Cancer registration statistics of economically advanced countries indicate that bladder
carcinoma incidence ranks fourth in men and eighth in women, but a reliable
tumor marker for predicting the disease course is still lacking. We designed an immunohistochemical study to comprehensively assess the trophoblastic
hormone production profile of
transitional cell carcinoma (TCC) of the bladder. Moreover, we correlated histological differentiation and
tumor stages with marker expression and, finally, evaluated a potential
tumor origin of hCGbeta
core-fragment (hCGbetacf). To this end,
formalin-fixed,
paraffin-embedded
tumor tissues from 104 patients with urothelial
neoplasms of various histological grades (23 GI, 24 GII, and 38 GIII) and stage (19pTis, 21pTa, 29pT1, and 35pT2-T4) were analyzed by the immunoperoxidase technique using our own well-characterized
monoclonal antibodies against the
glycoprotein hormones human chorionic gonadotropin (hCG) and its derivatives hCGalpha, hCGbeta, hCGbetacf,
luteinizing hormone (LH, LHbeta),
follicle-stimulating hormone (FSH, FSHbeta), and the
protein hormones placental lactogen (hPL) and
growth hormone (hGH-V/N). Overall, trophoblastic
hormone immunoreactivity was found in 36% of TCC. Detailed analysis showed 35% hCGbeta, 17% hCGbetacf, 9% hCGalpha, 4% hCG, and 2% hPL-positive cases. The
tumors produced neither GH-N, placental GH-V, nor the
pituitary gonadotropins FSH/FSHbeta and LH/LHbeta. Marker positivity significantly increased with high-grade lesions (26% GI- v 55% GIII-TCC) and advanced
tumor stages (24% pTa v 63% > or = pT2).
Hormone immunoreactivity was frequently observed in highly proliferating areas. Our findings, together with recent structural and clinical studies, strongly suggest that these
hormones, or derivates thereof, might act as local
tumor growth factors. Normal urothelium, urothelial
papillomas, and
carcinoma in situ showed no positive reactions. All
tumors producing hCG-derived molecules were negative for the concommitantly analyzed neuroendocrine markers
chromogranin A,
synaptophysin, and
neuron-specific enolase (NSE). In summary, one third of TCC ectopically produce trophoblastic
hormones, which is specifically correlated with stage and grade. Apart from hCGbeta (97% of the marker-positive cases), the intracellular occurrence of hCGbetacf, apparently the second most frequently produced marker, was surprising, and there was also a lesser degree free hCGalpha and intact holo-
hormone expression. The placental
protein hormones PL and GH-V are not appropriate
tumor marker candidates. Finally, our histogenetic findings support a metaplastic origin of the hCG producing choriocarcinomatous phenotype of some TCC.