Desmoplastic Small Round Cell Tumor: Diagnosis and Therapeutics

Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive malignancy primarily affecting adolescents and young adults. It belongs to the family of small round blue cell tumors, known for high metastatic potential and poor prognosis. Due to its rarity and nonspecific symptoms, DSRCT is often diagnosed at an advanced stage, complicating treatment. Early detection and a multimodal approach combining surgery, chemotherapy, and emerging targeted therapies are critical for improving outcomes.

Histopathological Features

DSRCT exhibits a distinctive histopathological profile characterized by small, round, blue cells embedded in a dense desmoplastic stroma. Tumor cells are arranged in nests, sheets, or trabeculae, surrounded by an abundant fibrous matrix rich in collagen. This desmoplastic reaction helps differentiate DSRCT from other small round blue cell tumors like Ewing sarcoma or neuroblastoma. Tumor cells display hyperchromatic nuclei with scant cytoplasm, contributing to their small, round appearance. Mitotic figures are frequent, reflecting the tumor’s aggressive nature.

Immunohistochemical staining plays a crucial role in diagnosis. DSRCT exhibits a unique polyphenotypic expression pattern, co-expressing epithelial, mesenchymal, and neural markers. Cytokeratins (AE1/AE3 and CAM 5.2) and epithelial membrane antigen (EMA) highlight epithelial differentiation, while desmin, often showing a perinuclear dot-like pattern, confirms mesenchymal lineage. Neural markers such as neuron-specific enolase (NSE) and synaptophysin may be positive, further underscoring the tumor’s heterogeneous differentiation. WT1 staining, particularly with antibodies targeting the C-terminal region, is a highly specific finding distinguishing DSRCT from other small round cell tumors.

Ultrastructural examination via electron microscopy provides additional insights. Tumor cells contain primitive intercellular junctions and scant organelles, with occasional rudimentary microvilli. The dense desmoplastic stroma, composed of fibroblasts and extracellular matrix proteins, contributes to the tumor’s firm consistency and invasive nature. Tumor-stromal interactions likely play a role in disease progression and therapy resistance.

Genetic And Molecular Characteristics

DSRCT is defined by the chromosomal translocation t(11;22)(p13;q12), resulting in the EWSR1-WT1 gene fusion. This genetic anomaly is a primary driver of tumorigenesis. The fusion combines the EWSR1 gene, which encodes a protein involved in RNA binding and transcriptional regulation, with the WT1 gene, a transcription factor critical for cellular differentiation and development. The resulting fusion protein acts as an aberrant transcriptional regulator, dysregulating key pathways involved in proliferation, survival, and invasion.

The EWSR1-WT1 fusion leads to upregulation of growth-promoting and anti-apoptotic genes, facilitating DSRCT’s aggressive behavior. One notable target is PDGFA (platelet-derived growth factor A), which enhances autocrine and paracrine signaling to stimulate tumor proliferation and stromal remodeling. Additionally, the fusion protein modulates IGF2 (insulin-like growth factor 2) expression, a key factor in sarcoma progression, enhancing tumor cell migration and invasion.

Epigenetic modifications also contribute to DSRCT pathogenesis. Hypermethylation of tumor suppressor genes such as CDKN2A (p16) leads to unchecked cell cycle progression. Altered histone acetylation affects chromatin accessibility, amplifying the transcriptional effects of the EWSR1-WT1 fusion protein. These findings highlight potential therapeutic targets involving epigenetic regulators.

Common Sites Of Involvement

DSRCT predominantly arises within the abdominal and pelvic peritoneum, often presenting as widespread peritoneal nodules at diagnosis. The tumor typically originates in the omentum or mesentery and spreads along serosal surfaces, leading to complications such as bowel obstruction, ascites, and peritoneal carcinomatosis. Unlike other small round blue cell tumors that may present as localized masses, DSRCT’s multifocal peritoneal disease contributes to its aggressive course.

Metastasis to visceral organs is common, with the liver being a frequent site of secondary involvement. Hepatic metastases usually present as multiple nodular lesions rather than a solitary mass. Lung metastases manifest as diffuse pulmonary nodules or pleural implants, further complicating respiratory function. Bone metastases, though less common, typically affect the axial skeleton, causing pain and an increased risk of pathological fractures.

DSRCT has also been reported in extra-abdominal locations, including the thoracic cavity, paratesticular region, and intracranial structures. These rare presentations highlight the tumor’s capacity for widespread dissemination. Nodal involvement, particularly in the retroperitoneal and mediastinal lymph nodes, emphasizes the importance of comprehensive staging at diagnosis.

