Comprehensive next generation sequencing of middle ear neuroendocrine tumors

Abstract

Middle ear neuroendocrine tumor (MeNET) is a distinctive, uncommon neoplasm of the ear. Previously regarded as “middle ear adenoma” among other names, it was found to be consistently positive for neuroendocrine markers, with differentiation analogous to normal intestinal L cells, and has therefore been classified similarly to other neuroendocrine tumors throughout the body. Nevertheless, MeNETs have an unusual two-cell population and therefore may be unique among NETs. We sought to characterize a group of MeNETs by next-generation sequencing (NGS).

Six MeNETs from the authors' archives were retrieved, with histologic and immunohistochemical results tabulated. Targeted DNA and RNA NGS were attempted on all cases. Clinical follow-up was obtained.

The MeNETs arose in the middle ears of five men and one woman, ranging from 31 to 57 years (median, 47.5 years). Four cases were grade 1 and two cases grade 2 (one based on necrosis and one based on an elevated Ki67 index). DNA NGS was successful in five of six cases, with probable pathogenic variants including: ATRX mutations in two cases, chromosome 22 deletion, and DNMT3A, STAG2, RB1, HRAS, NF1, and SF3B1 mutations in one case each. In general, the variants were found at low allele frequencies. RNA NGS was successful in all cases, with one case harboring a fusion of unknown significance (R3HDM2::EP400). Follow up available in all cases, with five patients without disease (mean, 74 months; median, 17 months), with one patient (one of the grade 2 tumors) experiencing widespread distant metastases and dying 96 months after diagnosis.

Despite the consistent appearance of MeNET, they are heterogeneous at the molecular level, with low mutational burdens but lacking consistent, recurrent alterations. This is similar to well-differentiated NETs of other organs, in particular the small intestine and lung. Overall, our findings support the grouped classification of MeNET within the larger NET scheme.