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

See more in PubMed

Singh D, Chan JM, Zoppoli P, Niola F, Sullivan R, Castano A, Liu EM, Reichel J, Porrati P, Pellegatta S, Qiu K, Gao Z, Ceccarelli M, Riccardi R, Brat DJ, Guha A, Aldape K, Golfinos JG, Zagzag D, Mikkelsen T, Finocchiaro G, Lasorella A, Rabadan R, Iavarone A (2012) Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 337:1231–1235 PubMed PMC

Wu YM, Su F, Kalyana-Sundaram S, Khazanov N, Ateeq B, Cao X, Lonigro RJ, Vats P, Wang R, Lin SF, Cheng AJ, Kunju LP, Siddiqui J, Tomlins SA, Wyngaard P, Sadis S, Roychowdhury S, Hussain MH, Feng FY, Zalupski MM, Talpaz M, Pienta KJ, Rhodes DR, Robinson DR, Chinnaiyan AM (2013) Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov 3:636–647 PubMed PMC

Frattini V, Pagnotta SM, Tala Fan JJ, Russo MV, Lee SB, Garofano L, Zhang J, Shi P, Lewis G, Sanson H, Frederick V, Castano AM, Cerulo L, Rolland DCM, Mall R, Mokhtari K, Elenitoba-Johnson KSJ, Sanson M, Huang X, Ceccarelli M, Lasorella A, Iavarone A (2018) A metabolic function of FGFR3-TACC3 gene fusions in cancer. Nature 553:222–227 PubMed PMC

Dhami J, Hirshfield KM, Ganesan S, Hellmann M, Rojas V, Amorosa JK, Riedlinger GM, Zhong H, Ali SM, Pavlick D, Elvin JA, Rodriguez-Rodriguez L (2018) Comprehensive genomic profiling aids in treatment of a metastatic endometrial cancer. Cold Spring Harb Mol Case Stud 4:a002089 PubMed PMC

Moore A, Bar Y, Maurice-Dror C, Ospovat I, Sarfaty M, Korzets Y, Goldvaser H, Gordon N, Billan S, Gutfeld O, Popovtzer A (2020) Next-generation sequencing in salivary gland carcinoma: targetable alterations lead to a therapeutic advantage-multicenter experience. Head Neck 42:599–607 PubMed

Pal SK, Bajorin D, Dizman N, Hoffman-Censits J, Quinn DI, Petrylak DP, Galsky MD, Vaishampayan U, De Giorgi U, Gupta S, Burris HA, Soifer HS, Li G, Wang H, Dambkowski CL, Moran S, Daneshmand S, Rosenberg JE (2020) Infigratinib in upper tract urothelial carcinoma versus urothelial carcinoma of the bladder and its association with comprehensive genomic profiling and/or cell-free DNA results. Cancer 126:2597–2606 PubMed PMC

Wang Y, Liang D, Chen J, Chen H, Fan R, Gao Y, Gao Y, Tao R, Zhang H (2021) Targeted therapy with anlotinib for a patient with an oncogenic FGFR3-TACC3 fusion and recurrent glioblastoma. Oncologist 26:173–177 PubMed PMC

Ou SI, Horn L, Cruz M, Vafai D, Lovly CM, Spradlin A, Williamson MJ, Dagogo-Jack I, Johnson A, Miller VA, Gadgeel S, Ali SM, Schrock AB (2017) Emergence of FGFR3-TACC3 fusions as a potential by-pass resistance mechanism to EGFR tyrosine kinase inhibitors in EGFR mutated NSCLC patients. Lung Cancer 111:61–64 PubMed PMC

Pros E, Saigi M, Alameda D, Gomez-Mariano G, Martinez-Delgado B, Alburquerque-Bejar JJ, Carretero J, Tonda R, Esteve-Codina A, Catala I, Palmero R, Jove M, Lazaro C, Patiño-Garcia A, Gil-Bazo I, Verdura S, Teulé A, Torres-Lanzas J, Sidransky D, Reguart N, Pio R, Juan-Vidal O, Nadal E, Felip E, Montuenga LM, Sanchez-Cespedes M (2020) Genome-wide profiling of non-smoking-related lung cancer cells reveals common RB1 rearrangements associated with histopathologic transformation in EGFR-mutant tumors. Ann Oncol 31:274–282 PubMed

