RESUMO
Salivary gland tumors represent a diverse group of neoplasms that occasionally pose a diagnostic challenge for pathologists, particularly with limited sampling. Gene fusions, which may reflect genetic drivers, are increasingly recognized in a subset of these neoplasms, and can be leveraged for diagnostic purposes. We performed a retrospective analysis on a cohort of 80 benign and malignant salivary gland tumors, enriched for subtypes known to harbor recurrent fusion events, to validate the diagnostic use of a targeted RNA sequencing assay to detect fusion transcripts. Testing identified fusion genes in 71% (24/34) of pleomorphic adenoma and carcinoma-ex-pleomorphic adenoma, with 56% of cases showing rearrangement of PLAG1 and 15% HMGA2. In addition to confirming known partners for these genes, novel PLAG1 fusion partners were identified, including DSTN, NTF3, and MEG3; CNOT2 was identified as a novel fusion partner for HMGA2. In adenoid cystic carcinoma, 95% of cases (19/20) were positive for a fusion event. MYB was rearranged in 60% (12/20), MYBL1 in 30% (6/20), and NFIB in 5% (1/20); two tumors exhibited novel fusion products, including NFIB-TBPL1 and MYBL1-VCPIP1. Fusion genes were identified in 64% (9/14) of cases of mucoepidermoid carcinoma; MAML2 was confirmed to partner with either CRTC1 (43%) or CRTC3 (21%). One salivary duct carcinoma was found to harbor a novel RAPGEF6-ACSL6 fusion gene. Finally, as anticipated, gene fusions were not detected in any of the five acinic cell carcinomas included in the cohort. In summary, targeted RNA sequencing represents a diagnostically useful ancillary technique for identifying a variety of existing, and novel, fusion transcripts in the classification of salivary gland neoplasms.
Assuntos
Adenoma Pleomorfo/patologia , Biomarcadores Tumorais/genética , Carcinoma Adenoide Cístico/patologia , Regulação Neoplásica da Expressão Gênica , Proteínas de Fusão Oncogênica/genética , Neoplasias das Glândulas Salivares/patologia , Análise de Sequência de RNA/métodos , Adenoma Pleomorfo/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Adenoide Cístico/genética , Criança , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias das Glândulas Salivares/genética , Adulto JovemRESUMO
A novel DEK-AFF2 fusion was recently reported in 4 nonkeratinizing squamous cell carcinomas of the sinonasal region and skull base, including 1 with exceptional response to immunotherapy, but it is not yet clear if this rearrangement defines a unique clinicopathologic category or represents a rare event. This study aims to characterize a larger cohort of carcinomas with DEK-AFF2 fusions to assess whether they truly constitute a distinctive entity. Among 27 sinonasal and skull base nonkeratinizing squamous cell carcinoma that were negative for human papillomavirus and Epstein-Barr virus, RNA sequencing identified DEK-AFF2 fusions in 13 cases (48%). Nine were centered in the nasal cavity, 2 in the middle ear/temporal bone, 1 in the nasopharynx, and 1 in the orbit. These tumors displayed recurrent histologic features including (1) complex endophytic and exophytic, frequently papilloma-like growth, (2) transitional epithelium with eosinophilic to amphophilic cytoplasm, (3) absent or minimal keratinization with occasional compact keratin pearls, (4) monotonous nuclei, and (5) prominent tumor-infiltrating neutrophils or stromal lymphocytes. This appearance not only overlaps with high-grade basaloid sinonasal carcinomas but also with benign papillomas and tumors reported as low-grade papillary Schneiderian carcinoma. However, DEK-AFF2 carcinomas showed frequent local recurrence, cervical lymph node metastases, and distant metastasis with 2 deaths from disease, confirming they are aggressive malignancies despite relatively bland histology. Overall, the distinctive molecular, histologic, and clinical features of DEK-AFF2 carcinomas suggest they represent a unique entity in the sinonasal region. This tumor merits increased pathologic recognition to better understand its prognostic and therapeutic implications.
Assuntos
Biomarcadores Tumorais/genética , Proteínas Cromossômicas não Histona/genética , Fusão Gênica , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Neoplasias dos Seios Paranasais/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , Neoplasias da Base do Crânio/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/análise , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Neoplasias dos Seios Paranasais/química , Neoplasias dos Seios Paranasais/patologia , Fenótipo , RNA-Seq , Neoplasias da Base do Crânio/química , Neoplasias da Base do Crânio/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/química , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Adulto JovemRESUMO
Squamous cell carcinoma of the sinonasal tract is relatively rare and morphologically and genetically heterogeneous. We report the case of an adult male with a left sphenoid sinus mass. A biopsy revealed an undifferentiated carcinoma composed of sheets of epithelioid cells lacking keratinization and glandular formation. The tumor was associated with a prominent lymphoplasmacytic inflammatory infiltrate. Immunohistochemical staining demonstrated diffuse expression of pankeratin and p63; it was negative for p16. In addition, EBER was also negative. Morphologically the findings raised the possibility of non-keratinizing squamous cell carcinoma. RNA sequencing was undertaken to exclude the possibility of NUT carcinoma; interestingly, this revealed a novel ETV6-TNFRSF8 fusion transcript, which was independently confirmed by fluorescence in situ hybridization. The current case is illustrative because it broadens our understanding of the molecular pathogenesis of non-keratinizing squamous cell carcinoma and adds to the diversity of ETV6-rearranged malignancies.
Assuntos
Carcinoma de Células Escamosas/genética , Antígeno Ki-1 , Neoplasias dos Seios Paranasais/genética , Idoso , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Diagnóstico Diferencial , Humanos , Antígeno Ki-1/genética , Imageamento por Ressonância Magnética , Masculino , Neoplasias dos Seios Paranasais/patologia , Neoplasias dos Seios Paranasais/terapia , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Tomografia Computadorizada por Raios X , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
Nasopharyngeal adenocarcinoma is a rare malignancy that is classified into conventional/surface- and salivary-types. Herein we report the case of a 52-year-old male who presented with a right nasopharyngeal mass and right-sided hearing loss. Diagnostic imaging revealed a circumscribed 1.7 cm mass centred in the right antero-lateral aspect of the nasopharynx. A biopsy showed a gland-forming neoplasm that was in continuity with the surface epithelium. The tumor exhibited a nested to micro-papillary architecture, with mild cytologic atypia. Immunohistochemistry demonstrated diffuse staining for CK7, SOX10, and p16; the abluminal layer was highlighted by CK5 and p63, while the luminal cells expressed CD117. The tumor was not amenable to subclassification and was diagnosed as a low-grade nasopharyngeal adenocarcinoma, not otherwise specified (NOS). Subsequent RNA sequencing was performed which identified a novel GOLGB1-BRAF fusion product. Based on its unique morphology and molecular findings, this is presumed to represent a novel subtype of nasopharyngeal adenocarcinoma. In addition to being of diagnostic relevance, this fusion may ultimately represent a potential therapeutic target.
