Proliferative activity of normal and neoplastic urothelium and its relation to epidermal growth factor and transferrin receptors.

AIMS: To investigate the proliferative activity (given by the Ki67 index) of the normal, atypical, and neoplastic urothelium and its relation to the cellular reactivity for the epidermal growth factor (EGFr) and transferrin (Tfr) receptors. METHODS: The Ki67 index and the level of EGFr and Tfr reactivity were determined on frozen sections from 82 patients with urothelial cancer. Relevant clinical material was reviewed to establish correlations with the degree of atypia and invasion. RESULTS: Morphologically normal urothelium, whether derived from controls or patients with cancer, exhibited a low Ki67 index (less than 0.1%) and weak receptor reactivity. In transitional cell carcinomas (TCCs) the Ki67 index was increased: it ranged between 0.7% and 10% in non-invasive and exceeded 10% in 88% of the invasive TCCs. Strong positive reactions for EGFr were seen only in invasive TCCs, but in 47% of invasive TCCs the EGFr was not "overexpressed" and did not match the Ki67 index. A better correlation was found between the Ki67 index and the Tfr which was positive in 26% of the non-invasive and in 71% of the invasive tumours. All three variables were increased in severe atypia but varied considerably in lesser degrees of atypia. CONCLUSIONS: Despite the absence of a close correlation, accelerated growth and enhanced receptor expression were characteristic of invasive cancers. These results suggest that the growth rate in TCCs is not causally related to overexpression of growth factor receptors but that the latter is an abnormality which may accompany the malignant phenotype.

Proliferative activity of urothelial neoplasms: comparison of BrdU incorporation, Ki67 expression, and nucleolar organiser regions.

AIMS: To evaluate the proliferative activity of urothelial neoplasms, compare it with that of the normal urinary tract epithelium, and determine its relation to morphological grade and presence of invasion. METHODS: Multiple biopsy specimens from 53 individuals--eight normal controls, five patients with severe urothelial atypia, and 40 with transitional cell carcinomas (TCCs)--were studied using in vitro bromodeoxyuridine (BrdU) incorporation, Ki67 antigen expression, and quantitation of the nucleolar organiser regions (NORs). RESULTS: The percentage of nuclei labelled by BrdU (BrdU index) correlated well with the percentage of nuclei expressing the Ki67 antigen (Ki67 index). These proliferation indices were very low (less than 0.1% in 60% of samples) in the urothelium of normal controls and the morphologically unremarkable epithelium of patients with TCCs. Non-invasive TCCs had increased proliferation (BrdU index 6.32 (SD 0.8)%, Ki67 index 5.04 (0.6)% but lagged behind the invasive tumours (BrdU 20.9 (3.2)%, Ki67 18.6 (2.8)%). The average NOR count was 1.57 (0.03) in morphological normal epithelium, which increased progressively with grade in non-invasive TCCs, but varied greatly in invasive tumours and did not correlate with the proliferation indices. The spectrum of values for both proliferation indices and NORs was particularly wide in grade 2 TCCs. Severe atypias without exophytic growth had an increase in BrdU and Ki67 indices comparable with that found in grade 3-4 invasive TCCs; these also had the highest NORs per nucleus. CONCLUSIONS: The growth potential of urothelial neoplasms is an important indicator of their aggressive course. In particular, growth indices over 10% are strongly associated with the presence of invasion. Papillary grade 2 TCCs show heterogeneity in their growth characteristics which may relate to their diverse clinical course. The mitotic count underestimates the growth potential of papillary TCCs and the addition of proliferation indices such as BrdU incorporation or the Ki67 index may enhance the prognostic accuracy of conventional morphological grading.