FUMARASE DEFICIENT UTERINE LEIOMYOMAS – AN IMMUNOHISTO-CHEMICAL, MOLECULAR GENETIC, AND CLINICOPATHOLOGIC STUDY OF 86 CASES

Loss-of-function germline mutations in the fumarase ( FH )-gene of the Krebs cycle characterize hereditary leiomyomatosis and renal cell cancer (HLRCC)-syndrome. Fumarase (FH)-deficiency can be diagnosed by the loss of immunohistochemical expression. In this study, we investigated the occurrence and clinicopathologic features of FH-deficient uterine smooth muscle tumors (SMTs). A total of 1583 uterine and 157 non-uterine SMTs were examined using a polyclonal FH antibody and automated immunohistochemistry, and 86 uterine leiomyomas with an FH loss were identified. The frequencies of FH-deficiency for subcohorts of uterine SMTs were 1.6% for unselected non-atypical leiomyomas, 1.8% for cellular leiomyomas, 37.3% for atypical leiomyomas, and 0% for leiomyosarcomas. One extrauterine, retroperitoneal ER-positive leiomyoma, was also FH-deficient. The patient age of FH-deficient uterine leiomyomas was 20-52 years (median, 38 years). Grossly these tumors were often soft and amorphous resembling a fibrothecoma. Histologically the FH-deficient non-atypical leiomyomas lacked cellular packeting and distinct collagenous zones and showed chain-like or palisading nuclear arrangements, prominent staghorn-shaped blood vessels, oval nuclei with no or at most, mild atypia, small eosinophilic nucleoli, and a low mitotic rate (0-1/10 HPFs). The FH-deficient atypical leiomyomas had nuclear atypia often manifesting as multinucleation, prominent eosinophilic nucleoli, and mitotic activity up to 7/10 HPFs, with atypical mitoses seen in 32% of cases. However, similar histologic changes were seen in some non FH-deficient atypical leiomyomas. Loss-of-function FH -gene mutations including 5 whole gene deletions and 3 frameshift mutations were identified in 8 of 16 FH-deficient non-atypical leiomyomas using multiplex ligation-dependent probe amplification and Sanger sequencing, respectively. Follow-up data on patients with FH-deficient atypical uterine leiomyomas revealed 19 patients alive (median follow-up 27 years) and 5 patients dead. Deaths were 9-30 years after surgery at median age of 72 years; causes of death could not be determined. These results indicate that FH-deficient uterine leiomyomas occur with a high frequency among atypical leiomyomas and infrequently in non-atypical leiomyomas and are often histologically distinctive. They seem to have a low biologic potential and lack any significant association with leiomyosarcoma.