Papillary‐cystic neoplasms of the middle ear are distinct from endolymphatic sac tumours

Abstract

Aims Papillary neoplasms of the middle and inner ear are rare and poorly characterised. The current World Health Organization classification divides them into two major subtypes: aggressive papillary tumours (APTs) and endolymphatic sac tumours (ELSTs). The aim of this article is to present two papillary neoplasms of the middle ear that do not fit into either the classic APT category or the classic ELST category, and compare them with three ELSTs. Methods and results The patients were a 48‐year‐old female and a 59‐year‐old male without a history of other neoplasms. Histology showed papillary‐cystic growth of predominantly oncocytic (Case 1) or mucinous (Case 2) cells surrounded by a p63‐positive basal layer. The overall histology was reminiscent of oncocytic sinonasal papilloma (Case 1) and pancreatobiliary or salivary intraductal papillary mucinous neoplasms (Case 2). Ovarian‐type stroma, invasion and malignant features were absent. Immunohistochemistry revealed expression of cytokeratin (CK) 7, but not carbonic anhydrase IX (CAIX) or paired box gene 8 (PAX8) (except for very focal PAX8 expression in Case 1). The TST15 gene panel and HRAS sequencing revealed no pathogenic mutations in BRAF, KRAS, EGFR, AKT1, or HRAS. The TruSight RNA fusion panel revealed an MKRN1–BRAF fusion in Case 1. No fusion was detected in Case 2. The three ELSTs showed classic features of the entity, expressed CK7, epithelial membrane antigen, PAX8, and CAIX, and lacked a basal cell layer. Conclusion These novel cases suggest that papillary tumours of the ear represent a heterogeneous spectrum of distinct neoplasms unified by a prominent papillary‐cystic pattern rather than a single entity. Future studies should clarify whether the MKRN1–BRAF fusion is a defining recurrent driver event, especially in those cases reported as sinonasal‐type middle ear papillomas.

Detection of salivary gland and sinonasal fusions by a next‐generation sequencing based, ligation‐dependent, multiplex RT‐PCR assay

“…Gene fusions are increasingly recognised in epithelial and mesenchymal tumours. Recently, several recurrent gene fusions have been described in SGSN tumours (over 100 at this time) 1–7,14–85 . These molecular alterations have improved the knowledge about their molecular pathology and their classification, which can serve as powerful diagnostic tools and have a clinical impact in the management through potential therapeutic targets.…”

“…These fusions cover 100% of the 29 head and neck histological entities known to be associated with gene fusion (listed in Table 1, Figure 2, Table S1). 1–7,14–85 Seven gene fusions are associated with secretory carcinomas (SC), three with mucoepidermoid carcinoma (MEC), six with adenoid cystic carcinoma (ACC), seven with intraductal carcinoma (IC), three with clear cell carcinoma (CCC), three with clear cell odontogenic carcinoma (CCOC), 18 with pleomorphic adenoma (PA) and carcinoma ex‐pleomorphic adenoma (CA ex PA), one with adamantinoma‐like Ewing Sarcoma (ALES), one with DEK::AFF2 sinonasal carcinoma (DAC), one with EWSR1::COLCA2 sinonasal sarcoma (ECSS), one with acinic cell carcinoma (AiCC), two with microsecretory carcinoma (miC), two with cribriform adenocarcinoma of minor salivary glands (CAMSG), three with salivary duct carcinoma (SDC), 14 with myoepithelioma (M), six with clear cell myoepithelial carcinoma (CCMC), four with myoepithelial carcinoma (MC), five with nasopharyngeal carcinoma (NPC), nine with NUT carcinoma, five with biphenotypic sinonasal sarcoma (BSNS), one with sinonasal squamous cells carcinoma (SNSC), one with low‐grade nasopharyngeal adenocarcinoma (LGNA), one with low‐grade sinonasal adenocarcinoma (LGSA), one with microcribriform adenocarcinoma (MicC), one with adenocarcinoma NOS (ACA, NOS), one with papillary‐cystic neoplasms of the middle ear, and nine with Ewing sarcoma. Some genes are implicated in several fusions, such as EWSR1 ( n = 16) in Ewing sarcoma, ALES, CCC, CCOC, CCMC, PLAG1 ( n = 12) in PA and CA ex PA, myoepithelioma, myoepithelial carcinoma, myoepithelial carcinoma (clear cells), NUTM1 ( n = 9) in NUT carcinoma, HMGA2 ( n = 6) in PA and CA ex PA, RET ( n = 6) in SC, IC, and SNLGA, ETV6 ( n = 5) in SC, SNLGA, and SNSC, MAML2 ( n = 3) in MEC and NC, ALK ( n = 4) in IC, SDC, and SC.…”

“…BRD4 NUTM1 [63] CIC*** NUTM1*** [64] MXD1*** NUTM1*** [62] YAP1*** NUTM1*** [65] ZNF592 NUTM1 [66] ZNF532*** NUTM1*** [67] NSD3 NUTM1 [68] Papillary-cystic neoplasms of the middle ear MKRN1 BRAF [69] Pleomorphic adenoma HMGA2 WIF1 [70] HMGA2 NFIB [70] HMGA2 FHIT [70] HMGA2 HELB [71] HMGA2 TMTC2 TCEA1 PLAG1 [74] C1orf116 PLAG1 [59] HMGA2 CNOT2 [6] Carcinoma-ex-pleomorphic adenoma…”

Expression Level of Keratin 7 in Epithelial Ovarian Cancer and Malignant Metastasis of Benign Epithelial Ovarian Tumors

“…Therefore, understanding the prognostic factors of EOC patients is essential for providing more personalized treatment and disease management. Indepth study of the specific mechanism of malignant progression of EOC, exploring new targets for diagnosis and treatment of EOC, and improving prognosis are urgent problems to be solved (6).…”