Bladder cancer

BLADDER CANCER MICHAEL J. DROLLER, M.D.

0011-3840/81/040205-0279-$06.50 9 1981, Year Book Medical Publishers, Inc.

TABLE OF CONTENTS SELF-AssESSMENT QUESTIONS

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INTRODUCTION

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EPIDEMIOLOGY .

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BIOLOGY AND NATURAL HISTORY OF BLADDER CANCER . . . . STAGING OF BLADDER CANCER . METHODS OF DIAGNOSIS .

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THERAPY CONCLUSIONS

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SELF-AssESSMENT ANSWERS

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SELF-ASSESSMENT QUESTIONS 1. Which of the following has not been implicated in the etiology of transitional cell carcinoma of the bladder? a. Naphthylamine. b. Cigarette smoking. c. Artificial sweeteners. d. Schistosomiasis. 2. Cigarette smoking has not been clearly demonstrated as an etiologic factor in the development of bladder cancer. True or false? 3. The occurrence of bladder cancer is a signal that ultimately each patient affected by transitional cell cancer will progress to the advanced form of the disease. True or false? 4. Urine cytology is a reliable index of the presence of disease in all phases and manifestations of transitional cell carcinoma. True or false? 5. H e m a t u r i a is an important finding in a patient with transitional cell carcinoma only if it is grossly visible. True or false? 6. Transitional cell carcinoma, when successfully resected and found only to be superficial, does not require any further treatment. True or false? 7. In the evaluation of transitional cell carcinoma, an intravenous pyelogram is important for the following reasons: a. To determine the presence of upper tract disease. b. To determine the possibility of ureteral obstruction. c. To determine the presence of tumor in the bladder. d. All of the above. e. Items a and b only. 8. In the determination of stage of transitional cell carcinoma, which of the following is most important? a. CT scan staging. b. Bimanual examination of the bladder. c. Random biopsy samples of the bladder mucosa. d. Fractional resection of the presenting lesion. 9. Radiation therapy is useful in the t r e a t m e n t of both superficial and deeply invasive transitional cell carcinoma of the bladder. True or false? . 10. Segmental cystectomy is to be preferred in the treatment of invasive disease since the objective of conserving bladder function m u s t be paramount in the mind of the physician. True or false? 11. The occurrence of carcinoma in situ is always an ominous prognostic sign and should signal the immediate removal of the bladder. True or false? 207

12. The only tumors t h a t are found to metastasize are those t h a t extend into the muscularis of the bladder wall. True or false? 13. There is no difference between tumors and their potential behavior if tumors are found to have penetrated the muscularis o f the bladder wall. True or false? 14. The us~ ~of a segment of ileum in diverting the urine is f r a u g h t with complications and is to be avoided. True or false? 15. The advantage of the use of colon over the use of an ileal segment is for which of the following? a. The possibility of creating an antirefluxing anastomosis between ureter and bowel. b. The decreased likelihood of stomal stenosis. c. The absorbent effect of the stool on the urine in preventing reflux. d. All of the above. e. Items a and b only. 16. Ureterosigmoidostomy is to be avoided in which of the following situations? a. Prior pelvic irradiation. b. Neurogenic bladder. c. Diverticulosis. d. Items a and b only. e. All of the above. Answers to these questions are listed at the end of this monograph.

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is Associate Professor of Urology and Associate Professor of Oncology at Johns Hopkins Medical School, and staff urologist at Johns Hopkins Hospital. He graduated from Harvard College and did his postgraduate work at Harvard Medical School. His residency training was at Peter Bent Brigham Hospital in general surgery and at Stanford University Hospital in urology. Dr. Droller spent two years as Clinical Associate in the National Institute of Arthritis and Metabolic Diseases and one year in the Department of Immunology at the University of Stockholm, where he pursued his interests in the effects of prostaglandins and cyclic adenosine monophosphate on cell function. His scientific interests are focussed in the area of tumor immunology and the role of various mediators (prostaglandins, interferons) in the cellular immune response and tumor progression.

INTRODUCTION BLADDER CANCER is not simply a single disease entity. Rather, it comprises a spectrum of neoplastic diatheses ranging from those curable with minimal therapeutic manipulations to those t h a t lead inexorably to a rapid death. Most patients with bladder cancer do not necessarily suffer the more aggressive forms of disease, and projections of an annual incidence in the United States of 20,000-30,000 new cases and 10,000 deaths tend to obscure this. An appreciation of this distinction, however, is important in order to explore the variety of factors t h a t m a y affect the biology and n a t u r a l history of the disease. In recent years, several important insights into the n a t u r a l history of the tumor diathesis have been gained through efforts to characterize behavioral differences among various types of bladder cancer. The attempt to define predictive indices of potential behavior of an early neoplastic lesion has demonstrated substantial gaps in our knowledge of what determines or reflects tumor behavior. Thus, we are as yet unable to predict with cert a i n t y whether an early bladder cancer will or will not recur in an innocuous form, or whether it will progress to a more adNOTE:This work was supported by Grant No. R26 CA24592 from the National Cancer Institute through the National Bladder Cancer Project. 2O9

vanced stage. Similarly, we are not yet able to establish with precision the probable timing of these events in the overall course of a patient's disease. The overriding importance of these objectives is underscored by the limited progress that has been made in the treatment of more advanced disease. There is thus general agreement on the need to characterize new indi~es that can be used with clinical consistency as guidelines in the accurate identification of patients at particular risk from their disease. Of equal importance is the need to establish the appropriate form and timing of intervention.

EPIDEMIOLOGY Of the 30,000 new cases of bladder cancer seen in the United States annually, approximately 23,000 occur in the male and 7,000 in the female population. 6 This male preponderance is seen in nearly all countries. '~~ The factors that have been implicated etiologically in the development of bladder cancer fall into two general categories. The first consists of factors that may directly alter transitional cells themselves and thus "initiate" the processes necessary for neoplastic transformation. The second consists of factors t h a t , through their continued action on appropriately "prepared" cells, may either individually or in concert "promote" neoplastic development. The concept of initiators and promoters in tumor development has largely been generated by observations both in experimental animal models and in tissue culture. 36'232 Though little is presently known of the intricacies of such mechanisms in human tumors, the concept is important as a background in an examination of the epidemiology of bladder cancer. ENVIRONMENTALFACTORS INDUSTRIAL CARCINOGENESIS.--In 1895, Rehn observed several cases of bladder cancer in an aniline dye factory's5 (Table 1). Epidemiologic studies ultimately suggested that intermediates of aniline production (2-naphthylamine, benzidine) were the agents actually responsible for the bladder cancers. 15~ Animal studies designed to explore these phenomena only became successful in producing bladder tumors when dogs were used. It thus appeared that other species might lack the enzymes required for transformation of aniline such as those found in dogs and man, and introduced an important caveat for epidemiologists to consider in the interpretation of carcinogenicity studies using different species: The subsequent implication of other industrial substances in the development of bladder cancer prompted an understanding that the norm was a long latency period between carcinogen exposure and appearance of bladder cancer,99 that carcinogens of210

TABLE

I.~OccUPATIONAL EXPOSURES AND BLADDER CANCER

OCCUPATION

CARCINOGEN

Aniline dye workers Rubber and cable workers Hairdressers Leather finishers Spray painters Textile weavers Petroleum workers Medical personnel

[~-Naphthylamine, benzidine, 4-aminodiphenyl Antioxidants (naphthylamine?) Dyes (?) Dyes (?) Dyes (?) Dyes (?) Aromatic residues Benzidine

ten required enzymatic transformation by the host to become carcinogenic,25. 5s.97 and that some substances that might have been expected to be carcinogenic were enzymatically detoxified prior to reaching the bladder so t h a t no tumors would occur. 79 It also became apparent that the identification of chemicals responsible for the development of bladder cancer might be complicated by exposure to multiple agents and the possibly synergistic action of some of them. 2~1Intensive research by epidemiologists has provided a long list of chemicals that appear to be associated in a primary sense as "initiators" in the development of bladder cancer. The mechanisms by which these and other agents m a y then act as "promoters" of neoplastic transformation remains unclear, as' ,94 CIGARE'I'rE SMOKING.~Several retrospective and prospective epidemioIogic studies have documented a causal relationship between cigarette smoking and bladder cancer and suggested t h a t cigarette smoking doubles one's risk of developing bladder cancer.l~3,14s, 243 The prevalence of cigarette smoking in the United States has prompted estimates that one third of all new cases of bladder cancer can be directly~attributed to cigarettes. 9~'243 I n these studies, dose of smoking, length of time since onset, and degree of inhalation have each been related to bladder cancer occurrence. Studies using successive birth cohorts to document these associations have effectively excluded the possible influence of occupational exposure on the development of cancer in these patients. 99 At least one study has suggested t h a t cessation of smoking once bladder cancer is diagnosed m a y decrease the likelihood of disease recurrence. 9 This suggests that a constituent of cigarette smoke m a y not only initiate but may also promote neoplastic transformation. Two biochemical pathways have been hypothesized to account for the carcinogenic activity of cigarette smoke. According to one hypothesis, tryptophan metabolites (see below), which were seen in high concentration in the urine of smokers, were suggested to be responsible for neoplastic transformation. 242 According to the other, cigarette smoke contains a carcinogen, such as 2-naphthy211

lamine, that is absorbed in in amounts that may have role of such pathways in transformation, however, is

the lungs and excreted in the urine a cumulative effect.243 The possible initiating or promoting neoplastic presently undefined.

ARTIFICIALSWEETENERS.--Although early epidemiologic studies reported no increased risk in patients who had ingested either saccharin or cyclamates,9' 14s the numbers of patients origiL nally analyzed in these studies may have been too small to detect such risk. 149"~42 Experimental studies in a variety of animal species, however, clearly documented the carcinogenic effects of both substances in association with the development of bladder cancer.26"96'156 These animal studies were especially important since they emphasized an assessment of the roles of initiators (cyclamates) and promoters (saccharin, cyclamates) in tumor development.9~ For example, of 165 rats receiving intravesical instillation of a subcarcinogenic dose of methyl-N-nitrosourea (MNU) and then fed either saccharin (96 animals) or cyclamates (69 animals), half of each group developed bladder tumors, while none of 150 animals given MNU alone and only 1% of 520 animals fed saccharin or cyclamates alone developed tumors. 96 In addition, the delay between contact with the presumed carcinogens and tumor development was only eight weeks in rats fed saccharin or cyclamates after instillation of MNU versus 95 and 87 weeks for those fed saccharin or cyclamates alone. The use of animals to establish carcinogenic risk has been criticized because the dose of carcinogens used may often be greater than the levels achieved in human exposure. However, the detection of carcinogens under such circumstances is based on the concept that carcinogenicity is the result of the intrinsic property of a chemical, independent of dosage and duration of exposure. 2u Recent observations in man have detected an actual increased risk for development of bladder cancer among heavy users of artificial sweeteners. 1~176 Interestingly, risk appeared in these studies to rise but moderately with increasing frequency of use of artificial sweeteners (an initiator role?) in women who did not smoke and in heavy smokers (a promoter role?) of both sexes. As the widespread use of artificial sweeteners is still a relatively short-term phenomenon, it is possible that the increased risk for development of bladder cancer may become clinically manifest only in the future. ANALGESIC ABUSE.--The earliest association between phenacetin ingestion and .the development of transitional cell carcinoma was made in 1965 by Hultergren, who reported six cases of transitional cell carcinoma among 103 patients with papillary necrosis; five had had a large intake of phenacetin-containing analgesics. 1~ Bengtsson subsequently reported nine patients 212

with transitional cell tumors of the renal pelvis and two with transitional cell tumors of the bladder associated with phenacetin abuse. '4 All of these patients were female, reversing the male preponderance usually seen in transitional cell cancer. A similarly high proportion of bladder cancer in women, most likely reflecting a greater degree of analgesic abuse by women than men, was also seen in this clinical setting. 224 Overall, the incidence of carcinoma of the renal pelvis was calculated to be nine times greater in kidneys damaged by analgesics than in those with nonanalgesic inflammatory disease. In addition, the incidence of cancer was observed to be higher in patients with papillary necrosis than in other forms of chronic pyelonephritis.355 In subsequent studies examining this association, two thirds of habitual analgesic users were found to be heavy smokers. 129 Thus, of 26 patients with primary carcinomas of the renal pelvis and five with primary ureteric tumors, although 15 (48%) had consumed more than 5 kg of compound analgesic powders or tablets, 19 (61%) had also smoked 15 or more cigarettes per day for at least 20 years. The mechanism of carcinogenesis in these instances has been reported to involve orthoaminophenol metabolites of phenacetin. Hydroxylation and aromatization of the N-hydroxy group of phenacetin produces N-hydroxy-4-phenetidin, a compound similar in structure to known bladder carcinogens.28 The underlying mechanism of the development of cancer in this setting remains undefined. SCHISTOSOMIASIS.--An association between schistosomiasis and the development of bladder cancer (usually squamous cell) was first reported by Ferguson in 1911. Originally thought to be due to chronic irritation caused by schistosome eggs deposited in the bladder wall, additional factors such as chronic bacterial infections34 and foreign body ~eactions2~ were also suggested to play a role. In the former, cleavage of glucuronides by bacteria was thought to produce active carcinogens in the urine, ss' 164Furthermore, bacteria were found to be a rich source of nitrate reductase, which could reduce nitrates to nitrites 93 that, in turn, could react with amines presgnt in the urine to form nitrosamines, well-known bladder carcinogens.6~ In addition, the chronic foreign body reaction and fibrosis seen in schistosomiasis was postulated to block lymphatics, presumably allowing carcinogenic chemicals or metabolites to accumulate. The reaction itself, which normally might result in epithelial proliferation, was hypothesized to lead instead to abnormal hyperplasia because of the presence of carcinogens and then to metaplasia and ultimate neoplastic change.2~ Although this particular etiology appears rarely if ever to be important in cases of bladder transitional cell cancer seen in the continental United States, the genesis of neoplasia in this setting may be relevant to other conditions with chronic foreign 213

body irritation and infection. This occurs with noticeable frequency in paraplegics or in patients who may have a similar history of foreign body irritation (such as indwelling catheters or bladder calculi), recurrent or chronic infection, and urinary stasis. In these cases, squamous cell carcinoma, rather than transitional cell cancer, is seen. Interactions between these factors and early identi~cation of patients at risk require further attention and study. HOST FACTORS The association of bladder cancer with environmental carcinogens has been clearly documented in more than 50% of patients. 1~~ While this has prompted further exploration of additional agents that might act as environmental carcinogens, several reports have suggested that other factors intrinsic to the host might also set the stage for tumors to develop, either separately or in concert with environmental agents.

GENETIC PREDISPOSITION.-:--Several investigators have called attention to the possible effect of genetic predisposition in the development of bladder cancer. 6~176176 For example, McCullough described families in which transitional cell carcinoma of the bladder developed in six of 34 relatives who survived beyond the age of 30. T M Similarly, Sharma reported on familial clustering of transitional cell carcinoma as being consistent with an autosomal dominant trait. ~~176 Other reports failed to document such patterns 243 and have suggested instead that familial clustering could just as well implicate commonality of environment. Extrafamilial increased frequencies of HL-A antigen 9, HL-AB5, and HL-A-CW 4 genes among patients with bladder cancer as compared with controls, however, have been reported, s~ VIRAL FACTORS.--Pertinent to these observations were reports of a viral etiology for bladder cancer. Thus, some investigators observed viruses in freshly excised bladder tumors as well as in t u m o r cells in either primary or first passage tissue cultures. 59' 70 These investigators also examined the serums of tumor patients and found virus-neutralizing antibody in patients from whom tumors had been obtained, b u t not in controls. 59 Herpesvirus virions were observed by other investigators in a squamous cell carcinoma of the bladder, and C-type viral particles have been reported in bladder cancer specimens, ~57 although in both instances, support for this being a generalized phenomenon was not strong. Of relevance to these reports were observations that oncogenic oncorna viruses, complex enveloped RNA viruses that have the capacity to synthesize a DNA genome copy that can be inserted into host cell DNA, were observed to be horizontally transmitted 214

and could remain latent indefinitely within host cells, ls4 However, it remains to be shown whether such viruses are responsible for creating a milieu in cells that is conducive to the action of other carcinogenic agents. Their mere presence within primary host or cultured cells, which may in fact be a reflection merely of tissue contamination,79 does not guarantee oncogenesis. ENZYME PATrERNS AND

METABOLISM.--Tryptophan Metabo-

l i s m . ~ N u m e r o u s attempts have been made to discover enzymatic or metabolic end product markers that identify patients who may be at greater risk for development of bladder cancer. The most intensively studied of these have been tryptophan metabolites, which have been suggested to represent endogenously produced carcinogenic substances. Impetus for this idea was originally provided by Ekman and Strombeck, who observed the appearance of tryptophan metabolites in the urine of patients with bladder cancer.5~ In follow-up studies, Brown observed that 20 of 41 bladder cancer patients without known carcinogen exposure excreted abnormal levels of kynurenine, acetyl kynurenine, kynurenic acid, and 3-hydroxykynurenine in their urine. 24 It was subsequently shown that 50% of a group of patients with "spontaneous" (noncarcinogeninduced) bladder cancer, given a loading dose of L-tryptophan, excreted increased amounts of these metabolites as compared with controls. 242 Moreover, the abnormal group in these studies excreted elevated levels of metabolites even without a loading dose of tryptophan. That abnormal tryptophan, metabolism was not merely a result of the presence of the bladder cancer was suggested by findings that patients with occupational bladder cancer did not demonstrate abnormal tryptophan metabolism and that patients studied after removal of their tumor did not recover normal tryptophan metabolism. 242 Aberrations in tryptophan metabolism were not a generalized finding specific to all bladder cancer patients. For example, among bladder cancer patients in Boston, only 17% had abnormal tryptophan metabolism, whereas in Wisconsin 47% had abnormal metabolism. 242 Furthermore, tryptophan metabolites were also found to be excreted in increased amounts in patients with other types of cancer as well as with various non-neoplastic diseases.24.24~ It was suggested that pyridoxine (vitamin B e) deficiency might have some bearing on these observations, since administration of this vitamin appeared to correct the abnormal excretion of tryptophan metabolites b y the affected bladder cancer patients. The suggestion that pyridoxine deficiency might also play an indirect role in the enhancement of the presumed direct carcinogenic effects of tryptophan metabolites was based on the assumed importance of pyridoxine in association with the devel215

opment and expression of an immune response to tumor development. Thus, most bladder cancer patients who were unable to respond positively to a variety of skin test antigens in comparison with controls were also found to have abnormal tryptophan metabolism, whereas those who responded tended to have normal tryptophan metabolism. ~93 Findings of both an abnormal tryptophan response and immunosuppressive effects in the face of pyridoxine deficiency prompted the administration of pyridoxine to those bladder cancer patients who were anergic. This was found to reverse their immunologic skin response defect. ~93 The significance of these observations in the development of bladder cancer, however, requires further study.

Galactosyl Transferase.--The enzyme galactosyl transferase has been associated with cell differentiation, cell recognition, cell adhesion, and clearance of serum glycoproteins. 2~ Cell surface galactosyl transferase has also been observed to increase in tissue culture cells after viral transformation. 147 A nearly tenfold increase in the specific activity of galactosyl transferase has been demonstrated in exfoliated neoplastic cells from the urine of rats with carcinogen-induced bladder tumors. 172 Biopsy samples of h u m a n transitional cell tumors have shown galactosyl transferase activity greater than that found in nonneoplastic vesical mucosa. ~s Although tissue from invasive lesions in these studies tended to fall into the upper range of normal activity, all bladder epithelium seemed to have elevated galactosyl transferase activity if tumor was present, regardless of tumor stage or g r a d e Y 4 What role this m a y play in the potential behavior of a particular tumor or of host predisposition to tumor development remains to be determined. However, it suggests that host enzymes m a y reflect a propensity for the development of bladder cancer, either actively, through their action in creating or d~toxifying potential carcinogenic agents, or passively, through their induction as a part of the overall process of neoplastic transformation. SUMMARY

A variety of host and environmental factors may interact to predispose one to bladder cancer. Even after neoplastic transformation has occurred, many as yet poorly understood factors m a y determine the behavior of the tumor and its ultimate clinical course. Although initiating factors in bladder cancer m a y require the briefest of exposures of an appropriately prepared host, promoting factors m a y require prolonged exposures to have any impact or may act in concert with each other to achieve their ultimate carcinogenic effect. 15'3G,232 Much remains to be learned of these complex interactions. More must also be done to limit exposure to those factors in which a clear risk has been shown. 216

BIOLOGY AND NATURAL HISTORY OF BLADDER CANCER EMBRYOLOGY

The bladder is derived from entoderm of the cloaca and allantois. 192During the fifth week of gestation, a division between the dorsal (rectal) and ventral (urogenital) cloaca begins to appear. By this time, the mesonephric (wolffian) ducts have entered the cloaca laterally and given rise to ureteric buds. '92 The ventral cloaca then elongates; its upper dilatation becomes the future bladder. Because mesonephric ducts and ureters are mesodermal structures, the mucosa of the bladder, actually formed by incorporation of these ducts, is of mesodermal origin. With time, however, the mesodermal lining is replaced by entodermal epithelium. 8s This epithelium remains a single layer up to the seventh week of gestation, at which time it gradually assumes the appearance of transitional epithelium. With completion of development by the ninth week, the transitional epithelium lines the calyces, renal pelvis, ureter, bladder, and the major part of the urethra with extension into the prostatic utricle and ejaculatory ducts. It is at this time that the fetal metanephros becomes functional, thus exposing the new transitional epithelium to substances derived either from the fetus or from the mother that early on may theoretically influence the later development of bladder cancer. EPITHELIAL GROWTH

Normal transitional epithelium appears to have a relatively low turnover rate. 3s In contrast, in vivo kinetic studies have suggested that transitional cell tumors express a higher mitotic index and shorter doubling tin~e, and that both of these indices increase as tumors become more undifferentiated.75 That this does not lead to the production of massive tumors is thought to reflect the shedding of large numbers of cells into the urine. 3s The morphologic counterpart of this is seen in the composition of normal urothelium, in which neighboring cells share intricate interdigitations and tight junctions, whereas neoplastic cells appear to lose these features as they become transformed, presumably leading to an increased likelihood of their being shed in the urine. 72 TUMOR DEVELOPMENT

Clayson defined cancer as "a group of cells which have permanently lost [their] ability to respond to some or all of the mechanisms which in the normal organism control the number and position of the cell type from which the tumor arose. 217

9 . .[However,] neoplastic transformation has to do much more than j u s t increase mitotic rate; the cell has to acquire properties which enable it to penetrate the basement membrane and exist in the subepithelial environment." 35 Preliminary insight into the nature of some of the events that might characterize the earliest aspects of bladder tumor development was provided by studies of an animal model of carcinogen-induced bladder cancer in which a temporal relationship was suggested to exist between epithelial hyperplasia, dysplasia, carcinoma in situ, and invasive transitional cell carcinoma. 72' 73 In these studies, the preneoplastic lesion was defined as a proliferation of epithelial cells without neoplastic histologic features, which later became associated with the development of in situ or invasive carcinoma of the same histologic type. 73 It was of particular interest that when carcinogen in these studies was withdrawn after an exposure of only four weeks, any epithelial hyperplasia that had occurred in response to the carcinogen regressed completely after several more w e e k s Y In contrast, when animals were fed the carcinogen for 12 weeks or longer, all were found to have bladder tumors when sacrificed after 50 weeks. Moreover, it appeared that carcinoma in situ following epithelial hyperplasia was the earliest histologic premalignant lesion observed to be irreversible. The mechanisms necessary to induce initial neoplastic transformation along these lines are unknown. Some have suggested that a variety of cell surface changes are necessary for tumor cells to assume aggressive infiltrative characteristics. As was recently reviewed, 229 it was possible to see in tumors abnormal growth patterns that modified the intercellular communications between adjacent cells. 137'202.231 This was said to alter cell-to-cell cohesion 2a9 and permit cells to enter into anchorage-independent growth. 53 Extracellular proteases 3' 14, were thought to influence changes in cell polarity and cytoplasmic and cell surface structure as well, whereas others proposed the presence of cell surface-bound or cell-released enzymes that could degrade the basal lamina and other connective tissue elements and thereby permit submucosal invasion. 16s The earliest events underlying each of these processes, prior to histologically evident changes, have remained poorly defined. Moreover, present understanding of later events in the biologic behavior of transitional cell cancer is limited largely to histologic observations at the initial clinical presentation of the tumor, which provides only a limited correlation with the subsequent clinical course of the cancer. PATTERNS OF TUMOR BEHAVIOR

Certain distinctions among bladder tumors in terms of their different presentation in a variety of settings were already rec218

Hypothetical Events and Pa~ways in the Natural H~to~ of : Bladder Cancer

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(p~pillary)

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(w~L~ perm~dc~

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--

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9 ll--

Fig 1.--It appears as though several pathways may characterize the variable course of bladder cancer (see text). This concept is presented schematically. Arrows suggest different pathways of sequential events; their size implies frequency of occurrence. Epithelial hyperplasia in the absence of dysplasia may lead only to superficial lowgrade papillary tumors. Multiplicity or recurrence may imply generalized field changes ("atypical" hyperplasia?) or implantation (either at the time of resection or from prior shedding of cells). On the other hand, occurrence of hyperplasia and dysplasia together may imply development of higher grade papillary lesions that may have a greater tendency to extend into lamina propria (papillary invasion) and penetrate lymphatic or vascular structures, In the absence of hyperplasia, dysplasia alone may lead to carcinoma in situ. This may then lead to invasion of transformed cells into the lamina propria (solid tumor invasion) and into muscle, lymphatics, or vascular structures without ever growing to any major extent into the bladder lumen. Or, hyperplasia may also occur, in which case a tumor may express papillary and solid features together with a degree, of anaplasia that suggests the potential for lymphatic and/or vascular penetration and dissemination. All of these pathways may be interconnected. Clinical course of disease is probably determined by early events in neoplastic transformation and tumor development. The critical stages are probably those that involve vascular and lymphatic infiltration; early lamina propria infiltration by dysplastic cells may well be an expression of this potential. Recognition of the likelihood of occurrence of each of these events, the sequence of occurrence, and potential developmental pathways may assist in the identification of predictive features of the different bladder tumors. This, in turn, may ultimately permit appropriate intervals at critical stages in which tumor progression may be effectively interrupted.

