Prognostic factors

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PierFrancesco Bassi and Francesco Pagano*

Department of Urology, Catholic University Medical School, (Rome), Italy and *University of Padova Medical School, Italy

Introduction

Bladder cancer is a heterogeneous disease with considerable variations of its natural history, with five-year survival rates ranging from 97-98% of a monofocal, well-differentiated and small papillary tumour to 0% of an invasive bladder cancer extending throughout the bladder wall and with gross nodal metastases.1 Among superficial bladder cancers, tumour recurrence after initial therapy varies from 30% in patients with a solitary papillary tumour to more than 90% in patients with multiple tumours.2 Most tumours recur in six to 12 months but remain non-invasive and pose little risk to the patient.

The desire to predict which superficial bladder cancer will recur or progress to invasive cancer, and which invasive bladder cancer will metastatize has lead to the evaluation and identification of several prognostic factors. In this chapter we will provide a contemporary review of invasive bladder cancer prognostic factors related to the tumour, the host as well as the environment: a particular emphasis will be on the effective role in the clinical practice.

Classical prognostic factors

For many years ittle data, and of that unreliable data has been available about the factors predictive in survival ofinvasive bladder cancer. The major part of the published series has evaluated small patient cohorts undergoing different therapeutic modalities in a non-contemporary setting and with unsatisfactory statistical methods. More recently the problem has been clarified by two wide-ranging studies.3,4 A large and non-contemporary series of patients encompassing 21 years was retrospectively evaluated to establish a hierarchy of predictive variables of cancer specific survival. On multivariate analysis only tumour stage and grade, nodal involvement, positive surgical margins and patient age at surgery were independent predictors of poor cancer specific survival in the Frazier series.3 Different results have been reported by Bassi et al. in a homogeneous cohort of patients undergoing radical surgery at a single institution as monotherapy for bladder cancer.4 Only tumour stage and grade were independent predictors of survival; other variables, such as age at surgery, sex, tumour grade, perineural, lymphatic and vascular invasion, ureteral obstruction and previous superficial bladder cancer history were shown to be unable to predict the prognosis.

The anatomical extent of the tumour, or the depth of wall invasion, is universally accepted as the most important prognostic factors from large patient series. The five-year survival ranges from 70% for T2 tumours to 10% for T4 tumours. The prognosis is substantially related to the presence of organ confined or extravesical disease respectively.3-7

Nodal involvement has been universally associated to a poor outcome.3-12 Nodal involvement is an independent predictor of survival in patients with invasive bladder cancer.4,8,11,12 Furthermore, the prognosis of invasive bladder cancer is directly related to the extent of the nodal involvement, namely the number and size of the positive nodes. Patients with N1 disease seem to benefit from pelvic node dissection and radical cystectomy, as evidenced by similar outcome in those with node negative disease and similar P stage of the primary tumour. However, the observed benefit quickly disappears when more than one node is involved. Additional therapy, other than surgery, seems appropriate in the latter group.

The presence of obstructive uropathy has been reported by some authors as an ominous prognostic factor, but in a most recent series the independent predictive value of such variable hasn't been confirmed.4,13

Positive surgical margins have been shown in the Frazier series to be associated with a poor outcome and to be an independent predictor of survival.3 No further information about this important finding is available in the literature.

Transitional cell carcinoma encompasses more than 90% of all bladder cancers. The remaining proportion of patients have pure squamous cell carcinomas or adenocarcinoma, rarely mixed histotypes.14 Even though a direct relationship between tumour extent and survival has been demonstrated for such histotypes, no reliable information is available regarding the comparative impact of histological type on outcome.15,16

Tumour differentiation, namely grade, has been considered an imp ortant prognostic factor for invasive bladder cancer for several decades. Several reports claim grade to be also an independent predictor of survival.17-19 Bassi et al.'s recent series on a homogeneous cohort of patients undergoing radical cystectomy as a definitive and single treatment for invasive bladder cancer clearly showed that grade is a significant prognostic factor at the univariate analysis but without independent prognostic value at the multivariate analysis.4 This observation is explained by the fact that in all the major published literature most of the invasive bladder tumours have been graded 3, according to WHO classification.4,14,19

Newer prognostic factors

Next to tumour properties and the former history of an individual patient, which can be recorded easily, a more sophisticated procedure may be used to evaluate the likelihood of recurrence or progression by DNA ploidy measurement, immuno-histochemical staining of the basement membrane components, evaluation of cell adherence molecules, growth factors, proteases, cell surface antigens and blood group antigens, as well as by the determination of cell-cycle related proteins in bladder carcinoma. All of these are experimental and none have reached clinical significance or become part of clinical routine.

