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.