MMR IHC in Upper Urinary Tract Urothelial Carcinoma
AL Wilson, WG Watkin, R Thornburg, M Morgan, KL Kaul. Evanston Hospital, NorthShore University HealthSystem, Evanston, IL
Background: Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) tumors characteristically have a high level of microsatellite instability (MSI-H) due to a mutation in one of the DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6, or PMS2. MMR defects can be demonstrated by immunohistochemistry (IHC). The MSI phenotype can occur in up to 15% of sporadic colorectal cancers, which do not exhibit germline mutations in the MMR genes. The MSI phenotype has been studied in other tumors associated with HNPCC, including ovarian and endometrial cancers. We assessed MMR IHC and the MSI phenotype in upper urinary tract urothelial carcinomas, which have a lifetime risk of 1-12% in HNPCC patients.
Design: 80 patients who had a resected urothelial carcinoma of the renal pelvis or ureters entered in our hospital's electronic surgical pathology database between September 1992 to July 2008 were identified. All had archived, formalin-fixed, paraffin-embedded tissue and clinical follow-up. We performed the MMR IHC panel (MLH1, MSH2, MSH6, and PMS2) on all cases. We tested for MSI in 35 cases using PCR based techniques. Clinicopathologic features were documented.
Results: 5/80 (6%) cases showed loss of at least one MMR marker: two cases with loss of MSH6 alone, one with loss of PMS2 and MLH1, and two with loss of MSH2 and MSH6. One of the latter was a previously known HNPCC case with a germline MSH2 mutation; it was not tested for MSI due to a limited specimen. Four of the 5 cases (80%) were invasive and high grade, as compared to 47/75 cases (63%) with normal MMR IHC. Two of the four cases tested were MSI-H. One case with loss of MMR expression exhibited mucinous morphology. The mean age for patients with loss of MMR was 64 vs. 72 for those with normal MMR IHC. Four of the patients with loss of MMR expression had no family history suggestive of HNPCC, but one case had a personal history of prostate cancer, renal clear cell carcinoma, and melanoma.
Conclusions: Six percent of upper urinary tract urothelial carcinomas exhibited loss of MMR expression; 2 (of 4 tested) of these were MSI-H. The most common defect in MMR was in MSH6, differing from colorectal cancers, in which MLH1 is the most common defect. Our data demonstrates that some of upper urinary tract urothelial carcinomas do have the MMR phenotype associated with HNPCC. MLH1 methylation studies, which are ongoing, may further define this association.
Category: Genitourinary (including renal tumors)
Monday, March 9, 2009 1:00 PM
Poster Session II # 125, Monday Afternoon