K-ras and p53 mutations in the pathogenesis of classical and goblet cell carcinoids of the appendix.
BACKGROUND
Mutations in the K-ras oncogene and the p53 tumor suppressor gene are present in approximately 50% of colonic adenocarcinomas. Goblet cell carcinoids (GCCs) are uncommon neoplasms of the appendix that appear to be intermediate between carcinoid tumors and adenocarcinomas, both histologically and biologically. The current study was undertaken to examine the role of p53 and K-ras mutations in the pathogenesis of GCCs and typical carcinoids (TCs) of the appendix.


METHODS
Archival materials from 22 GCCs and 18 TCs were analyzed. K-ras mutations in codons 12, 13, and 61 were studied by a polymerase chain reaction (PCR) based designed restriction fragment length polymorphism method using mismatched nested primers. Mutations in exons 5-8 of the p53 tumor suppressor gene were analyzed in 16 GCCs and 18 TCs by PCR and single-strand conformational polymorphism followed by direct sequencing. Immunostains for p53 and chromogranin were performed in all cases.


RESULTS
K-ras mutations and nuclear accumulation of p53 by immunohistochemistry were not detected in any of the GCCs or TCs. p53 mutations were found in 4 of 16 GCCs (25%) and 8 of 18 TCs (44%). Immunoreactivity for chromogranin was seen in the vast majority of GCCs and TCs.


CONCLUSIONS
p53 mutations appear to play a role in the pathogenesis of some GCCs and in approximately 50% of TCs of the appendix, whereas mutations in the K-ras oncogene do not appear to be important in the development of these tumors. The minimal cytologic atypia, low incidence of metastases, and lack of K-ras mutations in goblet cell appendiceal neoplasms suggest that they are variants of carcinoid tumors. Our findings lend support to the recommendation that the therapeutic guidelines applied to TCs of the appendix should be the same for GCCs.
Ramnani
D M
DM
Department of Pathology, University of Texas Southwestern Medical Center, Dallas 75235-9073, USA.
Wistuba
I I
II
Behrens
C
C
Gazdar
A F
AF
Sobin
L H
LH
Albores-Saavedra
J
J
D001063:Appendiceal Neoplasms / Q000209:etiology / Q000235:genetics*; D001483:Base Sequence; D002276:Carcinoid Tumor / Q000209:etiology / Q000235:genetics*; D004252:DNA Mutational Analysis; D016158:Genes, p53 / Q000235:genetics*; D011905:Genes, ras / Q000235:genetics*; D020397:Goblet Cells / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction