The clinicopathological and molecular features of primary high-grade neuroendocrine tumour in the breast

Nottingham grade for breast cancers, rather than gastro-entero-pancreatic (GEP) grade for neuroendocrine tumours (NETs), is currently applied to primary breast NETs, which need further clarification. High-grade NETs in breast also remain poorly recognised. Among 595 breast carcinomas with diffuse synaptophysin (Syn) or chromogranin A (CgA) immunostaining (≥ 90%), 197 eligible cases were selected, including 69 NETs, 123 invasive breast carcinomas of no special type (IBC-NSTs) and five neuroendocrine carcinomas (NECs). The prognostic significance of these two grading systems in breast NETs was assessed. Furthermore, the clinicopathological features were compared in Nottingham G3 cases among three entities. Targeted sequencing and immunostaining (INSM1/p53/Rb/p16) were also performed in all Nottingham G3 NETs, NECs and 10 Nottingham G3 IBC-NSTs. All Nottingham G3 NETs (9 of 69, 13.0%) fell into GEP G3 cases (20 of 69, 29.0%). Nottingham grade provided better prognostic discrimination between G1/G2 and G3 NETs than GEP grade. Among Nottingham G3 cases, there was a trend towards reduced progression-free survival (PFS) in NETs compared with IBC-NSTs (P = 0.057), and the former were more often immunoreactive for INSM1 (44.4 versus 0%, P = 0.033). Nottingham G3 NETs were all of luminal-like phenotype (P