Guo G, Sun X, Chen C, Wu S, Huang P, Li Z, Dean M, Huang Y, Jia W, Zhou Q, Tang A, Yang Z, Li X, Song P, Zhao X, Ye R, Zhang S, Lin Z, Qi M, Wan S, Xie L, Fan F, Nickerson ML, Zou X, Hu X, Xing L, Lv Z, Mei H, Gao S, Liang C, Gao Z, Lu J, Yu Y, Liu C, Li L, Fang X, Jiang Z, Yang J, Li C, Zhao X, Chen J, Zhang F, Lai Y, Lin Z, Zhou F, Chen H, Chan HC, Tsang S, Theodorescu D, Li Y, Zhang X, Wang J, Yang H, Gui Y, Wang J, Cai Z (2013) Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation. Nat Genet 45:1459–1463 PubMed PMC

Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507:315–322 PubMed PMC

Qin A, Johnson A, Ross JS, Miller VA, Ali SM, Schrock AB, Gadgeel SM (2019) Detection of known and novel FGFR fusions in non-small cell lung cancer by comprehensive genomic profiling. J Thorac Oncol 14:54–62 PubMed

Wang R, Wang L, Li Y, Hu H, Shen L, Shen X, Pan Y, Ye T, Zhang Y, Luo X, Zhang Y, Pan B, Li B, Li H, Zhang J, Pao W, Ji H, Sun Y, Chen H (2014) FGFR1/3 tyrosine kinase fusions define a unique molecular subtype of non-small cell lung cancer. Clin Cancer Res 20:4107–4114 PubMed

Mizukami T, Sakai K, Naruki S, Taniyama T, Horie Y, Izawa N, Tsuda T, Fujino T, Boku N, Yasuda H, Fukunaga T, Nakajima TE, Nishio K (2017) Identification of a FGFR3-TACC3 fusion in esophageal cancer. Ann Oncol 28:437–438 PubMed

Carneiro BA, Elvin JA, Kamath SD, Ali SM, Paintal AS, Restrepo A, Berry E, Giles FJ, Johnson ML (2015) FGFR3-TACC3: a novel gene fusion in cervical cancer. Gynecol Oncol Rep 13:53–56 PubMed PMC

Tamura R, Yoshihara K, Saito T, Ishimura R, Martínez-Ledesma JE, Xin H, Ishiguro T, Mori Y, Yamawaki K, Suda K, Sato S, Itamochi H, Motoyama T, Aoki Y, Okuda S, Casingal CR, Nakaoka H, Inoue I, Verhaak RGW, Komatsu M, Enomoto T (2018) Novel therapeutic strategy for cervical cancer harboring FGFR3-TACC3 fusions. Oncogenesis 7:4 PubMed PMC

Yuan L, Liu ZH, Lin ZR, Xu LH, Zhong Q, Zeng MS (2014) Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma. Cancer Biol Ther 15:1613–1621 PubMed PMC

Mata DA, Benhamida JK, Lin AL, Vanderbilt CM, Yang SR, Villafania LB, Ferguson DC, Jonsson P, Miller AM, Tabar V, Brennan CW, Moss NS, Sill M, Benayed R, Mellinghoff IK, Rosenblum MK, Arcila ME, Ladanyi M, Bale TA (2020) Genetic and epigenetic landscape of IDH-wildtype glioblastomas with FGFR3-TACC3 fusions. Acta Neuropathol Commun 8:186 PubMed PMC

Shaver TM, Lehmann BD, Beeler JS, Li CI, Li Z, Jin H, Stricker TP, Shyr Y, Pietenpol JA (2016) Diverse, biologically relevant, and targetable gene rearrangements in triple-negative breast cancer and other malignancies. Cancer Res 76:4850–4860 PubMed PMC

Ha JH, Lee C, Lee KS, Pak CS, Sun CH, Koh Y, Chang H (2020) The molecular pathogenesis of trichilemmal carcinoma. BMC Cancer 20:516 PubMed PMC

Robinson JT, Thorvaldsdóttir H, Winckler W, Guttman M, Lander ES, Getz G, Mesirov JP (2011) Integrative genomics viewer. Nat Biotechnol 29:24–26 PubMed PMC

