[592] Loss of Heterozygosity at 18q21 and Increased Proliferative Index Are Associated with Appendiceal Mucinous Carcinomatosis
DJ Hartman, GS Mantha, AM Krasinskas, MN Nikiforova, JM Davison. University of Pittsburgh Medical Center, Pittsburgh, PA
Background: Disseminated appendiceal mucinous neoplasms are categorized as low grade appendiceal mucinous neoplasia (LAMN) and high grade appendiceal mucinous carcinoma (AMC), a classification which is associated with prognosis. Few studies to date have examined genetic or immunophenotypic differences between low grade and high grade disseminated appendiceal neoplasms.
Design: 30 consecutive cases of disseminated primary appendiceal mucinous neoplasms from 1/2007- 7/2008 were reviewed and 27 cases could be classified as LAMN or AMC. Three cases regarded as intermediate were excluded from analysis. The cases were evaluated for KRAS mutation in codons 12 and 13; loss of heterozygosity (LOH) at 16 microsatellite markers on chromosomes 1p36, 3p25, 5q23, 7q31, 7q22, 9p21, 10q23, 17p13, 18q21; and expression of p53, p16, Smad4 and Ki-67 by immunohistochemistry (IHC).
Results: 13/27 cases were classified as AMC. Oncogenic KRAS mutations were found in 10/13 AMC and 10/14 LAMN. Results of LOH analysis at selected loci are shown below; other loci showed no association with tumor grade.
| 18q21 LOH (D18S487) | 10q23 LOH (D10S1173) | 17p13 LOH (D17S1289) | |
| LAMN | 0/9 | 0/12 | 1/8 |
| AMC | 5/11 * | 3/11  | 4/8  |
p=0.09,p=0.28(Fisher's exact)Ki-67 proliferative index >10% was seen in 12/12 AMC and 4/11 LAMN (p=0.001, Fisher's exact). Strong nuclear p53 expression was seen in 3/12 AMC and 0/11 LAMN. Smad4 and p16 expression by IHC showed no correlation with tumor grade, LOH at 18q21 or LOH at 9p21. However, there was abnormal p53 nuclear expression in 4/4 cases with LOH at D17S1289 on 17p13. Interestingly, LOH at 18q21 and 10q23 exclusively occurred in AMC with KRAS mutations. Loss of Smad4 protein expression was also more common in appendiceal neoplasms with KRAS mutations.
Conclusions: In this series, elevated Ki-67 proliferative index, LOH at 18q21 and 10q23 are associated with high tumor grade (AMC). Oncogenic KRAS mutations are frequently found in appendiceal mucinous neoplasms, including localized appendiceal adenomas, indicating that KRAS mutation may be a tumor initiating event. Given that LOH at 18q21 and 10q23 were found exclusively in appendiceal carcinomas with KRAS mutations, LOH at these loci may be associated with genetic progression to carcinoma. Additional studies to evaluate mutations in candidate genes and confirmation of copy number changes involving these chromosomal loci is required.
Category: Gastrointestinal
Wednesday, March 11, 2009 9:30 AM
Poster Session V # 83, Wednesday Morning