Aneuploidy, as determined by FCM, has been associated with decreased survival in both low- and high-stage transitional cell carcinoma, although the correlations are better and more consistent for low-stage tumours.20 Aneuploidy correlates well with histological grade and with lymph node metastasis.20 Nuclear morphometry, an image analysis technique for evaluation of nuclear shape, correlates with metastasis.21

One potential option is to estimate the proliferative activity of tumour cells as an indicator of prognosis by cell-cycle-related proteins such as Ki-67 and PCNA (proliferating cell nuclear antigen). These proteins are detected in higher stage tumours and are associated with reduced survival, although this association is stronger with lower stage (Ta/T1) than invasive bladder cancers.22-24 This may also be accomplished by specific labeling of S-phase cells with bromodeoxyuridine. Unfortunately, these sophisticated techniques have added little further prognostic information than that obtained from standard prognosticators.20,24

Cell division is regulated by cell-cycle-associated proteins, including cyclins and their associated kinases. Loss of regulation of proliferation is an early and essential step in cancer development. Several genes and gene products associated with regulation of the cell-cycle have been the subject of recent intensive investigation. Two of these, the p53 and Rb tumour suppressor genes have been shown to be important prognostic factors for patients with bladder cancer.

The retinoblastoma tumour suppressor gene was the first such gene identified through the study of patients with retinoblastoma. Inactivation of the Rb gene is thought to be an important step in bladder cancer progression. The results of two small studies have suggested that loss of expression ofthe Rb protein may be ofprognostic significance in transitional cell carcinoma of the bladder. Logothetis et al. studied 43 patients with locally advanced bladder cancer (T2-T4a) and found that patients whose tumours had lost Rb expression had a shorter three-year survival (p = 0.01) suggesting that loss of Rb expression is a prognostic factor in patients with advanced cancer.25 Cordon-Cardo et al. reported that patients with muscle-invasive bladder tumours that had lost Rb expression had a shorter five-year survival (p = 0.001) than those patients whose tumours expressed normal Rb protein.26

The p53 tumour suppressor gene mutations are thought to be the most common genetic defect in human tumours.27 This protein has an important role in preventing cell-cycle progression by delaying cell division, allowing time for DNA repair. Molecular analysis has shown that abnormal nuclear accumulation of p53 protein in bladder tumours, as detected by immunohistochemical staining, correlates closely with gene mutations detected by DNA sequencing.28 Large series have shown that abnormal p53 expression is found more frequently in higher grade and higher stage bladder tumours and is a predictor of poor outcome.29,30 Mutations in p53 have been associated with progression of superficial bladder cancer.31-35: Sarkis et al. showed that progression of patients with Ta, T1 and CIS correlated with p53 mutation.31 Nuclear over-expression of p53 was an independent predictor of death from bladder cancer for patients with CIS and T1 tumours.31,38 P53 status has been evaluated as a predictor of response to BCG in patients with superficial bladder cancer.34 Although pre-treatment p53 over-expression was an independent predictor for progression, it did not predict response to BCG. However, in patients with residual disease after BCG treatment, post-therapy p53 over-expression was predictive of disease progression. Esrig et al. investigated the role of p53 over-expression in 243 patients treated by radical cystectomy for transitional cell carcinoma of the bladder, and found that p53 overexpression was the sole independent predictor of relapse (75% versus 40%, p<0.001) in the entire cohort.29 When patients were stratified by stage, nuclear p53 accumulation was associated with an increased risk of disease for patients with stage pTl, pT2 and pT3a, but was not significant for stage pTa or extravesical disease (pT3b, pT4 or lymph node metastasis). Lipponen investigated the role of p53 over-expression by immunohistochemistry in 212 patients treated by a variety of different modalities, and found a 29% incidence of p53 mutations in the entire cohort.30 Over-expression of p53 protein was an adverse prognostic factor in patients with muscle-invasive disease. However, p53 over-expression was not an independent prognostic factor and provided no more predictive information than could be obtained from tumour stage and mitotic index.

