Grade Progression of Well Differentiated Neuroendocrine Tumors (WDNETs) of the Enteropancreatic System Is Distinct from Poorly Differentiated (PD) High Grade Neuroendocrine Carcinomas (PDHGNECas)
LH Tang, L Song, J Shia, E Vakiani, DS Klimstra. Memorial Sloan-Kettering Cancer Center, New York, NY
Background: The grade of NETs is generally assessed by proliferative activity. High mitotic rate defines the group of HG and aggressive tumors. Often designated HGNECa, these tumors exhibit poorly differentiated (PD-) and HG histopathology and poor outcome, and they are regarded as distinct from well differentiated (WD) NETs. However, in addition to PD-HGNECas, there exist tumors that display features of both a WD-NET and high proliferative activity. We investigated clinicopathological features and the status of RB1 gene mutation and loss of Rb expression in WD-NETs with HG features and PD-HGNECas.
Design: High grade was defined using WHO classification of lung NETs (>10 mitoses/10 HPF). Clinicopathological features were compared between each grade and differentiation group. Immunostain for Rb was performed. Tumors of relevant component were micro-dissected followed by RNA and genomic DNA extraction. RB1 gene expression was evaluated by real time PCR and RB1 mutation was carried out by whole genome amplification, RB1 exon-specific PCR and subsequent sequencing.
Results: 49 NETs satisfied the criteria of >10 mitoses/10 HPF. Thirty-nine cases (80%) revealed features of PD-NECa, and ten tumors (20%) exhibited foci of HG features, but had >50% component of low grade WDNET. The component of an adenocarcinoma was not identified in WD-NETs of any grade; in contrast it was present in 29/39 (74%) cases of PD-HGNECa. Immunostains demonstrated Rb protein loss in 74% PD-NECas and retained all WD-NETs regardless the grade. There was a complete concordance between Rb protein loss and RB1 gene expression by RT-PCR and RB1 mutation.
|NET Subtype||Adenocarcinom Component||Mitoses/50 HPF||Ki67||Metastasis||Nen FU (Mons)||RB1 Mutation/Rb loss||NED/AWD/DOD%|
|PD-HG||29/39 (74%)||>100||50-90%||100%||14||30/39 (77%)||25/unk/50|