Clonality and field cancerization in intraductal papillary-mutinous tumorsof the pancreas

BACKGROUND. Multiple lesions of intraductal papillary-mutinous tumor of the pancreas (IPMT) in the same pancreas often are encountered. To elucidate f ield (multicentric) cancerization and clonality of IPMT, clonal analyses of IPMT and its precursor lesion of ductal hyperplasia were performed. K-ras codon 12 mutations and X-chromosome inactivation of human androgen receptor gene (HUMARA) were investigated. METHODS. Paraffin embedded tissue samples from the pancreata of 37 patients who underwent resection for IPMTs were microdissected manually or by laser capture microdissection. Multiple samples from each surgical specimen were microdissected representing each IPMT and discrete ductal hyperplasias. DN A was extracted, and K-ras codon 12 mutations were examined by two-step pol ymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The mutations were analyzed by direct DNA sequence. The HUMARA locus was d igested with or without HpaII and HhaI prior to amplification. The HUMARA a ssay was conducted by fluorescence-labeled PCR-RFLP and was analyzed with s pecialized software. RESULTS. All 37 pancreata had at least two lesions of ductal hyperplasia, a nd 23 of 37 pancreata (62%) had K-ras codon 12 mutations in these precursor lesions. Of 23 pancreata with mutated K-ras hyperplasia, 15 (65%) had mult iple, distinct mutations in different lesions of hyperplasia in the same pa ncreas, suggesting a field defect. Thirty-two of 37 IPMTs (86%) had K-ras c odon 12 mutations. Among these, 16 IPMTs (50%) had multiple, distinct mutat ions at K-ras codon 12. The HUMARA assay showed that 12 of 15 IPMTs were in formative, and 9 were considered polyclonal and/or oligoclonal origin in or igin. With the combined results of multiple K-ras mutation detection and th e HUMARA assay, 12 of 15 IPMTs from female patients (80%) were considered p olyclonal and/or oligoclonal in origin. CONCLUSIONS. The current results suggest that multiple, distinct K-ras muta tions of different ductal hyperplasias in a given pancreas are due to afiel d (multicentric) cancerization effect in IPMTs. Thus, most of IPMTs are pol yclonal and/or oligoclonal in origin, i.e., IPMTs may originate from multip le (molecularly distinct) precursor lesions. (C) 2001 American Cancer Socie ty.