August 2020 — Bone and Soft Tissue, Surgical, Cytogenetics, & Molecular

22-year-old female, gravida 1, para 1, came to ED for evaluation of abdominal pain 7/10 and complaints of constipation for 3 weeks. She was a smoker with a family history of lung cancer. On exam, rectal and uterine adnexa was abnormal (nodularity posterior to uterus, fixed tender). CT scan of chest, abdomen, and pelvis showed multiple large confluent masses, measuring 2.5 cm - 9.3 cm. CT-guided multiple core pelvic biopsies with H&E is showed in the photomicrograph. Immunohistochemical stains were positive for Keratin AE1/AE3 (focally), keratin CAM 5.2 (focally), SALL4, NUTM1 and negative for CD99, SOX10, desmin, PAX8, TTF1, Synaptophysin and OCT4.

What is the diagnosis and gene rearrangement associated with the lesion?

  • Alveolar rhabdomyosarcoma { t(2;13)(q35;q14): PAX3-FOXO1}
  • Ewing sarcoma {t(11;22)(q24;q12) FLI1-EWSR1}
  • Desmoplastic small round cell tumor {t(11;22)(p13; q12) WT1-EWSR1}
  • NUT carcinoma {t(15;19)(q14;p13) NUTM1-BRD4}

The correct answer is...

The correct answer is NUT carcinoma {t(15;19)(q14;p13) NUTM1-BRD4}.

NUT stands for nuclear protein in testis. Formerly called NUT midline carcinoma due to tendency for midline sites, can occur anywhere in the body. ~35% involve the head and neck, most commonly in the sinonasal tract. Although originally described in children it can affect people of all ages. No sex or geographic predilection. Highly aggressive malignancy with median survival of < 1 year.

Highly infiltrative tumor frequently involving multiple anatomic subsites. Nonspecific white-tan cut surface commonly demonstrating prominent necrosis. Histologically defined by primitive monotonous round to oval nuclei with variably prominent nucleoli and areas of abrupt keratinization. Small to medium sized cells with minimal indistinct to clear cytoplasm. High mitotic rate with prominent tumor necrosis. Foci of abrupt squamous differentiation with clear to eosinophilic cytoplasm and keratin pearl formation.

IHC positive for NUT 1, pancytokeratin, EMA, P63/ P40, CD34, INI 1 retained. IHC negative for CD 99, S100, synaptophysin, chromogranin.

Defined by translocations involving the NUT gene on 15q14 with BRD4-NUT (19p13) fusion in 67% of cases. Other cases show BRD3-NUT or NSD3-NUT fusions. Fusions block epithelial differentiation and maintains proliferation in tumor cells. In clinical trials, some patients show rapid response to extra terminal bromodomain inhibitors although prognosis remains poor.

1. Rearrangement of the NUTM1 gene at 15q14 has been observed in NUT midline carcinoma (Bauer et al., Clin Cancer Res 18:5773-5779, 2012).

Photo of Vishnu Serla, M.B.B.S. Vishnu Serla, M.B.B.S.
Resident, Molecular Genetic Pathology
Mayo Clinic
Photo of Jorge Torres-Mora, M.D. Jorge Torres-Mora, M.D.
Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
MCL Education (@mmledu)

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