Desmoplastic Small Round Cell Tumors: Clinical Presentation, Molecular Characterization, and Therapeutic Approach of Seven Patients

Intra-Abdominal Desmoplastic Small Round Cell Tumor: Case Report and Brief Review of the Literature

Merkel cell carcinoma (MCC) is a rare neuroendocrine cutaneous malignancy that shares cytologic, histopathologic, and immunohistochemical features with other small round blue cell (SRBC) tumors. Although the trabecular pattern is anecdotally associated with MCC, objective data are lacking. This was a retrospective institutional review board-approved observational study conducted on microscopic images of 79 MCCs and 74 other SRBC tumors (desmoplastic small round cell tumor, primitive neuroectodermal tumor, neuroblastoma, embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, synovial sarcoma, carcinoid, metastatic small cell lung cancer, non-Hodgkin small cell lymphoma, retinoblastoma, medulloblastoma, nephroblastoma, small cell osteosarcoma, and round cell liposarcoma). An expert dermatopathologist evaluated blinded and randomized microscopic specimens and recorded histologic patterns (diffuse, infiltrative, large anastomosing nests, small islands, any trabecular, focal trabecular, mixed trabecular, and predominately trabecular). Trabecular features were identified in over 72% of MCCs but only rarely in non-MCC SRBC tumors. The presence of any amount of a trabecular pattern favored a diagnosis of MCC over SRBC tumors with a sensitivity of 72.2% and a specificity of 87.8%. If "any" and "focal" trabecular patterns were discounted, specificity rose to 93.2%. The presence of a trabecular pattern helps to differentiate MCC from other SRBC tumors, and specificity approaches that achieved with immunostaining.

Sox9, a master regulator of chondrogenesis, distinguishes mesenchymal chondrosarcoma from other small blue round cell tumors

Patient: Male, 9-year-oldFinal Diagnosis: Desmoplastic small round cell tumor • pancreatic cancerSymptoms: Abdominal painMedication:—Clinical Procedure: —Specialty: PathologyObjective:Rare diseaseBackground:Desmoplastic small round cell tumor (DSRCT) is a rare lethal malignant tumor with young male predominance. The majority of cases arise in the abdominopelvic region and are hypothesized to have a mesothelial origin. However, extra-abdominal and extraperitoneal DSRCT have been reported. It is extremely uncommon for the pancreas to be a primary site for DSRCT, and only 5 cases have previously been reported in the English literature. Clinically, DSRCT has a wide range of presentations from asymptomatic to life-threatening comorbidity, and it responds poorly to treatment despite aggressive therapy.Case Report:We report a previously healthy 9-year-old boy with an incidentally discovered abdominal mass of pancreatic origin. All necessary laboratory investigations were within normal limits. Computed tomographic imaging showed a huge left-side retroperitoneal mass measuring 15 cm in the greatest dimension that was accompanied by vascular encasement. The mass was resected successfully. Histopathological examination along with ancillary tests favored a diagnosis of DSRCT over other small round blue cell tumors. Detection of translocation t(11;22)(p13;q12) with EWSR1-WT1 gene fusion, based on reverse transcription-polymerase chain reaction analysis, confirmed the diagnosis. Approximately 7 months later, the tumor recurred with mesenteric lymph nodes metastasis and the child was placed on palliative therapy.Conclusions:It is worthwhile to consider DSRCT in the differential diagnosis of small round blue cell tumors, even in unusual sites, in a pediatric age group. Due to the poor prognosis, owing to chemotherapy resistance and a high rate of recurrence with significant tumor burden, reaching a precise diagnosis of DSRCT is essential. Almost all cases harbor the hallmark molecular alteration of t(11;22)(p13;q12) with EWSR1-WT1 gene fusion. Debulking surgery paired with a chemotherapy regimen comprising vincristine, doxorubicin, and cyclophosphamide and ifosfamide + etoposide has been shown to improve overall survival rate compared with other chemotherapeutic agents. However, no targeted therapeutic modality has been developed.

