A Case of CDKN2C/CIC Null Epithelioid Leiomyosarcoma With a Low-grade Component Indistinguishable From Leiomyoma

Numerous emerging molecularly defined subtypes of uterine leiomyosarcoma (LMS) have been described in recent years. Here we report our experience with a challenging case of the recently described CDKN2C/CIC null subtype of LMS - a LMS subtype that is frequently epithelioid in appearance, is wild-type for both TP53 and RB1 and may exhibit low-grade histology that falls short of LMS. The 48-year-old patient was initially diagnosed with an epithelioid leiomyoma with a component of intravenous leiomyomatosis. Recurrence occurred 5 years later with an extensive disease burden in the abdomen and pelvis. Upon review, the lesion in the hysterectomy specimen and the recurrent tumor had similar morphology. This included (1) focal epithelioid morphology meeting current diagnostic criteria for epithelioid LMS and (2) other areas with morphology indistinguishable from leiomyoma (LM), including conventional spindle cell LM, cellular LM, and LM with bizarre nuclei. Targeted next-generation molecular analysis performed on both the original tumor in the hysterectomy specimen and the tumor from the recurrence showed the same CDKN2C/CIC null profile. This case highlights the striking intratumoral heterogeneity that is possible in CDKN2C/CIC null LMS, including areas morphologically indistinguishable from LM. Clinicopathological findings in this case, including features that may assist in recognizing this challenging LMS subtype, are discussed. We underscore the importance of early diagnosis, which can facilitate appropriate adjuvant and/or maintenance therapy that may decrease the morbidity associated with extensive debulking surgery.