NUT Carcinoma of the Submandibular Gland: A Case at This Uncommon Site with Review of the Literature

Abstract

Nuclear protein in testis (NUT) carcinoma is a rare, highly aggressive, undifferentiated carcinoma that harbors a characteristic rearrangement of the NUTM1 gene. The majority arise in adolescents and young adults especially from the midline structures of the thorax, head, and neck. Until the present, there have only been three reported cases of NUT carcinoma of the submandibular gland, two of which were reported in children and another one in an adult from Korea. Here, we report the first case of NUT carcinoma arising in the submandibular gland of an adult female in the United States, representing the fourth case worldwide. A fine needle aspiration and biopsy was performed, and the diagnosis was confirmed by NUT immunohistochemical staining and fusion of the BRD4 (19p13.12) and NUTM1 (15q14) gene loci by fluorescence in-situ hybridization on the resection specimen. Salivary gland is an unusual site for NUT carcinoma and is rarely described in submandibular gland. We reviewed the clinicopathologic features of this entity at this site along with role of NUTM1 gene rearrangements in NUT tumorigenesis.

Keywords: BRD4-NUTM1; NUT carcinoma; NUT midline carcinoma; NUTM1; Salivary gland; Submandibular gland.

Fig. 1

Imaging findings, pre- and post-surgical: A Pre-operative, axial neck CT scan with contrast showing a 4.2 × 3.5 × 3.4 cm mass (yellow arrow) involving the right submandibular gland. B Two-weeks post-operative PET-CT scan of the neck showing focal radiotracer uptake (bright area) at the right neck surgical resection site (yellow arrow), which could represent either residual tumor or post-surgical changes. C Post-operative (2 weeks after surgery) PET-CT scan of the whole body show no metastatic disease with lack of FDG-uptake (bright areas) elsewhere in the body

Fig. 2

Gross, cytology, and microscopic findings: A Cytology smear from FNA showing moderate to hypercellular lesion with tumor cells either forming loose aggregates or dispersed as single cells (Diff-Quik stain, ×100). B Tumor cells are monotonous, primitive appearing with round to oval nuclei, prominent nucleoli, and scant cytoplasm. Background neutrophilic infiltrate is prominent. The loosely aggregated tumor cells focally show nuclear “molding”, mimicking neuroendocrine neoplasm (Diff-Quik stain, ×200). C Tumor cells are discohesive and show similar features as described above (Papanicolaou stain, ×200). D Grossly, sections show an infiltrating tumor with pushing borders, tan-gray to tan-yellow cut surfaces with areas of necrosis. E Histologic section shows sheet of undifferentiated tumor diffusely infiltrating the submandibular gland (H&E, ×40). F Extensive areas of necrosis are present (H&E, ×100)

Fig. 3

Microscopic and immunohistochemical findings: A tumor exhibiting areas with clear cell features (H&E, ×100). B Discohesive, medium to large-sized, monomorphic tumor cells associated with tumoral neutrophilic inflammatory infiltrate. Entrapped salivary serous and mucinous acini are noted (H&E, ×200). C Perineural invasion (H&E, ×100). D Tumor metastasis involving level II lymph nodes (H&E, ×20). E Tumor cells demonstrating patchy keratin staining. Normal ducts showing strong complete staining as internal control (pancytokeratin AE1/AE3, ×100). F Tumor cells diffusely positive for anti-NUT antibody (NUT stain, ×100); inset (lower right) shows characteristic “speckled” nuclear staining (NUT stain, ×200)

Fig. 4

Detection of BRD4-NUTM1 fusion in the tumor by dual color, bring-together FISH. Green probes detect the telomeric side of the NUTM1 locus breakpoint, whereas red probes detect the centromeric side of the BRD4 breakpoint. The tumor cells are diploid: overlapping red-green signals indicate BRD4-NUTM1 fusion loci, whereas non-overlapping signals indicate wild type alleles of the respective genes