CIC-NUTM1 fusion: A case which expands the spectrum of NUT-rearranged epithelioid malignancies

Abstract

NUT carcinoma (NC) shows very aggressive clinical behavior, occurs predominantly in the thorax and head and neck region of children and adults, and is defined by the presence of NUT (aka NUTM1) rearrangement, mostly BRD4-NUTM1 fusion resulting from t(15;19)(q13; p13.1). So-called "NUT variants" harbor alternate fusions between NUTM1 and BRD3, NSD3, ZNF532, or unknown partners. Rare cases of pediatric tumors with CIC-NUTM1 fusion were recently reported in somatic soft tissue, brain, and kidney. However, such cases have not been identified in adult patients and the presence of a fusion between CIC, characteristic of CIC-rearranged sarcoma, and NUTM1-a defining feature of NC-poses a diagnostic challenge. We herein report a case of malignant epithelioid neoplasm with myoepithelial features harboring CIC-NUTM1 fusion arising in soft tissue of the head in a 60-year-old man. Immunohistochemistry revealed strong expression of NUT, but only weak ETV4 staining and negativity for keratins, EMA, p40, CD99, and WT1. SMARCB1 expression was retained. Fluorescence in situ hybridization and targeted next-generation sequencing identified a CIC-NUTM1 fusion resulting from t(15;19)(q14;q13.2). In light of morphologic features that overlap with those of NC from typical anatomical sites we have seen previously, the tumor was best classified as falling within the NC spectrum rather than CIC-associated sarcoma. This case highlights the emerging diagnostic challenges generated by newly detected gene fusions of unknown clinical and biologic significance. Careful integration of cytogenetic, molecular, and immunohistochemical findings with morphologic appearances in the diagnostic workup of undifferentiated neoplasms is essential.

FIGURE 1

Imaging findings of NUT variant with CIC-NUTM1 fusion. Magnetic resonance imaging revealed an infiltrative 4.7-cm mass in the right masticator space (A, B, arrows)

FIGURE 2

Histologic features of NUT variant with CIC-NUTM1 fusion. The tumor consisted of round to ovoid cells arranged in A, sheets or B, strands embedded in a variably prominent C, chondroid or D, myxoid to hyalinized stromal background. The tumor cells exhibited intermediate to large, irregular, and occasionally grooved, atypical nuclei with occasional rhabdoid inclusions (D, inset). Immunohistochemical staining was positive for E, NUT, F, multifocal weak for ETV4, and G, negative for p40 and H, AE1/AE3

FIGURE 3

Molecular genetic and cytogenetic findings in NUT neoplasm with CIC-NUTM1 fusion. A, Targeted next-generation sequencing demonstrated the presence of a fusion between CIC exon 17 and NUTM1 intron 4. B, Fluorescence in-situ hybridization confirmed rearrangement of the CIC locus at chromosome 19q13.2 and C, the NUTM1 locus at chromosome 15q14 using break-apart probes (arrows). D, Partial GTG banding karyotype showing the presence of t(15;19)(q14;q13.2)

FIGURE 4

Histologic features of NUT variant with NSD3-NUTM1 fusion. A, The tumor consisted of round to ovoid cells mostly arranged in variably cohesive sheets embedded in a myxoid stroma. B, The tumor cells showed diffuse nuclear expression of NUT. C, Focal heterologous cartilage formation and D, areas with prominent rhabdoid cytomorphology were present, resembling features of myoepithelial carcinoma