Neoadjuvant Therapy Induces Loss of MSH6 Expression in Colorectal Carcinoma
F Bao, H Rennert, RK Yantiss. Weill Cornell Medical College, New York, NY
Background: The use of immunostains to detect abnormal DNA repair protein expression has become routine practice in the evaluation of patients with colorectal carcinoma, particularly when they have clinical features that raise the possibility of hereditary non-polyposis colon cancer (HNPCC). However, many distally located adenocarcinomas are neoadjuvantly treated prior to definitive surgical treatment, and we have noted that some treated rectal cancers display loss of DNA repair protein expression, despite the lack of underlying microsatellite instability (MSI). The purpose of this study was to determine the frequency and clinical significance of decreased DNA repair protein expression among neoadjuvantly treated colorectal carcinomas.
Design: We identified 51 patients with neoadjuvantly treated adenocarcinoma of the distal colorectum, all of whom underwent surgical resection of their tumors. Immunostains for MLH1, MSH2, MSH6, and PMS2 were performed on tissue sections obtained from post-treatment tumor samples. Cases that showed loss of staining for any of the DNA repair proteins were subjected to molecular testing for MSI. Pretreatment biopsy samples from these tumors were also evaluated for DNA repair protein expression using the abovementioned panel of immunohistochemical stains.
Results: The study group included 26 males and 25 females (mean age: 58 years). Ten (20%) tumors showed decreased MSH-6 nuclear staining, including 9 with loss of staining in greater than 75% of the tumor cells and 1 that showed complete loss of MSH6 staining. Loss of MSH6 staining did not reflect MSI in any of the cases and was not associated with patient age, gender, tumor grade, stage, or degree of post-treatment tumor regression. All 9 post-treatment tumors that showed near-complete loss of MSH6 staining displayed strong, diffuse MSH6 expression in pretreatment biopsy samples, but the one with complete loss also lacked MSH6 expression in the pretreatment biopsy sample. All of the cases showed preserved nuclear staining for MLH1, MSH2 and PMS2.
Conclusions: Neoadjuvant therapy frequently induces partial loss of MSH6 immunoexpression in colorectal carcinomas, which may be extensive in nearly 20% of cases. This finding does not correlate with underlying MSI. Rather, it probably reflects a therapeutic effect, such as cell cycle dysregulation, in mismatch repair proficient tissues. When loss of MSH6 expression is noted in neoadjuvantly treated tumors, evaluation of pretreatment biopsy samples for DNA repair protein expression may be considered prior to further assessment for HNPCC.
Tuesday, March 23, 2010 9:30 AM
Poster Session III # 116, Tuesday Morning