Sinonasal carcinomas
2025-07-17 Paola Dal Cin, PhD Affiliation1.Brigham and Women's Hospital , Harvard Medical School, Boston , MA (USA)
Keywords
Nasopharyngeal squamous cell carcinoma ,poorly differentiated and undifferentiated sinonasal carcinoma, SWI/SNF chromatin-remodeling gene complex, a NUT carcinoma, human papillomavirus (HPV)-Classification
Definition
Sinonasal carcinomas include keratinizing and non-keratinizing squamous cell carcinoma NUT carcinoma, SWI/SNF complex-deficient sinonasal carcinoma, sinonasal lymphoepithelial carcinoma, sinonasal undifferentiated carcinoma, sinonasal teratocarcinoma and human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma. 1
Nasopharyngeal squamous cell carcinoma (NPSCC) is endemic to certain regions in East Asia, such as Hong Kong, China, and Singapore and uncommon in non-endemic regions. HPV-16 to be the most common genotype and 2 major histologic subtypes are recognized: keratinizing (KSCC) and nonkeratinizing (NKSCC) with the nonkeratinizing histology been the more frequent, but the keratinizing one carrying a worse overall prognosis. HPV is more frequently detected in nonkeratinizing SCC (NKSCC) compared with keratinizing (KSCC).2
Poorly differentiated and undifferentiated sinonasal carcinomas (SNUC), a "wastebasket” category, have undergone a significant refinement of their subtyping, with the identification of several new novel molecular subgroups in sinonasal carcinomas e.g., NUTM1-rearranged carcinoma (a.k.a NUT carcinoma) and carcinomas associated with inactivation of different members of the SWI/SNF chromatin-remodeling gene complex SMARCB1 and less frequently SMARCA4. Then, a significant proportion of what remains in the SNUC group has underlying IDH2 hotspot mutations with better prognosis. 3,4
| Sinonasal carcinomas | Genetic event(s) |
|---|---|
| Keratinizing squamous cell carcinoma (KSCC) | About 60% of KSCCs arise from inverted papillomas present synchronously. and have a distinct molecular phenotype, including more frequent EGFR, KRAS, CDKN2A and TP53 mutations, TERT copy-number gains, and low-risk human papilloma virus (HPV) infection. 5,6 The majority of EGFR mutations identified in patients with primary SNSCC are exon 20 insertions (Ex20ins) associated with inverted sinonasal papilloma (ISP), a benign epithelial neoplasm. 7 |
| Non-keratinizing squamous cell carcinoma (NKSCC) | Non-keratinizing squamous cell carcinomas,is associated with high-risk HPV infection and with a lower clinical stage at sinonasal squamous cell carcinoma(SNSCC) diagnosis and improved overall survival. 8 |
| NKSCC of the sinonasal region and skull base, negative for HPV and EBV , harbor DEK::AFF2 fusions.9-11 AFF2 C-terminus immunohistochemistry has been demonstrated to be a sensitive and specific ancillary marker.12 A ETV6::TNFRSF8 fusion was reported in a single case arising at the base of skull.13 | |
| A FGFR3::TACC3 fusion has been reported in the head and neck carcinoma by seveal studies, 14 subsets of diverse cancers including including sinonasal squamous cell carcinomas (SCC) , mainly HPV-positive. 15,16,16 | |
| Adenosquamous carcinomas are less frequent variants of SCC, and somewhat heterogeneous tumors , driven by high-risk HPV, a few by low-risk HPV, and even occasional cases by DEK::AFF2 fusion , negative so far MAML2 rearrangememt. 17 | |
| NUT carcinoma | The head and neck region is the second most common primary site of NUT carcinoma, a highly aggressive, mostly lethal malignancy characterized by t(15;19)(q14;p13.1)/ BRD4::NUTM1 fusion in ~75% of the cases. 18-20 Other partner genes have been reported either belonging to the same BET family e.g., BRD2,BRD3 and BRDT or non-BET genes e.g. NSD3, ZNF532, ZNF59 or CIC.21 BRD4::NUTM1 is associated with a poorer prognosis than non-BRD4 fusion.22 |
