Durable Response to Pazopanib (Tyrosine Kinase Inhibitor) in a Patient With EWSR1::CREM Gene Fusion Positive Intra-Abdominal Unclassified Epithelioid Sarcoma

Abstract

EWSR1::CREM fusion positive intrabdominal sarcomas defines a rare emerging group of aggressive mesenchymal neoplasms with a predilection for the celomic cavity and often manifesting perplexing immunophenotypic profile. There is no specific standard of care therapeutic option though anecdotal reports response to pazopanib have been reported. We report herein a case of a 62-year-old lady who presented with lower abdominal mass and pain. Right hemicolectomy performed showed a malignant epithelioid neoplasm. By immunohistochemistry, the tumor cells were positive for CD117, keratins, and mutation analysis was positive for KIT p.V5301 mutation, initially prompting a diagnosis of epithelioid gastrointestinal stromal tumor. However, the patient developed omental relapses while on imatinib and progressive disease persisted despite change to sunitinib. A re-review of the histopathology of both the hemicolectomy and relapsed omental sites showed marked cellular atypia, increased cellularity and mitosis in metastatic omental sites. By immunohistochemistry, the tumors in addition to CD117 positivity were also immunoreactive to keratins, synaptophysin, chromogranin, CD56, and MUC4. Next generation sequencing performed on both the primary and relapsed sites were positive for EWSR1::CREM gene fusion in addition to the KIT. P.V5301 mutation. The tumor was then reclassified as EWSR1::CREM fusion positive intrabdominal unclassified epithelioid sarcoma with concomitant KIT mutation of unknown significance. The patient was treated with cytotoxic chemotherapy and radiation therapy with partial response, but treatment was stopped because of complications and lack of tolerance. Pazopanib as a single agent was then initiated, and patients have continued to respond for the past 7 months. We highlight the significant immunophenotypic heterogeneity in these tumors and perform an extensive review of the literature of this specific entity and broader group of EWSR1::CREM/FUS fusion positive tumors ranging from quasi-benign to malignant and finally we underscore the therapeutic utility of pazopanib as a single agent in this rare group of aggressive sarcomas.