NR1D1-rearranged soft tissue tumour: A clinicopathological and molecular analysis of four additional cases.

AIMS: Nuclear receptor subfamily 1 group D member 1 (NR1D1)-rearranged soft tissue tumour is a newly described entity with an epithelioid morphology and a potential for aggressive behaviour. Largely due to under-recognition, this tumour type has not yet been widely acknowledged. Herein, we report four additional cases to further expand its clinicopathological and molecular spectrum. METHODS AND RESULTS: Four mesenchymal tumours with NR1D1 rearrangement were identified from our consultation files. There were one male and three females with ages ranging from 19 to 47 years (median = 28.5 years). Tumour occurred in the tongue, neck, hip and index finger, respectively. Histologically, two tumours were composed predominantly of epithelioid cells; one tumour had admixed epithelioid-spindle cells and one tumour consisted of monomorphic small round to ovoid cells. By immunohistochemistry, none of the tumours expressed lineage-specific markers. Targeted RNA-sequencing identified NR1D1 fusions in all four tumours, the partner genes being MAML2, MAML3, KMT2A and NCOA2, respectively. The novel MAML3 and NCOA2 rearrangements were confirmed by fluorescence in-situ hybridisation analysis. On follow-up (2-23 months), one patient experienced local recurrence due to incomplete resection and one patient developed lung metastasis. The other two patients were alive without disease. CONCLUSIONS: This study adds more support for NR1D1-rearranged soft tissue tumour as an emerging entity. The occurrence of two additional tumours in the head and neck region, description of a small round cell variant and identification of novel MAML3, KMT2A and NCOA2 partners further expand its clinicopathological and molecular spectrum. More studies on larger series are necessary to validate the fully malignant potential of NR1D1-rearranged soft tissue tumour.

Gastrointestinal Ewing Sarcoma: A Clinicopathological and Molecular Genetic Analysis of 25 Cases.

Occurrence of extraskeletal Ewing sarcoma (ES) in the gastrointestinal (GI) tract is extremely rare. Here, we report 25 cases of ES arising primarily in the GI tract with a focus on the clinicopathological and molecular features, differential diagnosis, and biological behavior. Thirteen patients (52%) were male, and 12 (48%) were female with age ranging from 9 to 59 years (mean: 36.2 years; median: 38 years). Twenty-one tumors (84%) occurred in the small intestine, 3 (12%) in the stomach, and 1 (4%) in the anal canal. At operation, 8/18 (44.4%) patients presented with abdominopelvic disseminated disease. Tumor size measured from 2 to 25 cm (mean: 8.2 cm; median: 6 cm) in maximum size. Microscopically, the tumors were composed of infiltrative small round, ovoid, or short spindle cells arranged mostly in lobular and solid sheet-like patterns with a rich capillary vasculature. Focal formation of Homer Wright-type rosettes and pseudoalveolar architecture was noted each in 2 (8%) cases and 3 (12%) cases. Besides CD99 (25/25; 100%), Fli-1 (15/15, 100%), and NKX2.2 (14/16; 87.5%), the tumor cells also showed variable staining of CD117 (14/17; 82.4%). Of 25 cases, 23 (92%) demonstrated EWSR1 rearrangement by fluorescence in situ hybridization analysis. The 2 cases with negative fluorescence in situ hybridization results were found to harbor EWSR1::ERG and EWSR1::FLI1 fusion by further RNA sequencing, respectively, with a median follow-up of 12 months (range: 1 to 42 months), 5/19 (26.3%) patients developed visceral metastasis and 12/19 (63.2%) patients died of the disease (range:1 to 33 months; median: 9 months). This study showed that GI ES had a predilection for the small intestine, although other sites of the GI tract could also be involved. GI ES had a poor prognosis with a high rate of mortality, particularly in patients with abdominopelvic disseminated disease. In light of appropriate therapeutic strategies and prognostic considerations, it is essential not to misdiagnose GI ES as gastrointestinal stromal tumor owing to the expression of aberrant CD117.

Desmoplastic Small Round Cell Tumor of the Head and Neck: A Clinicopathological, Immunohistochemical and Molecular Analysis of Three Cases with Literature Review.

Desmoplastic small round cell tumor (DSRCT) is a rare aggressive malignancy typically originating from the abdominal or pelvic cavity. DSRCT presenting as a primary head and neck tumor has rarely been described in the literature. We present three cases of DSRCT arising in the head and neck to further characterize its clinicopathological features. All three patients were male and aged 36, 30 and 17 years. The involved sites included the orbit (1 case) and submandibular gland (2 cases). The tumors ranged in size from 2.4 to 3.5 cm (mean, 2.1 cm). Histologically, all tumors showed irregular-shaped, variable-sized nests of small round cells deposited in an abundant desmoplastic stroma. Tumor cells contained scant amounts of eosinophilic cytoplasm and small hyperchromatic nuclei with inconspicuous nucleoli. Immunohistochemically, the tumors were positive for keratin (AE1/AE3) (3/3), desmin (3/3), vimentin (2/2), NSE (1/1) and EMA (1/1). Fluorescence in situ hybridization (FISH) analysis demonstrated the presence of EWSR1 and WT1 rearrangements in all three cases. All patients received surgery and adjuvant chemotherapy and/or radiotherapy. There was no evidence of recurrence and metastasis in two patients, and the third suffered lung metastasis. DSRCT arising in the head and neck represents an extremely rare condition. It is easily mistaken as poorly differentiated carcinoma due to similar morphology and expression of epithelial markers. Immunohistochemistry assay in conjunction with molecular detection of EWSR1::WT1 fusion will be helpful for arriving at an accurate diagnosis to avoid misdiagnosis and inappropriate treatment.