The FGFR3::TACC3 fusion has been reported in subsets of diverse cancers including urothelial and squamous cell carcinomas (SCC). However, the morphology of FGFR3::TACC3-positive head and neck carcinomas has not been well studied and it is unclear if this fusion represents a random event, or if it might characterize a morphologically distinct tumor type. We describe nine FGFR3::TACC3 fusion-positive head and neck carcinomas affecting six males and three females aged 38 to 89 years (median, 59). The tumors originated in the sinonasal tract (n = 4), parotid gland (n = 2), and one case each in the oropharynx, submandibular gland, and larynx. At last follow-up (9-21 months; median, 11), four patients developed local recurrence and/or distant metastases, two died of disease at 11 and 12 months, one died of other cause, one was alive with disease, and two were disease-free. Three of six tumors harbored high risk oncogenic HPV infection (HPV33, HPV18, one unspecified). Histologically, three tumors revealed non-keratinizing transitional cell-like or non-descript morphology with variable mixed inflammatory infiltrate reminiscent of mucoepidermoid or DEK::AFF2 carcinoma (all were HPV-negative), and three were HPV-associated (all sinonasal) with multiphenotypic (1) and non-intestinal adenocarcinoma (2) pattern, respectively. One salivary gland tumor showed poorly cohesive large epithelioid cells with prominent background inflammation and expressed AR and GATA3, in line with a possible salivary duct carcinoma variant. Two tumors were conventional SCC. Targeted RNA sequencing revealed an in-frame FGFR3::TACC3 fusion in all cases. This series highlights heterogeneity of head and neck carcinomas harboring FGFR3::TACC3 fusions, which segregates into three categories: (1) unclassified HPV-negative category, morphologically distinct from SCC and other entities; (2) heterogeneous group of HPV-associated carcinomas; and (3) conventional SCC. A driver role of the FGFR3::TACC3 fusion in the first category (as a potential distinct entity) remains to be further studied. In the light of available FGFR-targeting therapies, delineation of these tumors and enhanced recognition is recommended.

Comprehensive Cancer Center European Metropolitan Area Erlangen Nuremberg Friedrich Alexander University of Erlangen Nuremberg Erlangen Germany

Department of Head and Neck Surgical Oncology University Medical Center Utrecht Utrecht The Netherlands

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN USA

Department of Otorhinolaryngology Head and Neck Surgery Bundeswehrkrankenhaus Berlin Berlin Germany

Department of Pathology and Laboratory Medicine Institute Cleveland Clinic Cleveland OH USA

Department of Pathology Memorial Sloan Kettering Cancer Center New York NY USA

Department of Pathology University Medical Center Utrecht Utrecht The Netherlands

Department of Pathology University of Texas Southwestern Medical Center Dallas TX USA

Head and Neck Endocrine Pathology Center of Excellence Division of Anatomic Pathology University of Pittsburgh Medical Center Pittsburgh PA USA

Institute of Pathology Erlangen University Hospital Friedrich Alexander University of Erlangen Nuremberg Krankenhausstrasse 8 10 91054 Erlangen Germany

Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands

The Fingerland Department of Pathology Charles University Faculty of Medicine in Hradec Kralove and University Hospital Hradec Kralove Hradec Kralove Czech Republic

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