[862] DNA Mismatch Repair Deficiency in Urothelial Carcinoma: An Immunohistochemical Study in Upper Versus Lower Genitourinary Tract Tumors

Lan L Gellert, Rohit Mehra, Jinru Shia, Ying-Bei Chen, Anuradha Gopalan, Samson Fine, Satish Tickoo, Victor E Reuter, Hikmat Al-Ahmadie. MSKCC, New York, NY

Background: The loss of mismatch repair proteins (MMR) has been reported in Lynch syndrome (LS)-associated as well as sporadic urothelial carcinoma (UC). Few studies have focused on the expression of MMR proteins in UC with different histological grade and/or location.
Design: We retrospectively identified 88 UC cases, including 41 bladder tumors and 47 upper tract (ureter and renal pelvis) tumors. MMR proteins (MLH1, MSH2, MSH6, and PMS2) were evaluated by immunohistochemistry (IHC) on whole sections. Abnormal staining was defined as total loss of protein in the tumor with appropriate internal control. The IHC findings were correlated with clinical and pathological characteristics.
Results: In upper tract tumors, loss of MMR proteins was detected in 4 of 47 cases (8.5%). Two of these 4 cases lost both MSH2 and MSH6 proteins. The other 2 cases lost MSH2 and less than 1% of the tumors cells showed weak nuclear staining for MSH6.
In bladder urothelial carcinoma, loss of MMR proteins were detected in 2 of 41 cases (5%); one tumor lost both MSH2 and MSH6 proteins, and the other tumor lost both PMS2 and MLH1 proteins.
The loss of MMR protein expression was present in both non-invasive and invasive components. In the normal urothelium adjacent to the tumor, all MMR proteins were retained. Tumors of both low grade and high grade morphology showed loss of MMR protein expression. Detailed results are summarized in table 1.

Table 1.MMR proteins in upper and lower tract urothelial carcinoma.
TumorGradeNLoss of MSH2/MSH6Loss of MLH1/PMS2
Renal pelvis UCHigh grade3310
 Low grade420
Ureter UCHigh grade810
 Low grade200
Bladder UCHigh grade3911
 Low grade200

Conclusions: Overall, alterations in MMR protein expression are present in a minority of urothelial carcinoma of both upper and lower tracts. MSH2 and/or MSH6 protein was lost in 8.5% (4/47) of the upper tract UC but only 2% (1/41) of bladder UC. As loss of MSH2/MSH6 is highly suggestive of hereditary MMR deficiency, our findings support the inclusion of upper tract UC in the LS tumor spectrum, and suggest that the urinary bladder may be affected as well in LS patients, albeit at a lower frequency. The finding that none of the 47 upper GU tract tumors had loss of MLH1/PMS2 suggests that sporadic epigenetic inactivation of the MLH1 gene is likely a rare event. Loss of MMR proteins in both non-invasive and invasive components of urothelial carcinoma suggests that these aberrations are early events in the tumorgenesis and it may have implications in testing urothelial tissues for detecting LS patients.
Category: Genitourinary (including renal tumors)

Wednesday, March 21, 2012 1:00 PM

Poster Session VI # 158, Wednesday Afternoon


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