Both p53 and Rb have been evaluated as predictors of response to therapy for muscle-invasive bladder cancer. Pollack et al. recently re-evaluated the role of pre-operative radiation therapy in patients with stage T3b transitional cell carcinoma.35 They found that p53 mutations predicted a poor response to pre-operative radiation, while Rb status was the only independent predictor of response to radiation. Logothetis et al. looked at the prognostic significance of Rb status in patients with advanced transitional cell carcinoma treated with MVAC chemotherapy and cystectomy: in this study altered Rb expression predicted a poor response to therapy.25 Sarkis et al. conducted a similar analysis and evaluated the significance of altered p53 expression in patients with muscle-invasive transitional cell carcinoma treated with neoadjuvant MVAC.36 They reported that patients with p53 mutations had a significantly higher proportion of cancer deaths, so that p53 mutations predicted a poor response to MVAC chemotherapy. However, Cote et al. presented conflicting results related to p53 expression and response to chemotherapy.37 In their study, p53 mutations predicted a positive response to chemotherapy.

An alternative pathway to disrupt p53 function without mutation of p53 is through amplification of MDM2, which inhibits the function of p53 and may contribute to progression in tumours that are immunohistochemically negative for p53. Amplification of the MDM2 gene or over-expression of its product has been reported in some bladder cancer tissues.38,39 Although Lianes et al. suggest that this pathway may be more important in low stage tumours, Habuchi et al. hypothesize that this pathway is involved in genetic instability and oncogene expression in higher stage tumours.40,41 Further work is necessary to clearly identify the role of MDM2 in bladder cancer progression.

P21 is a negative cell-cycle regulator transcriptionally regulated by p53 that also prevents the inactivation of Rb. Abnormal immunohistochemical staining of p21 is reported to be a risk factor for progression of TCC in patients with wild type p53 expression.42

Interestingly, two preliminary reports examining the prognostic importance of the combination of altered p53 and Rb expression suggest that patients whose tumours exhibit both p63 and Rb dysfunction have the poorest prognosis, and patients whose tumours exhibit dysfunction of one gene have an intermediate prognosis.43,44 Although it is impossible to predict which tumours with mutations in both genes will progress, no tumours that had wild type p53 and Rb expression progressed. These results suggest that mutation of the p53 and Rb genes have independent and synergistic roles in the development of bladder cancer.

Recently, two other genes, p15 and p16, which encode proteins that also regulate the activity of cyclins, have been studied in bladder cancer.45 These two genes are localized to chromosome 9, at 9p21, and are putative tumour suppressors which may be lost early in the pathogenesis of TCC.

Neoangiogenesis, the neovascularity associated with tumours, may facilitate the transition ofcells from the local tumour bed into the circulation, resulting in metastasis.46 High tumour vascularity in invasive bladder cancers was reported to be a strong predictor of lymph node metastasis and an independent prognostic indicator for survival in two other reports conveying a 2.5-fold greater risk of dying of bladder cancer for those patients with high microvessel counts.47-49 However, there are conflicting reports in the literature regarding the prognostic value of vascular density in bladder cancer. Babkowski et al. evaluated the prognostic significance of microvessel density in 54 patients with stage T1 bladder, and found that vascular density did not correlate with prognosis using any of the three antibodies.38 The risk of progression to metastatic disease was relatively low in this study, compared to those in which microvessel density was found to be prognostic. Therefore this study does not eliminate the possibility that microvessel density could be a marker for metastasis in bladder cancer.

Specific antibodies to cell surface antigens from human bladder cancer have been produced. Two of these antibodies, developed by Fradet et al., M344 and I9A211, are expressed preferentially on low-grade transitional cell carcinoma.39 One or both of these markers are present on approximately 80% of low-grade, non-invasive TCC, and approximately 10% ofmuscle-invasive tumours. Their presence may enhance the detection of bladder cancer, in combination with cytology. The expression of both these markers has been associated with an increased recurrence rate. Two other antibodies developed by Fradet's group are the T138 and the T43 antibodies.50 These antibodies preferentially react with higher stage tumours and in several studies of locally invasive bladder cancer have shown some prognostic value.

Loss of expression of blood groups A, B and H antigens in bladder cancer have long been recognized as prognostic indicators for patients with bladder cancer.51-53 However, in carefully performed studies, the loss of ABO antigens was found to be relatively common and provides no prognostic information.51-53 More recently, a group of antibodies reactive with the Lewis X blood group determinant have been studied, including 486 P3/12, and E7.52 These antibodies were useful for detecting recurrence in low-stage bladder cancers, with a reported sensitivity of 81% and a specificity of 86%. The Thomsen-Friedenreich (T) antigen is another blood-group antigen that is expressed in bladder cancers but not in normal urothelial cells.53 The T antigen is associated with recurrence in low-stage bladder cancers, but offers no prognostic information for invasive bladder cancers.53,54

