QUALITATIVE AND QUANTITATIVE HISTOPATHOLOGY IN TRANSITIONAL-CELL CARCINOMAS OF THE URINARY-BLADDER - AN INTERNATIONAL INVESTIGATION OF INTRAOBSERVER AND INTEROBSERVER REPRODUCIBILITY

BACKGROUND: Histopathologic, prognosis-related grading of malignancy b y means of morphologic examination in transitional cell carcinomas of the urinary bladder (TCC) may be subject to observer variation, result ing in a reduced level of reproducibility. This may confound compariso ns of treatment results. Using objective, unbiased stereologic techniq ues and ordinary histomorphometry, such problems may be solved. EXPERI MENTAL DESIGN: A study of 110 patients with papillary or solid transit ional cell carcinomas of the urinary bladder in stage Ta through T4 wa s carried out, addressing reproducibility of both qualitative and quan titative grading methods. Grading of malignancy was performed by one o bserver in Japan (using the World Health Organization scheme), and by two observers in Denmark (using the Bergkvist system). A ''translation '' between the systems, grade for grade, and kappa statistics were use d in evaluating the reproducibility. Unbiased estimates of nuclear mea n volume, nuclear mean profile area, nuclear volume fraction, nuclear profile density index, and mitotic profile density index were obtained twice in 55 of the studied cases by one observer in Japan and one in Denmark, using a random, systematic sampling scheme. RESULTS: The resu lts were compared by bivariate correlation analyses and Kendall's tau. The international interobserver reproducibility of qualitative gradin gs was rather poor (kappa = 0.51), especially for grade 2 tumors (kapp a = 0.28). Likewise, the interobserver agreement on the Bergkvist sche me was poor (kappa = 0.43). On the other hand was the interobserver ag reement on invasion high (kappa = 0.75). The intraobserver reproducibi lity of the quantitative histopathologic variables was excellent in bo th Japan and Denmark for estimates of nuclear mean volume (r = 0.93), for nuclear mean profile area (0.78 <r <0.83), and for nuclear profile density index (0.85 <r <0.89), whereas the reproducibility for nuclea r volume fraction was somewhat poorer (0.68 <r <0.64). The slopes of t he correlation lines were not significantly different from unity. Esti mates of mitotic profile density index also showed acceptable intraobs erver reproducibility (Kendall's tau >0.53). CONCLUSIONS: The internat ional, interobserver reproducibility of the quantitative estimators yi elded similar results for all histopathologic variables investigated, except for nuclear volume fraction (r = 0.54). This can probably be re lated to the manual design of the sampling scheme and may be solved by introducing a motorized object stage in the systematic selection of f ields of vision for quantitative measurements. However, the nuclear me an size estimators are unaffected by such sampling variability. The re sults obtained in this study stress the need for objective, quantitati ve histopathologic techniques substituting qualitative, subjective met hods in prognosis-related grading of malignancy.