Desmoplastic Small Round Blue Cell Tumor in a Young Adult Man: A Rare Case of Abdominal Sarcoma

Introduction

Desmoplastic small round blue cell tumor (DSRCT) is a rare, highly aggressive soft tissue sarcoma characterized by small, round tumor cells that exhibit a distinctive pattern of polyphenotypic differentiation, surrounded by a prominent desmoplastic stroma [1]. DSRCT typically presents as a large abdominal mass and is usually diagnosed at advanced or metastatic stages, often featuring multiple peritoneal metastatic nodules and, in some cases, distant metastases [2]. The prognosis for advanced DSRCT is poor, with a reported 5-year survival rate of 15% [3].

First identified as a distinct pathological entity in 1989 by Gerald and Rosai [4], DSRCT remains exceedingly rare and shows a strong male predominance, with the average age at diagnosis being approximately 22 years [5]. While patients often present with nonspecific symptoms, such as abdominal pain, weight loss, or bowel discomfort [6,7], liver-predominant metastatic disease is not a usual initial finding in DSRCT and can lead clinicians to consider alternative diagnoses, such as metastatic carcinoma, lymphoma, or other small round blue cell tumors. In this context, early recognition and appropriate tissue sampling become critical, as fine-needle aspiration can be insufficient to detect the characteristic desmoplastic stroma, delaying molecular confirmation of the Ewing sarcoma breakpoint region 1–Wilms tumor 1 (EWSR1–WT1) fusion gene.

The present case is notable for the therapeutic complexity associated with rare liver-dominant DSRCT, which complicates both systemic treatment delivery and surgical decision-making. Despite advances in multimodal therapy, including VAC/IE (vincristine, doxorubicin, cyclophosphamide/ifosfamide, etoposide)-based chemotherapy, cytoreductive surgery, and emerging targeted treatments, outcomes remain poor [8], and there is no consensus on optimal sequencing for atypical presentations, such as liver-dominant disease.

By highlighting an uncommon clinical pattern and its associated diagnostic and therapeutic implications, this case underscores the need for heightened clinical awareness and contributes to the growing discussion on refining treatment strategies and exploring novel targeted approaches in DSRCT.

Case Report

A 23-year-old man with no significant past medical history presented to the emergency department with severe acute onset right upper abdominal pain, rated 10 out of 10, which began 1 day earlier. The patient described the pain as sharp and initially intermittent. He also reported experiencing constipation, nausea, and vomiting. The pain did not appear to be related to his eating habits, and he had not been taking any daily medications or herbal supplements. He denied having a prior history of constipation, abdominal discomfort, or pain. Additionally, he had experienced a significant weight loss of 30 pounds in less than a month.

Three years earlier, the patient had an episode of bloody diarrhea that resolved spontaneously. An esophagogastroduodenoscopy (EGD), colonoscopy, and computed tomography (CT) scan of the abdomen and pelvis at that time were unremarkable. This prior episode was assessed as an isolated, self-limited gastrointestinal event with no residual abnormalities, and there was no evidence to suggest a relationship to the current presentation, which was considered a new and unrelated clinical onset.

The patient was admitted to the hospital, and a CT scan of the abdomen and pelvis was performed (Figure 1). The findings indicated hepatomegaly with a neoplastic etiology and multiple metastatic hepatic nodules. The largest lesion measured 10.3×8.5×9.8 cm in segment V of the liver. Additionally, enlarged mesenteric lymph nodes were observed, which further raised concerns about a metastatic cause. An abnormal mucosal thickening and under-distention involving the proximal small bowel was observed, limiting the evaluation of the lumen.

Lactate dehydrogenase level was 205. Carbohydrate antigen 19-9 and carcinoembryonic antigen were within normal limits. Viral etiologies, including HIV, hepatitis C virus, and hepatitis B virus, were negative. Alpha-fetoprotein level was normal. The patient had transaminitis, with alanine aminotransferase, 126; aspartate aminotransferase, 71; and alkaline phosphatase, 198. Total bilirubin was within the reference range.

Magnetic resonance imaging was performed, demonstrating multiple hepatic masses, most consistent with metastases, a mesenteric mass and/or lymphadenopathy, and multiple small mesenteric lymph nodes (Figure 2). The predominance of extensive hepatic tumor burden at this stage was unusual for typical patterns of intra-abdominal malignancy in young patients and broadened the diagnostic considerations beyond common diffuse peritoneal disease.

The patient underwent a CT-guided biopsy of a liver lesion, during which serosanguinous fluid was extracted and sent for culture and cytology. Both tests returned negative results for infection and malignant cells. The patient also underwent EGD, given the radiographic evidence of proximal small bowel thickening and narrowing. EGD findings were suggestive of either malignant or benign non-traversed severe duodenal stenosis. Additionally, there were mucosal changes in the duodenum, possibly due to extrinsic compression or a submucosal mass. Duodenal biopsy was obtained. Immunohistochemical stains performed on the duodenal biopsy specimen indicated that the tumor was positive for keratin and desmin, raising suspicion for a DSRCT (Figure 3). An EWSR1 break-apart fluorescence in situ hybridization test was ordered, which was positive for the EWSR1-WT1 fusion gene.

