Stains & molecular markers
MLH1
Copyright: 2002-2021, PathologyOutlines.com, Inc.
PubMed Search: MLH1 [title]
MLH1
Authors: Maryam Abdelghani, M.D., Brian Quigley, M.D.
Topic Completed: 1 January 2014
Minor changes: 7 April 2021
Copyright: 2002-2021, PathologyOutlines.com, Inc.
PubMed Search: MLH1 [title]
Table of Contents
Definition / general | Terminology | Pathophysiology | Diagrams / tables | Interpretation | Uses by pathologists | Microscopic (histologic) imagesCite this page: Abdelghani M. MLH1. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainsmlh1.html. Accessed April 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-