E-cadherin, an epithelial cell adhesion molecule associated with differentiation, is lost in many types of cancers.55 E-cadherin appears to act as a tumour suppressor. Several recent reports have shown an association between a decrease in E-cadherin expression at the cell border and increased bladder cancer stage.56 In two of these studies, decreased E-cadherin expression was also associated with a poorer survival rate.57,58

Integrins function as receptors for extracellular matrix proteins.59 Liebert et al. noted a progressive loss of a2fi1 expression with increasing bladder cancer stage.60 This finding could result in a loss of cell-cell adhesion similar to E-cadherin loss. The loss of a2fi1 expression was observed in low-stage bladder cancers, suggesting that the loss of this expression occurs early in bladder cancer progression. The expression of another member of the integrin family, the a6fi4 heterodimer, is associated with a basal anchoring structure in normal epithelial tissues, including the urinary bladder.61 However, in invasive bladder cancer, the association between a6fi4 and the anchoring structure is lost. In many cases the a6fi4 integrin is over-expressed, suggesting that the cancer cells use this receptor to move through the basement membrane.

The epidermal growth factor receptor (EGFr) is found on most epithelial cells, including transitional cells. Clinically, over-expression of EGFr correlates with tumour stage and is associated with a poor prognosis, especially for lower stage bladder cancers.62-64 In a subset analysis, Neal et al. found that EGFr did not predict survival for patients with higher stage tumours.64 Similar results in high-stage tumours were obtained by Lipponen et al., whose observations, combined with observations that high levels of EGFr are observed in normal-appearing urothelium distant from the tumour, suggest that increased expression of EGFr is an early event and may occur in pre-cancerous cells or is supported by changes in the bladder environment.24,63

The c-erb-B2 oncogene encodes a cellular surface protein. However, many bladder tumours that show strong staining for the c-erb-B2 product do not have gene amplification. Several studies report that high expression of c-erb-B2 protein is associated with higher stage increased metastasis and poorer outcome.65-67

Fibroblast growth factors (FGFs) are a large family of polypeptide growth factors, and contribute significantly to the induction of angiogenesis by their effects on endothelial cell migration and growth.68 Since angiogenesis correlates with poor prognosis in bladder cancer, it is expected that expression of FGFs in the urine would be valuable predictors of disease state. Furthermore, FGFs affect many cell types, and treatment with FGFs induce a highly motile, fibroblastoid cell type in a rat bladder cancer epithelial cell line.69 Two members of the FGF family, FGF-1 (acidic FGF) and FGF-2 (basic FGF) have been identified in the urine of patients with bladder cancer.70-72 Levels of expression of FGF-2 correlated with higher stage and metastasis. Patients with higher stage tumours were more likely to have a positive urinary test for FGF-1.70 Bladder cancer cells in tissues were also shown to express FGF-1: a greater number of high-stage tumours expressed FGF-1 and expression was also related to metastasis.70-72

Since penetration of the basement membrane is thought to be an essential step in the progression of bladder cancer, expression by cancer cells of enzymes capable of destroying the basement membrane should correlate with metastasis. Several families of proteases have been evaluated in bladder cancers.73,74

One group of proteases are the metalloproteinases that degrade collagen IV (also called type IV collagenase or MMP2 and MMP9). Slightly contradictory results were obtained in two reported studies. In the first, the urinary levels of72 kilodalton type-IV collagenase (MMP2) were found to be higher in patients with invasive cancers, and immunohistochemical staining revealed that the tumour cells were producing collagenase.69 In contrast, in the other study, both the 72 and the 92 kilodalton type-IV collagenases were studied.74 Again, increased levels were observed in invasive bladder cancers, but in situ localization showed that stromal cells produced the collagenase.

A second type of protease, the urokinase plasminogen activator (uPA), is a serine protease that is associated with fibrinolysis. Presence of active uPA may activate other cellular components, including metalloproteinases, and may also directly contribute to matrix degradation. Low-stage bladder cancers with low expression of uPA had significantly better survival that high expressors, although these differences were not independent of grade.75

A final group of proteases, the cathepsin family of cysteine proteases, has been the subject of preliminary analysis in bladder cancer. The T24 invasive human bladder cancer cell line showed high level of expression of cathepsin B, while the non-invasive human bladder cancer cell line RT4 had low expression.76However, in a clinical study of cathepsin D expression in bladder cancers, Dickinson et al. observed the opposite association: a decreasing expression of cathepsin D with increasing bladder cancer stage; invasive bladder tumours expressing cathepsin D had a better outcome than those not expressing it.77,78 Cathepsin D expression was not an independent predictor in multivariate analysis. The authors noted that normal urothelium expressed high levels of cathepsin D, and that loss of expression might be related to loss of differentiation in higher stage tumours.78