The patient was referred to a sarcoma center, where he was started on systemic chemotherapy with a VAC/IE regimen, with plans for restaging via CT imaging before the third cycle of chemotherapy. The VAC/IE regimen was selected because it remains the most widely used first-line protocol for DSRCT, due to its proven activity in Ewing sarcoma family tumors, which share chemosensitivity profiles.

The patient tolerated the chemotherapy well. Restaging CT that was done prior to cycles 3 and 5 demonstrated decreased numerous bilobar hepatic tumors, unchanged thoracic nodal metastases, and slightly decreased abdominal nodal metastases. The patient’s significant symptom burden related to his tumor burden improved, both due to supportive care regimen optimization and treatment response, as evidenced by his restaging scans. A repeat restaging CT of the chest, abdomen, and pelvis with triphasic liver was planned before cycle 7.

Discussion

DSRCT is an exceptionally aggressive cancer with few available therapeutic strategies. Research suggests that DSRCT may arise from a developmental progenitor cell capable of differentiating into multiple tissue types [9,10]. While DSRCT typically presents with abdominal masses and nonspecific symptoms, such as pain and weight loss, our case was notable for the liver-dominant tumor burden, which is an uncommon initial pattern, compared with the more frequently reported peritoneal-based disease.

The neoplastic cells in DSRCT display multilineage differentiation, often expressing markers from various cell types. The defining molecular hallmark of DSRCT is the EWSR1–WT1 fusion gene, resulting from the t(11;22)(p13;q12) translocation, which produces an aberrant transcription factor driving oncogenesis.

Given the small round blue cell morphology observed in this case, the differential diagnosis initially included Ewing sarcoma/primitive neuroectodermal tumor, rhabdomyosarcoma, neuroblastoma, and lymphoma. Ewing sarcoma was considered owing to the patient’s age and the presence of small round tumor cells; however, Ewing sarcoma typically demonstrates strong CD99 membranous staining and harbors the EWSR1–FLI1 or related translocations rather than the EWSR1–WT1 fusion identified in our patient. Rhabdomyosarcoma was also a consideration, particularly the alveolar subtype, but the absence of myogenin and MyoD1 nuclear positivity made this diagnosis less likely. Neuroblastoma can present with small round blue cells and abdominal involvement, but it is usually associated with elevated catecholamines and immunoreactivity for PHOX2B and synaptophysin, which were not seen in this case. Lymphoma was ruled out based on the lack of lymphoid marker expression (CD45) and the presence of a desmoplastic stroma, which is atypical for hematologic malignancies. The characteristic perinuclear dot-like desmin staining pattern, combined with keratin positivity and molecular confirmation of the EWSR1–WT1 fusion gene, was highly specific for DSRCT and allowed for a definitive diagnosis.

Consistent with prior reports, contrast imaging identified multifocal hepatic disease, but a definitive diagnosis required core biopsy rather than fine-needle aspiration, due to the characteristic stromal features needed to confirm DSRCT.

The EWSR1–WT1 fusion protein is the principal oncogenic driver in DSRCT, contributing to tumor formation by enhancing the transcription of numerous genes [11]. Acting as a dominant transcriptional activator, this chimeric protein promotes the expression of several growth-related genes, such as PDGFRA, IGF1R, EGFR, IL2, and IL15, along with key regulatory transcription factors, including MYC, PAX2, and WT1 [12].

DSRCT typically exhibits widespread metastatic spread at presentation [13], making complete surgical resection challenging. Current management relies on multimodal therapy, combining systemic chemotherapy, cytoreductive surgery, and radiotherapy, as recommended by existing sarcoma treatment protocols [14,15].

Complete cytoreductive surgery has been associated with improved survival (47 vs 16 months in one series), although relapse remains common even after initial chemotherapy response [16]. The optimal chemotherapy protocol for achieving a cure in DSRCT remains uncertain. Nevertheless, most regimens are modeled after treatments for other small round cell sarcomas and typically combine an anthracycline, an alkylating agent, and a vinca alkaloid.

Radiation therapy is used either palliatively or after cytoreduction, although evidence for long-term survival benefit remains limited. Hyperthermic intraperitoneal chemotherapy has also been explored but offers little advantage in cases with extra-abdominal spread [15].

While most reported DSRCT cases describe widespread peritoneal involvement at diagnosis, liver-dominant presentation such as in our patient has only been described in isolated case reports and small institutional series. In a review by Subbiah et al and data from the French national sarcoma registry, hepatic lesions were typically secondary findings rather than the leading disease burden. This distinction is clinically relevant, as liver-predominant involvement may delay consideration of DSRCT in the differential and affect early management decisions. These differences in presentation underscore the importance of individualized treatment planning, particularly when hepatic tumor burden dominates disease behavior.

