Molecular evidence for the neoplastic potential of hepatic Von-Meyenburg complexes.
Von-Meyenburg complexes (VMCs) have been shown to progress to cholangiocarcinoma (CC) in some cases. Histologic examination in such cases reveals a gradual transition of VMCs to intermediate lesions and finally to CC. The goal of this study was to determine if this histologic progression was also accompanied by sequential genetic alterations. Two cases that showed many VMCs with a transition to cholangiocarcinoma through intermediate lesions were analyzed. Multiple VMCs (away from the tumor), intermediate lesions and areas of frank CC were microdissected under stereoscopic guidance and were analyzed for allelic imbalance [loss of heterozygosity (LOH)] using a panel of 20 polymorphic microsatellite markers by polymerase chain reaction/electrophoresis. The 2 cases of CCs revealed LOH at 5 and 7 different genomic loci specific for each patient, respectively. Coexisting VMCs also exhibited LOH ranging from 0 to 3 loci in each case. Intermediate lesions showed LOH at a single locus in case 1, whereas the assay could not be performed in case 2 due to inadequate DNA yield. In case 2, the earliest acquired mutations were present in the VMCs supporting a causal relationship for neoplastic progression. Discordant LOH mutations were also present in the VMCs and the adenomatous lesions providing support that LOH detected at these sites did not passively migrate or reflect contamination. The results of the present study show that the histologic progression observed through these stages is also accompanied by LOH at loci harboring key oncogenes. The findings also support that VMCs are preneoplastic lesions that could progress to CC with time.
Jain
Dhanpat
D
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520-8023, USA. Dhanpat.jain@yale.edu
Ahrens
William
W
Finkelstein
Sydney
S
D000369:Aged, 80 and over; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D018281:Cholangiocarcinoma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002869:Chromosome Aberrations; D004252:DNA Mutational Analysis; D015972:Gene Expression Regulation, Neoplastic; D006222:Hamartoma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008113:Liver Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D016133:Polymerase Chain Reaction