The intact basement membrane, composed of collagen-IV, pro-teoglycans, laminin and other extracellular matrix components, presents a physical barrier to tumour cell invasion and metastasis. The dissolution of this barrier is one pathologic criterion for disease progression. Although the presence of the basement membrane may be evaluated in routine histological staining, advanced techniques to specifically identify the integrity of this barrier may be useful in determining invasion. A number of investigators have evaluated immunohistochemical staining for extracellular matrix components of the basement membrane, including collagen-IV and laminin.79-81 In general, increasing defects in basement membrane integrity are noted with increasing stage of tumour. Daher et al. noted the development of gaps in collagen-IV in the basement membrane, and divided their patient cohort into two groups based on intact or defective collagen-IV.80 Of the invasive bladder cancer patients in this study, 29 were observed for a three-year follow-up period. Of the 16 evaluable patients with intact collagen-IV, 11 were still alive at three years; of the 13 patients with defective collagen-IV, none were alive at three years. These data suggest that even within high-stage tumours, evaluation of basement membrane integrity may be of prognostic significance. Laminin immunohistochemical staining has also been used to evaluate basement membrane integrity.81 Disrupted basement membrane laminin was associated with metastasis. This same group detected the presence of laminin p1, a laminin degradation product, in the blood and urine of patients with invasive cancers.82 The blood tests were neither highly sensitive nor discriminatory.81,82 Of the non-cancer patients, 31% showed a positive result, and of bladder cancer patients, 57% of those with intact basement membrane were positive while 82% of patients with interrupted basement membrane were positive. The urine tests showed promise for following patients with invasive bladder cancers, demonstrating 58% sensitivity, 96% specificity and 87% positive predictive value.82 Unfortunately, no follow-up of these patients was provided.

Host-related prognostic factors

In nearly all populations, men are 2.5-5.0 times more likely to develop bladder cancer than women. Incidence of bladder cancer rises monotonically with age: the disease is rare prior to age 35 and two-thirds of the cases occur in people aged 65 or older.1,83

There is a marked racial-ethnic variation in bladder cancer incidence: in the United States, non-Latino white men show the highest incidence of bladder cancer among all races. Their rate is twice that for Latino and African-American men, and 2.5 times higher than males in the Chinese and Japanese-American community. A similar pattern is observed in women, even though within race the male rate is about 3-4 times higher than the female rate.83,84

As far as hereditary bladder cancer is concerned, numerous case reports document the clustering of transitional cell carcinoma in families, several of which demonstrate an extremely early age of onset of disease, which argues in favour of a genetic component to familial transitional cell carcinoma. The results of large epidemiological studies also suggest the existence of familial bladder cancer, and first-degree relatives appear to have an increased risk for disease by a factor of 2: familial clustering of smoking does not appear to be the cause of this increased risk. However, further studies are required to identify candidates' genes that may be responsible for this form of bladder cancer.1,85

Age has been reported as a prognostic factor of outcome in superficial and invasive bladder cancer.17 Contradictory results have been observed in two large patient series treated with radical surgery.3,4 Also, performance status has been shown to be an ominous variable of survival in patients undergoing systemic chemotherapy for advanced bladder cancer.86 No reliable information on this variable has been reported in patients undergoing definitive surgical therapy for invasive disease: in fact, in such cases the anaesthesiological risk has been taken more frequently into account. Finally, anaemia has been found to be an adverse prognostic factor in patients treated with radiation therapy for muscle-invasive bladder cancer.87,88 The opposite has been reported in surgically treated bladder cancer.4

Environment-related prognostic factors

Since the publication of a classic paper at the end of the 20th century postulating the higher incidence of bladder cancer among aniline dye-workers, multiple occupational, environmental and genetic factors have been identified: chemical dye exposure, 2-naphthylamine, 4-aminobiphenyl, benzidine, arylamines, cigarette-smoking, schistosomiasis, etc.84,89

Cigarette-smoking has been shown to be the single most important cause of bladder cancer. There is a good correlation between duration and severity of exposure to smoking and incidence of this tumour, and furthermore, continuing smokers experience worse disease-associated outcomes than quitters or ex-smokers.90

In contrast to Europe and the United States, in some regions of Africa schistosomiasis is the endemic bladder cancer and the most frequent tumour, with the majority of the patients being diagnosed with squamous cell carcinoma and one-third giving a history of bilharziasis.16,84,89,91

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