[587] 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.

Table 1. Clinicopathologic features and RB1 Status of Subtypes of NETs

NET Subtype	Adenocarcinom Component	Mitoses/50 HPF	Ki67	Metastasis	Nen FU (Mons)	RB1 Mutation/Rb loss	NED/AWD/DOD%
WE-LG	0	0-36	1-10%	28%	44	0	63/17/20
WD-HG	0	>50	20-50%	100%	30	0	14/80/6
PD-HG	29/39 (74%)	>100	50-90%	100%	14	30/39 (77%)	25/unk/50

NED=no evidence of disease; AWD=alive with disease; DOD=died of disease

The most common RB1mutations occurred at exon 8, followed by additional mutation of exon 2, 4, 6, 7, 18, and 21.
Conclusions: WD- NETs may rarely exhibit high proliferative activity, but they can be distinguished from PD-HGNECas by their clinical behaviors and by their status of RB1 gene expression and mutation.
Category: Endocrine

Monday, March 22, 2010 9:15 AM

Platform Session: Section H 1, Monday Morning