THE MULTIFOCALITY OF BRONCHIOLOALVEOLAR LUNG-CARCINOMA - EVIDENCE ANDIMPLICATIONS OF A MULTICLONAL ORIGIN

Bronchioloalveolar lung carcinoma (BAC) is a unique type of lung cance r with distinguishing pathologic, biologic, epidemiologic, and perhaps etiologic features that set it apart from all other forms of lung can cer, including general adenocarcinoma, into which it is traditionally grouped. Recent studies at our institution have demonstrated a near ex ponential increase in BAC cases with 25% showing evidence of multifoca lity. Although some theories suggest that this multifocality is caused by intrapulmonary aerosol/aspiration or lymphatic spread, this study provides evidence for multiclonality as the basis for some cases of mu ltifocal BAC by exploiting a novel strategy for clonality determinatio ns that involves polymerase chain reaction amplification of a 511-base pair region located within the first intron of the human hypoxanthine phosphoribosyltransferase gene, a site that contains inactive X chrom osomal obligately methylated HpaII/MspI sites and single-base allelic polymorphisms in 5 to 10% of females. BAC cells, obtained by enzymatic dissociation of different fresh/paraffin-embedded tumoral foci from p olymorphic individuals with multi-lobar or bilateral BAC, were sorted to homogeneity with a fluorescein-conjugated anticarcinoembryonic anti gen and then subjected to genomic DNA extraction and HpaII digestion b efore polymerase chain reaction amplification and subsequent analysis of the product on denaturing gradient gel electrophoresis. The differi ng migrations of the single homoduplexes generated were indicative of BAC clonal nonidentity or multiclonality in three separate cases. The demonstration of multiclonality in some cases of BAC provides an alter nate explanation for multifocality.