DNA Mismatch Repair Deficiency in Malignant Pleural Mesotheliomas
Y Karamurzin, JKL Rutgers. University of California, Irvine, CA; Todd Cancer Institute, Long Beach Memorial Medical Center, Long Beach, CA
Background: DNA mismatch repair (MMR) abnormality is the pathway of carcinogenesis in hereditary non-polyposis colorectal cancer (HNPCC) syndrome and in a minority of sporadic neoplasms. Sporadic MMR abnormalities may be caused by methylation of the hMLH1 gene promoter or loss of heterozygosity (LOH). We recently encountered a sentinel case of sarcomatous pleural malignant mesothelioma (MM) in an HNPCC patient with germline complete hMLH1 deletion; MM has not previously been described in HNPCC. As hMLH1 is located on 3p21.3, and 3p21.3 deletion has been described in 69% of MM, we hypothesized that MLH1 LOH and MSI may occur in MM.
Design: We retrieved 25 cases of MM diagnosed at Long Beach Memorial Medical Center between 1993 and 2008. The sentinel case is not included in this study. IRB approval was obtained. Formalin fixed paraffin embedded tissue (FFPE) was used for 4 mm tissue microarray after reviewing the H&E sections for selection of tumorous areas. Immunohistochemistry (IHC) using standard techniques, for hMLH1, hMSH2, hMSH6, and hPMS2 was performed on the microarray. Cases with abnormal staining on microarray were confirmed on whole FFPE blocks. In addition, MSI was evaluated by PCR using the 5 National Cancer Institute recommended microsatellite primers. LOH of hMLH1 was evaluated employing primers targeting an hMLH1 intronic region using PCR.
Results: H&E examination showed 8 sarcomatous, 13 epithelioid, and 4 biphasic tumors. 2 of 8 sarcomatous MM were desmoplastic type. DNA was obtained for molecular analysis in 21 cases. 2 of 25 (8%), both of desmoplastic variant, showed a marked loss of nuclear expression of hMLH1 and hPMS2 by IHC on both the tissue microarray and whole FFPE blocks. These 2 cases also showed MSI (2 and 3 of 5 microsatellites unstable respectively), and hMLH1 LOH. 2 additional cases, both epithelioid type, showed MSI only. 4 of 21 (19%) cases showed hMLH1 LOH, including the 2 cases with MSI and abnormal IHC. The other 2 cases with hMLH1 LOH were microsatellite stable and showed normal IHC results. In summary, IHC abnormality was found in 8% of cases, MSI in 19% and LOH in 19%.
Conclusions: MMR deficiency is a feature of a subset of MM. Our small series suggests a relationship between the desmoplastic subtype of MM and MMR deficiency. MM may be a rare neoplasm in the spectrum of tumors seen in patients with HNPCC syndrome, or MM may occur through sporadic abnormalities of MMR.
Tuesday, March 23, 2010 1:00 PM
Poster Session IV # 248, Tuesday Afternoon