Microsatellite Instability in Urothelial Carcinoma of the Upper Urinary Tract
Samuel A Henderson, Joseph P Heitzman, Bogdan Czerniak, Charles C Guo. University of Texas MD Anderson Cancer Center, Houston, TX
Background: Lynch syndrome (or hereditary non-polyposis colon carcinoma) is caused by germline mutations in DNA mismatch repair (MMR) genes, resulting in microsatellite instability (MSI). Patients with Lynch syndrome have an increased risk for urothelial carcinoma of the upper urinary tract (UC-UUT). However, there is limited information about the prevalence of MMR gene defects in UC-UUT patients and their clinicopathologic significance.
Design: We identified 101 cases of UC-UUT in nephroureterectomy specimens from our pathology files between 1991 and 2006. Tissue microarrays (TMAs) were constructed using three 0.4-mm cores from each case. The expressions of MMR genes, including MLH1, MSH2, MSH6 and PMS2 were analyzed on the TMA slides using immunohistochemistry. Clinicopathologic information was collected from the patients' medical records.
Results: UC-UUT samples were available for immunochemical analysis in 95 cases. In 6 cases, UC-UUT was absent or lost during the immunostaining process. All 95 cases showed positive immunoreactivity for both MSH1 and PMS2 proteins. But 27 cases (28%) lost immunoreactivity for the MSH6 protein. Immunoreactivity of the MSH2 protein was absent in 5 cases (5 %), which also lost immunoreactivity for the MSH6 protein. Compared with MSS (microsatellite stable, positive immunoreactivity for all 4 MMR proteins, n=68), MSI (negative immunoreactivity for MSH2 and/or MSH6, n=27) was more common in UC-UUTs with lower grade and lower stage. The presence of MSI-high was also associated with a lower mortality rate in UC-UUT patients.
|No. cases||27 (28%)*||68 (72%)||95|
|Tumor grade||High||17 (63%)||50(74%)||67|
|Tumor stage||pTa/Tis||7 (26%)||14 (21%)||21|
|pT1||7 (26%)||8 (12%)||15|
|pT2||4 (15%)||17 (25%)||21|
|pT3||6 (22%)||23 (34%)||29|
|pT4||3 (11%)||6 (9%)||9|
|Metastasis||10 (37%)||27 (40%)||37|
|Patient outcome||Alive||15 (56%)||25 (37%)||40|
|Dead||12 (44%)||43 (63%)||55|