BLADDER: Risk and Prognostic Factors—a Pathologist's Perspective

Great strides have been made in the genetic and molecular genetic characterization of solid tumors, including bladder cancer. As knowledge in this area continues to grow, the new information can be used to classify tumors, establish prognosis, and guide therapy in a more precise fashion. Although several molecular alterations have been associated with advanced stage and aggressive behavior, their use in a routine clinical setting remains controversial because none of the changes have been confirmed in a prospective randomized fashion. In addition, the methodology to perform these tests has not been standardized, and there is no consensus on cut-off points to interpret the results. For the foreseeable future, therapy for urothelial cancer will be based on a host of clinical and pathologic factors. This fact places a great burden of responsibility on the pathologist who must strive for diagnostic accuracy and to identify those morphologic features of the tumor that are relevant in predicting aggressive disease, clinical outcome, and response to therapy. Included in this process is a constant questioning and refining of criteria in an attempt to make a subjective yet powerful discipline even more relevant for clinical care. As new techniques and concepts emerge, they must be submitted to rigorous scientific scrutiny, including prospective validation and multivariate analysis in which new putative markers are tested against those that have withstood the test of time. The pathologist's first encounter with a bladder tumor is usually a transurethral resection specimen. These specimens can be used to assess several important morphologic parameters which seem to be straightforward but are not owing to the inherent subjectivity of the field and the lack of universal standardized criteria to assess them (Table 1). Because of a recent series of events, including a significant increase in interest in urologic disease on the part of pathologists, the creation of an International Society of Urological Pathologists (ISUP), and improved lines of communication between dissenting parties, these issues are now being addressed in a more systematic fashion. The end result has been an injection of excitement and scientific rigor to the field. At initial diagnosis, most transitional cell carcinomas are papillary and superficial, and as many as 70% are characterized by a prolonged clinical course over which the patient experiences multiple recurrences following local resection without tumor progression. 57,73 In contrast, a smaller but significant percentage of patients present with tumors that have an aggressive clinical course over a short period of time. The most important predictors of clinical course are the depth of invasion at presentation, multiplicity (multifocality), a history of prior urothelial tumors, tumor size, and grade. Tumor size and grade do not have as great an impact on the recurrence rate as tumor multiplicity (multifocality), a prior history of tumors, and the depth of invasion at diagnosis. 26,34,35,49,57,73 As a rule, only high-grade tumors develop regional lymph node metastasis. Cytologically benign papillary tumors may and do recur but do not invade. Tumors are as likely to recur at a different site in the bladder, indicating multifocal occurrence rather than recurrence of the original tumor. Tumor configuration is another important prognostic variable. Papillary tumors tend to be of lower grade and earlier stage and to exhibit less aggressive behavior than nonpapillary tumors. 17,35,49,80 Kakizoe and co-workers 47 studied 186 cystectomies and found that tumors with a nodular (sessile) configuration presented at a higher stage when compared with exclusively papillary tumors. Survival was adversely ( P 26 found that among a group of patients with superficial bladder carcinoma, patients who had lamina propria small vessel invasion had a significantly higher risk of subsequent tumor progression. Larsen and co-workers 55 disagree that lymphatic invasion is of clinical significance in pT1 disease and raise the valid issue that the presence of lymphatic invasion may be difficult to evaluate by light microscopy alone. An original diagnosis of vascular invasion was confirmed in only 5 of 36 biopsy specimens when immunohistochemical studies to identify endothelial cells were performed. Heney and co-workers 35 reported on 86 patients who underwent radical cystectomy for invasive carcinoma infiltrating at least into muscularis propria. Patients who exhibited small vessel invasion had regional lymph node metastasis in 38% of cases and a 5-year survival rate of 30%, whereas patients who did not have small vessel invasion had a regional lymph node metastatic rate and survival rate of 16% and 52%, respectively.