December 2023 – Gastroenterology Pathology

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.

Figure 1: Histologic section of the resected tumor involving muscularis propria with a focus of vascular involvement in the submucosa.
(Hematoxylin & eosin, 20x magnification)
Figure 2: Histologic section of the resected tumor infiltrating to mucosa and submucosa.
(Hematoxylin & eosin, 40x magnification)
Figure 3: High magnification histologic section of the resected tumor.
(Hematoxylin & eosin, 200x magnification)
Figure 4: NUT immunostain of the resected tumor showing positive nuclear staining pattern.
(200x magnification)

What is the most appropriate diagnosis based on the pathologic evaluation?

  • Gastrointestinal stromal tumor
  • Primitive neuro-ectodermal tumor
  • Leiomyosarcoma
  • NUTM1-rearranged colorectal sarcoma

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.

References

  1. Van Treeck BJ, Thangaiah JJ, Torres-Mora J, Stevens TM, Rothermundt C, Fassan M, Loupakis F, Diebold J, Hornick JL, Halling KC, Folpe AL. NUTM1-rearranged colorectal sarcoma: a clinicopathologically and genetically distinctive malignant neoplasm with a poor prognosis. Mod Pathol. 2021 Aug;34(8):1547-1557. doi:10.1038/s41379-021-00792-z. Epub 2021 Mar 13. PMID: 33714983.
  2. Stevens TM, Morlote D, Xiu J, Swensen J, Brandwein-Weber M, Miettinen MM, Gatalica Z, Bridge JA. NUTM1-rearranged neoplasia: a multi-institution experience yields novel fusion partners and expands the histologic spectrum. Mod Pathol. 2019 Jun;32(6):764-773. doi:10.1038/s41379-019-0206-z. Epub 2019 Feb 5. PMID: 30723300; PMCID: PMC8194366.
  3. Hakun MC, Gu B. Challenges and Opportunities in NUT Carcinoma Research. Genes (Basel). 2021 Feb 5;12(2):235. doi:10.3390/genes12020235. PMID: 33562801; PMCID: PMC7915910.
  4. Giridhar P, Mallick S, Kashyap L, Rath GK. Patterns of care and impact of prognostic factors in the outcome of NUT midline carcinoma: a systematic review and individual patient data analysis of 119 cases. Eur Arch Otorhinolaryngol. 2018 Mar;275(3):815-821. doi:10.1007/s00405-018-4882-y. Epub 2018 Jan 22. PMID: 29356890.

Tommy Zhao, M.B., Ph.D.

Resident, Anatomic and Clinical Pathology
Mayo Clinic

Eric Chen, M.D., Ph.D.

Consultant, Anatomic Pathology
Mayo Clinic
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

MCL Education (@mmledu)

MCL Education

This post was developed by our Education and Technical Publications Team.