Genetic Alterations in Goblet Cell Carcinoids of the Vermiform Appendix and Comparison with Gastrointestinal Carcinoid Tumors

Abstract

Goblet cell carcinoid is a relatively rare neuroendocrine tumor of the vermiform appendix with poorly understood molecular pathogenesis. We studied the clinicopathologic features and genetic alterations, including allelic loss of chromosomes 11q, 16q, and 18q; sequencing of the K-ras, beta-catenin, and DPC4 (SMAD4) genes; and p53 overexpression and loss of DPC4 by immunohistochemistry; in 16 goblet cell carcinoids. We compared the allelic loss in goblet cell carcinoids to those in 18 gastrointestinal carcinoid tumors. For goblet cell carcinoids, appendiceal perforation was the most common (70%, 7/10) clinical presentation. The mean tumor size was 2.0 +/- 1.5 cm (range, 0.4 to 4.5 cm). The tumor invaded to appendiceal serosa in 50% (8/16) of patients, and two patients had metastasis in lymph nodes or adjoining viscera. With mean follow-up of 24 +/- 14 months (median, 23 mo), 1 of 10 patients had died of disease, and 2 others had tumor recurrence. All four patients with metastases, recurrences, and/or death from disease had serosal involvement at presentation (P =.02). Loss of heterozygosity of chromosome 11q was present in 25% of goblet cell carcinoids, 14% of ileal carcinoid tumors, and 9% of nonileal carcinoid tumors; of chromosome 16q in 38%, 29%, and 0 (P =.02); and of chromosome 18q in 56%, 86%, and 9% (P =.002), respectively. No mutations of K-ras, beta-catenin, or DPC4 genes; p53 overexpression; or loss of staining for DPC4 was present in any tumors. These findings suggest that allelic loss of chromosomes 11q, 16q, and 18q in goblet cell carcinoids and ileal carcinoids may have an important role in the pathogenesis of these tumors.

Clinicopathologic and molecular analysis of disseminated appendiceal mucinous neoplasms: identification of factors predicting survival and proposed criteria for a three-tiered assessment of tumor grade

“…Previous studies have shown that goblet cell carcinoid tumors seldom harbor KRAS mutations. 27,28 Unfortunately, in most cases in our series, the appendix was entirely obliterated by infiltrating adenocarcinoma precluding assessment for a precursor lesion.…”

Comparison of genetic alterations in neuroendocrine tumors: frequent loss of chromosome 18 in ileal carcinoid tumors

“…Loss of heterozygosity of chromosomal arms was defined by allelic loss of one or more polymorphic (informative) microsatellite markers present on that chromosomal arm. Loss of chromosome 11q using five markers, 16q using five markers, and 18q using eight markers has been previously reported for 12 tumors, 22 but all chromosome 18 markers were repeated using microdissected DNA. Previously characterized colon carcinoma samples with loss of chromosome 18q were used as positive control and nontumor DNA from the same patient was used as negative control.…”

“…42,43 Data from the present study and the previous studies show that chromosome 18q loss is infrequent in pancreatic endocrine tumors 44 but common in midgut carcinoid tumors 32 and goblet cell carcinoid tumors of appendix. 22 However, these tumors lack DPC4 gene mutations or loss of DPC4 protein expression suggesting that DPC4 gene is not the target of this chromosomal loss. Loss of heterozygosity of chromosome 18q was a frequent event associated with poor prognosis in pancreatic adenocarcinomas, and restoration of chromosome 18 reduced the tumorigenicity.…”

“…The nonileal carcinoid tumors included five pulmonary, three gastric, two duodenal, one appendiceal, three cecal and one rectal tumor. Immunohistochemistry was performed by using standard techniques including antigen retrieval as described previously, 22 …”

High-resolution genomic profiling reveals gain of chromosome 14 as a predictor of poor outcome in ileal carcinoids

“…Using microsatellite markers, chromosome-based comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) analysis, recurrent copy number alterations (CNAs) have been identified. The most common CNA is loss of chromosome 18 (Terris et al 1998, Zhao et al 2000, Kytölä et al 2001, Löllgen et al 2001, Tönnies et al 2001, Stancu et al 2003, Wang et al 2005, Kim do et al 2008, Kulke et al 2008. Other recurrent CNAs include losses involving chromosomes 9, 11q and/or 16q, and gains involving chromosomes 4, 5, 7, 14 and/or 20.…”