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NUTM1-rearranged colorectal sarcoma: a clinicopathologically and genetically distinctive malignant neoplasm with a
Benjamin J Van Treeck1, Judith Jebastin Thangaiah1, Jorge Torres-Mora1
1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Abstract:
NUTM1 gene rearrangements were originally identified in NUT carcinoma. Recently, NUTM1 has been discovered to rearrange with a variety of gene partners in malignancies of diverse location and type. Only one NUTM1-rearranged tumor occurring in the colon has been reported. Herein we report five such tumors. The five tumors occurred in four females and one male, ranging from 38 to 67 years of age (median 51 years). The masses occurred in the colon (cecum, descending, sigmoid) and ileocecal valve region, measuring 2.5-20 cm in size (median 7 cm). Four patients had metastases at presentation (liver, n = 4; lymph nodes, n = 3). Histologically, the lesions arose in the submucosa, infiltrating into the mucosa and muscularis propria, and grew in fibrosarcoma-like fascicles and sheets of epithelioid or rhabdoid cells, with foci of hyalinized to vaguely osteoid-like matrix. The tumors were composed of relatively monomorphic, spindled to epithelioid cells with focal rhabdoid morphology, hyperchromatic nuclei, and small nucleoli. Mitotic activity was usually low (range 1-14/10 HPF; median 5/10 HPF); necrosis was present in two cases. Variable keratin expression and uniform nuclear NUT expression was present; KIT/DOG1 were negative and SMARCB1/SMARCA4 were retained. Next-generation sequencing identified MXD4-NUTM1 rearrangement in all cases (breakpoints: MXD4 exon 5, NUTM1 exons 2 or 3). Follow-up showed one of the four patients who presented with metastases to be dead of disease at 30 months; the other three patients were alive with metastatic disease. The final patient is disease-free, 5 months after diagnosis. NUTM1-rearranged colorectal sarcomas have characteristic morphologic, immunohistochemical, and molecular genetic features, suggesting that they represent a distinct entity within the family of NUTM1-rearranged neoplasia. A NUTM1-rearranged tumor should be considered for any difficult-to-classify submucosal spindle cell neoplasm of the gastrointestinal tract, in particular keratin-positive tumors showing an unusual combination of fibrosarcomatous, epithelioid to rhabdoid and hyalinized morphologies. Recognition of MXD4-NUTM1 rearranged sarcomas may be therapeutically important, even though best treatment is currently elusive/unknown.
Insights
NUTM1 gene rearrangements, previously linked to NUT carcinoma, are now identified in five new colorectal sarcomas. These MXD4-NUTM1 rearranged tumors present unique features and may represent a distinct entity within NUTM1-rearranged neoplasia.
Area of Science:
- Oncology
- Genetics
- Pathology
Background:
- NUTM1 gene rearrangements are known drivers of NUT carcinoma.
- Recent studies reveal NUTM1 rearrangements in diverse malignancies.
- NUTM1-rearranged colorectal tumors are rare, with only one prior case reported.
Purpose of the Study:
- To characterize the clinicopathologic and molecular features of NUTM1-rearranged colorectal sarcomas.
- To determine if these tumors represent a distinct entity.
- To highlight diagnostic considerations for challenging gastrointestinal submucosal neoplasms.
Main Methods:
- Histopathological analysis of five colorectal tumors.
- Immunohistochemical staining for keratin, NUT, KIT/DOG1, SMARCB1, and SMARCA4.
- Next-generation sequencing to identify gene rearrangements.
Main Results:
- Five cases of NUTM1-rearranged colorectal sarcomas were identified in patients aged 38-67.
- Tumors exhibited fibrosarcoma-like, epithelioid, or rhabdoid morphology with variable keratin expression.
- All cases showed MXD4-NUTM1 rearrangement (breakpoints in MXD4 exon 5 and NUTM1 exons 2 or 3).
- Metastatic disease was common at presentation, with varied outcomes.
Conclusions:
- NUTM1-rearranged colorectal sarcomas possess distinct morphologic, immunohistochemical, and molecular profiles.
- These findings suggest a unique entity within NUTM1-rearranged neoplasia.
- Consideration of NUTM1-rearranged tumors is crucial for difficult-to-classify submucosal gastrointestinal neoplasms, particularly keratin-positive variants.