BACKGROUND Desmoplastic small round cell tumor (DSRCT) is a rare and highly aggressive soft tissue sarcoma, mainly occurring in male adolescents and young adults. It most commonly arises from the peritoneum and is characterized by the EWSR1-WT1 fusion gene. Patients typically present with widespread intra-abdominal disease and have a poor prognosis, with a 5-year survival rate of less than 15%. CASE REPORT A 23-year-old man presented with acute right upper quadrant abdominal pain, significant unintentional weight loss, early satiety, and constipation. Computed tomography (CT) of the abdomen and pelvis revealed multiple large hepatic masses, mesenteric lymphadenopathy, and duodenal thickening with partial luminal narrowing. CT-guided biopsy of a hepatic mass was performed but was inconclusive. Subsequent upper endoscopy with duodenal biopsy revealed a characteristic perinuclear dot-like Desmin staining pattern consistent with small round blue cell tumor, with immunohistochemistry positive for epithelial and myogenic markers. The patient was referred to a sarcoma center where he was started on systemic chemotherapy with a VAC/IE (vincristine, doxorubicin, cyclophosphamide/ifosfamide, etoposide) regimen. CONCLUSIONS This case highlights the diagnostic complexity of DSRCT, particularly in atypical liver-dominant presentations, and reinforces the importance of comprehensive tissue sampling and molecular confirmation to guide early, appropriate therapy. Continued research into targeted strategies is crucial to improve outcomes in this aggressive malignancy.

Desmoplastic small round cell tumor (DSRCT) is a rare, highly aggressive neoplasm typically presenting with widespread involvement of the abdominopelvic peritoneum of adolescent males, usually without organ-based primary. Although it is believed to originate from the serous (mainly peritoneal) membranes, intracranial, sinonasal, intraosseous, and other soft tissue sites are also documented. A chromosomal translocation t(11:22)(p13;q12) signature that fuses EWSR1 and WT1 genes results in the production of a chimeric protein with transcriptional regulatory activity that drives oncogenesis. Integration of clinical, morphologic, immunohistochemical, and genetic data is necessary to arrive at the correct diagnosis, especially when the tumor arises in an atypical site. A 15-year-old male presented with hematuria and was found to have a large renal tumor associated with adrenal, liver, lung, and bone metastases. Histopathologic and immunophenotypic features were distinctive for DSRCT. This diagnosis was confirmed by means of fluorescence in situ hybridization and cytogenetic analysis, which documented the pathognomonic t(11;22) translocation, and by reverse transcription polymerase chain reaction on snap-frozen tissue, which revealed the EWSR1/WT1-specific chimeric transcript. Despite high-dose chemotherapy and radiation therapy targeted to a single T11 vertebral metastasis, the disease progressed, and the patient died 4 years after the diagnosis. A search of electronic databases for DSRCT yielded 16 cases of well-documented renal primaries out of around 1570 cases from all sites gathered from the global literature. Desmoplastic small round blue cell tumor and other primary renal tumors considered in the differential diagnosis with DSRCT are discussed.

EWSR1 fusions: Ewing sarcoma and beyond.

Detection of Common Chromosomal Translocations in Small Round Blue Cell Pediatric Tumors

Ovarian neoplasms composed predominantly or exclusively of small round cells with scant cytoplasm are relatively rare. However, there is a wide differential, and pathologists often struggle to make a correct diagnosis because of overlapping histologic features. Perhaps the best known of these neoplasms is ovarian small cell carcinoma of hypercalcemic type (OSCCHT), a tumor of unknown histogenesis. This may be confused with a wide range of neoplasms ranging from sex cord-stromal tumors (some of which may exhibit a small cell phenotype) to neoplasms in the family of small round blue cell tumors to various undifferentiated malignancies. A neuroendocrine small cell carcinoma, so-called small cell carcinoma of pulmonary type, may also arise within the ovary, and this may be a component of a typical ovarian surface epithelial-stromal tumor. In addition to the well-known family of small round blue cell tumors of childhood, other small cell neoplasms that may arise within the ovary or involve the ovary include intra-abdominal desmoplastic small round cell tumor, metastatic small cell carcinoma, peripheral and central primitive neuroectodermal tumor, and endometrial stromal sarcoma. Malignant melanoma, undifferentiated carcinoma, and various germ cell tumors, especially dysgerminoma and immature teratoma, also on occasion enter into the differential diagnosis of an ovarian small cell neoplasm. In this review, the morphologic features of some of these neoplasms are described, as is the value of immunohistochemistry and other ancillary techniques in establishing a diagnosis.

