Cancer heterogeneity and its biologic implications in the grading of urothelial carcinoma

BACKGROUND. Urothelial carcinoma of the bladder often contains areas with d ifferent histologic grades. The Influence of cancer heterogeneity on gradin g and its relation to patient outcome is uncertain. METHODS. The study group consisted of 164 patients with Ta urothelial carci noma diagnosed at the Mayo Clinic between 1985 and 1986. None had previous or coexistent urothelial carcinoma in situ or invasive carcinoma. The prima ry (most common) and secondary (second most common if at least 5% of the ca ncer) patterns of cancer growth were graded by the newly proposed World Hea lth Organization and International Society of Urological Pathology (WHO/ISU P) grading system. Scores of 1, 2, and 3 were assigned to urothelial neopla sms of low malignant potential (LMP), low grade urothelial carcinoma, and h igh grade urothelial carcinoma, respectively. The mean follow-up was 7.7 ye ars (range, 0-13.3 years; median, 9.2 years). Progression was defined as th e development of invasive carcinoma, distant metastasis, or death due to bl adder carcinoma. RESULTS. Patient ages ranged from 36 to 96 years (mean, 69 years), and the male-to-female ratio was 4:1. Disease progression developed in 32 patients during a mean follow-up of 7.7 years. The mean interval from diagnosis to p rogression was 3.1 years (range, 0.01-8.7 years). Progression free survival was 82%, 77%, and 76% at 5, 7, and 10 years, respectively. Primary and sec ondary grades were different for 52 patients (32%). Based on the worst grad e, 19 patients (12%) had urothelial neoplasms of low malignant potential (L MP), 92 (56%) had low grade carcinoma, and 53 (32%) had high grade carcinom a. Histologic grades based on worst, primary, secondary, and combined prima ry and secondary grades were all significant for predicting progression (P = 0.0009, 0.0004, 0.001, and 0.0001, respectively). Seven-year progression free survival rates for patients with LMP, low grade, and high grade carcin oma (based on worst grade) were 93%, 82%, and 61%, respectively; for patien ts with combined scores of 2, 3, 4, 5, and 6, survival rates were 93%, 80%, 82%, 68%, and 40%, respectively. The difference between patients with comb ined scores of 5 or 6 was statistically significant (P = 0.02). CONCLUSIONS. Histologic grade of urothelial carcinoma based on the newly pr oposed WHO/ISUP grading system stratifies patients into prognostically sign ificant groups. Grading should also take cancer heterogeneity into consider ation, and prognostic accuracy appears to be increased when the combined pr imary and secondary grades are applied. [See editorial counterpoint on page s 1509-12 and reply to counterpoint on pages 1513-6, this issue.] (C) 2000 American Cancer Society.