[750] Transformation of Appendiceal Goblet Cell Carcinoid Tumor to Adenocarcinoma Is Correlated with the Status of KRAS Mutation

LH Tang, C Lau, A Schoepflin, J Shia, S Lassmann, M Ladanyi, M Werner, DS Klimstra. Memorial Sloan-Kettering Cancer Center, New York, NY; Freiburg Institute of Pathology, Freiburg, Germany

Background: Appendiceal tumors of goblet cell carcinoid (GCC) family display a spectrum of histologic features and possess the potential to transform to an adenocarcinoma phenotype. A recent study has proposed a classification of these tumors into typical GCC and adenocarcinoma ex GCC based on evaluation of their morphological features. This approach has provided guidelines for both the diagnosis and the prediction of prognosis of GCCs. The aim of this study was to carry out further molecular investigations to support the concept of GCC transformation to adenocarcinoma genotype.
Design: Cases of morphological variants of typical GCC (n=11) and adenocarcinoma ex GCC (n=15) were dissected using laser-microscopy from formalin fixed and paraffin embedded tissue sections. Genomic DNA was then extracted using a micro-extraction kit from Qiagen. Screening for point mutations in KRAS, N-RAS, HRAS, BRAF, EGFR, PIK3CA, ERBB2, and MEK1 was performed using the Sequenom MassArray System.
Results: KRAS mutation was identified at codon 12 in 42% of all cases examined. They were present in 2/11 cases of typical GCC (18%) and in 9/15 cases of adenocarcinoma ex GCC subtype (60%). The most common mutation was KRAS G12V; additional HRAS and NRAS mutations were identified in adenocarcinoma ex GCC only. Of all genes analyzed, more mutations, either by number of cases or by number of mutations per case, were identified in the group of adenocarcinoma ex GCC.

Table 1. Mutation Frequency in Subtypes of GCC Tumors

GCC Subtype	Single Mutatins	Multiple Mutations	RAS Mutation	BRAF Mutation	EGFR Mutation	PIK3CA Mutation	MEK1 Mutation
Typical GCC (n=11)	4 (36%)	1 (9%)	2 (18%)	0	2 (18%)	1 (9%)	0
Adenocarcinoma ex GCC (n=15)	9 (60%)	6 (40%)	9 (60%)	2 (13%)	5 (33%)	1 (7%)	8 (53%)

Conclusions: KRAS mutation is generally not associated with well differentiated (neuro)endocrine tumors of the gastroenteropancreatic system. We show here that KRAS mutations, commonly associated with conventional adenocarcinoma, are also present in the clinically more aggressive variants of GCC tumors. These findings support the hypothesis that tumors of the GCC family possess the potential to transform to an adenocarcinoma phenotype and genotype, and this pathologic process may be correlated with the presence of KRAS mutation as well as other genetic defects.
Category: Gastrointestinal

Tuesday, March 23, 2010 9:00 AM

Platform Session: Section E, Tuesday Morning