Immunohistochemical and putative morphological markers related to lynch syndrome in ovarian endometrioid adenocarcinoma

AIM: Hereditary gynecologic cancer accounts for 5% to 15% of ovarian cancers. 10-15% of hereditary ovarian cancer is associated with Lynch syndrome. The mostfrequent histologic subtype of Lynch syndrome-associated ovarian cancer isendometrioid adenocarcinoma. In addition to clinical criteria, tumor morphology(including tumor infiltrating lymphocytes-TIL, peritumoral lymphocytes-PTL), MMRprotein immunohistochemistry, and MSI testing are also useful screening tools foridentifying women with endometrial cancer who may benefit from further geneticevaluation and definitive germline testing for Lynch syndrome. The aim in this studyis to define the incidence of putative morphologic markers of MMR defects and theirassociation with MMR status in primary ovarian cancer, which has not been studiedbefore and to research whether such an association is valuable in identifying ovariancancer patients who may be candidates for further Lynch syndrome geneticevaluation and in predicting prognosis or not. For this purpose, we studied theimmunoexpression profile of MMR proteins MLH-1, MSH-2, MSH-6 and PMS-2 inthese tumors and the association between morphologic markers and MMR proteinstatus.METHODS: The study included 71 patients with primary ovarian endometrioidadenocarcinoma who underwent primary surgical management at California SanFrancisco Universtity Hospital between 1985 and 2009. All slides for each case werereviewed by 2 gynecologic pathologists to confirm the tumor classification, histologicsubtype, grade and stage. Morphologic markers (presence of TIL, PTL anddedifferentiated component) that have been reported in uterine tumors as potentialpredictors of abnormal MMR protein status were evaluated in the primary ovariantumors and, when present, in the concurrent uterine tumors. Immunohistochemicalevaluation of MMR protein expression was performed on tissue microarrays (TMA).The antibodies used were MLH-1, MSH-2, MSH-6 and PMS-2. A positive result wasrecorded if any tumor cell nucleus expressed the marker for each case. Cases inwhich all four MMR protein antibodies yielded a positive result were considered tohave normal/intact MMR status.RESULTS: Among 71 patients, 29 had an ovarian pure endometrioidadenocarcinoma with a concurrent uterine endometrioid adenocarcinoma. Among theovarian tumors, TIL were present in 13% of the cases, PTL were present in 3% ofthe cases. Dedifferentiated component was not detected among all cases. MMRprotein defects are detected in 10% (7/71) of all cases with ovarian endometrioidadenocarcinoma. There was no association between the presence of MMR proteindefects and behaviour. Comparing patients aged 50 years or older to those youngerthan 50 years, there was no statistical difference in the incidence of TIL or PTL andthe incidence of MMR protein defects. No correlation was found between morphologymarkers and MMR status in the ovarian tumors.CONCLUSION: In our study, although abnormal MMR was present in a subset ofovarian endometrioid adenocarcinoma, there were no morphologic features identifiedthat were associated with MMR status. Therefore, current Lynch syndromescreening algorithms that utilize morphologic markers in uterine cancer patients maynot be applicable in ovarian cancer patients. Strategies to identify ovarian cancerpatients at risk for Lynch syndrome will require investigation into clinical andbiomarker screening criteria for MMR/MSI testing other than patient age androutinely-assessed tumor morphology.