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ognized in the early part of this century. For example, both A1b a r r a n 1 and Broders 23 suggested that varying degrees of differentiation in bladder tumors represented different degrees of aggressiveness. Extensions of such studies led to proposals that bladder cancer might present in a superficial or noninvasive form, for which treatment was usually successful, and an invasive form, for which therapy was generally unsuccessful, for the vast majority of those patients died within two to three years of diagnosis. 1~ From a variety of observations such as these, a pattern of tumor behavior gradually emerged. It is from them, as well as from subsequent observations of tumor appearance in the variable setting of more diffuse urothelial changes, that the natural history of bladder tumors can be studied and patterns of tumor behavior analyzed, either in the absence of treatment or in the context of various therapeutic strategies (Fig. 1). CARCINOMA IN SIWU.--Insight into the development, progression, and natural history of bladder cancer as a sequence of transformational and developmental events only became possible with the Melicow's recognition in 1952 of vesical carcinoma in situ and the type of diathesis that this entity appeared to represent ~4~(Fig 2). Interestingly, the earliest descriptions of vesicle carcinoma in situ in m a n did n o t portray a leisurely progression of disease beginning with in situ neoplastic changes and culminating in invasion and metastasis. 139'~4~ This was because initial observations were made in patients with previous or concomitant invasive transitional cell tumors. In this setting, the course of bladder cancer generally appeared to be rapid and progressive. For example, Melamed described 25 patients with carcinoma in situ, 24 of whom had,had prior tumors; of 12 of those treated with resection and radiation but not cystectomy, 9 (75%) progressed to invasive cancer. ~39 Similarly, Utz observed that of 62 patients with carcinoma in situ seen after their primary bladder cancer had been treated by resection and fulguration, 82% developed recurrence and 7 3 % developed infiltrative cancer. ~17 Twenty-four (40%) of these patients were dead of their disease within five years. Attempts to examine carcinoma in situ in the absence of previous or concomitant tumor did not paint a more optimistic picture. Anderson reported 15 patients with in situ carcinoma, 12 (80%) of whom developed invasive cancer within three years, v Daly observed 18 patients with positive urinary cytology with no evidence of overt tumor at cystoscopy, 11 (61%) of whom developed invasive cancer within 19 months of diagnosis. `s On this basis, the first interpretations of the significance of carcinoma in situ, while suggesting the possibility that it represented an 220

h,

lu

Fig 2.mCarcinoma in situ is considered by many to be the earliest stage in tumor development. Neoplastic transformation in these specimens involves changes in celJular morphology without extension of cells into lumen (/u) of bladder or penetration through basement membrane (bm) of basal epithelial cell layer into the lamina propria (/p). These changes may comprise .either small (A) or large (B) cells with atypical nuclei and relatively small amounts of cytoplasm in each. Epithelial thickness is markedly increased in each case, and adhesiveness between adjacent cells is decreased. This predisposes cells to slough into the lumen of the bladder. (From Koss L.G.: Tumors of the urinaw bladder, in Firminger H.I. (ed): Atlas of Tumor Pathology, Washington: Armed Forces Institute of Pathology, 1975, fascicle 11. Used by permission.}

early stage in the neoplastic diathesis, emphasized its implications of tumor aggressiveness and ominous prognosis. Later reports, however, Were less pessimistic. In a prospective study of the natural history of industrial bladder cancer, for example, carcinoma in situ was found to develop in 35 of 560 men who had been followed with periodic urinary cytologic exami221

nations after exposure to xenylamine. H7,13s A latent period of variable duration from several months to eight years with negative cytology in these patients was followed by a period of a few to 77 months of positive u r i n a r y cytologic studies without histologic confirmation of in situ cancer. This ultimately was followed by a period of cytologically and histologically evident carcinoma during which only seven of 13 men developed invasive cancer. In effect, only 20% of patients who initially developed carcinoma in situ ultimately progressed to invasive disease, and this only after a relatively prolonged interval of time and in a highly selected group of patients. Similarly, Farrow reported a series of 27 patients with persistently positive urinary cytology, or histologically documented in situ carcinoma, in whom the average duration of symptoms before the first positive cytologic examination had been 32 months and of whom only 3 (11%) developed invasive carcinoma. 69 In these three the duration of carcinoma in situ ranged from 23 to 58 months, while 24 others at risk were under observation for an average of 33 months. When these reports of the temporal aspects of isolated in situ disease were applied in a reassessment of patients who had both carcinoma in situ and a primary bladder tumor, it was observed that while 73% (of 62 patients) developed infiltrative disease, 17 patients were found not to progress, and two thirds of these were alive and well for more t h a n five years. 2~7 Implications in these reports of the occasional benign n a t u r e of this tumor diathesis contrasted with implications in earlier work t h a t the presence of carcinoma in situ nearly always constituted an ominous finding. Conceivably, however, these disparate observations m a y have reflected the occurrence of different types of neoplastic disease, the one being relatively innocuous and the other, more pervasive and aggressive (see Fig 1). This possibility was supported by the results of one study of 21 bladders removed for presumably unifocal carcinoma in situ: microscopic zones of invasion into the submucosa were found in 20% of patients. 76 In addition, there appeared to occur in these patients an accrual of normal mucosa into the malignant process by direct spread of malignant cells along the basement membrane, which seemed to lift normal cells from their basilar footings. H2 Additional descriptions of a pagetoid spread of malignant cells as far as 4 m m from the margin of in situ cancer implied the sequential occurrence of both spatial and temporal steps in tumor progression. ~12 However, these findings were characteristic of only a small group of patients. All of these reports dramatize the concept that carcinoma in situ, presumably an early stage of the neoplastic process, m a y provide a ready source of malignant cells capable of forming new intraepithelial tumors in the bladder and that may also even222

tually invade the submucosal connective tissue. On the other hand, intraepithelial neoplastic changes might be prolonged and actually pose little immediate threat to the patient. Awareness of the distinctive spatial and temporal nature of these neoplastic events, however, is only now beginning to emerge. SUPERFICIAL CANCERS.--In time, the concept of tumor multicentricity came to denote a generalized urothelial field change wherein new tumor growth was more likely to occur. Thus, frequent recurrence was likely to be seen in the presence of initial multicentricity, whereas in its absence, tumor recurrence appeared to be less likely. Within this framework, however, different patterns of multicentricity could be observed, the impact of which was manifested in different behavioral patterns of neoplastic diathesis (see Fig 1). One pattern of biologic behavior appeared to consist of inconsistent t u m o r recurrence with only a rare instance in which tumor progression might take place. In another pattern there was a strong likelihood of tumor recurrence with presentation in a more advanced state. Appreciation of these differences was critical to an understanding of the different types of tumor behavior. Awareness of the type of diathesis implied by the presence of superficial tumors alone or in the presence of unifocal or diffuse carcinoma in situ enhanced this understanding and has added significantly to the design of diagnostic and therapeutic approaches to bladder cancer.

Superficial tumors without progression.raThe most common of these patterns was represented in one s t u d y in which 60% of patients with superficial tumors were found to be Free of tumor at five years 11 (see Fig 1; Fig 3). A similar study of superficial, low-grade bladder tumors disclosed that while 73% of 100 consecutive patients with this type of initial presentation had recurrent tumors, the incidence of recurrent tumors was substantially higher in patients who presented initially with multiple tumors (88% recurrence) than in those whose original tumor was single (68% recurrence). Moreover, only 22 patients with recurrent tumors in this series ultimately presented with a lesion of higher grade, and only ten patients (10%) were then found to have tumors that invaded the bladder wall. That tumors in these instances generally appeared to retain benign behavioral characteristics prompted suggestions that recurrence of tumors under these circumstances might simply reflect implantation of cells onto other portions of the urothelium rather than the development of tumors de novo from an unstable urothelium. 17'234 This was supported by findings of a single m a r k e r chromosome in many cells of the same tumor 1~ as well as by observations that the karyotypic profile of each tumor appeared to be maintained through many recurrences. ~' 85 223

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Fig 3.--Low-grade papillary transitional cell cancer. The most common manifestation of neoplastic transformation consists of the multicellular epithelium's being thrown into papillary excrescences. A, an entire bladder in cross-section in which multiple superficial papillary tumors are seen. Examination of epithelium discloses numerous diffuse areas of papillary hyperplasia (asterisks) as well. Each of the tumors contains a central vascular core and connective tissue (/p) stroma (B), In lowgrade lesions, the basement membrane of the basal epithelial cell layer appears rarely if ever to be penetrated by neoplastic cells. (From Koss L.G.: Tumors of the urinary bladder, in Firminger H.I. (ed): At~as of Tumor Patho/ogy. Washington: Armed Forces Institute of Pathology, 1975, fascicle 11. Used by permission of Dr. R.O.K. Schade, Newcastle upon Tyne, England.

224

Whether this is the major mechanism of tumor recurrence in this behavioral pattern, or whether there exist numerous foci of neoplastic change that are not readily appreciated but will later be expressed, remains to be determined.

Superficial tumors with progression.--In contrast to this most common tumor pattern, broad field change seen in association with carcinoma in situ appeared to imply an entirely different behavioral pattern of neoplastic diathesis, a pattern that suggested more strongly the presence of an unstable urothelium with the connotation that a more aggressive bladder cancer might be more likely to occur (see Fig 1; Fig 4). Addressing this question, Althausen and co-workers observed in a study of 129 patients with superficial transitional cell tumors that whereas 70% of the patients did not develop an infiltrating lesion during a five-year period of observation, 30% of patients did develop muscle-invasive tumors during this interval. 4 In 78 patients whose tumor biopsy samples permitted an analysis of the adjacent epithelium, 12 (15%) were found to have carcinoma in situ, and ten (83%) of these developed muscle invasion within five years. In contrast, 41 patients (53%) had normal epithelium at the margin of the initial presenting tumor and only 3.8% of these patients developed invasion. Intermediate to these groups, 25 patients (32%) had atypical epithelium at the tumor margin and only 11.5% of these went on to develop invasive cancer. Subsequent studies reported that sites remote from an initial tumor also might be abnormal. 195'21o,212 Thus, the incidence of abnormal biopsy samples taken from endoscopically normal mucosa at the time of superficial tumor resection was 77-86%, and 30-40% of these showed carcinoma in situ; a corresponding incidence was found on examination of cystectomy specimens removed for invasive cancer. 349" Relevant to these observations was the finding that tumor grade might also relate to the degree of multicentricity and potential recurrence with progression. In one series, five of 33 patients (15%) with grade 1 superficial carcinoma, 17 of 29 patients (59%) with grade 2 carcinoma, and 10 of 13 patients (77%) with grade 3 carcinoma showed significant urothelial abnormalities at sites distant from the presenting tumor2 ~ The invasive potential of recurrences in such tumors 8s' 24o bespeaks a pattern of behavior quite distinct from that implied by the recurrence of low-grade tumors in the absence of in situ disease elsewhere in the bladder. IINFILTRATIVE CANCERS.--Although only 10-15% of initially superficial tumors have been found actually to progress to invade muscle75' 240 a substantial number of patients upon initial presentation with bladder cancer have a tumor that has already extended into and through the muscle wall 7 (see "Stages of Blad225

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Fig 4.--High-grade, invasive transitional cell cancer. A, high-grade lesion, even if of papillary configuration, appears to have a greater tendency to break through the basement membrane of the basal layer of epithelial cells (asterisks). Ultimately, cells that have broken through may penetrate into lymphatic and vascular structures and then extend through the submucosal tissue to muscle (B, asterisks). The precise time or stage at which vascular or lymphatic invasion takes place is unknown but may occur early if such an event is purely the reflection of intrinsic tumor behavior. (From Koss L.G.: Tumors of the urinary bladder, in Firminger H.I. (ed): Atlas of Tumor Pathology. Washington, D.C.: Armed Forces Institute of Pathology, 1975, fascicle 11. Used by permission.)

der Cancer" below). At least 50% of such patients die within 18 months of diagnosis and t r e a t m e n t and only 20-40% of these patients survive for five years. 132'237 Marshall and Whitmore 133 reported t h a t the survival rate in this group of patients, if untreated, was less t h a n 3% at one year from the time of diagnosis (92% failed to survive six months from diagnosis) and was 0 at two years. Dated from the onset of symptoms, only 35% of these patients survived one year, 5.4% survived three years, and 2.7% survived five years. 223 226

Several observations are particularly relevant in attempting to characterize the behavior of bladder cancer at this stage of disease. Failures are as often due to distant metastatic disease as they are to local recurrence. 1~9'237 Prout et al. 179 observed that 78% of patients in one large series with advanced regional disease developed metastases that were clinically evident within one year after cystectomy, most of which occurred outside the soft tissues of the pelvis. In a[similar study, a substantial percentage of patients developed distant metastases even though local recurrence was said to have been controlled. 237 It seems clear that once a tumor has expressed its local aggressiveness by infiltration into or through the bladder wall, it has also often expressed its capacity to metastasize. Weinstein has listed the events theoretically necessary for tumor dissemination and metastases. ~29 These include: (1) degradation of the epithelial basement membrane and local invasion of the underlying connective tissue stroma by cells emigrating from the prim a r y tumor; (2) penetration of lymphatic vessels or blood vessels by tumor cells; (3) release of tumor cells into the lymphatic and/ or cardiovascular circulation; (4) arrest of tumor cells in the vacular bed of distant organs; (5) penetration of tumor cells through the wall of the arresting vessel with invasion of the organ; (6) multiplication of tumor cells at the secondary sites; and (7) stromal proliferation and vascularization of the tumor by the host. Although much emphasis has been given the importance of muscle invasion as representative of the likelihood of more extensive tumor dissemination, there is evidence to suggest that metastasis m a y take place early rather than late in the natural history of the disease (see Fig 1). For example, J e w e t t et al. n~ observed in a review of 365 patients with "invasive" tumors that 9 of 47 (27%) stage T~ tumors, i.e., those with invasion only of the lamina propria, already showed lymphatic permeation (Fig 5). Of these, six (67%) of the tumors "had metastasized through the bladder wall by way of the lymphatics." Other investigators have correlated lymphatic invasion with vascular invasion. ~~ 135 Patient survivals of 2 0 - 4 5 % when tumors had become "regionally" invasive were observed to correlate well with the frequency of vascular and lymphatic invasion.13. ~o, ~35,212 Thus, although an increase in the frequency of vascular invasion might be observed with an increased depth of penetration by a particular tumor, 1~ 13s it is likely that both events merely reflect characteristics of the tumor that are actually expressed early on in its course (see Fig. 1). Indeed, it is not unlikely that the very .factors that permit tumor cells to penetrate the epithelial basement membrane, invade submucosal lymphatics and blood vessels, and take hold in lymph nodes and at distant organ sites are the same factors that may initially have been expressed in the form of temporal and spatial multi227

Fig 5.--Lymphatic invasion in bladder cancer. Invasive tumors such as those described in Figure 4 can often be shown to have penetrated lymphatic and vascular structures (asterisks) and thence to metastasize. (Courtesy of Jewett H.J., et al.: J. UroL 92:668, 1964. Used by permission.)

centricity of an unstable urothelium. These characteristics m a y ultimately determine the progressive nature of a particular bladder cancer that is often only discovered relatively late (in a biologic sense) in a patient's clinical course. Clearly, the implication is that the progression of events m a y be rapid once the epithelial basement membrane has been violated. The presence of a broad field change at the time that early infiltration is recognized, 9~'2o4 as well as the appearance of undifferentiated cells in biopsy specimens, m a y constitute primitive indices of those features that correlate with and m a y reflect aggressive behavior of bladder cancer and its rapid progression. STAGING OF BLADDER CANCER PATHOLOGY

