Use of X-chromosome inactivation pattern and laser microdissection to determine the clonal origin of focal nodular hyperplasia of the liver

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Abstract

Aim:

To determine the clonal origin of the whole lesion and each nodule of focal nodular hyperplasia (FNH) and elucidate its nature, simultaneously comparing the clonal composition with hepatocellular adenoma (HA).

Methods:

Nine FNHs from eight women, two HAs and four hepatocellular carcinomas (HCCs) were examined by clonality assays based on X-chromosomal inactivation mosaicism in females and laser microdissection. Genomic DNA was isolated from each nodule, the whole lesion and surrounding liver parenchyma, pretreated with Hpa II or Hha I, and amplified via nested PCR for phosphoglycerate kinase (PGK) and androgen receptor (AR) genes. The single nucleotide polymorphism at the PGK locus was identified by incubation with Bst XI and agarose gel electrophoresis, and the CAG repeat length polymorphism at AR locus was revealed on denaturing polyacrylamide gels and visualised by silver staining.

Results:

Monoclonality was confirmed in both of the two HAs and all of the four HCCs examined, while polyclonality was shown in all nine FNHs as determined by the whole lesions, demonstrating their distinction from neoplastic lesions. A total of 108 nodules, including 96 nodules of altered hepatocytes (NAH) and 12 ordinary regenerative nodules (ORN), were microdissected from eight of the nine FNH lesions. Loss of X-chromosomal inactivation mosaicism was demonstrated in 39 (40.6%) of 96 NAHs, indicating the monoclonal, neoplastic nature. In contrast, polyclonality was demonstrated in all of the 12 ORNs and the surrounding liver parenchyma.

Conclusions:

FNH is composed of numerous NAHs and ORNs. The whole lesion shows a polyclonal cell composition, but neoplastic transformation has occurred in some of the nodules. Clonal assay is useful for its distinction from HA, and sampling the whole or larger part of the lesion is necessary.

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