This report represents the first study in the literature linking development of severe
gynecomastia, in
a 17 1/2-yr-old boy, to high levels of
aromatase expression in a large
fibrolamellar hepatocellular carcinoma, which gave rise to extremely elevated serum levels of
estrone (1200 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,
gynecomastia partially regressed, and essentially, normal
hormone levels were restored (
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 C19
steroids to
estrogens occurs in a number of human tissues and is catalyzed by
aromatase P450 (
P450arom), the product of the
CYP19 gene in a number of human tissues. Tissue-specific promoters are used to regulate
P450arom 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 liver uses promoter I.4 to express markedly high levels of
P450arom, whereas hepatic
P450arom expression normally becomes undetectable in postnatal life. Using immunohistochemistry, diffuse intracytoplasmic
aromatase expression was detected in the
liver cancer cells from this severely feminized boy. Northern analysis indicated the presence of
P450arom transcripts in total
RNA from the
hepatocellular cancer but not in the adjacent liver nor in disease-free adult liver samples. Promoter use for
aromatase expression was determined by a specific RT-PCR method. Promoters I.3 and II were used for
P450arom gene expression in the
hepatocellular cancer tissue. Because
aromatase is not expressed in the disease-free adult liver, the presence of extremely high levels of
aromatase expression in this
fibrolamellar hepatocellular carcinoma tissue is intriguing, particularly because there is preferential use of the proximally located
P450arom promoters I.3 and II by the
tumor, instead of the much more distally located fetal liver-type promoter I.4.