We report 2 cases of high-grade sinonasal adenocarcinoma with a distinct morphological and immunohistochemical phenotype. Albeit histologically different from secretory carcinoma of the salivary glands, both tumors presented here share an ETV6::NTRK3 fusion. The highly cellular tumors were composed of solid and dense cribriform nests, often with comedo-like necroses in the center, and minor areas with papillary, microcystic, and trabecular formations without secretions, mostly located at the periphery of the lesion. The cells displayed high-grade features, with enlarged, crowded, and often vesicular nuclei with conspicuous nucleoli and brisk mitotic activity. The tumor cells were immunonegative for mammaglobin while showing immunopositivity for p40/p63, S100, SOX10, and GATA3, as well as for cytokeratins 7, 18, and 19. For the first time, we describe 2 cases of primary high-grade non-intestinal type adenocarcinomas of the nasal cavity, distinct from secretory carcinoma by morphology and immunoprofile, harboring the ETV6::NTRK3 fusion.

Bioptical Laboratory Pilsen Czech Republic

Department of Biology and Medical Genetics 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Pathology Centre Henri Becquerel Rouen France

Department of Pathology Faculty of Medicine in Pilsen and University Hospital Plzen Charles University Alej Svobody 80 323 00 Pilsen Czech Republic

Department of Pathology Hopital Gui de Chauliac Montpellier France

Molecular Genetic Laboratory Bioptical Laboratory Pilsen Czech Republic

Zobrazit více v PubMed

Thompson LDR, Loney EL, Bishop JA, et al. WHO Classification of Tumours Editorial Board. Head and neck tumours. [Internet; beta version ahead of print] Lyon (France): International Agency for Research on Cancer; 2022. Chapter 2: Nasal, paranasal, and skull base tumours.

Agaimy A. SWI/SNF-deficient sinonasal carcinomas. Adv Anat Pathol. 2023;30(2):95–103. doi: 10.1097/PAP.0000000000000372. PubMed DOI

French CA. NUT midline carcinoma. Cancer Genet Cytogenet. 2010;203(1):16–20. doi: 10.1016/j.cancergencyto.2010.06.007. PubMed DOI PMC

Dogan S, Chute DJ, Xu B, et al. Frequent IDH2 R172 mutations in undifferentiated and poorly-differentiated sinonasal carcinomas. J Pathol. 2017;242(4):400–408. doi: 10.1002/path.4915. PubMed DOI PMC

Mito JK, Bishop JA, Sadow PM, et al. Immunohistochemical detection and molecular characterization of IDH-mutant sinonasal undifferentiated carcinomas. Am J Surg Pathol. 2018;42(8):1067–1075. doi: 10.1097/PAS.0000000000001064. PubMed DOI

Leivo I. Update on sinonasal adenocarcinoma: classification and advances in immunophenotype and molecular genetic make-up. Head Neck Pathol. 2007;1(1):38–43. doi: 10.1007/s12105-007-0025-2. PubMed DOI PMC

Brayer KJ, Frerich CA, Kang H, Ness SA. Recurrent fusions in MYB and MYBL1 define a common, transcription factor-driven oncogenic pathway in salivary gland adenoid cystic carcinoma. Cancer Discov. 2016;6(2):176–187. doi: 10.1158/2159-8290.CD-15-0859. PubMed DOI PMC

Mitani Y, Liu B, Rao PH, et al. Novel MYBL1 gene rearrangements with recurrent MYBL1-NFIB fusions in salivary adenoid cystic carcinomas lacking t(6;9) translocations. Clin Cancer Res. 2016;22(3):725–733. doi: 10.1158/1078-0432.CCR-15-2867-T. PubMed DOI PMC

Okumura Y, Nakano S, Murase T, et al. Prognostic impact of CRTC1/3-MAML2 fusions in salivary gland mucoepidermoid carcinoma: a multiinstitutional retrospective study. Cancer Sci. 2020;111(11):4195–4204. doi: 10.1111/cas.14632. PubMed DOI PMC

Haller F, Bieg M, Will R, et al. Enhancer hijacking activates oncogenic transcription factor NR4A3 in acinic cell carcinomas of the salivary glands. Nat Commun. 2019;10(1):368. doi: 10.1038/s41467-018-08069-x. PubMed DOI PMC

