ETV6 Gene Rearrangements Characterize a Morphologically Distinct Subset of Sinonasal Low-grade Non–intestinal-type Adenocarcinoma

Abstract

Low-grade sinonasal adenocarcinomas (low-grade SNACs) of the sinonasal tract comprise a poorly characterized and histologically heterogeneous group of tumors. We describe three cases of a histologically distinct variant of low-grade SNAC characterized by ETV6 gene rearrangements. The patients included 2 women (aged 32 and 88 y) and a man (aged 75 y); all were initially treated with surgery alone. Follow-up ranged from 9 to 170 months with one patient having 2 local recurrences and none experiencing distant or regional metastases. Tumors were composed of cytologically bland columnar and cuboidal eosinophilic tumor cells with basally located nuclei arranged in tubular and tubulotrabecular patterns. Immunohistochemically, CK7, DOG1, GCDFP-15, and SOX10 were positive in all cases, and vimentin was positive in 2 cases. Scattered single cells or small groups of tumor cells were S-100 positive. Only one case had weak, focal expression of GATA3, and mammaglobin was consistently negative. Two cases had ETV6-NTRK3 gene fusions, whereas ETV6 had an unknown fusion partner gene in one case. The highly similar morphology, immunohistochemical profile, and genetics of the presented cases are suggestive of a specific disease. Although translocation-associated adenocarcinomas in the sinonasal tract have previously been described exclusively as salivary-type carcinomas, we present the first type of carcinoma characterized by recurrent genetic rearrangements and distinct phenotype occurring exclusively in the sinonasal tract with no known major salivary gland counterpart. We provisionally designate this tumor ETV6-rearranged low-grade SNAC. Identification of additional cases is necessary to fully appreciate the morphologic and biological spectrum of this disease.

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“…ETV6‐rearranged low‐grade sinonasal adenocarcinoma (ETV6‐rearranged low‐grade SNAC) is well‐circumscribed and composed of eosinophilic, cylindrical tumor cells with apical diastase‐resistant PAS‐positive granules growing in tubular and trabecular formations (Fig. A; ). Immunohistochemically, S100 is expressed in a patchy pattern and SOX‐10 is consistently positive.…”

“…Biphenotypic sinonasal sarcoma is a strictly localized disease with local recurrences in one‐third of cases and only two fatal cases reported . Only few cases of SRCLA and ETV6‐rearranged low‐grade SNAC have been reported, but the prognosis seems favorable with only rare local recurrences and no distant metastases or cases with fatal outcome reported to date .…”

“…ETV6-rearranged low-grade sinonasal adenocarcinoma share the ETV6-NTRK3 and ETV6-RET fusions with SC of the salivary gland, but are histologically and clinically distinct with an indolent clinical course ( Fig. 6B, C; 19,80,81,90,91). Demonstration of rearranged ETV6 with FISH is mandatory for the diagnosis.…”

“…Biphenotypic sinonasal sarcoma is a strictly localized disease with local recurrences in one-third of cases and only two fatal cases reported (84,95,(105)(106)(107). Only few cases of SRCLA and ETV6-rearranged low-grade SNAC have been reported, but the prognosis seems favorable with only rare local recurrences and no distant metastases or cases with fatal outcome reported to date (80,82). Primary surgery is preferred whenever possible for securing free margins and precise definition of tumor extension, which is important for adjuvant RT.…”

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“…This discovery sparked the identification of a specific inhibitor of the fusion protein, which has dramatically improved the prognosis for this patient group (127). Since then, numerous types of recurrent fusion genes have been identified across a wide spectrum of different tumor types, a large proportion of which are tumor-type specific, whereas others are more promiscuously involved in various malignancies (128)(129)(130)(131). Initially, fusion genes were thought to be predominantly found in hematological malignancies, but they have since been shown to be frequent in sarcomas and carcinomas (123,128).…”