| The monoclonal NUT antibody is highly specific for NUT carcinoma 23, and offers a simple and reliable way to diagnose this malignancy.However, molecular testing e.g., FISH analysis , or next-generation sequencing, may be useful prognostically by identifying the fusion partner to identify very rare non-NUT carcinoma tumors at non-midline locations, with non-bromodomain partners and with varied morphology but with NUPM1 rearrangements.24,25 | |
| SWI/SNF complex-deficient sinonasal carcinoma | SMARCB1-deficient sinonasal carcinoma is by far is the most common subtype than SMARCA4-deficient sinonasal carcinoma. 26,27 Immunohistochemical staining with INI1 antibody is a sensitive tool for SMARCB1 loss. Biallelic (homozygous) or monoallelic (heterozygous)deletions affecting the SMARCB1 gene locus are also detectable by FISH analysis in the majority of cases. |
| SMARCA4/BRG1-deficient sinonasal teratocarcinosarcoma is a highly invasive malignant tumor with BRG1 antibody is sensitive diagnostic tools for SMARCA4 loss. Concurrent CTNNB1 and SMARCA4 mutations have been also reported. 28 A case with PIK3CA mutation was also reported. 29 | |
| Sinonasal lymphoepithelial carcinoma (SNLEC) | Limited reported cases, positive for Epstein-Barr virus (EBV) by immunohistochemistry. 30 |
| Sinonasal undifferentiated carcinoma (SNUC) | IDH2 mutations were identified in a majority of the case defined as"true" SNUC. 3,31.The multispecific mutant IDH1/2 immunohistochemistry is usfull for detection. This mutation is associated with high-risk HPV (usually type 33) and, unlike adenoid cystic carcinoma, is restricted to the sinonasal tumors. SWI/SNF inactivation e.g., SMARCB1 and SMARCA4 and IDH2 mutations seem mutually exclusive, |
| HPV-related multiphenotypic sinonasal carcinoma (HMSC) | Most cases of HMSC harbor high-risk of HPV, with an uncommon HPV type 33, as the predominant viral serotype, however, individual cases of infection with HPV 16, 26, 52, and 56 have also recently been reported. Unlike adenoid cystic carcinoma consistentl yare lacking MYB rearrangements. 32,33 |
Article Bibliography
| Reference Number | Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|---|
| 1 | 35307773 | 2022 | Proceedings of the North American Society of Head and Neck Pathology, Los Angeles, CA, March 20, 2022: SWI/SNF-deficient Sinonasal Neoplasms: An Overview. | Agaimy A et al |
| 2 | 24733735 | 2014 | Nasopharyngeal squamous cell carcinoma: a comparative analysis of keratinizing and nonkeratinizing subtypes. | Vazquez A et al |
| 3 | 31876536 | 2020 | Sinonasal Undifferentiated Carcinoma (SNUC): From an Entity to Morphologic Pattern and Back Again-A Historical Perspective. | Agaimy A et al |
| 4 | 37591773 | 2023 | Update from the 5th Edition of the WHO Classification of Nasal, Paranasal, and Skull Base Tumors: Imaging Overview with Histopathologic and Genetic Correlation. | Agarwal A et al |
| 5 | 29145573 | 2018 | Human papillomavirus (HPV) and somatic EGFR mutations are essential, mutually exclusive oncogenic mechanisms for inverted sinonasal papillomas and associated sinonasal squamous cell carcinomas. | Udager AM et al |
| 6 | 33203919 | 2021 | TP53 mutations and CDKN2A mutations/deletions are highly recurrent molecular alterations in the malignant progression of sinonasal papillomas. | Brown NA et al |
| 7 | 35053553 | 2022 | EGFR Exon 20 Insertion Mutations in Sinonasal Squamous Cell Carcinoma. | Pacini L et al |
| 8 | 32582473 | 2020 | Sinonasal Squamous Cell Carcinoma: Etiology, Pathogenesis, and the Role of Human Papilloma Virus. | Elgart K et al |
| 9 | 33002918 | 2021 | Nonkeratinizing Squamous Cell Carcinoma of the Sinonasal Tract With DEK-AFF2: Further Solidifying an Emerging Entity. | Bishop JA et al |