Skálová A, Vanecek T, Sima R, et al. Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity. Am J Surg Pathol. 2010;34(5):599–608. doi: 10.1097/PAS.0b013e3181d9efcc. PubMed DOI

Baneckova M, Agaimy A, Andreasen S, et al. Mammary analog secretory carcinoma of the nasal cavity: characterization of 2 cases and their distinction from other low-grade sinonasal adenocarcinomas. Am J Surg Pathol. 2018;42(6):735–743. doi: 10.1097/PAS.0000000000001048. PubMed DOI

Skálová A, Vanecek T, Majewska H, et al. Mammary analogue secretory carcinoma of salivary glands with high-grade transformation: report of 3 cases with the ETV6-NTRK3 gene fusion and analysis of TP53, β-catenin, EGFR, and CCND1 genes. Am J Surg Pathol. 2014;38(1):23–33. doi: 10.1097/PAS.0000000000000088. PubMed DOI

Skalova A, Leivo I, Hellquist H, et al. High-grade transformation/dedifferentiation in salivary gland carcinomas: occurrence across subtypes and clinical significance. Adv Anat Pathol. 2021;28(3):107–118. doi: 10.1097/PAP.0000000000000298. PubMed DOI

Andreasen S, Skálová A, Agaimy A, et al. ETV6 gene rearrangements characterize a morphologically distinct subset of sinonasal low-grade non-intestinal-type adenocarcinoma: a novel translocation-associated carcinoma restricted to the cinonasal tract. Am J Surg Pathol. 2017;41(11):1552–1560. doi: 10.1097/PAS.0000000000000912. PubMed DOI

Rooper LM, Thompson LDR, Gagan J, et al. Low-grade non-intestinal-type sinonasal adenocarcinoma: a histologically distinctive but molecularly heterogeneous entity. Mod Pathol. 2022;35(9):1160–1167. doi: 10.1038/s41379-022-01068-w. PubMed DOI

Andreasen S, Kiss K, Melchior LC, Laco J. The ETV6-RET gene fusion is found in ETV6-rearranged low-grade sinonasal adenocarcinoma without NTRK3 involvement. Am J Surg Pathol. 2018;42(7):985–988. doi: 10.1097/PAS.0000000000001069. PubMed DOI

Kishikawa S, Hayashi T, Shimizu J, et al. Low-grade tracheal adenocarcinoma with ETV6::NTRK3 fusion: unique morphology akin to subsets of sinonasal low-grade non-intestinal-type adenocarcinoma. Virchows Arch. 2022;481(5):793–797. doi: 10.1007/s00428-022-03353-0. PubMed DOI

Rupp NJ, Nemes C, Rushing EJ, Huber GF, Freiberger SN. High-grade salivary gland adenocarcinoma harboring ETV6-NTRK3 fusion: defined by morphology or molecular aberration? Head Neck Pathol. 2021;15(3):1082–1084. doi: 10.1007/s12105-021-01297-6. PubMed DOI PMC

Todorovic E, Dickson BC, Weinreb I. Salivary gland cancer in the era of routine next-generation sequencing. Head Neck Pathol. 2020;14:311–320. doi: 10.1007/s12105-020-01140-4. PubMed DOI PMC

Lanic MD, Guérin R, Wassef M, et al (2023) Detection of salivary gland and sinonasal fusions by a next-generation sequencing based, ligation-dependent, multiplex RT-PCR assay [published online ahead of print, 2023 Jun 22]. Histopathology. 10.1111/his.14971 PubMed

Purgina B, Bastaki JM, Duvvuri U, Seethala RR. A subset of sinonasal non-intestinal type adenocarcinomas are truly seromucinous adenocarcinomas: a morphologic and immunophenotypic assessment and description of a novel pitfall. Head Neck Pathol. 2015;9(4):436–446. doi: 10.1007/s12105-015-0615-3. PubMed DOI PMC

Stelow EB, Jo VY, Mills SE, Carlson DL. A histologic and immunohistochemical study describing the diversity of tumors classified as sinonasal high-grade nonintestinal adenocarcinomas. Am J Surg Pathol. 2011;35(7):971–980. doi: 10.1097/PAS.0b013e31821cbd72. PubMed DOI

SMARCB1-deficient sinonasal adenocarcinoma: a rare variant of SWI/SNF-deficient malignancy often misclassified as high-grade non-intestinal-type sinonasal adenocarcinoma or myoepithelial carcinoma