Clinicopathologic and molecular features of intracranial desmoplastic small round cell tumors

Abstract

Desmoplastic small round cell tumors (DSRCTs) are highly aggressive sarcomas that most commonly occur intra‐abdominally, and are defined by EWSR1‐WT1 gene fusion. Intracranial DSRCTs are exceptionally rare with only seven previously reported fusion‐positive cases. Herein, we evaluate the clinical, morphologic, immunohistochemical and molecular features of five additional examples. All patients were male (age range 6–25 years; median 11 years), with four tumors located supratentorially and one within the posterior fossa. The histologic features were highly variable including small cell, embryonal, clear cell, rhabdoid, anaplastic and glioma‐like appearances. A prominent desmoplastic stroma was seen in only two cases. The mitotic index ranged from <1 to 12/10 HPF (median 5). While all tumors showed strong desmin positivity, epithelial markers such as EMA, CAM 5.2 and other keratins were strongly positive in only one, focally positive in two and negative in two cases. EWSR1‐WT1 gene fusion was present in all cases, with accompanying mutations in the TERT promoter or STAG2 gene in individual cases. Given the significant histologic diversity, in the absence of genetic evaluation these cases could easily be misinterpreted as other entities. Desmin immunostaining is a useful initial screening method for consideration of a DSRCT diagnosis, prompting confirmatory molecular testing. Demonstrating the presence of an EWSR1‐WT1 fusion provides a definitive diagnosis of DSRCT. Genome‐wide methylation profiles of intracranial DSRCTs matched those of extracranial DSRCTs. Thus, despite the occasionally unusual histologic features and immunoprofile, intracranial DSRCTs likely represent a similar, if not the same, entity as their soft tissue counterpart based on the shared fusion and methylation profiles.

The spectrum of rare central nervous system (CNS) tumors with EWSR1‐non‐ETS fusions: experience from three pediatric institutions with review of the literature

“…Our case showed atypical morphology and immunophenotype in a pattern that is similar to some of the previously reported pediatric brain cases (11, 39). Importantly, recent methylation studies have demonstrated that intracranial desmoplastic round cell tumors cluster along with their intrabdominal counterparts, supporting their shared histogenesis (39) and highlighting the importance of further molecular characterization and epigenetic profiling of primary EWSR1‐ rearranged neoplasms of the CNS.…”

“…Because this tumor most often arises within the abdominal cavity, it was initially thought that this entity originated from primitive mesothelial progenitors; however, several cases have been reported arising from different other locations (78). The occurrence of desmoplastic small round cell tumor within the CNS is an exceptionally rare event, with only 14 reported cases (2,11,39,47,69,77,80,87), 12 of which have been confirmed by molecular techniques and with only 6 verified pediatric cases (2,11,39) (Table 2). Our case showed atypical morphology and immunophenotype in a pattern that is similar to some of the previously reported pediatric brain cases (11,39).…”

“…The occurrence of desmoplastic small round cell tumor within the CNS is an exceptionally rare event, with only 14 reported cases (2,11,39,47,69,77,80,87), 12 of which have been confirmed by molecular techniques and with only 6 verified pediatric cases (2,11,39) (Table 2). Our case showed atypical morphology and immunophenotype in a pattern that is similar to some of the previously reported pediatric brain cases (11,39). Importantly, recent methylation studies have demonstrated that intracranial desmoplastic round cell tumors cluster along with their intrabdominal counterparts, supporting their shared histogenesis (39) and highlighting the importance of further molecular characterization and epigenetic profiling of primary EWSR1rearranged neoplasms of the CNS.…”

Intracranial mesenchymal tumor with FET‐CREB fusion—A unifying diagnosis for the spectrum of intracranial myxoid mesenchymal tumors and angiomatoid fibrous histiocytoma‐like neoplasms

“…A subset of these tumors demonstrates MUC4 immunopositivity, a protein marker previously thought to be highly specific to low‐grade fibromyxoid sarcoma and sclerosing epithelioid fibrosarcoma, tumor entities which are defined by fusion of FUS (or rarely EWSR1 ) to either CREB3L1 or CREB3L2 . The subset of tumors with round cell morphology, collagenous stroma, and polyphenotypic differentiation by immunohistochemistry with the combination of desmin, EMA, and synaptophysin positivity overlaps with desmoplastic small round cell tumor (DSRCT), which do rarely occur intracranially (39). Fluorescence in situ hybridization showing EWSR1 break‐apart does not allow distinction between DSRCT with EWSR1 ‐ WT1 fusions and those intracranial mesenchymal tumors with EWSR1 fusions to CREB family members.…”

Rationale for Early Detection of EWSR1 Translocation-Associated Sarcoma Biomarkers in Liquid Biopsy

“…In addition, the analysis of oncogenic mutations measured by PCR, tumour associated DNA methylation [ 21 ], and DNA-nucleosome complexes [ 26 ] can be detected and quantified. The epigenetic landscape of sarcoma tumours has been explored in several studies [ 27 , 28 , 29 , 30 ], and, although a consensus on epigenetic targets, therapies, and biomarkers in sarcoma is yet to emerge, recent perspectives on this area of research have attempted to refine the progress made so far [ 31 , 32 , 33 ]. In the context of liquid biopsy, several methylation sites have been described as predictive of prognosis for colorectal cancer [ 34 ], breast cancer [ 35 ], and liver cancer [ 36 ].…”