Stage progression in TA papillary urothelial tumors: Relationship to grade, immunohistochemical expression of tumor markers, mitotic frequency and DNA ploidy

Purpose: We studied 363 patients with stage Ta bladder tumors during long-t erm followup who were classified according to the 1998 WHO and Internationa l Society of Urological Pathology consensus classifications. We determine w hether various immunohistochemical and molecular markers could predict tumo r progression. Materials and Methods: A total of 680 patients in western Sweden with a fir st diagnosis of bladder carcinoma in 1987 and 1988 were registered and foll owed for at least 5 years. There were 363 (53%) tumors that were papillary stage pTa. The tumors were classified as papillary urothelial neoplasm of l ow malignant potential in 95 patients, low grade papillary urothelial carci noma in 160 and high grade carcinoma in 108. Of the patients in the latter group 95 were subdivided into WHO grade 2 and 13 into WHO grade 3. Tissue f rom the primary tumors that progressed in stage during followup was further analyzed with immunohistochemical methods (p21, p53, Ki67 and pRb), DNA pl oidy and mitotic frequency. The results were compared with those in matched controls (nonprogressors). Results: Recurrence developed in 35% of patients with papillary urothelial neoplasm of low malignant potential compared to 71% with low grade urotheli al carcinoma and 73% with high grade carcinoma (p < 0.0001). No papillary u rothelial neoplasm of low malignant potential progressed in stage. Disease progressed in 4% of patients with low grade compared to 23% with high grade carcinoma (p < 0.0001). Of the patients with WHO grade 3 disease progresse d in 45% compared to grade 2 in 20% (p < 0.0011). At first diagnosis p53 sc ore was significantly higher (p < 0.0022) among patients with WHO grade 2 c arcinoma which later progressed compared to that in matched controls but th ere was no significant difference regarding the other markers. In contrast to grade 2 most grade 3 carcinoma was aneuploid, had high mitosis frequency , high p53 and Ki67 scores as well as loss of retinoblastoma gene expressio n. Conclusions: The 1988 WHO and International Society of Urological Pathology consensus classifications divide noninvasive papillary bladder tumors into 3 subgroups with different clinical behavior, which seems to be an advanta ge compared with the 1973 WHO classification. A disadvantage is that the hi gh grade carcinoma group contains 2 subgroups with different progression ra tes and immunohistochemical marker profiles, corresponding to the 1999 WHO grades 2 and 3. Grade 2 tumors in patients that progressed in stage years l ater seem to have different immunohistochemical and molecular marker profil es compared to those in matched controls.