Desmoplastic small round cell tumor (DSRCT) is a rare and high malignant soft tissue tumor with very poor prognosis. It usually occurs in the abdominopelvic cavity of adolescents and young males. DSRCT is prone to occur distant metastasis, mainly in the liver and lung. The histopathological manifestation is featured with nests of small round blue cells separated by desmoplastic stroma. DSRCT can co-express epithelial, neural and mesenchymal markers. The molecular characteristic of DSRCT is the production of EWS-WT1 fusion protein via the translocation of chromosome t (11; 22) (p13; q12). Treatments of DSRCT include radical resection or cytoreductive surgery, high intensity systemic chemotherapy, local radiotherapy and hyperthermic intraperitoneal chemotherapy. Key words: Diagnosis; Therapy; Desmoplastic small round cell tumor

Evaluation of ETV4 and WT1 expression in CIC-rearranged sarcomas and histologic mimics

Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive, malignant tumor usually present with widespread abdominal serosal involvement. Isolated cases occur in limbs, head and neck, and brain. We present a case of primary DSRCT of the kidney in a 41-year-old man. The tumor showed morphologic, immunohistochemical, and molecular characteristics similar to DSRCTs arising in other sites. Epithelial and mesenchymal markers were coexpressed in the tumor cells. RT-PCR analysis showed EWS-WT1 fusion transcripts resulting from the t(11;22)(p13;q12) reciprocal translocation. DSRCT should be considered in the differential diagnosis of small blue round cell tumors of the kidney.

BackgroundEwing's sarcoma (ES) and desmoplastic small round cell tumors (DSRCT) are small round blue cell tumors driven by an N-terminal containing EWS translocation. Very few somatic mutations have been reported in ES, and none have been identified in DSRCT. The aim of this study is to explore potential actionable mutations in ES and DSRCT.MethodologyTwenty eight patients with ES or DSRCT had tumor tissue available that could be analyzed by one of the following methods: 1) Next-generation exome sequencing platform; 2) Multiplex PCR/Mass Spectroscopy; 3) Polymerase chain reaction (PCR)-based single- gene mutation screening; 4) Sanger sequencing; 5) Morphoproteomics.Principal FindingsNovel somatic mutations were identified in four out of 18 patients with advanced ES and two of 10 patients with advanced DSRCT (six out of 28 (21.4%));KRAS (n = 1), PTPRD (n = 1), GRB10 (n = 2), MET (n = 2) and PIK3CA (n = 1). One patient with both PTPRD and GRB10 mutations and one with a GRB10 mutation achieved a complete remission (CR) on an Insulin like growth factor 1 receptor (IGF1R) inhibitor based treatment. One patient, who achieved a partial remission (PR) with IGF1R inhibitor treatment, but later developed resistance, demonstrated a KRAS mutation in the post-treatment resistant tumor, but not in the pre-treatment tumor suggesting that the RAF/RAS/MEK pathway was activated with progression.ConclusionsWe have reported several different mutations in advanced ES and DSRCT that have direct implications for molecularly-directed targeted therapy. Our technology agnostic approach provides an initial mutational roadmap used in the path towards individualized combination therapy.

We evaluated the feasibility and usefulness of reverse transcriptase-polymerase chain reaction (RT-PCR) on fine-needle aspirates for categorization of small blue round cell tumors (SBRCTs). A total of 51 cases, including 25 Ewing sarcoma/peripheral primitive neuroectodermal tumors (PNETs), 11 rhabdomyosarcomas, 13 neuroblastomas, and 2 desmoplastic small round cell tumors (DSRCTs) were analyzed. The detection of the EWS-FLI1 (20/25) and EWS-ERG (4/25) fusion transcripts resolved 24 of 25 cases of Ewing sarcoma/PNET. The PAX3/7-FKHR fusion transcript was detected in 2 of 4 cases of alveolar rhabdomyosarcoma and the EWS-WT1 transcript in both cases of DSRCT. Tyrosine hydroxylase and 3,4-dihydroxyphenylalanine (dopa) decarboxylase transcripts were demonstrated in 10 of 13 cases of neuroblastoma. In comparison, immunocytochemical analysis resolved 19 (76%) of 25 Ewing sarcomas, 9 (82%) of 11 rhabdomyosarcomas, 6 (46%) of 13 neuroblastomas, and 1 (50%) of 2 DSRCTs. Overall, RT-PCR resolved 38 (86%) of 44 vs 35 (69%) of 51 cases by immunocytochemical analysis. RT-PCR is easily applied to fine-needle aspirates of SBRCT and greatly facilitates accurate tumor typing.

The Expression of WT1 in the Differentiation of Rhabdomyosarcoma from Other Pediatric Small Round Blue Cell Tumors