Over 90% of patients with a diagnosis of bladder cancer are found to have tumors of neoplastic transitional cells. 152 These range from flat cancers in situ (see Fig 2) to papillary lesions that extend into the bladder lumen and m a y or m a y not penetrate the basement lamina to infiltrate the bladder wall (see Fig 3) and to more sessile lesions that usually penetrate into or through the muscularis (see Fig 4). Although some investigators have noted heterogeneity among cells within a single tumor, ~9 uniformity of cell appearance 228

within a single tumor and often in a recurrent tumor as well has been a reasonably consistent.finding in bladder cancer. T M Transitional epithelium can occasionally undergo transformation into squamous or glandular epithelium, and neoplastic transformation of these epithelial types m a y occur, although with less frequency. Only 6 - 8 % of bladder cancers are squamous cell carcinomas, and only 1 - 2 % are adenocarcinomas. ~s2 Pure histologic lesions of these types are to be distinguished from areas within transitional cell cancers that have squamous (20%) or glandular foci (7%). 152'153 Well-differentiated squamous cell carcinomas have a better prognosis than either transitional cell carcinomas with squamous areas or poorly differentiated squamous carcinomas. ~2 Adenocarcinomas, most frequently located in the trigone and posterior wall, originate in areas of well-differentiated glandular epithelium associated with cystitis glandularis and mucous metaplasia. T M These should be distinguished from adenocarcinomas of urachal origin, which are principally intramural with secondary involvement of the bladder mucosa. Other tumors that have been observed in the bladder include sarcomas (rhabdomyosarcomas, leiomyosarcomas, myosarcomas, fibrosarcomas, liposarcomas, osteogenic sarcomas), lymphomas, pheochromocytomas or paragangliomas, and metastatic malignant melanomas. ~s~'2o9 All of these are rare. STAGES OF BLADDER CANCER

Distinctions in the behavioral patterns of bladder tumors and observations of the results of various forms of therapy have led to the gradual evolution of a staging system in bladder cancer (Fig 6, Table 2). This has assisted in the establishment of prognosis of a particular lesion at the time of its initial diagnosis, the planning of therapy and assessment of the results of therapy as correlated with the particular stage of disease, and, most important, the evaluation of factors within this system that m a y further refine our ability to understand the course of tumor behavior. At the turn of the century, Albarran ~ distinguished three types of epithelial tumors of the bladder and suggested that prognosis could be based on the macroscopic and microscopic structure of the tumor. Subsequently, Broders 23 noted that malignant tumors of the bladder epithelium varied in behavior and prognosis according to the proportion of undifferentiated cells they contained. Neither of these classifications obtained widespread clinical use. It was not until J e w e t t and Strong 112 reported a staging system based on the extension of a tumor through the bladder wall that staging of tumors became clinically useful. In the earliest report, a series of autopsy cases was used to separate bladder 229

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Lymphatic ondlor Vascular Penetration Lymph Node ondlor Visceral Metastases Fig 6.--Thisdiagramof differentstagesin bladdercancershows appearanceof tumor atvariousstagesof itsclinicalpresentationand the likelihood(arrow size) of simultaneousoccurrenceof eithersubclinicalor demonstrablemetastasesat different stages of disease. Staging In this diagram is based on a combination of systems described by Jewett"2 and Marshall'~~ and takes into account the type of invasion thought to correlate with a lesser (0, A, B~) or greater (B2, C) likelihood of lymphatic and vascular penetration with resultant regional or distant metastatic disease. ClS, carcinoma in situ; stage (9, papillary configuration with no extension into lamina propria; stage A, papillary configuration with extension into lamina propria; stage B 1, extension into superficial muscle layer; stage B2, extension into deep muscle; stage (7, extension through muscle into perivesical fat; stage D, metastatic disease, either regional (D,) or distant (D2). (Modified after Jewett H.J.: J. Urol. 82:92, 1959.)

tumors into three groups: those with submucosal invasion (Stage A), those with muscular invasion (Stage B), and those with perivesical extension (Stage C) (see Table 2). According to this system, when tumors were confined to the submucosa, 100% were "potentially curable," whereas when perivesical infiltration was present, only 26% were'"potentially curable" (these figures were described as "theoretical"). Tumors that invaded muscle were described as being 86.6% "potentially curable," reflecting the one person with incurable metastases among the 16 patients examined. Upon analysis of segmental resections and cystectomy specimens, it subsequently became apparent that tumors that only superficially invaded muscle (Stage B 1) behaved like tumors that had invaded only the submucosa, whereas those that were deeply invasive of muscle (Stage B~) behaved like those that had extended perivesically l~ m (see Fig 6 and Table 2). The classification of bladder tumors was extended by Marshall, ~~ who distinguished a stage in which no submucosal infiltration had occurred (Stage 0), and a stage in which lymph node involvement was already present (Stage D) (see Table 2). In addition, the significance of a distinction between superficial and deep muscle invasion suggested by Jewett was confirmed. 230

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Adaptation of these systems to the TNM classification by the American Joint Committee for Cancer Staging, and then by the International Union Against Cancer (UICC), resulted in a classification system in which tumors invading deep muscle and those going through deep muscle were grouped as one stage (T3) and in which both infiltrating and noninfiltrating papillary tumors not extending beyond the lamina propria were also grouped in a single stage (T~)~zs (see Fig 6 and Table 2). This was later modified when it was observed that approximately 20% of tumors that had penetrated the lamina propria showed lymphatic permeation, two thirds of which were also found to have metastasized through the bladder wall via these lymphatics. ~~ This distinction has been substantiated in more recent studies in which 78% of patients with tumor in lymphatics died within three years of cystectomy, a rate nearly twice that of patients without demonstrable lymphatic invasion. 8' 22~ In a recent review of these systems, Skinner 2~ suggested that separation of muscle invasion into superficial and deep stages was not clinically meaningful since the means for establishing the depth of invasion were only 80% accurate. 131'la3 Moreover, other studies had suggested that a n y degree of muscle infiltration could significantly influence survival as compared to survival at tumor stages without muscle infiltration or those with penetration into perivesical fat. ~SsThis controversial question is difficult to resolve satisfactorily with the information presently available. However, recent reports have described distinctions between different types of tumors and their patterns of invasion in association with the likelihood that such invasion extends into either superficial or deep muscle212 (see below). These reports have also correlated the tumor types observed with the likelihood of vascular or lymphatic invasion. The important question therefore appears to concern not simply whether a particular tumor has extended beyond an arbitrary level in the muscle wall but rather whether or not the distinction in tumor stage as a predictor of tumor behavior actually reflects intrinsic differences in basic tumor characteristics. NEW FACTORS Other factors may ultimately have to be incorporated into a clinically valid staging system. Features such as .tumor multicentricity and the various forms it may take, either with or without concurrent epithelial atypia or carcinoma in situ, have been discussed above. Differentiation of.the tumor may also be important. Lowgrade lesions seem less likely to recur rapidly or to become invasive than do high-grade lesions. In one study, for example, only 19% of grade one superficial lesions progressed to invasion while 69% of grade 3 tumors developed infiltrating cancer, T M 232

half of them within six months. In addition, the ultimate occurrence of high-grade, truly superficial tumors appears to be a much less frequent finding than high-grade, invasive lesions. Patients with well-differentiated tumors in one series had 67% three-year survival, whereas approximately 50% of patients with poorly differentiated tumors survived one year and only 20-30% survived three years. 2~ Tumor configuration has also been found to reflect tumor behavior and affect interpretation of the results of treatment. Thus, patients with papillary tumors were reported to have a 91% three-year and 48% five-year survival rate, whereas patients whose tumors had a solid histologic pattern were found to have a 30% three-year and a 12% five-year survival rate. 182 These differences were suggested to reflect other findings that papillary tumors generally appeared to show less extensive infiltration, ls2 Soto and colleagues212 observed that 15 of 21 papillary tumors in full bladder sections of cystectomy specimens were actually superficial, whereas 16 of 17 tumors of solid pattern were actually deeply invasive. 349 Thus, it appears as if the nature of the tumor itself may be associated with the likelihood of penetration, which in turn is likely associated with a particular prognosis. The type of invasion also has been seen as a potentially important prognostic factor. 212 Broad front invasion, found more frequently with superficial papillary lesions and characterized by cohesive masses of tumor cells sharply demarcated from the stroma, was accompanied b y b l o o d vessel invasion in only 33% of patients. However, when the invasive pattern was characterized by cords or clusters of tumor cells extending in tentacular fashion between muscle fascicles, as was more commonly seen in the solid types of tumor, blood vessel invasion was present in 68% of patients. Vascular invasion, in turn, correlated with a more limited prognosis. Those tumors that by their nature appeared to penetrate less deeply into the substance of the bladder also appeared less likely to penetrate vascular and lymphatic structures and thus appeared to express a less aggressive behavior. 212 The implications of bladder tumor extension into adjacent structures have undergone revision 196 and may be important in characterizing tumor behavior. In most series, direct penetration of pelvic structures (myometrium, vagina) has been correlated with a particularly aggressive cancer and a poor prognosis. Similar correlations were assumed to characterize a bladder cancer that involved the prostate gland. Recent observations, however, have not supported this assumption. For example, in one series of 42 of 350 cystectomies there was tumor involvement of the prostate; 22 of these showed invasion of stroma while 16 showed only epithelialchanges in s i t u J 96' 1~7 In the latter group, superficial involvement appeared to present a decidedly more favor233

able outlook. It was suggested that stromal involvement represented penetration of transitional cell cancer through the bladder wall with subsequent extension into the prostatic substance, whereas superficial epithelial changes reflected a broad-field uroepithelial neoplastic invasion. The latter situation, if detected early, conceivably would permit intervention before penetration and dlssemmahon " ~ " " occurred and atlow a generally more favorable outlook. Whether it also reflects tumor factors corresponding to a lower stage of disease in the bladder, however, is unknown. Each of these factors, as it m a y reflect the behavior of a particular tumor, m a y therefore ultimately require incorporation into a staging system of bladder cancer. This is critical if such a system is to permit both a valid assessment of the future behavior of a particular lesion and the determination of its optimum therapy. METHODS OF DIAGNOSIS The word "diagnosis" refers to the process of identifying or determining the nature of h disease. This process, therefore, concerns not only the establishment of the presence of disease b u t also the identification of factors that permit the characterization of its behavior and prediction of its course (Table 3).

SYMPTOMS H e m a t u r i a is the most common presenting symptom in patients with bladder cancer. In one series, either gross or microscopic hematuria was the primary symptom in 85% of patients. 221 Neither the number of lesions nor their size were reflected in the degree of hematuria. The mean duration of symptoms before diagnosis of tumor ranged between three and eight months. While hematuria in most instances is described as painless, some studies have shown that symptoms of vesical irritability such as urgency or frec~uency, often misinterpreted as reflecting cystitis, m a y actually represent the presence of carcinoma in situ, regardless of the presence or absence of other lesionsY' 139,2~ Therefore, symptoms of vesical irritability in the absence of documented infection should prompt a thorough examination for tumor. CYSTOSCOPY A N D BIOPSY

In general, the impact of spatial multicentricity, tumor architecture, and generalized instability of the urethelium on the prognosis of a particular neoplasm have prompted the enumer234

TABLE 3.--CtYRRENT METHODS OF DIAGNOSIS IN BLADDER CANCER

Symptoms

Hematuria Vesical irritability Cystoscopy,~ Transurethral resection of tumor Superficial (mucosal, submucosal) Deep (muscle) Random mucosal biopsies Urinary cytology (voided; washed bladder) Bimanual examination (under anesthesia) Intravenous pyelogram Ureteral obstruction Upper tract lesions CAT scanning Nodal enlargement Extension to perivesical fat Pathological assessment Histologic tumor characteristics ABO surface blood group antigens Although the major method used in the diagnosis of bladder cancer involves cystoscopy and careful fractional transurethral resection of a presenting tumor, other modalities have grown in importance as they have become associated with the determination of the extent of a cancer diathesis and the likelihood of tumor recurrence or progression.

ation of several guidelines for accurate assessment of a particular lesion. 23~ These include cystoscopy to establish the presence of a lesion and to determine if it is papillary, sessile, or flat (i.e., carcinoma in situ with an erythematous velvety appearance); intravenous pyelography to seel~ evidence of tumor multicentricity elsewhere in the urinary tract; biopsy procedures to obtain histologic evidence of the grade, architecture, and local extent of the neoplasm; random biopsies of apparently uninvolved bladder wall as well as of prostatic urethra to evaluate the epithelium for possible multicentricity of disease and to establish the potential for further tumor formation and aggressive behavior; and washed bladder cytology for evaluation of cellular atypia or neoplastic abnormalities that may not be endoscopically visible and that may occur in areas that have not been biopsied. The most important means of assessing the tumor is through careful excisional biopsy of the tumor itself (Fig 7). For accurate determination of stage, both superficial and deep biopsy samples should be assessed separately; the latter should include a sample of the deep muscularis. Tumor architecture, cell grade, depth of penetration of the tumor, and infiltration of lymphatics and vasculature can then each be ascertained. Occasionally, a biopsy sample of only a superficial portion of 235

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tumor may reveal a well-differentiated lesion when the base of the tumor actually discloses the presence of poorly differentiated invasive cells. In one study, for example, the histologic grade of tumor found in the excised bladder of half of the patients examined was found to be of higher degree of malignancy than a previous superficial biopsy sample had indicated.46 A related study demonstrated that transurethral fractional biopsy, if properly done, would give an accurate picture of the histologic grade of the bladder cancer when compared with the grade of tumor in the surgically resected bladder. 14s At the time of fractional resection, random biopsy samples of the margin of the visible lesion, any areas that appear to be suspicious, and endoscopically normal areas in the bladder, as well as samples of the prostatic urethra, are highly indicated because of the importance of assessing the status of the entire bladder epithelium. Carcinoma in situ at sites remote from the tumor or at the tumor margin has been found to signify an ominous prognosis, and even cellular atypia has been associated in some studies with a greater likelihood of the'later development of invasive disease. 4"174 236

