MOLECULAR-BASIS OF SEVERE GYNECOMASTIA ASSOCIATED WITH AROMATASE EXPRESSION IN A FIBROLAMELLAR HEPATOCELLULAR-CARCINOMA

This report represents the first study in the literature linking devel opment of severe gynecomastia, in a 171/2-yr-old boy, to high levels o f aromatase expression in a large fibrolamellar hepatocellular carcino ma, which gave rise to extremely elevated serum levels of estrone (120 0 pg/mL) and estradiol-17 beta (312 pg/mL) that suppressed FSH and LH (1.3 and 2.8 IU/L, respectively), and consequently testosterone (1.53 ng/mL). After removal of a 1.5-kg hepatocellular carcinoma, gynecomast ia partially regressed, and essentially, normal hormone levels were re stored (estradiol-17 beta, <50 pg/mL; estrone, 74 pg/mL; testosterone, 6.85 ng/mL; and FSH/LH, 6.3/3.7 mIU/mL). Conversion of C-19 steroids to estrogens occurs in a number of human tissues and is catalyzed by a romatase P450 (P450arom), the product of the CYP19 gene in a number of human tissues. Tissue-specific promoters are used to regulate P450aro m gene transcription in adult human tissues, e.g. promoters I.4 and I. 3 in adipose fibroblasts, and promoter II in the gonads. Human fetal l iver uses promoter I.4 to express markedly high levels of P450arom, wh ereas hepatic P450arom expression normally becomes undetectable in pos tnatal life. Using immunohistochemistry, diffuse intracytoplasmic arom atase expression was detected in the liver cancer cells from this seve rely feminized boy. Northern analysis indicated the presence of P450ar om transcripts in total RNA from the hepatocellular cancer but not in the adjacent liver nor in disease-free adult liver samples. Promoter u se for aromatase expression was determined by a specific RT-PCR method . Promoters I.3 and II were used for P450arom gene expression in the h epatocellular cancer tissue. Because aromatase is not expressed in the disease-free adult liver, the presence of extremely high levels of ar omatase expression in this fibrolamellar hepatocellular carcinoma tiss ue is intriguing, particularly because there is preferential use of th e proximally located P450arom promoters I.3 and II by the tumor, inste ad of the much more distally located fetal liver-type promoter I.4.