Histologic grade is a powerful prognostic factor for recurrence and progression in noninvasive tumors. Urothelial papilloma has the lowest risk for either recurrence or progression, whereas papillary urothelial neoplasm of low malignant potential has a risk for recurrence but still has a low risk for progression. Invasion is not seen in association with these tumors, and patients with papilloma and neoplasms of low malignant potential have essentially a normal age-related life expectancy (see Chapter 3). Risk of progression in
grade, stage, and mortality increases from low-grade carcinomas to highgrade carcinomas. High-grade disease is a stratifier for management and therapeutic decisions in the recent NCCN guidelines for noninvasive tumors (6). Glandular differentiation may occasionally occur in noninvasive tumors, and approximately 50% of these patients develop invasive carcinoma, although the invasive component is unlikely to be adenocarcinoma (2, 7, 8).

Large tumors (often greater than 3 cm) are at an increased risk for recurrence and progression (9, 10, 11, 12).

Patients with multifocal tumors in the bladder and involving other regions of the urothelial tract (ureters and urethra) are at increased risk for recurrence, progression, or death due to disease (10, 13, 14). The number of tumors has been shown to correlate with higher risk of recurrence (8, 11, 15).

Clinical history of prior recurrence and female sex has been associated with bladder cancer recurrence in non-muscle-invasive bladder cancer (15).

Although the impact of the presence of dysplasia in the nonpapillary urothelium is controversial as a prognostic factor and at best may represent a marker of urothelial instability, the presence of urothelial CIS is a known adverse prognostic factor in terms of recurrence and progression (16, 17).

Once a urothelial carcinoma is invasive, the most seminal prognostic factor is the American Joint Committee on Cancer/International Union against Cancer pathologic stage (21) (Table 7.2). The pT system of staging has excellent

correlation with prognosis and distinguishes distinct prognostic groups. Tumors invasive into the lamina propria (pT1) have a better survival than tumors invasive into the muscularis propria (pT2), with poor survival for tumors with extravesicular extension (pT3, pT4) (1, 22, 23, 24). Although substaging of urothelial tumors (pTla-tumors invasive up to muscularis mucosae, pTlb-tumors invasive into or beyond muscularis mucosae) has shown prognostic value, it is currently not recommended because it may not always be possible to substage pT1 tumors due to the absence of muscularis mucosae in some bladders or because of a lack of orientation in transurethral resection specimens precluding orientation (4). Chapter 5 outlines the diagnostic criteria, pitfalls, and reporting recommendations for pT1 disease. In T1 disease, several substaging strategies have been proposed to improve outcome prediction (25, 26, 27) but have been difficult to adopt due in part to the inherent lack of orientation of the specimen. One strategy separates T1 disease into that above the muscularis mucosae (T1a), below the muscularis mucosae but above the venous plexus (T1b), and beyond the venous plexus (T1c) or separates microinvasive (T1m) disease from more deeply invasive disease (T1e) (25, 28). Whereas T1a and T1b corresponded to a 5-year survival rate of 75%, T1c disease was associated with a 5-year survival rate of only 11% (29). A second strategy separates superficial from deep lamina propria invasion into T1a and T1b categories, respectively, with T1b showing higher rates of progression (58% vs. 36%) and death from disease (46% vs. 23%) than T1a (30). Finally, the depth of invasion, a maximum diameter of invasive carcinoma of less than 1 high-power field versus ≥1 high-power fields (irrespective of direction), and a cutoff of 1 mm maximum invasive diameter have all been shown to be associated with prognosis (31). Based on the available data, it is recommended to provide an assessment of the depth and/or extent of subepithelial tissue invasion in T1 cases.