CYTOLOGY Attempts to define the extent of the tumor involvement should also include assessment of urinary cytology at the time of bladder tumor evaluation. Although the technique was demonstrated in 1946,187 it was not until many years later that appreciation of the importance of carcinoma in situ and broad epithelial field changes in the presence of bladder tumor led to recognition of the clinical usefulness of cytologic evalution. It was further found that cytology might be positive although cystoscopic examination failed to disclose the presence of any lesion. '38 In such instances, sources such as the prostate gland, prostatic urethra, upper tracts, and endoscopically normal areas of bladder epithelium were often found to harbor neoplastic cells. In many of these instances, the reliability of urinary cytology in diagnosing carcinoma in situ was found to depend on the extent of the diathesis and the degree of anaplasia of the cells. Thus, Farrow et al. 69 observed in 106 patients without previous bladder neoplasm that positive cytologic findings had occurred in the absence of cystoscopic evidence of neoplasm. Although the source of abnormal cells remained undetermined in nearly a third of these patients, the remaining two thirds (69 patients) were subsequently proved by biopsy to have carcinoma in situ of the bladder, their irritative symptoms suggesting a more diffuse extent of the disease. A lack of cellular cohesiveness has been described as characteristic of carcinoma in situ and has been said to account for its sloughed appearance on biopsy and the appearance of malignant cells in the urine. 19~ This has been found to correspond to an absence of tight junctions and desmosomes between contiguous cells and the loss of interdigitations between these cells.4s Urinary cytology may occasionally be less useful in the diagnosis of grossly visible tumors. Low-grade tumors, for example, are ordinarily found to have a negative urinary cytology. In one study, only 3% of papillary tumors of grade 0 - 1 showed cancer cells in the cytological smear, ~whereas more than 50% of grade 2 and the majority of grade 3 - 4 tumors had a positive cytology.69 False negative readings in the case of low-grade lesions occur because the cells themselves, if not in a papillary configuration, appear normal. ~ On the other hand, difficulties in distinguishing low-grade tumors and normal traumatic or inflammatory conditions have led to a false positive rate that has reached 15% in some studies. ~' 63.77 Washing of the bladder, has been reported to provide a more reliable indication of positive urinary cytology than a voided urine specimen.92 There are several reasons for this. First, when compared microscopically with catheterized urine, irrigated urine has been characterized by better preservation of cells, better cellular yield, better representation of bladder epithelium, and less contaminating background debris. Second, low-grade 237

papillary transitional cell carcinomas and papillomas cannot be recognized on the basis of cellular criteria alone but can be diaguosed only i f a tissue fragment appears on the sediment smear and aspirated urine is more likely to produce such fragments and provide a specimen useful for diagnosis in this setting. Recent reports on the possible use of computerized systems to assist in the diagnosis of malignant cells in-voided or aspirated urines have described an ability to discriminate between normal and cancer cells2 ~' ,,6. 2,5 The rate of misclassification was approximately 5-10% in both directions. Highly differentiated tumors usually appeared to be euploid while low differentiation was accompanied by aneuploid appearances. This was documented by means of chromosome studies or by quantitative determination of DNA content of individual cell nuclei. 2'5 Scanning microphotometry with cell identification by computer disclosed that the average cell size for normal cells was practically twice that of tumor cells; the nuclear area is similar in benign and malignant cells. ''6 It was therefore the ratio of nuclear area to total cell area that seemed to be important for the distinction between malignant and benign cells. There was also a clear trend toward denser chromatin granules in urethelial cancer cells, and the coarse nuclear granularity seemed to contribute more than other descriptors to the visual identification of urotheIial cancer cells. This methodology may ultimately prove to be especially useful in the screening of patients at high risk. BIMANUALEXAMINATION Jewett's original staging system of bladder cancer was in part based on a prior report by Geraghty, TM who stated that no patient with a palpable tumor had been cured of this disease. Careful bimanual examination u~der anesthesia (Fig 8) with confirmation of the impression of such examination either by fractional transurethral resection or segmental or total cystectomy became the basis for Jewett's staging system. '~ Its main strength rested on its presumed ability to distinguish superficial disease from penetration through the muscularis to perivesical tissue. However, Marshall '3~ observed that preoperative estimate of tumor extent was accurate in only 81% of patients. Others have observed similar difficulties, although overstaging has appeared to predominate over understaging in a given bladder tumor,3O. ,8~. ,98 (Table 4). Thus, in clinical staging of superficial (0, A, B,) tumors, understaging has ranged between 15% and 33%. In clinical staging of more extensive (B2, C) tumors, overstaging has occurred in up t o 13%. On the other hand, recognition of regional metastatic disease at operation has appeared to correlate nicely with probabilities suggested by clinical staging. Thus, clinically low-stage tumors have been found to have a lower incidence of metastatic disease than clinically high-stage 238

Fig 8.~Bimanuai examination of bladde'r tumors. Assessment of depth of penetration of bladder tumors, as determined by bimanual examination under anesthesia, originally constituted an important adjunctive method in the derivation of a staging system in bladder cancer. Although fraught with substantial inaccuracies, this method remains useful in the determination of fixation of the bladder mass, palpability of a tumor (which may connote a solid rather than papillary configuration), and potential resectability of the tumor and bladder. (From Jewett H.J., in The Cyclopedia of Medicine, Surgery, Specialb'es. Philadelphia: F.A. Davis Co., 1950. Used by permission.) TABLE 4--CUmcAL STAGINGERRORSIN BLADDERCANCER INVESTIGATOR (REFERENCE)

CLINICAL STAGE

Marshall 13~

O, A, B~

29

19 (66%)*

7 (24%)t

3 (10%)$

B2, C

40 66 34 67 66 65 21

19 (48%) 52 (79%) 21 (62%) 9 (13%)w 13 (20%) 0 (0) 2 (10%)

13 (33%) 10 (15%) 10 (29%) 25 (37%)* 31 (47%) 41 (63%) 16 (76%)

8 (20%) 4 (6%) 3 (9%) 33 (49%)$ 22 (33%) 24 (37%) 3 (14%)

Prout 17s Whitmore~ Kennym Marshall x3~ Prout 17s Whitmore~5 Kennym

PATIENTS (NO.)

O, A, B1

OPERATIVE STAGE B2, C

D

*Number in parentheses represents percentage of accurately staged tumors. tNumber in ~arentheses represents percentage of understaged tumors. SNumber in parentheses represents percentage of unrecognized stage D tumors. w in parentheses represents percentage of overstaged tumors. Clinically staged superficiallesions (stages O, A, or B 1) have been accurately staged in only 50-80% of instances. Pathologic demonstration of actual stage B2 and C in clinically staged superficial lesions has ranged between 15% and 33%, whereas unrecognized metastases (stage D) have been found in 6-20% of these cases. In contrast, lesions clinically staged as more advanced (stages B2 and C) have been overstaged in up to only 20% of patients, while unrecognized metastases in such lesions have ranged between 14% and 49%. 239

tumors in which the incidence of metastatic disease at operation has ranged between 14% and 49%. Errors in clinical staging are important not only because inadequate treatment may be applied in situations where a lesion may have been understaged, but also because interpretation of good treatment results may be biased if lesions are overstaged. In a recent review of this problem, Skinner observed that a palpable mass with histologic evidence of tumor in muscle almost always seemed to indicate deep penetration unless the induration disappeared following resection of the tumor. 2~ If no induration was palpable, the tumor was most probably superficial. Preoperative estimation by this criterion alone achieved 81% accuracy. Because 50% of patients with %uperficial" tumors survived five years after cystectomy, compared to a five-year survival rate of only 15% for those with deeply infiltrating tumors, Skinner concluded that the depth of muscle infiltration was far less significant than the fact of a n y degree of muscle infiltration. Although this suggestion may ultimately prove to be valid for '~indurated postresected" bladder lesions that may indeed represent deeply infiltrating tumors, it disregards the possibility that depth of penetration may simply reflect a characteristic of the tumor in question, in which case superficial muscle involvement may be associated with other morphological characteristics that reflect a less aggressive neoplasm (see previous discussion on staging). Careful bimanual examination under anesthesia must therefore be placed in the context of these potential staging errors, and categorical interpretations of assessments of the extent of a bladder tumor solely by bimanual palpation should be viewed with reservation. RADIOGRAPHICASSESSMENT OF BLADDER CANCER EXCRETORY UROGRAPHY.--The purpose of excretory urography in bladder cancer is to determine the possible multicentricity of the neoplastic process by visualizing upper tract lesions and to demonstrate ureteral obstruction by an infiltrative lesion near the ureteral orifice o~ the base of the bladder (Fig 9, A and B). However, vagaries in bladder filling by this technique prevent an accurate assessment of intravesical lesions.

FRACTIONAL CYSTOGRAPHY.--In this method, the bladder is filled with approximately 200 ml of contrast medium and an exposure is made. As fractionated amounts of dye are withdrawn and exposures made, the normal bladder wall collapses concentrically, but a rigid or fixed bladder wall does not collapse. The resultant lack of successive concentric images is said to characterize the bladder wall at the site of tumor infiltration. A variation of the technique, using double or triple contrast cystography, makes use of the same principle of restriction of 240

Fig 9.--The intravenous pyelogram can sometimes demonstrate the presence of a bladder neoplasm in its cystogram phase. When the neoplasm occurs at or near the ureteral orifice, the absence of ureteral obstruction may imply that the lesion is noninvasive (A, arrows). In contrast, when ureteral obstruction is seen, the likelihood of deep invasion of the bladder wall by the tumor is great (B, arrows).

bladder movement but uses either combined air and contrast medium in the bladder or air and contrast medium in the bladder with perivesical gas insufflation. False positive results m a y occur with this technique when there has been a previous operation in the pelvis or another cause for extravesical fixation of the bladder wall. False negative results can occur when the lesion does not prevent the overall pattern of normal bladder distention or when the location of the t u m o r is such that restriction of bladder movement cannot be appreciated. 19s PELVIC ARTERIOGRAPHY.--Arteriography has been used to define the extent of a bladder tumor in the pelvis. Gittes 79 has commented that pelvic arteriography may demonstrate a vascular stain of t u m o r vessels in some cases of invasive lesions, while the t u m o r itself, though often relatively avascular, may be outlined by a soft tissue shadow and deformity of the vessels feeding the tumor. The technique is said to be useful in defining perivesical infiltration and can occasionally help to differentiate a bladder wall that is thickened because of inflammation from one that is thickened by neoplastic invasion. 132 Corkscrew type vessels and venous lakes'have been associated with poorly differentiated invasive lesions. 79 In one study with selective injection of both hypogastric arteries, accuracy of arteriographic staging in pathologic stage A lesions was only 29% and in stage B lesions was only 53%. 241 Stag241

ing accuracy was better with stages C and D (89 and 92%, respectively). False positives occur in the presence of inflammatory bladder disease or prior pelvic operations when other tumors are present in the pelvis, or in the presence of normally tortuous uterine vessels in females. False negatives may occur when small invasire tumors are relatively avascular or when the tumors invade the prostate gland. 79 Although the overall accuracy of arteriography in establishing bladder wall penetration has been stated to be as high as 80%, 196 in practice this technique has not proved either necessary or particularly helpful in assessing patients with bladder cancer. LYMPHANGIOGRAPHY.--Pedal lymphangiography permits the detection of metastases in pelvic lymph nodes, the extent of which might alter an approach in the management of bladder cancer. Important points in interpretation are: (1) evidence of lymphatic obstruction demonstrated by lack of filling of lymph nodes 24 hours after injection of contrast material; (2) peripheral defects in lymph nodes; (3) enlargement of lymph nodes with a foamy appearance that suggests reactive hyperplasia, fatty infiltration, and/or lymphoproliferative disorders. 241 Lymphangiography, however, does not permit visualization of obturator nodes, which appear to constitute the earliest echel0n of lymph node metastases from bladder tumors. 2~ The limited usefulness of lymphangiography in this setting has prompted most investigators to abandon this technique. ULTRASOUND.--UItrasound scanning with a transrectal probe has been used to define tumors of the bladder wall using as criteria both distortion of the wall around the tumor base and echo' masses protruding into the bladder lumen, ls~ Accuracy with ultrasound in staging bladder cancer in one study ranged between 70% in 25 patients with stage T1 tumors, 87% in 92 patients with stage T2 tumors, and 83% in 30 patients with stage T3 tumors. ~36 The commonest problem in interpretation, however, occurred in bladders with reduced capacity and marked detrusor irritability, and most of these situations appeared in cases clinically staged as T2 or T 3. Recent reports of a transurethral ultrasound probe have provided promising, albeit preliminary, data. l~s Further study along such lines to determine applicability in accurate staging seems indicated. COMPUTERIZED TOMOGRAPHY (CT) SCANNING.--CT scanning, like ultrasound, has had less success than anticipated in the diagnosis of bladder cancer. Although interpretational accuracy of CT scanning could be enhanced by injection of negative contrast (air or carbon dioxide) into the bladder to complement intravenous contrast that had been injected to permit visualization of 242

the upper tracts, this has not resulted in consistent clarification of stages. In one study, for example, Seidelman was unable to distinguish stages O, A, B1 and B2.S32.-Although true stage B2 lesions were found in this series to result in a localized thickening of the bladder wall, perivesical fat remaining well defined, 332 and early stage C lesions were identified by a loss of definition of the perivesical fat margin compared with uninvolved portions of the Fig IO.mCT scanning aided by double contrast amplification (transurethral introduction of air and intravenous injection of contrast medium) can be used to examine bladder contour and lesions of bladder wall. Bladder tumors can readily be seen to extend into the lumen of the bladder (A). Although absence of bladder wall thickening implies absence of invasion, microscopic penetration of muscle fibers cannot be excluded (arrows). In contrast, bladder wall thickening in the absence of prior resection or irradiation (B) implies extension through the wall of the bladder and possible involvement of perivesicular structures (arrows).

