also occur in MSH6, PMS2 and PMS1 (10% combined) (Sao Paulo Med J 2009;127:46)
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 / tables

Images hosted on other servers:

Colorectal carcinoma: MMR status

Interpretation

Any nuclear staining is considered retained (normal); loss of nuclear staining (with positive directly adjacent internal control) indicates an abnormal result, with caveats:
- When MLH1 is lost by IHC, PMS2 should also be lost
- Many colon carcinoma cases with loss of MLH1 expression show a few tiny scattered brown dots in tumor cell nuclei on IHC (still considered lost; correlate with PMS2 staining)
- If a colon carcinoma has two distinct morphologies (e.g. gland-forming and mucinous) and MLH1 is lost by IHC in one component while retained in the other, this could still represent true loss and Lynch syndrome is a possibility (correlate with PMS2)
- If there is no nuclear staining whatsoever in tumor or background cells, this is uninterpretable and may represent either a failed stain or (rarely) germline homozygous MLH1 mutation (correlate with control slides and PMS2)
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

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)

Microscopic (histologic) images

Images hosted on other servers:

Colorectum:

Colorectal, gastric tumors

Medullary carcinoma, MLH1-