Neoadjuvant Therapy Induces Loss of MSH6 Expression in Colorectal Carcinoma

Abstract

Immunohistochemical stains are routinely used to detect abnormal DNA mismatch repair (MMR) protein expression in colorectal carcinomas, particularly when Lynch syndrome is suspected. Complete loss of MMR protein expression is often associated with underlying microsatellite instability (MSI), and the combined results of mutL homolog 1 (MLH1), postmeiotic segregation increased 2 (PMS2), mutS homolog 2 (MSH2), or mutS homolog 6 (MSH6) immunostains may point to the defective MMR protein in tumors with MSI. We have noted that some neoadjuvantly treated colorectal carcinomas display loss of MMR protein immunoexpression, despite a lack of underlying MSI and preserved staining in pretreatment tumor samples. The purpose of this study was to determine the frequency of this finding. We identified 51 neoadjuvantly treated resected colorectal cancers. Posttreatment tumor samples were immunohistochemically stained with MLH1, PMS2, MSH2, and MSH6 antibodies. Loss of staining for any marker was followed by analysis for MSI and assessment of MMR protein expression in pretreatment tumor samples. All of the 51 posttreatment tumor samples showed preserved MLH1, PMS2, and MSH2, but 10 posttreatment tumor samples (20%) showed decreased MSH6 staining. Of these, 9 posttreatment tumor samples displayed loss of staining in less than 100% of tumor cells, but preserved MSH6 expression in pretreatment tumor samples. One case showed a complete absence of MSH6 staining in both pretreatment and posttreatment tumor samples. All 10 cases were microsatellite stable. We conclude that extensive loss of MSH6 immunoexpression is common among neoadjuvantly treated colorectal carcinomas, but generally does not reflect underlying MSI. Therefore, diminished MSH6 staining in treated tumors should prompt immunohistochemical evaluation of pretreatment biopsy samples before genetic testing for Lynch syndrome.

A two-antibody mismatch repair protein immunohistochemistry screening approach for colorectal carcinomas, skin sebaceous tumors, and gynecologic tract carcinomas

“…43 In addition, recently, partial intact MSH6 expression in colorectal carcinoma has been demonstrated to occur after neoadjuvant therapy or rarely in MLH1-and/or PMS2-deficient colorectal carcinomas. 44,45 In our analysis, we identified a small number of gynecologic tract and skin sebaceous tumors with focal MSH6 immunoreactivity; none of these patients had received chemotherapy or had concurrent loss of immunohistochemical expression of any other mismatch repair proteins. Interestingly, in our analysis, focal MSH6 immunoreactivity was limited to extracolonic tumors with no cases of colorectal carcinoma demonstrating this pattern of immunoreactivity.…”

Evaluation of colorectal cancers for Lynch syndrome: practical molecular diagnostics for surgical pathologists

“…8 Staining of the pretreatment biopsy may be helpful in such cases to determine whether the MSH6 loss is real. 'Clonal' or focal MSH6 loss may also occur (unrelated to chemoradiation), in which some areas of the tumor show intact MSH6 staining and other areas show loss (with intact internal control staining).…”

Microsatellite instability in colorectal cancer: clinicopathological significance

“…In these cases, pre-treatment endoscopic biopsies rather than operative material may be used as the primary material for immunohistochemistry [105]. Of note, reduced expression of MSH6 due to neoadjuvant treatment [106,107] should be differentiated from loss of MSH6 expression due to secondary frameshift mutations in the MSH6 gene in cancers with MLH1/PMS2 deficiency [107].…”