243

bladder; thickening could occasionally also be seen in purely superficial tumors. In addition, previous operations, transurethral resection, and radiation therapy were found to result in fibrosis and thickening that on CT scanning was indistinguishable from carcinoma. Our own studies have supported these observations. Though purely superficial disease (Fig 10, A) has generally differed in appearance from invasive cancer (Fig 10, B) with thickening of the vesical wall, deformity, and loss of a smooth serosal contour characterizing the latter stage of disease, microscopic extension of tumor into the muscle and through the bladder wall has occasionally been undetectable and certainly indistinguishable from fibrotic or inflammatory processes. In addition, although identification of pelvic lymph nodes has been found to be possible with CT scanning, the ability of CT scanning to detect pelvic lymphadenopathy with metastatic disease is based solely on lymph node enlargement. Micrometasrases have not been discernible, 199 thus limiting the usefulness of this technique for this purpose as well. CT scanning has clearly-been useful, however, in certain instances in which the anatomic assessment of a particular bladder lesion was not readily assessable by other means. For example, evaluation of the intramural ureter (Fig 11, A) or a diverticulum that might harbor a transitional cell tumor (Fig 11, B) has been possible by CT scanning when other methods were unproductive. Further refinement of methodology to permit determination of the depth of penetration of a bladder tumor by CT scanning will be necessary, however, before accurate assessment of the stage of disease based on the presence or absence of muscle invasion is possible. PATHOLOGICASSESSMENT An important aspect of diagnosing bladder Cancer consists of characterizing the biologic nature of the bladder tumor. Once a lesion has been identified by endoscopy, cytology, or radiographic means, and its neoplastic nature confirmed by pathologic evaluation of fractionally resected specimens complemented by random biopsy samples, further characterization of the tumor is needed to indicate the propensity of the disease to recur or progress, and thereby to provide a guideline as to how therapeutic intervention may be most effectively introduced. Basic to this aspect of diagnosis is the determination of the stage of disease through thorough histologic evaluation of tumor specimens obtained by fractional resection. However, it has become increasingly evident that several additional features of the tumor require histologic evaluation within this system in order to provide an indication of the pattern of tumor behavior that may be expected. These features include spatial multicentricity, 244

Fig 11.--CT scanning is useful in the diagnosis of bladder cancer under unusual circumstances in which anatomic localization of the tumor is not possible by other methods. For example, a bladder tumor at or near a ureteral orifice (A) may be shown by CT scanning to be superficial and not to obstruct the ureteral orifice (arrows). When a diverticulum is present that is not evaluable by endoscopic means, CT scanning may assist in the deZineation of lesions both in the bladder or in its diverticulum (B, arrows).

tumor architecture, pattern of penetration, involvement of lymphatic or vascular structures, and extension to adjacent viscera. EXPERIMENTAL ASPECTS TO DIAGNOSIS IN BLADDER CANCER CELL SURFACE BLOOD GROUP ANWIGENS.--Neoplastic t r a n s f o r m a t i o n has been associated with alterations of various compo-

nents of t h e cell surface. Several investigations have described reductions in sialic acid levels at the surface of virus-trans245

formed cells in culture, s~ which has led to the view that transformation results in the synthesis of incomplete surface polymers. Using phosphotungstic acid surface staining of the terminal sialic acid residues of glycoproteins, Demer observed that epithelium from grade 2, 3, or~4 invasive bladder cancer exhibited only 60% of the number of phosphotungstic acid or ironbinding sites at cell surfaces as did normal epithelium or grade 1 carcinomas.49 This was thought possibly to reflect changes in the activity of glycosyl transferases, or increased levels of extracellular glycosidases and proteases, both of which might lead to reduced levels of surface sialic acid in tumors that, in turn, might be associated with the invasive tendency of malignant cells. Of related interest were findings by Kovarik and co-workers11s that deletion of surface blood group antigens was associated with neoplastic transformation in a variety of tumor tissues. The significance of this observation for bladder tumors was suggested by studies that documented the absence of surface blood group antigens from transitional cell tumor cells derived from high-grade tumors and their persistence in cells from low-grade tumors. 47 Confirmation of these findings led to the intriguing observation that deletion of blood group antigens in superficial bladder tumors might be associated with a strong likelihood of tumor recurrence and, more important, that there was a strong likelihood of recurrence at a higher stage. 62'1~4.16o In one series, for example, 53 patients had recurrent tumors (six apparently did not) and 26 of them eventually developed invasive bladder cancer. Of the 26 patients whose initial tumors were positive for blood group antigens, 21 (81%) had no evidence of invasive disease, whereas of the 34 patients with superficial tumors that were negative on testing for surface blood group antigens, 21 (62%) subsequently developed invasive bladder cancer. 1~4The test appeared to be less useful in predicting superficial tumor recurrences, since recurrences were seen in all patients who tested negative and in 73% of those who tested positive for surface blood group antigens. Of particular interest in this regard, however, was,that among grade 3 lesions, in which risk for development of invasive disease was greater than 75%, only 25% of patients whose tumors were blood group antigen positive developed invasive cancers, whereas 100% of patients whose tumors were blood group antigen negative later developed invasion. ~24 Recent studies have reported that carcinoma in situ in most instances is blood group antigen negative. 6~'230Whether this represents the likelihood of tumor recurrence in an invasive form or is merely a characteristic peculiar to the cells that constitute this particular lesion is presently unknown. However, in view of the poor prognosis suggested by the presence of disease in situ when gross papillary disease is present, blood group antigen 246

testing would appear to make less difference in assigning treatment in carcinoma in situ. A cautionary note has been sounded because of the technical difficulties in the performance of this test and its interpretation, especially in patients with blood type~O, and because of its unacceptably high error in determining the likelihood of invasion. It must be remembered that the status of this test is at present investigational. Nonetheless, the possibility of predicting future invasiveness while the tumor is still at a superficial stage (and likely still confined to the bladder) merits continued study and attention. CHROMOSOMAL ANAT.YSIS.--The presumed cytogenetic hallmarks of invasive cancer, aneuploidy and morphologic abnormalities, have been found to characterize noninvasive as well as invasive bladder carcinoma.6~ In addition, ring chromosomes have been associated both with multiple recurrences and with bladder invasion. 67 Abnormally long A group chromosomes, classified as markers and characteristic of invasive carcinoma, have also been described.66 Several of these markers have appeared to precede histologic evidence of invasive carcinoma, but further study is required to see if markers such as these are commonly found and are observed to have predictive use in the diagnosis of bladder cancer. CARCINOEMBRYONIC ANTIGEN (CEA).--The glycoprotein known as carcinoembryonic antigen has been found in association with the cell surface of both normal and neoplastic epithelial cells. 82' lo~ A number of studies of plasma and urinary levels of CEA have failed to provide definitive evidence that measurement of this substance is useful in following patients with transitional cell carcinoma. In one study, for example, ohly 20 of 30 males with histologically proved transitional cell carcinoma of the bladder had elevated levels of urinary carcinoembryonic antigen (CEA).9~These levels were independent of tumor size, differentiation, or extent of invasion. Furthermore, though the presence of contaminating bacteria was said not to influence the measured levels of urinary CEA, eight patients with symptomatic urinary tract infection were found to have high CEA levels comparable to those found with carcinoma of the bladder. 149 When plasma levels of CEA were examined, only 17 of 40 male and two of ten female patients with proved active bladder carcinomas actually had plasma levels in excess of 12.5 ng/ml (upper limits of normal). Moreover, only in one was the value in excess of 40 ng/ml, the level considered diagnostic for the presence of tumor, and in no patient was there any consistent correlation between urinary and plasma CEA levels9~ Subsequent investigations have corroborated these findings but have also expressed reservations about the elevation of CEA 247

levels. I~ First, transurethral resection has been shown to elevate urinary CEA levels in as m a n y as 40% and plasma CEA levels in as many as 50% of patients. Second, there appears to be no overall distinction in CEA levels between superficial and deeply invasive tumors. Third,~ all patients with ileal conduits m a y have elevated urinary CEA levels, and 60% of these m a y have elevated plasma CEA levels as well. Fourth, the presence of u r i n a r y tract infection alone can lead to elevation of urinary CEA levels. It appears at present that neither urinary nor plasma CEA levels are particularly useful clinical indices of the presence or extent of transitional cell cancer.

RHEUMATOID FACTOR.--Although the exact nature of rheumatoid factor is undefined, it appears to be an antibody-like substance composed of a gamma-globulin complex of high molecular weight produced in response to the presence of antigen-antibody complexes. Its derivation from plasma cells has been suggested to represent the presence of tumor-associated antigens, but its significance in neoplasia is unclear. Elevation of rheumatoid factor in patients with transitional cell cancer has been reported in several studies in which titers rose in more advanced stages of the disease, s7 These elevations have been correlated with the blocking of lymphocyte-mediated cytotoxicity, clinical staging, and tumor recurrence. Is3 When rheumatoid factor has been absent, tumor has been found to recur in only 14% of patients, whereas when rheumatoid factor was present, tumor recurred in 77%. 87 With high-stage disease, t u m o r recurrence was seen in only 30% of patients in whom rheumatoid factor was absent, whereas it was seen in 100% of patients in whom rheumatoid factor was present, s7 Elevated titers were not observed in benign urinary diseases. LACTIC DEHYDROGEN~-SE ( L D H ) . - - I n studies of the LDH isoenzyme patterns in bladder tumors, specimens of normal bladder epithelium have been found to contain only LDH 1 and L D H 2.155 Biopsy samples of atypical epithelium have shown an increase in the L D H 5/LDH 1 ratio with a progressive increase in this ratio together with a decrease in the percentage of LDH 1 in biopsy samples of high-grade bladder cancer. 21 A predominance of LDH 5 and L D H 4 has been observed in the urine of all patients with bladder cancer. These observations, however, have not been studied in a prospective manner and have not been applied in an analysis of random biopsy material in which enzyme changes m a y be an earlier expression of neoplastic transformation than are later histologie features.

MISCELLANEOUS SUBSTANCES.--Many substances have been observed to increase in quantity in the urine of patients with bladder cancer. These have included ~-glucuronidase, 18 plasminogen activators, 9s and fibrinogen degradation products. 225 To 248

date, specificity of these markers and their clinical usefulness remain to be established and defined. IMMUNE RESPONSE MECHANISMS IN BLADDER C A N C E R . - - D e -

spite the assumption that bladder tumors contain tumor-associated antigens that would be expected~to permit early detection of neoplastic transformation either through direct identification of these antigens prior to the occurrence of histologic changes~ or through recognition of their effect in modifying immune response mechanisms, little is known of the influence of bladder cancer on the host immune response. Correspondingly, little in~ formation is available on ways in which immune response mechanisms can be used to diagnose the presence, extent, and potential behavior of bladder cancer. Identification of the presence of tumor-associated antigens has involved either direct attempts to prepare specific antisera against substances from tumor cells themselves84 or examination of lymphocyte activity in various cytotoxic assays to detect such antigens indirectly through their stimulation of an immune response in patients with bladder tumors. 12'27,89.166 Results in these studies have at best been mixed. Although initial observations in both types of study seemed to suggest that the stage of tumor could be correlated with lymphocyte cytotoxicity in patients with bladder cancer, that successful treatment with radiation therapy resulted in an abrogation of the lymphocyte cytotoxic response, and that return of the lymphocyte cytotoxic response implied the return of tumor, findings in any particular patient were highly variable and not selectively predictive. This led ultimately to generalized skepticism about clinical applicability of this type of testing. Depression of the cellular immune response in patients with advanced stages of transitional cell cancer was also suggested as a useful index to characterize a patient's neoplastic disease. Several investigators examined the ability of lymphocytes from patients with transitional cell cancer to function as stimulator and responder cells in mixed lymphocyte culture or to be stimulated by a variety of plant lectins. They observed decreased responses or suppressor cell activity in correspondence with a patient's tumor status. 43'163 Findings in these studies, though, were relatively nonspecific and subject to technical variability. Other investigators examined skin test antigen response and delayed hypersensitivity as a possible correlate of a bladder tumor patient's immune response capabilities. For example, Olssen 165compared 13 immunologically competent patients who had a history of bladder tumors without recurrence, with six immunologically incompetent patients, four of whom had recurrent tumors. Related studies demonstrated a correlation between the presence of tumor and depression of the immune response to a variety of skin test antigens. Thus, only 15-35% of tumor pa249

tients had positive responses to purified protein derivative, streptokinase-streptodornase, or mumps antigen as compared with a positive response rate of 60-90% to the same antigens in a cancer-free population. Similar studies by Catalona~nd co-workers33 using dinitrochlorobenzene as a sensitizing agent for delayed hypersensitivity responses demonstrated that all tumor-free bladder cancer patients had normal immunocompetence, whereas only 30% of patients with superficially invasive tumors had impaired reactivity. Yet 100% of patients in whom tumor extended through the bladder muscle were found to have impaired immunocompetence. The existence of vascular or lymphatic permeation in these studies was similarly associated with depressed immunocompetence. Finally, examination of regional lymph nodes in patients with different stages of bladder cancer was used to determine whether histologic appearance or in vitro functional activity of lymphocytes in these nodes correlated with the stage of disease. Herr et al. observed that 19 of 22 patients whose nodes appeared to be "stimulated" survived five years, whereas only five of 25 patients whose nodes appeared either unstimulated or depleted of lymphocytes survived. In addition, there appeared in these studies to be an increased inability of patient lymph node cells to stimulate normal lymph node cells in mixed lymphocyte culture, and patient lymph node cells responded poorly to stimulation by normal cells. Similar depressed responses were seen in mixed culture with phytohemagglutinin and concanavalin A. This depressed response was heightened in patients whose tumors had progressed outside of the bladder in comparison with patients who had only early disease. It therefore seemed that as disease advanced locally, the response of lymph node cells to leukocyte antigens and mitogens declined, a pattern not reflected by similarly depressed responses in peripheral blood lymphocytes. Stage for stage, those patients with stimulated-type lymph nodes seemed to have a better prognosis for five-year survival than those patients who appeared to have depleted nodes. 95 At present, the overall role of the immune response in controlling the progression of cancer is entirely unknown. Observations in which the immune response is depressed in the face of advanced disease, as determined either in vitro or in situ, may represent an effect as well as a cause of the extent of disease in that patient. No test available at present is sufficiently specific to permit valid interpretation in the individual patient. Thus, the clinical usefulness of such tests in the diagnosis of the neoplastic diathesis, i n t h e sense of attempting to understand what may ultimately influence tumor progression, requires further investigation. 250

