Conventional Morphologic, Prognostic, and Predictive Factors and Reporting of Bladder Cancer

The traditional morphologic, prognostic, and predictive factors for bladder cancer vary according to the type of bladder cancer presentation in the patient: noninvasive papillary tumors, primary urothelial carcinoma in situ (CIS), or invasive urothelial carcinoma (1). The prognostic factors are, hence, discussed separately for each category and are summarized in Table 7.1. There are several molecular and chromosomal markers (e.g., loss of chromosome 9, loss of material on chromosome 17, p53, retinoblastoma tumor suppressor gene status, cell cycle regulation markers including p21 and cell adhesion, angiogenesis and cell migration-related markers such as e-cadherin, and vascular endothelial growth factor) that are likely to complement traditional morphologic markers in the future, but these are not routinely used in current surgical pathology practice (2, 3, 4). Additionally, clinical parameters (e.g., comorbid disease) as well as clinical presentation (e.g., increased frequency of recurrence and short interval between recurrences) influence progression in grade and stage (5).

NONINVASIVE PAPILLARY TUMORS

Histologic Grade

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. Patients with papilloma and neoplasms of low malignant potential have essentially a normal age-related life expectancy (see Chapter 3). Progression risk in grade and stage, and mortality increases from low-grade carcinomas to high-grade carcinomas (3, 4). High-grade disease is a stratifier for management and therapeutic decisions in the recent National Comprehensive Cancer Network guidelines for noninvasive tumors (6). Glandular differentiation may occur in noninvasive tumors
and approximately 50% of these patients develop invasive carcinoma, although the invasive component is unlikely to be adenocarcinoma (7).

TABLE 7.1 Morphologic Prognostic and Predictive Factors of Bladder Cancer

Noninvasive papillary tumors

Histologic grade

Size of tumor

Multifocality

Status of nonpapillary urothelium—CIS

Urothelial CIS

Mode of presentation—primary (de novo) or secondary

Multifocality

Failure to respond to typical therapy

Invasive urothelial carcinoma

Depth of invasion in bladder wall (pT stage)

Lymph node involvement (pN stage)

Involvement of prostate gland and seminal vesicles

Histologic type

Histologic grade (controversial)

Vascular-lymphatic invasion (controversial)

Surgical margin status for invasive carcinoma

Multifocality and CIS of urethra or ureters

Size of Tumor

Large tumors (often greater than 3 cm) are at an increased risk for recurrence and progression (8, 9).

Multifocality

Patients with multifocal tumors in the bladder and involving other regions of the urothelial tract (ureters and urethra) are at an increased risk for recurrence, progression, or death due to disease (9, 10, 11).

Urothelial Carcinoma In Situ in Nonpapillary Mucosa

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 (12, 13).

UROTHELIAL CARCINOMA IN SITU

Patients with primary (de novo) CIS are more likely to have no evidence of disease (62% vs. 45%) and are less likely to progress (28% vs. 59%)
or die of disease (7% vs. 45%) as compared to patients who have CIS in association with high-grade papillary carcinoma (14). Patients with CIS often respond to intravesical installation of BCG but virtually experience tumor recurrence over time. Patients with multifocal disease, those with involvement of the prostatic urethra and those who fail to respond to intravesical therapy have a worse outcome (1, 12, 13, 15).

INVASIVE UROTHELIAL CARCINOMA

Depth of Invasion in Bladder Wall

Once a urothelial carcinoma is invasive, the most seminal prognostic factor is the American Joint Committee on Cancer/International Union against Cancer pathologic stage (16) (Table 7.2). The pT system of staging has an 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, 17, 18, 19). 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 (3).

For muscularis propria invasive tumors, the prognostic significance of tumors invading the inner half (pT2a) versus those invading the outer half is uncertain, with investigators reporting an overall similar outcome (20, 21). Tumor size (largest tumor dimension) may be a better predictor of cancer-specific survival in these patients (22). For tumors invading perivesical soft tissue, subdivision into pT3a—microscopic extravesical invasion versus pT3b—gross extravesical extension, is controversial, although studies suggest that grossly recognized tumor at margin is an adverse prognostic factor (23).

Lymph Node Involvement

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