Desmoplastic Small Round Cell Tumor: A Review of Main Molecular Abnormalities and Emerging Therapy

Abstract

Desmoplastic small round cell tumor (DSRCT) is an extremely rare, aggressive sarcoma affecting adolescents and young adults with male predominance. Generally, it originates from serosal surface of abdominal cavity. The hallmark characteristic of DSRCT is the EWSR1-WT1 gene fusion. This translocation up-regulates the expression of PDGFRα, VEGF and other proteins related to tumor and vascular cell proliferation. Current management of DSRCT includes a combination of chemotherapy, radiation and aggressive cytoreductive surgery plus intra-peritoneal hyperthermic chemotherapy (HIPEC). Despite advances in multimodal therapy, outcomes remain poor since the majority of patients present disease recurrence and die within 3 years. The dismal survival makes DSRCT an orphan disease with urgent need of new drugs. The treatment of advanced and recurrent disease with tyrosine kinase inhibitors, such as pazopanib, sunitinib, and mTOR inhibitors have been evaluated in small studies. Recent works using comprehensive molecular profiling of DSRCT identified potential therapeutic targets. In this review, we aim to describe the current studies conducted to better understand DSRCT biology and to explore the new therapeutic strategies under investigation in preclinical models and in early phase clinical trials.

The Small Round Cell Sarcomas Complexities and Desmoplastic Presentation

“…DSRCT exhibits polyphenotypic differentiation, but majority of cases show both keratins and desmin positivity [49, 53, 54]. Typical clinical presentation in addition to a unique translocation t(11;22)(p13;q12) with EWSRI-WT1 gene fusion [48, 49] helps to distinguish DSRCT from other small blue round cell tumors and small cell carcinomas.…”

“…An extra-abdominal location is rare, with the thorax and para testicular area being the most common sites. The prognosis of DSRCT is extremely poor and the average survival is less than 3 years [1, 47, 48].…”

“…DSRCT exhibits polyphenotypic differentiation, and neoplastic cells typically express epithelial (keratin and EMA), myogenic (desmin), mesenchymal (vimentin), neural (neuroendocrine), and WT1 markers [49, 53, 54]. DSRCT is characterized by a unique translocation t(11;22)(p13;q12) with EWSRI-WT1 gene fusion [48].…”

Selective Immunoreactivity for WT1 Carboxy-Terminus Distinguishes Desmoplastic Small Round Cell Tumor From its Histologic Mimics

“…DSRCT is a notoriously deadly tumor with a dismal median survival of 10 to 16 months, and approximately 60-70% of patients died of disease within 3 years. 24,25 The WT1 protein (encoded by the WT1 gene located on chromosome 11p13) is physiologically expressed in the mesoderm-derived tissues of the developing genitourinary system and mesothelial tissues. 26 It has also been demonstrated in some neoplasms including malignant mesotheliomas, ovarian serous adenocarcinomas, Wilms tumors, and some soft tissue sarcomas.…”

“…DSRCT is a notoriously deadly tumor with a dismal median survival of 10 to 16 months, and approximately 60–70% of patients died of disease within 3 years. 24,25…”