THERAPY SUPERFICIAL DISEASE RESECTION AND BIOPSY.--The management of superficial transitional cell tumors must take into account the concept that the initial tumor may actually represent a generalized diathesis, that recurrences will often continue to be superficial, and that only under certain circumstances will the tumor diathesis show progression (see Fig 1). In most instances, transurethral resection of superficial lesions is sufficient therapy in effecting a "cure" of the disease. However, the term "cure" in this context pertains only to the eradication of the presenting lesion and does not imply the prevention of recurrence. In this regard, cure actually depends in large part on the type of behavior pattern that a particular tumor may manifest (see Fig 1). In general, however, the survival in patients with simple low-grade, low-stage tumors approaches normal life expectancy.1~'85.~61 Certain steps should be taken at initial tumor resection to characterize the tumor being treated and to assess the status of the entire urethelium. Urinary cytology, either in voided urine or, preferably, in bladder washings, is indicated to determine the presence of neoplastic disease in situ elsewhere in the bladder. Multiple biopsy samples are taken with a cold-cup biopsy forceps in order to avoid cautery artifact and iatrogenic sloughing of a loosely adherent urethelium. Samples are taken at the margin of the presenting lesion, each ureteral orifice, the posterior floor, the lateral walls, the prostatic urethra, and, if possible, the bladder dome. Pathologic analysis at these sites can give some indication as to whether larger areas of the urothelium have undergone neoplastic transformation or whether the presenting lesion is a solitary aberration. Examination in this manner is indicated not only to characterize the extent of disease but also to determine whether more aggressive therapy is called for. Thus, the presence of epithelial atypia or carcinoma in situ at the margin of a superficial tumor may be associated with the development of muscle-invasive disease later on, in which case prognosis may be poor. 4 Multiple biopsy samples may thus alert the clinician to the potential temporal aspects of the tumor diathesis and the possible need for a therapeutic approach that encompasses a broader scope and signals the need for careful monitoring of an unstable urothelium. Evaluation of the urothelium in the case of apparent superficial disease also obviously requires a careful pathologic assessment of the resected tissue' specimen both to determine tumor grade and to establish whether lamina propria invasion has occurred. If so, it is then important to determine whether lymphatics may have been penetrated. Thus, high-grade lesions, 251

even if still superficial, have been shown to have a poorer prognosis than low-grade lesions, and are usually found to have been more extensive than m a y have been appreciated initially. 182 Lamina propria invasion has in many instances been found to be an ominous indication of tumor aggressiveness and, if lymphatics have been penetrated, metastases have not been uncommon.8, ~o6.Ho Finally, since bladder tumors are multicentric, both temporally and spatially, interval systematic endoscopic evaluation with assessment of urinary cytology is mandatory in all patients. Standard protocols call for such evaluation every three months. However, as the majority of recurrences are seen within two years, 8~'221 it is not unreasonable to prolong the interval between cystoscopies in those patients who, on initial tumor evaluation, have been considered to be at low risk and who, during the first two years of follow-up, have not been found to have visible or cytologic recurrence. In the event of recurrence, repeated full assessment of the tumor and the urothelium by cytology and multiple biopsy is indicated. Recurrence with a higher grade, lamina propria invasion, development of positive cytology, or occurrence of disease in situ are important warnings that the tumor may have become more aggressive and may rapidly extend beyond the confines of the bladder. INTRAVESICAL CHEMOTHERAPY.--Thiotepa.mA number of cytotoxic agents have been observed to be effective in the treatm e n t of superficial bladder tumors, and recent studies have promoted the use of these agents in a variety of clinical settings. The most commonly used agent, thiotepa, described by Jones and Swinney 11s in 1961 and Veenema et al. 223 in 1962, was initially used primarily in situations where tumors were so multiple as to be unresectable or recurred so rapidly as to make repetitive anesthesia unfeasible. In these and subsequent reports, bladder tumors were partially or completely destroyed in approximately 30% to 50% of patients. 115'223 Recent reports have described a response rate as high as 50%. 186 A number of studies have also suggested that an initial response to thiotepa might be an indication that a patient's particular neoplastic diathesis will respond to a prophylactic course of this agent. 115Thus, when patients who had had a successful initial response to weekly thiotepa were placed on a prophylactic regimen of monthly intravesical thiotepa and compared to patients rendered free of tumor by transurethral resection alone (who were then placed on the same regimen), overall recurrence in the first group was 44% compared with 79% in controls. In addition, the delay in onset of recurrence was 15 months in the first group versus four months in the latter. Patients who did not respond to the initial course of thiotepa 252

and had a recurrence seemed to fare significantly better after appearance of the first new tumor insofar as their later frequency of recurrence was concerned t h a n did a previously untreated group. 115 Moreover, grade of disease did not appear to influence these results. Of 13 grade 1 lesions, eight (62%) improved, as did seven of 13 grade 2 lesions (54%). Of further interest have been observations of the use of thiotepa in the management of patients with carcinoma in situ. Farrow et al. 69 reported that in only one of 14 adequately followed patients with carcinoma in situ treated by thiotepa alone did invasive cancer subsequently occur, and this was found to be not in the bladder but in the prostatic ducts, not accessible to the instilled thiotepa. Our own observations in this regard have included conversion of positive to negative cytology in two of three patients with carcinoma in situ, with a corresponding decrease in irritative symptoms. It is therefore conceivable that patients with recurrent superficial bladder cancer and/or carcinoma in situ can be managed effectively with intravesical chemotherapy in at least 50% of patients. Under these circumstances, continued systematic followup with endoscopic and cytologic monitoring is mandatory. It is important not to lose sight of the fact that positive cytology may reflect ureteral or urethral changes not affected by intravesical chemotherapeutic management. On the basis of these findings several investigators have suggested that earlier institution of topical chemotherapy, i.e., at the time of initial tumor resection, might prevent the implantation of tumor cells and growth of new tumors. MacDonald and Thorsen 12~ observed that carcinogen-induced bladder tumor cells could be implanted in mucosa-lined pouches in dogs, while Weldon and Soloway234 observed that when carcinogen-induced tumor cells were placed into traumatized bladders, there was a 54% incidence of new tumor formation compared with a 12% incidence in nontraumatized bladders. Clinically, Boyd and Bernand 17 observed a higher incidence of "recurrent" tumors located only in the vault of the bladder (18.7%) in comparison to the frequency of involvement of this site by the primary tumor (3.1%). They suggested that tumor cells shed during resection might be held at the dome by surface tension at the margin of the air bubble. On this basis, when thiotepa was instilled into the bladder immediately following transurethral resection of tumor, eight of 19 patients so treated remained free of recurrence, whereas only one of 32 patients not so treated had none. 29 Moreover, none of the patients in the group treated with thiotepa developed recurrence limited to the vault of the bladder, but seven of the patients in the control group developed recurrence only at this site. In those patients who developed recurrence, however, there was no significant difference in their frequency of recurrence 253

from that of patients not treated with thiotepa. Continued use of thiotepa in patients who developed recurrent tumor thus did not appear to diminish the frequency of recurrence. This was consistent with earlier descriptions that only 50% of patients had tumors responsive to thiotepa therapy. 7~' 1~5 Our present protocol is to initiate a course of thiotepa in the event of first tumor recurrence within six months or sooner if a superficial tumor is of high grade or there are at least four superficial tumors in the bladder. Although we may advise cystectomy if a lesion is high grade, if recurrence is rapid with lamina propria invasion, or if extensive carcinoma in situ is seen, a patient who is not a surgical candidate will receive thiotepa treatm e n t instead. Results in such patients may eventually encourage attempts to use similar regimens in younger patients so as to conserve bladder function. The regimen employed includes the instillation of thiotepa (30 m g in 30 ml water) into the bladder with retention for at least one to two hours. Patients are advised to restrict fluid intake for 12 hours prior to instillation. After four weekly treatments, monthly instillations are given for two years, followed by bimonthly treatments for three years, i f no recurrence has taken place, these treatments are then discontinued. Cytologic and cystoscopic monitoring are imperative during this course. The major problems in the use of thiotepa are its toxicity: leukopenia, thrombocytopenia, anemia, and occasionally cystitis and fever. Systemic toxicity (bone marrow suppression), seen in 1 0 30% of those treated, m a y necessitate either interruption or cessation of therapy.

Epodyl.--Epodyl has been used in the same manner as thiotepa with similar results. Using a 1% solution, Riddle ~8~ observed only a 23% failure rate at one year, 34% failure rate at two years, and 50% failure rate at three years. The theoretical advantage of this agent is that its high molecular weight m a y m a k e it less readily absorbed and decrease the likelihood of systemic effects. The yield of favorable results in more recent studies has ranged from 43% to 66%. ~62 Late recurrence has appeared predominantly in patients whose tumors showed only partial response early in treatment. The major toxicity of Epodyl has been a severe chemical cystitis. Mutomycin C (Mitomycin C).--A number of studies have examined the possible usefulness of mitomycin C in the t r e a t m e n t of recurrent superficial bladder tumors. Mishina et al. 146 used mitomycin C intravesically in a series of 50 patients and found a complete remission rate of 44% with a partial remission rate of 32% (he used 20 mg of mitomycin C, three instillations per week, for a total of 20 instillations). That no systemic side-ef254

fects were observed presumably reflected minimal absorption of the drug from the bladder. In more recent studies, patients who had failed to respond to prior intravesical thiotepa were treated with mitomycin C and achieved a 24% partial response and a 42% complete response; a maximum successful response occurred at a dose of 40 mg/ml instilled once per week.42 Preliminary observation s have also suggested that mitomycin C may be effective in patients with carcinoma in situ. These results, largely in patients who were thiotepa failures, require confirmation.

Other agents.--Other agents that have been used via intravesical instillation in a similar manner include adriamycin,1~ 5-fluorouracil,122 and bleomycin.19 All have had mixed results, and response to these agents has been unpredictable at best. Vesical irritability has often necessitated cessation of these drugs. OTHER WREAWMaNWS.--Irradiation.--FollowingKuler's initial use of radium in the treatment of bladder tumors, various attempts to use intravesical irradiation for bladder cancer were generally found to be unsuccessful.31 Moreover, most results were accompanied by substantial morbidity, including the formation of bladder calculi, the development of urinary fistulas, the occurrence of irradiation cystitis, and the seeding of tumor implants by way of the initial cystotomy. The application of external beam irradiation to patients who were not candidates for other forms of therapy controlled disease in only 50% of patients with superficial disease. 8~ Even then recurrence was not necessarily prevented. Taken together with its potential significant morbidity, radiotherapy has generally been regarded as ineffective in the treatment of low-stage disease.

Partial cystectomy.--Clinicians have generally frowned on the use of any surgical procedure that required opening of the bladder for treatment of superficial disease because of the likelihood of tumor spill. In fact, it has usually been only in those instances where multiple biopsy samples have shown tumor to be localized to one area of the bladder without evidence of epithelial changes elsewhere that partial cystectomy has been accepted, albeit reluctantly, as a therapeutic option. Usually transurethral resection of the lesion has not been possible, so that the open surgical approach has been necessary. Occasionally, the occurrence of a tumor in a bladder diverticulum not accessible to transurethral resection has lent itself well to "partial cystectomy" (or, more accurately, diverticulectomy). For effective partial cystectomy adequate margins around the tumor must be obtained, and special care is required to avoid wound implantation through tumor spill. Regardless of these precautions, however, it must be remembered that the procedure 255

does nothing to decrease the likelihood of tumor recurrence. In fact, open operation may significantly compromise later therapeutic approaches. These considerations have led most experts to abandon this procedure in other than extraordinary circumstances.

Immunotherapy.--Systemic immunization with BCG and subsequent intravesical instillation of BCG has been found to be effective in inducing tumor cell necrosis, and has been claimed to decrease the incidence of tumor recurrence. For example, in ten patients there were 35 new lesions observed during 67 patient months (6.7 months/patient) before bacille CalmetteGuerin (BCG) treatment and no recurrences in 47 patientmonths (4.7 months/patient) during subsequent to initiation of BCG therapy, s6 Although the reduction of tumor recurrence rate seems impressive, and other studies have reported comparable preliminary observations, 119 longer periods of follow-up and carefully randomized studies are required to evaluate this modality of treatment and possible prophylaxis. Miscellaneous treatments.--Irrigation of the bladder at high temperatures (hyperthermia) has been observed to produce tumor necrosis, but has had no effect in decreasing tumor recurrence. ~I Reduction in bladder capacity as a result of such therapy has in many instances necessitated urinary diversion. Cryotherapy has been even less effective than hyperthermia and has often led to bowel fistulas, hypovolemia, and hemorrhage. ~2s Laser beam therapy has had the advantages of producing d e e p necrosis of the bladder wall without causing bleeding and apparently without danger of perforation. Laser rays have been said to penetrate tissue with weak blood flow more deeply than tissue with intensive blood flow because the argon laser rays are near the absorption maximum of hemoglobin. 2~3The major disadvantage of this approach i~ that no tissue specimen is available for pathologic assessment, so that the course of a tumor cannot be predicted or followed. Pressure necrosis of tumor by the use of a balloon placed intravesically has also been described. Cells deep within the tumor are found not to be affected, and recurrence of tumor, especially when involvement of lamina propria has occurred, is not prevented, so All in all, careful transurethral resection and topical chemotherapy, both of which can be characterized as nonaggressive, appear to provide adequate treatment for superficial disease. As more is learned about those features of neoplastic changes that indicate the potential for aggressive behavior, topical therapy with adequate monitoring controls may also become applicable in the management of potentially more aggressive lesions in judiciously selected patients. Development of therapeutic modali256

ties along such lines is strongly indicated, for it is in the early stages of disease that the optimum chances for control are encountered. INVASIVE BLADDER CANCER