Despite the use of intensive multimodal therapy, long-term outcomes for patients with DSRCT remain poor, with 5-year survival rates ranging between 15% and 30% (8). In addition, most individuals derive little benefit from second-line chemotherapy regimens [12]. This has underscored the urgent need for innovative, targeted treatment strategies. DSRCT is known to be a highly vascular tumor, marked by elevated expression of proteins that drive and maintain angiogenesis, which is vital for tumor progression [12]. As a result, researchers have investigated the therapeutic potential of tyrosine kinase inhibitors that target vascular endothelial growth factor, vascular endothelial growth factor receptor, platelet-derived growth factor receptor alpha, and related angiogenic pathways [17–19]. Several agents – such as pazopanib, apatinib, sunitinib, ramucirumab, and bevacizumab – have been evaluated in clinical studies, with some reports documenting modest clinical benefit [16,18–21].

Neurotrophic receptor tyrosine kinase 3 (NTRK3) is a membrane-bound receptor that plays a vital role in nervous system development and function. The FDA-approved NTRK3-targeting agent entrectinib was assessed in 3 patient-derived xenograft models, demonstrating near-complete tumor growth suppression in 1 model and tumor size reductions of approximately 50% and 75% in the other 2 models. A current clinical trial (NCT04901806) is actively exploring the therapeutic potential of PBI-200, another NTRK3 inhibitor, in a study population that includes patients with DSRCT.

The predominance of DSRCT in young male patients has led researchers to explore whether the testosterone synthesis pathway contributes to the development of this malignancy. In a study involving 27 patients who had undergone multiple prior treatments, 37% were found to express androgen receptors [22]. Supporting this, a separate investigation using single-sample gene set enrichment analysis reported that most DSRCT cases showed higher androgen receptor pathway activity than did other sarcoma types [5]. Research by Lamhamedi-Cherradi revealed that enzalutamide and androgen receptor–targeted antisense oligonucleotides were capable of inhibiting dihydrotestosterone-stimulated DSRCT cell growth and reducing tumor mass in xenograft models [23]. Additionally, a recent in vitro analysis demonstrated that 3 DSRCT cell lines were sensitive to high concentrations of androgen receptor inhibitors, including enzalutamide, flutamide, and darolutamide [24].

Recent next-generation sequencing studies have identified a subset of DSRCT tumors harboring secondary mutations in genes involved in DNA damage repair pathways [25]. Additionally, new evidence indicates that the EWS–WT1 fusion gene induces replication stress through R-loop formation, revealing a therapeutic vulnerability [2]. Experimental models, in vitro and in vivo, have shown that DSRCT is responsive to inhibition by poly(ADP-ribose) polymerase (PARP; PARPi) and ATR (ATRi), whether administered individually or in combination.

The cyclin D–cyclin-dependent kinase 4/6 (CDK4/6)–retinoblastoma signaling pathway, which plays a central role in regulating the G1 phase to S phase of cell cycle transition, is frequently altered in many cancer types. Research by Magrath et al identified CDK4/6 inhibition as a potential treatment strategy in DSRCT, due to the pathway’s regulation by the EWSR1–WT1 fusion product [26]. In preclinical xenograft studies, the CDK4/6 inhibitor palbociclib significantly suppressed tumor growth in 2 DSRCT models [27].

The recent availability of new DSRCT samples and cell lines has significantly advanced our understanding of DSRCT biology and helped identify various new therapeutic targets. Many of these targets relate to pharmaceuticals with completed safety testing and FDA approval for the treatment of other cancers. Moving forward, trials that include single therapies and combination therapies should be prioritized by sarcoma researchers, as they may represent the most effective approach [27]. In the context of atypical presentations with high hepatic tumor burden, such as ours, future incorporation of molecularly guided therapies – including PARP inhibition in fusion-driven replication stress and NTRK or CDK4/6 inhibitors in selected molecular subsets – may offer a more personalized treatment pathway than do the current uniform chemotherapy-based regimens.

Conclusions

This report underscores a clinically rare liver-dominant presentation of DSRCT, a pattern that differs from the more typical peritoneal-based disease and contributes to significant diagnostic delay. In our patient, the liver-dominant pattern initially widened the diagnostic differential, and confirmation of the EWSR1–WT1 fusion gene through molecular testing was essential in establishing a definitive diagnosis after inconclusive initial biopsy. This case highlights the importance of thorough diagnostic workup, including tissue biopsy and molecular testing, in reaching a timely and accurate diagnosis. While treatment remains difficult and outcomes are often poor, this case reflects how early recognition and a multidisciplinary approach can lead to symptom improvement and disease control. While current treatment strategies offer limited long-term success, recent advances in molecular profiling and targeted therapies provide a promising frontier.

Given emerging evidence supporting targeted approaches such as PARP inhibition in fusion-driven replication stress, NTRK-directed therapy with agents like entrectinib, and CDK4/6 blockade in EWSR1–WT1–regulated pathways, future management of cases with dominant hepatic disease burden like ours may increasingly rely on molecularly stratified treatment strategies. Continued clinical research and prospective trials are critical to improving outcomes for patients with this aggressive malignancy. Future prospective studies should specifically evaluate whether earlier molecular stratification and inclusion of agents such as PARP, NTRK, or CDK4/6 inhibitors improve outcomes in patients with atypical liver-predominant DSRCT presentations.