Pure Discrete Punctate Nuclear Staining Pattern for MLH1 Protein Does Not Represent Intact Nuclear Expression.

Area of Science:

• Oncology
• Molecular Pathology
• Gastroenterology

Background:

• Immunohistochemical staining for DNA mismatch repair (MMR) proteins is standard for Lynch syndrome screening.
• A confusing discrete punctate nuclear staining pattern for MLH1 has been observed in laboratories.

Purpose of the Study:

• To investigate if the discrete punctate nuclear staining pattern for MLH1 signifies intact nuclear expression.
• To clarify the diagnostic implications of this staining pattern in colorectal cancer.

Main Methods:

• Retrospective review of MMR protein immunostaining and follow-up testing in 161 colorectal adenocarcinoma cases (biopsies and resections).
• Analysis of MLH1 and PMS2 staining patterns, including discrete punctate, diffuse nuclear, and negative staining.
• Correlation with molecular testing (BRAF V600E, MLH1 gene mutations) in relevant cases.

Main Results:

• Discrete punctate MLH1 staining was more common in biopsy specimens compared to resections.
• Pure discrete punctate MLH1 staining was invariably associated with loss of PMS2 expression.
• Molecular testing revealed BRAF V600E mutations in 4 patients and MLH1 gene mutation in 1 patient with pure punctate MLH1 and loss of PMS2.

Conclusions:

• Discrete punctate nuclear staining for MLH1 should not be interpreted as intact nuclear expression.
• This pattern, particularly in biopsies, suggests potential Lynch syndrome and warrants further investigation.
• The association with PMS2 loss and genetic mutations highlights its significance in diagnostic interpretation.