Zheng Z, Liebers M, Zhelyazkova B, Cao Y, Panditi D, Lynch KD, Chen J, Robinson HE, Kao YC, Sung YS, Zhang L, Huang SC, Argani P, Chung CT, Graf NS, Wright DC, Kellie SJ, Agaram NP, Ludwig K, Zin A, Alaggio R (2016) Recurrent BCOR internal tandem duplication and YWHAE-NUTM2B fusions in soft tissue undifferentiated round cell sarcoma of infancy: overlapping genetic features with clear cell sarcoma of kidney. Antonescu CR. Am J Surg Pathol 40:1009–20 PubMed PMC

Bell D, Afkhami M (2024) Conundrum of 3N: nasopharyngeal nonkeratinizing non-viral carcinoma-reappraisal of fusions and report of two consecutive cases with unusual molecular findings. Virchows Arch. 10.1007/s00428-024-03877-7. Online ahead of print PubMed

Zheng Z, Liebers M, Zhelyazkova B, Cao Y, Panditi D, Lynch KD, Chen J, Robinson HE, Shim HS, Chmielecki J, Pao W, Engelman JA, Iafrate AJ, Le LP (2014) Anchored multiplex PCR for targeted next-generation sequencing. Nat Med 20:1479–1484 PubMed

Hehir-Kwa JY, Koudijs MJ, Verwiel ETP, Kester LA, van Tuil M, Strengman E, Buijs A, Kranendonk MEG, Hiemcke-Jiwa LS, de Haas V, van de Geer E, de Leng W, van der Lugt J, Lijnzaad P, Holstege FCP, Kemmeren P, Tops BBJ (2022) Improved gene fusion detection in childhood cancer diagnostics using RNA sequencing. JCO Precis Oncol 6:e2000504 PubMed PMC

Gupta S, Sholl LM, Yang Y, Osunkoya AO, Gordetsky JB, Cornejo KM, Michalova K, Maclean F, Dvindenko E, Snuderl M, Hirsch MS, Anderson WJ, Rowsey RA, Jimenez RE, Cheville JC, Sadow PM, Colecchia M, Ricci C, Ulbright TM, Berney DM, Acosta AM (2024) Genomic analysis of spermatocytic tumors demonstrates recurrent molecular alterations in cases with malignant clinical behavior. J Pathol 262:50–60 PubMed

Bishop JA, Ma XJ, Wang H, Luo Y, Illei PB, Begum S, Taube JM, Koch WM, Westra WH (2012) Detection of transcriptionally active high-risk HPV in patients with head and neck squamous cell carcinoma as visualized by a novel E6/E7 mRNA in situ hybridization method. Am J Surg Pathol 36:1874–1882 PubMed PMC

Agaimy A, Koch M, Lell M, Semrau S, Dudek W, Wachter DL, Knöll A, Iro H, Haller F, Hartmann A (2014) SMARCB1(INI1)-deficient sinonasal basaloid carcinoma: a novel member of the expanding family of SMARCB1-deficient neoplasms. Am J Surg Pathol 38:1274–1281 PubMed PMC

Petry KU, Menton S, Menton M et al (2003) Inclusion of HPV testing in routine cervical cancer screening for women above 29 years in Germany: results for 8466 patients. Br J Cancer 88:1570–1577 PubMed PMC

de De Wardin HT, Cyrta J, Dermawan JK, Guillemot D, Orbach D, Aerts I, Pierron G, Antonescu CR (2024) FGFR1 fusions as a novel molecular driver in rhabdomyosarcoma. Genes Chromosomes Cancer 63:e23232 PubMed PMC

Dermawan JK, Vanderbilt CM, Chang JC, Untch BR, Singer S, Chi P, Tap WD, Antonescu CR (2022) FGFR2::TACC2 fusion as a novel KIT-independent mechanism of targeted therapy failure in a multidrug-resistant gastrointestinal stromal tumor. Genes Chromosomes Cancer 61:412–419 PubMed PMC

Lin DI, Killian JK, Venstrom JM, Ramkissoon SH, Ross JS, Elvin JA (2021) Recurrent urothelial carcinoma-like FGFR3 genomic alterations in malignant Brenner tumors of the ovary. Mod Pathol 34:983–993 PubMed

Costa R, Carneiro BA, Taxter T, Tavora FA, Kalyan A, Pai SA, Chae YK, Giles FJ (2016) FGFR3-TACC3 fusion in solid tumors: mini review. Oncotarget 7:55924–55938 PubMed PMC

Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C (2014) The landscape of kinase fusions in cancer. Nat Commun 5:4846 PubMed PMC

Guo T, Gaykalova DA, Considine M, Wheelan S, Pallavajjala A, Bishop JA, Westra WH, Ideker T, Koch WM, Khan Z, Fertig EJ, Califano JA (2016) Characterization of functionally active gene fusions in human papillomavirus related oropharyngeal squamous cell carcinoma. Int J Cancer 139:373–382 PubMed PMC

Ohmoto A, Sato Y, Asaka R, Fukuda N, Wang X, Urasaki T, Hayashi N, Sato Y, Nakano K, Yunokawa M, Ono M, Tomomatsu J, Toshiyasu T, Mitani H, Takeuchi K, Mori S, Takahashi S (2021) Clinicopathological and genomic features in patients with head and neck neuroendocrine carcinoma. Mod Pathol 34:1979–1989 PubMed PMC

(2015) Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 517:576–582 PubMed PMC

Chu YH, Mullaney K, DiNapoli SE, Cohen MA, Xu B, Ghossein R, Katabi N, Dogan S (2024) FGFR1/2/3-rearranged carcinoma of the head and neck: expanded histological spectrum crossing path with high-risk HPV in the sinonasal tract. Histopathology 84:589–600 PubMed PMC

Bishop JA, Andreasen S, Hang JF, Bullock MJ, Chen TY, Franchi A, Garcia JJ, Gnepp DR, Gomez-Fernandez CR, Ihrler S, Kuo YJ, Lewis JS Jr, Magliocca KR, Pambuccian S, Sandison A, Uro-Coste E, Stelow E, Kiss K, Westra WH (2017) HPV-related multiphenotypic sinonasal carcinoma: an expanded series of 49 cases of the tumor formerly known as HPV-related carcinoma with adenoid cystic carcinoma-like features. Am J Surg Pathol 41:1690–1701 PubMed PMC

Chung GT, Lung RW, Hui AB, Yip KY, Woo JK, Chow C, Tong CY, Lee SD, Yuen JW, Lun SW, Tso KK, Wong N, Tsao SW, Yip TT, Busson P, Kim H, Seo JS, O’Sullivan B, Liu FF, To KF, Lo KW (2013) Identification of a recurrent transforming UBR5-ZNF423 fusion gene in EBV-associated nasopharyngeal carcinoma. J Pathol 231:158–167 PubMed PMC

Rooper LM, Agaimy A, Dickson BC, Dueber JC, Eberhart CG, Gagan J, Hartmann A, Khararjian A, London NR, MacMillan CM, Palsgrove DN, Nix JS, Sandison A, Stoehr R, Truong T, Weinreb I, Bishop JA (2021) DEK-AFF2 carcinoma of the sinonasal region and skull base: detailed clinicopathologic characterization of a distinctive entity. Am J Surg Pathol 45:1682–1693 PubMed

Kuo YJ, Lewis JS Jr, Zhai C, Chen YA, Chernock RD, Hsieh MS, Lan MY, Lee CK, Weinreb I, Hang JF (2021) DEK-AFF2 fusion-associated papillary squamous cell carcinoma of the sinonasal tract: clinicopathologic characterization of seven cases with deceptively bland morphology. Mod Pathol 34:1820–1830 PubMed

Sarkar S, Ryan EL, Royle SJ (2017) FGFR3-TACC3 cancer gene fusions cause mitotic defects by removal of endogenous TACC3 from the mitotic spindle. Open Biol 7:170080 PubMed PMC

Daly C, Castanaro C, Zhang W, Zhang Q, Wei Y, Ni M, Young TM, Zhang L, Burova E, Thurston G (2017) FGFR3-TACC3 fusion proteins act as naturally occurring drivers of tumor resistance by functionally substituting for EGFR/ERK signaling. Oncogene 36:471–481 PubMed PMC

Granberg KJ, Annala M, Lehtinen B, Kesseli J, Haapasalo J, Ruusuvuori P, Yli-Harja O, Visakorpi T, Haapasalo H, Nykter M, Zhang W (2017) Strong FGFR3 staining is a marker for FGFR3 fusions in diffuse gliomas. Neuro Oncol 19:1206–1216 PubMed PMC