Mixed low- and high-grade papillary urothelial carcinoma: histopathogenetic and clinical significance

There are two pathways of urothelial carcinogenesis: low-grade urothelial carcinoma (LGUC) with low rates of gene alterations and high-grade urothelial carcinoma (HGUC) with numerous gene alterations. HGUC often displays strong reactivity for cytokeratin 20 (CK20) and p16. Despite distinct molecular changes, urothelial carcinoma (UC) with both low- and high-grade features is not uncommon. We examined cases with patterns of mixed low- and high-grade UC (MLHGUC). Consecutive cases of UC at our institution were reviewed. There were 45 cases that showed a mixture of both LGUC and HGUC. IHC for CK5, CK20, CD44, p16, and Ki67 was performed. Areas of HGUC displayed strong and diffuse reactivity for p16, CK20, and Ki67 in 20-50 % of the tumor, while LGUC areas had negative or focal reactivity for CK20 and Ki67 in 10-30 %. There were two distinct cohorts of MLHGUC: patients with a history of LGUC (group A) and those without (group B). Group A patients (n = 8) had a history of LGUC for 1-10 years. The tumor specimens weighed 1.5 +/- 1.7 g and had HGUC components of 25 +/- 20 % of the tissue. Superficial invasion was present in one case. All tumors had BCG treatment with one recurrence. In group B (n = 37), tumor specimens weighed 3 +/- 3.9 g and had HGUC components in 43 +/- 21 % of the tissue. Superficial invasion was present in five cases, and muscle invasion with lung metastasis occurred in one case. Four cases were refractory to BCG with an increased proportion of HGUC, and one case requiring cystectomy. Differences in size and proportion of HGUC between groups A and B MLHGUC were significant (P < 0.05), with group B presenting with a higher tumor burden and proportion of HGUC. MLHGUC is diagnostically challenging and is commonly assigned high grade since this determines prognosis. Group A MLHGUC likely develops as a result of progression from LGUC, whereas group B MLHGUC likely develops de novo, is associated with larger tumors, shows a higher proportion of HGUC, and follows a worse prognosis. Despite the similar histology of groups A and B, assignment to HGUC in a binary system may mask important prognostic information.