Oncocytic subtype of well differentiated neuroendocrine tumor: clinicopathologic and molecular associations of a cohort diagnosed on fine needle aspiration (FNA).

Abstract

Introduction: Classical well differentiated neuroendocrine tumors (C-NETs) have plasmacytoid morphology and neuroendocrine differentiation. Oncocytic NETs (O-NETs) have been shown to be more clinically aggressive. Whether O-NETs are more akin to C-NETs or poorly differentiated neuroendocrine carcinomas (PDNECs) is not established.

Materials and methods: Clinicopathologic characteristics and immunohistochemical expression of death domain-associated protein (DAXX), α-thalassemia/mental retardation syndrome X-linked genes (ATRX), retinoblastoma 1, p53, and SMAD4 in 30 O-NETs (25 pancreatic and 4 from luminal gastrointestinal tract) was compared to 32 C-NETs (23 pancreatic and 8 from luminal gastrointestinal tract). Whole exome sequencing was performed in a subset of each cohort.

Results: O-NETs were male-predominant (65.6%) and had higher mean Ki-67 index (7.4% versus 2.9% in C-NETs) (P = 0.03), corresponding to more grade 2 or above (53.3%) tumors. O-NET patients had more advanced disease (pT3/pT4, 75% versus 36.8%) (P = 0.024), distant metastasis (50% versus 25%) (P = 0.042), progression (increased size/recurrence/new metastases) (n = 8 versus 3; P = 0.1), and death (n = 3 versus 1; P = 0.32). Forty percent of O-NETs (versus 12.5% of C-NETs; P = 0.041) showed DAXX/ATRX loss, with one showing coexisting retinoblastoma 1 and SMAD4 loss. P53 staining pattern was wild type in all cases. Whole exome sequencing of 10 cases showed DAXX, ATRX, and multiple endocrine neoplasia type 1 alterations in O-NETs and C-NETs, and coexisting DNMT3A and MTOR alterations in one O-NET.

Conclusions: O-NET subtype is associated with advanced disease and unfavorable outcomes compared to C-NETs. O-NETs are cytologically distinct, male-predominant tumors that often present with higher grade and advanced disease. Their aggressive behavior is possibly related to frequent DAXX/ATRX loss and less likely PDNEC-related molecular alterations. Pathologists should be mindful of this aggressive morphologic subtype and clearly convey its presence in pathology reports.