A 57-year-old woman presented with a mass in her right colon. Biopsy and resected samples were sent to Mayo Clinic for consultation. Positive immunostains include NUT, CD99, and Vimentin. Negative immunostains include AE1/3, TdT, CD3, CD79, DOG1, CDX2, Synaptophysin, SMA, MOC31, SMARCB1, as well as clonal Kappa and Lambda light chains.
The correct answer is ...
NUTM1-rearranged colorectal sarcoma.
This is a case of NUTM1-rearranged colorectal sarcoma. The patient's tumor is primarily situated in the muscular wall of the right colon, infiltrating into the mucosa and submucosa. The tumor comprises sheets of uniform epithelioid/rhabdoid cells with eosinophilic cytoplasm and eccentrically placed nuclei. Immunohistochemistry reveals that the tumor cells are positive for NUT (diffuse pattern), CD99, and Vimentin, but negative for markers for common colorectal mesenchymal tumors, lymphoma, and primitive neuroectodermal tumor, and poorly/undifferentiated carcinoma. Further molecular testing has uncovered MXI1::NUTM1 fusion. The overall histological features and molecular analysis result support the diagnosis of NUTM1-rearranged colorectal sarcoma.
The discovery of NUTM1 (NUT midline carcinoma family member 1) gene rearrangements began with aggressive thymic carcinoma.1 Subsequently, it has become evident that NUTM1 gene rearrangements are not only unique to NUT carcinoma but also observed in poroma/porocarcinoma, B-lymphoblastic leukemia/lymphoma, central nervous system embryonal tumors, myeloid neoplasms, and various undifferentiated sarcomas.1 NUTM1-rearragnged colorectal sarcoma is a recently recognized entity.1
The NUTM1 rearranged tumors can exhibit distinct morphological patterns, including a fibrosarcomatous pattern (characterized by intersecting fascicles of relatively uniform spindled cells), an epithelioid/rhabdoid pattern (marked by the sheet-like proliferation of primitive epithelioid to rhabdoid cells), and a hyalinized/nested pattern (with nests and cords of tumor cells within abundant hyalinized collagen).1,2
Immunohistochemical analysis reveals characteristic NUT positivity. Other possible positive markers include CD34, SMA, Synaptophysin, ERG, and CD99, though these may only be observed in fewer than 25% of cells.1 Molecular studies have unveiled multiple NUTM1 fusion partners, with BRD4 or BRD3 being the most common. The fusion of NUTM1 with any of these partners results in the overexpression of the NUTM1 protein, which can be detected through immunohistochemistry.1,2
While the overexpression of the NUT gene is recognized as an important mechanism in tumorigenesis, there is still a lack of targeted therapy.3,4 Traditional cancer treatments, such as surgery, radiotherapy, and chemotherapy, can improve survival but often fail to provide long-term control, except in isolated cases. The prognosis remains grim, highlighting the need for further research to enhance future outcomes.3,4
In summary, NUTM1-rearranged colorectal sarcoma is a rare entity with poor prognosis. Lymphovascular involvement is frequent. Morphologically, it should be differentiated from sarcomatoid undifferentiated carcinoma and primitive sarcomas. Positive NUT immunostain is characteristic for the tumor and the diagnosis should be confirmed by molecular studies to demonstrate the NUTM1 gene rearrangement.
Tommy Zhao, M.B., Ph.D.
Resident, Anatomic and Clinical Pathology
Eric Chen, M.D., Ph.D.
Consultant, Anatomic Pathology
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science