Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix.

To the Editor: We read with interest the excellent paper Pathologic Classification and Clinical Behavior of the Spectrum of Goblet Cell Carcinoid Tumors of the Appendix by Tang et al published in the October issue of the journal. As stated by the authors the biologic behavior, histogenesis, histologic classification, and clinical management of the goblet cell carcinoid (GCC) tumors has been the subject of controversy. Because of its unusual morphologic features and aggressive clinical behavior some investigators believe that GCC is in fact a variant of adenocarcinoma The advanced clinical stage of most GCCs in Tang et al series and their classification into GCC and adenocarcinoma ex-GCC are useful to understand the more aggressive clinical course of these endocrine tumors when compared with that of classical or typical carcinoid tumors. Progression of GCC to adenocarcinoma has been previously reported. We would like to provide information about the peculiar anatomic distribution of GCCs, a feature not addressed by the authors. We have only seen these tumors in the appendix, colon, ampulla of Vater, and duodenum. We recently reviewed 13,721 carcinoid tumors of the gastrointestinal tract including 221 from the gallbladder and extrahepatic bile ducts collected during a 32-year period by the Surveillance, Epidemiology and End Results program of the National Cancer Institute. There were no GCCs in anatomic sites other than the appendix, colon, ampulla of Vater, and duodenum (Albores-Saavedra et al, unpublished data). We would like to emphasize the genetic abnormalities associated with these tumors. In 1990 Ramnani et al first reported the lack of K-ras mutations in 16 GCCs and 18 typical or classical carcinoid tumors of the appendix, a molecular event similar to that detected in classical or typical carcinoid tumors of the small intestine and different from that of appendiceal or colonic adenocarcinomas. This original observation not discussed in detail by Tang et al has been fully confirmed by others. The lack of K-ras mutations is not unique to carcinoids of the gastrointestinal tract as such mutations have not been found in endocrine tumors of the pancreas including insulinomas, gastrinomas, and glucanomas. Furthermore, neuroendocrine tumors of the lung, including typical and atypical carcinoid tumors, do not seem to involve K-ras mutations in their pathogenesis. Second, we recently had the opportunity to study 2 classical carcinoid tumors of the appendix with a minor but characteristic component of GCC (Fig. 1). Both tumors occurred in 2 adult males (the first patient 52 y of age and the second 63 y old) and represented incidental findings in appendectomy specimens surgically removed for acute appendicitis. One carcinoid tumor extended into the periappendiceal adipose tissue whereas the other was confined to the wall of the appendix. We believe that the molecular abnormalities and the association of classical carcinoid tumors with GCC provide strong additional support to the hypothesis that GCCs are part of the spectrum of classical carcinoid tumors and not adenocarcinomas of the appendix. We therefore favor the term GCC for this unique endocrine neoplasm of the appendix, colon, and ampulla of Vater. The more aggressive clinical course is probably related to advanced stage at presentation and progression to adenocarcinoma as emphasized by Tang et al.