| 10 | 34049316 | 2021 | DEK-AFF2 Carcinoma of the Sinonasal Region and Skull Base: Detailed Clinicopathologic Characterization of a Distinctive Entity. | Rooper LM et al |
| 11 | 39489551 | 2024 | DEK::AFF2 Carcinoma of the Sinonasal Tract and Skull Base: A Comprehensive Review. | Rivera JP et al |
| 12 | 35701667 | 2022 | Nuclear expression of AFF2 C-terminus is a sensitive and specific ancillary marker for DEK::AFF2 carcinoma of the sinonasal tract. | Kuo YJ et al |
| 13 | 33394379 | 2021 | A Poorly Differentiated Non-keratinizing Sinonasal Squamous Cell Carcinoma with a Novel ETV6-TNFRSF8 Fusion Gene. | Bubola J et al |
| 14 | 27409839 | 2016 | FGFR3-TACC3 fusion in solid tumors: mini review. | Costa R et al |
| 15 | 38010295 | 2024 | FGFR1/2/3-rearranged carcinoma of the head and neck: expanded histological spectrum crossing path with high-risk HPV in the sinonasal tract. | Chu YH et al |
| 16 | 39387893 | 2025 | FGFR3::TACC3 fusions in head and neck carcinomas: a study of nine cases highlighting phenotypic heterogeneity, frequent HPV association, and a morphologically distinct subset in favor of a putative entity. | Agaimy A et al |
| 17 | 36849671 | 2023 | Sinonasal Adenosquamous Carcinoma - Morphology and Genetic Drivers Including Low- and High-Risk Human Papillomavirus mRNA, DEK::AFF2 Fusion, and MAML2 Rearrangement. | Holliday D Jr et al |
| 18 | 12543779 | 2003 | BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. | French CA et al |
| 19 | 35417004 | 2022 | Report of the First International Symposium on NUT Carcinoma. | French CA et al |
| 20 | 37819236 | 2023 | The BRD4-NUT Fusion Alone Drives Malignant Transformation of NUT Carcinoma. | Durall RT et al |
| 21 | 34232599 | 2022 | Misleading Germ Cell Phenotype in Pulmonary NUT Carcinoma Harboring the ZNF532-NUTM1 Fusion. | Agaimy A et al |
| 22 | 32328562 | 2020 | An Anatomical Site and Genetic-Based Prognostic Model for Patients With Nuclear Protein in Testis (NUT) Midline Carcinoma: Analysis of 124 Patients. | Chau NG et al |
| 23 | 19363441 | 2009 | Diagnosis of NUT midline carcinoma using a NUT-specific monoclonal antibody. | Haack H et al |
| 24 | 29356724 | 2018 | NUTM1 Gene Fusions Characterize a Subset of Undifferentiated Soft Tissue and Visceral Tumors. | Dickson BC et al |
| 25 | 34898574 | 2021 | NUTM1-Rearranged Neoplasms-A Heterogeneous Group of Primitive Tumors with Expanding Spectrum of Histology and Molecular Alterations-An Updated Review. | Luo W et al |
| 26 | 36580412 | 2023 | SWI/SNF-deficient Sinonasal Carcinomas. | Agaimy A et al |
| 27 | 37198880 | 2023 | SMARCB1-Deficient Sinonasal Carcinoma: Case Report and Review of the Literature. | AlMadan NM et al |
| 28 | 36396744 | 2023 | Targeted next-generation sequencing reveals activating CTNNB1 mutations in SMARCA4/BRG1-deficient sinonasal carcinomas: a report of two new cases and a brief review of the literature with an emphasis on histogenesis. | Zhao M et al |
| 29 | 32389511 | 2021 | PIK3CA somatic mutation in sinonasal teratocarcinosarcoma. | Belardinilli F et al |
| 30 | 37235183 | 2023 | Lymphoepithelial Carcinoma Originated from the Sinonasal Cavity: Case Report and Literature Review. | Alhazzani H et al |
| 31 | 36537260 | 2023 | IDH2 -Mutated Sinonasal Tumors: A Review. | Alzumaili B et al |
| 32 | 30027386 | 2019 | Consistent LEF-1 and MYB Immunohistochemical Expression in Human Papillomavirus-Related Multiphenotypic Sinonasal Carcinoma: A Potential Diagnostic Pitfall. | Shah AA et al |
| 33 | 31473938 | 2020 | Human Papillomavirus-Related Multiphenotypic Sinonasal Carcinoma: A Recent Discovery. A Case Report and Literature Review. | Brzezinska K et al |
Citation
Paola Dal Cin, PhD
Sinonasal carcinomas
Atlas Genet Cytogenet Oncol Haematol. 2025-07-17
Online version: http://atlasgeneticsoncology.org/solid-tumor/209325/sinonasal-carcinomas
