Differences in mucus and K-ras mutation in relation to phenotypes of tumors of the papilla of Vater

Abstract

BACKGROUND To investigate their hypothesis that K‐ras mutation is correlated with epithelial metaplastic change, the authors classified tumors of the papilla of Vater histologically and according to mucin histochemistry as either intestinal type (complete or incomplete) or pancreaticobiliary type (ordinary or metaplastic) and analyzed the tumors for K‐ras mutation during tumorigenesis. METHODS Fifty‐two tumors of the papilla of Vater (5 adenomas, 24 carcinomas with adenoma component, and 23 carcinomas) obtained from surgical specimens were evaluated. The mucus phenotype was analyzed with MUC1, MUC2, MUC5AC, sialyl Lewisa (CA 19‐9), HID‐AB, and ConA III stainings. K‐ras codon 12 mutation was detected by nested polymerase chain reaction (PCR)‐restriction fragment length polymorphism and enriched PCR‐enzyme‐linked minisequence assay. RESULTS The presence of adenoma component and intramucosal tumor spreading in the ampulloduodenum was significantly higher in intestinal‐type tumors (90%, 27 of 30 tumors, and 100%, 30 of 30 tumors, respectively) than in pancreaticobiliary‐type tumors (9%, 2 of 22 tumors, and 23%, 5 of 22 tumors, respectively) (P < 0.0001). MUC2 expression was positive in intestinal‐type tumors but not in pancreaticobiliary‐type tumors. K‐ras mutation rates for incomplete intestinal‐type tumors (78%, 7 of 9) and metaplastic pancreaticobiliary‐type tumors (64%, 7 of 11), which showed MUC5AC (gastric‐type apomucin) expression in cytoplasm, were significantly higher than in complete intestinal‐type tumors (33%, 6 of 21) and ordinary pancreaticobiliary‐type tumors (18%, 2 of 11) (P = 0.01 and P = 0.03, respectively). In pancreaticobiliary‐type tumors, K‐ras mutation was more frequently recognized in tumors with ampullopancreatic duct tumor extension (75%, 3 of 4) than in those with ampullobiliary duct extension (0%, 0 of 6) (P = 0.01). Furthermore, sequences of K‐ras codon 12 were common in 17 carcinomas with adenoma component that were analyzed for both adenoma and carcinoma. CONCLUSIONS Tumors of the papilla of Vater can be classified histologically as either intestinal type or pancreaticobiliary type, and they have different features according to tumor location, association with adenoma, and MUC2 expression. Furthermore, K‐ras mutation is supposed to be associated with tumors arising in the area from the ampulloduodenum to the ampullopancreatic duct, with metaplastic mucus occurring in both intestinal and pancreaticobiliary types. Cancer 1999;86:596–607. © 1999 American Cancer Society.

Carcinogenesis of cancer of the papilla and ampulla: pathophysiological facts and molecular biological mechanisms

“…K-ras mutations are present in between 13% and 50% of ampullary carcinomas [9,33,34,35,36,37,38,39,40]. However, these studies are not completely comparable due to the number of cases included, ranging from two [36] to 93 [38]; the number of codons examined (in most of them only codon 12 was analyzed), and the materials and methods employed (DNA extraction from frozen vs. paraffin-embedded tissues, use of microdissection to enrich the neoplastic cell population, etc.).…”

“…However, these studies are not completely comparable due to the number of cases included, ranging from two [36] to 93 [38]; the number of codons examined (in most of them only codon 12 was analyzed), and the materials and methods employed (DNA extraction from frozen vs. paraffin-embedded tissues, use of microdissection to enrich the neoplastic cell population, etc.). Codon 12 is more frequently affected than codon 13 (88.2% vs 11.8% in Howe's series); its most common point mutation is the second base G→A transition that leads to the substitution of wild-type glycin with aspartic acid [9,38,40]. Other amino acidic substitutions at codon 12 which have been described are valine, arginine, cysteine, alanine and serine [9,38].…”

“…Codon 12 is more frequently affected than codon 13 (88.2% vs 11.8% in Howe's series); its most common point mutation is the second base G→A transition that leads to the substitution of wild-type glycin with aspartic acid [9,38,40]. Other amino acidic substitutions at codon 12 which have been described are valine, arginine, cysteine, alanine and serine [9,38]. If ampullary cancers are histologically classified as either intestinal type or pancreaticobiliary type and K-ras mutational rates are examined, the second group has a higher frequency [9] of ras alterations.…”

“…The intestinal type, which has a tubular structure and contains goblet cells and infrequently Paneth cells, is often associated with an adenomatous component (90%, vs. 9% in the pancreaticobiliary type) [9] and has a better outcome [1]. For this histotype, which is the most common among the ampullary cancers [1,9], an adenoma-carcinoma sequence has been postulated, and molecular biological studies have demonstrated its stronger similarity to colorectal than pancreatic cancer.…”

COX-2 expression of ampullary carcinoma: correlation with different histotypes and clinicopathological parameters

“…The papilla is covered by intestinal mucosa. The inner parts of the ampulla are lined by a simple mucinous epithelium like that of the pancreaticobiliary tree [17][18][19]. Therefore, ampullary carcinomas may arise from two different types of mucosa, which might reflect the broad histomorphologic spectrum of these tumors [10].…”