Clinical Presentation

Patients with DSRCT often experience vague, nonspecific symptoms, delaying diagnosis. The most common initial complaint is abdominal pain, which may be intermittent or persistent, worsening as the tumor burden increases. A growing abdominal mass is frequently noted, sometimes accompanied by progressive distension due to peritoneal involvement and ascites. Unlike gastrointestinal malignancies, DSRCT rarely causes early obstructive symptoms, though advanced disease can lead to bowel obstruction or organ dysfunction.

Weight loss and fatigue commonly develop as the disease progresses. Some patients report early satiety, particularly when tumor nodules encroach upon the stomach or intestines. In male patients, paratesticular involvement may present as a scrotal mass, mimicking other neoplasms. When the tumor spreads beyond the abdomen, respiratory symptoms such as dyspnea and pleuritic chest pain may emerge, often signaling pulmonary or pleural metastases. Skeletal involvement can manifest as bone pain or pathological fractures.

Diagnostic Approaches

Diagnosing DSRCT requires a combination of imaging, histopathology, and molecular testing. Radiological studies help assess disease extent, with computed tomography (CT) and magnetic resonance imaging (MRI) being primary modalities. CT scans typically reveal large, heterogeneous soft-tissue masses with peritoneal dissemination and ascites. MRI provides superior soft tissue contrast, aiding in visualization of tumor invasion. Fluorodeoxyglucose positron emission tomography (FDG-PET) is useful for detecting distant metastases but is not definitive.

Histological confirmation is necessary to distinguish DSRCT from other small round blue cell tumors. Tissue biopsy, often via laparoscopic or image-guided core needle techniques, provides samples for microscopic and immunohistochemical analysis. The presence of desmoplastic stroma and polyphenotypic marker expression supports the diagnosis. Molecular testing for the EWSR1-WT1 fusion using fluorescence in situ hybridization (FISH) or reverse transcription-polymerase chain reaction (RT-PCR) is a definitive diagnostic tool. Staging laparoscopy may be employed to assess disease burden and guide treatment planning.

Pharmacological Strategies

Systemic treatment is the cornerstone of DSRCT management, as most cases present with widespread disease at diagnosis. Chemotherapy remains the primary pharmacological approach, often supplemented by emerging targeted agents.

Chemotherapy

Multi-agent chemotherapy, typically using regimens employed in Ewing sarcoma, is the standard initial treatment. The P6 protocol, which includes cyclophosphamide, doxorubicin, and vincristine (CAV), alternating with ifosfamide and etoposide (IE), has shown efficacy in tumor reduction. High-dose alkylating agents, such as cyclophosphamide and ifosfamide, are particularly effective due to their cytotoxic effects on rapidly dividing cells. Despite significant tumor shrinkage, relapse rates remain high, necessitating consolidation with surgery and radiation.

Dose-intensified chemotherapy followed by autologous stem cell transplantation has been explored for long-term disease control. Some studies suggest myeloablative therapy with hematopoietic rescue may prolong survival, though benefits remain unproven in large cohorts. Resistance frequently develops, prompting investigation into novel agents.

Targeted Agents

Given the molecular drivers of DSRCT, targeted therapies are under investigation. Tyrosine kinase inhibitors (TKIs) like pazopanib and sunitinib inhibit angiogenic pathways critical for tumor progression. These agents target vascular endothelial growth factor receptors (VEGFR), disrupting blood supply and limiting tumor growth. Early studies suggest modest efficacy, though responses are often transient.

Other investigational approaches include insulin-like growth factor 1 receptor (IGF-1R) inhibitors, given the role of IGF2 upregulation in DSRCT. Agents such as linsitinib have been tested, with mixed results. Ongoing trials are assessing combination strategies to enhance treatment efficacy.

Hormone Receptor-Targeting Agents

DSRCT expresses WT1, and some cases exhibit androgen receptor (AR) positivity, raising the possibility of hormone-based interventions. Anti-androgen therapies such as enzalutamide or abiraterone, used in prostate cancer, have been considered, though clinical evidence is limited. Estrogen receptor (ER) and progesterone receptor (PR) expression is inconsistent, but selective estrogen receptor modulators (SERMs) like tamoxifen have been proposed in experimental settings.

Prognostic Factors

Survival outcomes in DSRCT are poor, with five-year overall survival rates ranging between 15% and 30%. Prognosis is influenced by tumor burden at diagnosis, response to chemotherapy, and the feasibility of complete surgical resection. Patients with limited peritoneal disease who undergo gross total resection have better outcomes. The presence of hepatic or pulmonary metastases worsens prognosis, given the difficulty in achieving local control. High IGF2 expression has been associated with more aggressive disease, highlighting the need for personalized treatment approaches.