Towards a Molecular Classification of Sinonasal Carcinomas: Clinical Implications and Opportunities

Abstract

Sinonasal carcinomas are a heterogeneous group of rare tumors, often with high-grade and/or undifferentiated morphology and aggressive clinical course. In recent years, with increasing molecular testing, unique sinonasal tumor subsets have been identified based on specific genetic alterations, including protein expression, chromosomal translocations, specific gene mutations, or infection by oncogenic viruses. These include, among others, the identification of a subset of sinonasal carcinomas associated with HPV infection, the identification of a subset of squamous cell carcinomas with EGFR alterations, and of rare variants with chromosomal translocations (DEK::AFF2, ETV6::NTRK and others). The group of sinonasal adenocarcinomas remains very heterogeneous at the molecular level, but some recurrent and potentially targetable genetic alterations have been identified. Finally, poorly differentiated and undifferentiated sinonasal carcinomas have undergone a significant refinement of their subtyping, with the identification of several new novel molecular subgroups, such as NUT carcinoma, IDH mutated sinonasal undifferentiated carcinoma and SWI/SNF deficient sinonasal malignancies. Thus, molecular profiling is progressively integrated in the histopathologic classification of sinonasal carcinomas, and it is likely to influence the management of these tumors in the near future. In this review, we summarize the recent developments in the molecular characterization of sinonasal carcinomas and we discuss how these findings are likely to contribute to the classification of this group of rare tumors, with a focus on the potential new opportunities for treatment.

Keywords: molecular subtyping; pathology; sinonasal carcinomas; tumor classification.

Figure 1

HPV related multiphenotypic carcinoma. The surface epithelium shows severe atypia ((A) Hematoxylin and eosin, 20× Objective original magnification). In this example, tumor cells presented a solid growth pattern with large lobules composed of spindle cells organized in fascicles intermixed with areas resembling non-keratinizing squamous cell carcinoma (B). Prominent dilated “hemangiopericytoma-like” vessels are present in the background (Hematoxylin and eosin, 10× Objective original magnification).

Figure 2

Sinonasal DEK-AFF2 fusion associated squamous carcinoma. The tumor shows an inverted growth pattern ((A), Hematoxylin and eosin, 5× Objective original magnification) and consists of nests and interconnecting trabeculae with no evidence of keratinization (B), (Hematoxylin and eosin, 10× Objective original magnification). Neutrophilic infiltrates are present both in the stroma and within the tumor ((C), Hematoxylin and eosin, 20× Objective original magnification). Tumor cells present a bland uniform appearance with no overt cytologic atypia ((D), Hematoxylin and eosin, 40× Objective original magnification).

Figure 3

SMARCB1 deficient carcinoma. The tumor consists of a relatively uniform population of undifferentiated basaloid cells organized in solid sheets (A). Immunohistochemistry shows complete loss of INI1 in neoplastic cells, while nuclear positivity is retained in stromal cells (B).

Figure 4

SMARCA4 deficient sinonasal carcinoma. Nests of undifferentiated tumor cells are present in the nasal mucosa (A) (Hematoxylin and eosin, 10× Objective original magnification). Tumor cells are large and show vesicular nuclei with multiple nucleoli and moderate amounts of cytoplasm (B) (Hematoxylin and eosin, 40× Objective original magnification). Immunohistochemistry shows complete loss of SMARCA4 in neoplastic cells, while nuclear positivity is retained in stromal cells (C).

Figure 5

Examples of sinonasal teratocarcinosarcoma showing the triphasic pattern. The epithelial component varies from disordered mucous glands (A) to primitive clear cell fetal-type squamous (B) or tubular (C) structures (Hematoxylin and eosin, 10× Objective original magnification). The stroma varies from primitive neuroectodermal-type (B) to lose spindled or primitive non-descript (C). Variable rhabdomyoblastic differentiation is frequent (D). Global loss of SMARCA4 in the epithelial (E) and the primitive and mesenchymal stroma (F).