The n a t u r a l history of high-stage bladder cancer is poorly understood. Although metastases are common and appear rapidly once invasive disease is diagnosed, regardless of the form of therapy or efficiency of its application, the time at which these metastases seed is entirely unknown. Limitations in our ability to treat metastatic disease (see below) imply the need to treat bladder cancer aggressively before metastasis has occurred. If this means at a time when a potential metastatic tumor is still superficial, so be it. But it then becomes mandatory to identify those tumors and distinguish them from the majority in which progression is unlikely and in which m a n a g e m e n t by less aggressive t r e a t m e n t is sufficient. Previous reports have shown t h a t survival of patients with high-stage tumors, if left untreated, is less t h a n 5% within two years of diagnosis. TM Unfortunately, the various t r e a t m e n t modalities t h a t have been employed in the m a n a g e m e n t of deeply invasive disease, though improving the chances of patients over those left untreated, have not produced over the years the benefits in overall survival that m i g h t ordinarily have been expected) 32 IRRADIATION THERAPY--The earliest approaches using irradiation in the t r e a t m e n t of invasive bladder cancer made use of radium capsules, gold seeds, and t a n t a l u m or iridium wires, usually in conjunction with segmental resection of the lesion. 31 The idea was to provide a high level of irradiation to the lesion with a penetration limited enohgh to prevent damaging effects to surrounding normal tissues and preserve bladder function. Unfortunately, these methods were found to be ineffective in the t r e a t m e n t of high-stage disease. 3' The advent of external beam high energy radiation therapy provided an opportunity to assess the role of radiation t r e a t m e n t without the need for concomitant open operation (Table 5). In most instances, the dose to the bladder was carried to 7,000 rad in seven and a half to eight weeks, usually with rotation or by multiple fields. Although this regimen was theoretically capable of completely eradicating tumor from 2 0 - 2 5 % of patients with invasive transitional ceil cancer, five-year survivals were found to range between 14-37% for patients with clinically staged B2 or C bladder cancers, a'' s,, 144" Radiation as a sole t r e a t m e n t would have been expected to fail because of the relatively low radiosensitivity of hypoxic tumor 257

TABLE

INVESTIGATOR

Friedman ~ Crigler~ Frank 7~ Edsmyr ~ Miller m Mort/son ~5~ Goffinetsl Cummings 44 Birkhead ~6 Rider TM Wallace=~

5.--SURVIVAL IN BLADDER CANCER PATIENTS AFTER EXTERNAL B E A M RADIATION THERAPY SURVIVAL CLINICAL STAGE B2~'C* 3-YEAR 5-YEAR

5/32 (15%) 24/59 (41%) 18/40 (48%)

4/21 13/46 8/26 1/9 14/71 12/66 35/128

55/123 (45%)t 33/95 (35%)$ 8/29 (28%) 41/162 (25%) 24/85 (28%)

5/14 5/28 29/162 18/85

(19%) (28%) (31%) (11%) (21%)t (18%)$ (28%) (35%)~ (25%)$ (36%) (18%) (18%) (21%)

REGIONAL FAILURE*

37/55 (67%) 136/201 (68%) 34/101 (34%) 29/75 (39%) 44/85 (41%) 176/358 (50%) 17/25 (68%) 44/66 (33%)

*Number of patients and percentage. ~Stage B2 patients only. *Stage C patients only.

cells found in the primary tumor mass. 17~This situation was not improved by the use of hyperbaric oxgen during irradiation. 171 However, radiation failures included not only patients with tumor persistence239 but also patients with tumor recurrence.31 Moreover, although patients retained bladder function, 4 12% of them developed contracted bladders that led to frequent, painful voiding; 2-6% developed significant bladder hemorrhage; 2-4% developed bowel stenosis; and nearly all patients developed rectosigmoid mucosal irritability. 31'm Ultimately, therefore, a substantial number of patients required cystectomy, and in these instances irradiation rendered the operation more complicated and substantially increased surgical morbidity and mortality. RADICAL C Y S T E C T O M Y - - T F e a t m e n t o f patients with invasive stage B2 or C disease by operation alone in early series led to an approximately 20% two-year and a 10-15% five-year survival rate ~32 (Table 6). Recent studies using cystectomy alone have shown little improvement in survival. ~86"2~9'23s Although some reports described an improved five-year survival rate in patients with stage B2 and C disease undergoing radical cystectomy (i.e., 20% five-year survival rate in patients treated after 1952 compared with 13% five-year survival rate in patients treated before 1952) this improvement appeared only to reflect a decreased postoperative mortality with better patient selection and no substantially improved significant effect in tumor management. 73 Whereas radiation therapy might have failed because of low radiation sensitivity of tumor cells within the primary mass, radical operation alone was said to have failed by 258

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having either left behind peripheral tumor processes, produced local implantation of cells, or induced vascular/lymphatic dissemination of tumor cells. 177 Failures at these high stages, however, most likely reflected the intrinsic nature of the tumor that'~was manifested in extension of neoplastic cells beyond the confines of the bladder. Thus, although inability to control pelvic disease was suggested by a pelvic recurrence rate of 40% for stage B2-C tumors 237'2~s that may have indicated local implantation at the time of operation, the rate of failure was consistent with the incidence of pelvic lymph node involvement observed in deeply infiltrating bladder cancer to begin with. 179'535 Furthermore, that a similar proportion of patients succumbed to distant metastatic disease appeared to reflect events that had taken place earlier on in tumor development rather than events occurring at the time of operation. 237 RADIATION THERAPY AND CYSTECTOMY.--The high incidence of pelvic recurrence prompted attempts to incorporate radiation therapy in a surgical protocol for treatment of deeply invasive bladder cancer (Table 7). The hope was that preoperative pelvic irradiation in moderate doses might prevent growth of tumor cells disseminated locally or systemically at the time of operation, eradicate microscopic pelvic disease already present, and destroy transected peripheral tumor extensions or tumor cells left behind. 1~ 1o4.176 On this basis, Whitmore instituted a protocol in which patients received 4,000 rad of preoperative radiation followed by radical cystectomy.233This group was compared with a historical group of 137 patients who had undergone cystectomy alone. UItimately, 119 patients received radiation therapy and cystectomy by this protocol. The proportion of patients with stages B2 and C disease who died of bladder cancer within five years in this series was highest in patients who had had cystectomy alone. 23s Survival of patients undergoing preoperative irradiation and cystectomy (17/ 50 or 34% five-year survival) was twice that of patients undergoing cystectomy alone (10/64 or 16% five-year survival). In addition, pelvic recurrence was 16% in those who had preoperative radiation therapy versus 28% in those with cystectomy alone. But although preoperative radiation may have led to a decreased frequency of disease recurrence in the pelvis, it did nothing to alter findings that most therapeutic failures were associated with distant metastases to bone, lung, or liver. Prospective randomized trials with radiotherapy have led to comparable observations, although in each of these studies, radiation and cystectomy was compared with "definitive" radiation alone rather than with cystectomy alone. For example, Wallace and Bloom227observed a rapid profound mortality in both groups 26O

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of patients during the first year after treatment; subsequent three- and five-year survival rates for 85 patients receiving fullcourse radiation therapy were 28 and 21% compared with 41 and 33%, respectively, for 77 patients receiving preoperative radiation followed by cystectomy. A similar study by Miller and Johnson m at M.D. Anderson Hospital reported a 51% actuarial five-year survival for p'atients receiving irradiation and cystectomy compared with a 14% actuarial survival for the group of patients treated only with definitive irradiation therapy. Several interesting observations emerged from studies such as these. For example, Van der Werf-Messing~19 noted the positive influence on prognosis that tumor downstaging following radiation therapy seemed to have. In these reports, when T-stage reduction following 4,000 rad preoperatively was observed in patients who had initially been staged as T3, there was a significantly increased survival rate. On the other hand, patients who had had radiation for TI and T2 disease did not demonstrate improved survival. A subsequent study by the Urologic Cancer Research Group comparing preoperative radiation (4,500 rad) with operation alone reported that patients who had received prior radiation and then had been found to have had no tumor in the surgical specimen had a substantially improved prognosis. T M The actuarial survival of this group was 51% whereas other patients with clinical stage B 2 or C disease with tumor remaining in the operative specimen had an actuarial survival of 26% whether or not preoperative irradiation had been used. However, several features of these studies suggest the need for a reappraisal. First, built into each of the studies was a clinical staging error that was not insubstantial. 131"l~s If, at the time of operation, extensive disease led to exclusion of a patient from protocol evaluation, a bias would have been introduced in favor of combined therapy. Similarly, an overstaged lesion (i.e., lowstage disease inaccurately assessed as being of higher stage) occurring in as many as 20% of patients (see Table 4) would have introduced a comparably favorable bias in interpreting results of therapy. Unfortunately, in several of these studies m' 220 histologic confirmation of muscle invasion was not necessarily a criterion for admission. Second, those patients in a surgical protocol would by selection alone have had to have been a better group of treatment candidates, and those not faring well enough during radiation would have been eliminated from the surgical group, thereby producing a bias in favor of the combined treatment approach. In the Wallace and Bloom report, for example, of the 98 patients allocated to the combined treatment, 21 (21%) actually did not receive protocol treatmentY 7 Third, "invasion" in some of the studies, although implying that muscle had been involved, in fact only signified lamina propria invasion, a stage at which prognosis, regardless of radiation, may have been bet262

ter.lO6. 133,238 Thus, lymph node involvement as determined clinically in the Van der Werf-Messing studies, led to 40% of the deaths of T3 patients and only 7% of the deaths in superficial T categories. 22~ Corresponding differences in the occurrence of distant metastases without clinical lymph node involvement (19% and 7%, respectively) were seen as well. Fourth, a separate study comparing preoperative irradiation plus cystectomy versus cystectomy alone demonstrated survival for each group to be equally poor with a similar number of skeletal and pulmonary recurrences in each group. 17s'206 In fact, significant survival differences were demonstrable only when no tumor remained in the bladders of patients in the irradiated group as compared with the group that had persistent tumor after transurethral resection and that had not been irradiated. 178 At first glance this would seem to imply a beneficial therapeutic effect of radiation. However, groups of patients were not truly comparable since transurethral resection alone m a y have removed all of the tumor in some patients, particularly in those in whom tumor was more superficial, 2~ 207 a finding that by itself would have been associated with an improved prognosis (see below). Unfortunately, there was insufficient dat~ to compare those patients with the same treatment groups in whose surgical specimens no tumor was present. In these instances, findings might not have supported the apparent survival differences. Finally, no randomized trial comparing cystectomy alone with radiation plus cystectomy has yet appeared. Until this is done, it would appear that no statistically valid statement regarding the relative efficacies of these therapeutic options can be made. A strong case for the therapeutic benefit of radiation has been made on the basis of findings that 34% of patients undergoing radiotherapy and cystectomy have been found to have no tumor in the surgical specimen, whereas only 9% of patients who have not had radiation are found to have no tumor in the cystectomy specimen. 2~ However, the absence of tumor in the surgical specimen appears to have occurred most frequently when the lesion has had a papillary configuration. 2~ Although this had been taken to imply a greater sensitivity to radiation by such a lesion, separate studies have suggested that papillary tumors tend to be more superficial than solid tumors and appear less likely to invade lymphatic or vascular structures. 182'212 This by itself could explain findings that patients with papillary tumors have tended to have an improved five-year survival rate when compared to patients with solid tumors.1 s2' 239 Thus, the possible importance of radiotherapy in this setting m a y be less obvious than initial reports have suggested, and reported survival results may actually reflect the intrinsic behavior of the tumor itself rather than the effects of extrinsic therapeutic manipulations. F u r t h e r confusion was introduced by the results of more recent protocols in which patients received 2,000 instead of 4,000 "~

263

rad before undergoing radical cystectomy.239 Survivals were comparable in both groups, as was disease recurrence outside and/or within the pelvis. 23~'239 In sum, our understanding of the role of radiation in the treatment of invasive bladder cancer remains incomplete. Our ability to identify patients or~characterize invasive tumors, either early on in their course or when they are already more deeply invasive, in order to determine situations in which radiation therapy might be most effective, is still limited. Although radiation therapy combined with cystectomy has led to local control in some situations and has appeared to diminish local recurrence,23~ much remains to be clarified if accurate dosage of radiation therapy is to be effectively integrated with operation. Our present approach in the treatment of invasive bladder cancer in this context is to deliver 4,000 rad of radiation via linear accelerator to the full pelvis and bladder and follow this within four weeks at most by radical cystectomy. The surgical procedure, which does not appear to be affected by this radiation, includes a full pelvic lymph node dissection (external iliac, hypogastric, obturator, and common iliac nodes) and en bloc removal of bladder and prostate in males, and bladder, uterus, adnexa, andanterior and lateral vaginal walls in females. Because the incidence of ureteral carcinoma in s i t u appears to vary between 10% and 20%, ~~ frozen sections of ureter are examined so that a tumor-free margin can be prepared for implantation into a segment of bowel. Frozen sections of lymph nodes are not obtained because the presence of microscopic metastases does not necessarily imply that operation will not be curative. Indeed, although less than absolute, there is evidence to suggest that lymph node dissection along with cystectomy may provide some therapeutic benefit in certain instances and does not serve merely to stage the tumor for prognosis. In one study, for example, it was shown that despite the presence of minimal microscopic involvement, 10-20% of such patients achieved greater than five-year survival. Thus, Dretler ~I observed that four of 12 patients with only one or two microscopically positive nodes survived beyond five years without evidence of disease after radical cystectomy. Findings by Laplante 121 of a 12.8% five-year survival rate in patients with positive pelvic lymph nodes undergoing radical cystectomy in contrast to a nil survival if adjacent viscera were invaded not only confirmed the therapeutic usefulness of lymph node dissection in select patients but also implied that lymphatic penetration takes place at an earlier stage of tumor progression than vascular penetration and distant dissemination. Urethrectomy is performed in all females. As the incidence of carcinoma in situ of the urethra has been reported to be less than 20% in males, 83 some reservation has been expressed about urethrectomy in all males at the time of cystectomy. However, 264

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Fig 12.--The most common form of urinary diversion is the ileal loop, as developed by Bricker. Isolation of a segment of terminal ileum with appropriate preservation of its mesenteric vasculature and that of remaining ileum are shown. The segment is brought inferior to reanastamosed bowel, its proximal portion is closed, and the ureters are separately anastomosed to ileum at its antimesenteric surface. (Courtesy of Skinner D.G., Richie J.B., in Harrison J.H., et al. (eds): Campbell's Urology. Philadelphia: W.B. Saunders Co., 1979. Used by permission.)

several considerations argue in favor of such a procedure. First, the procedure is simple and takes little extra time (especially when compared with a separate procedure and anesthetic at a later time). Second, it obviates the need for urethral aspiration for cytology as a routine at each follow-up visit. Third, preoperative prostatic urethral biopsy may not have accurately sampled the mucosa to determine the status of the urethra prior to cystectomy. Finally, studies reporting the results of delayed urethrectomy for tumor have described a high incidence of perineal recurrence and inguinal metastasis. 197 Supravesical urinary diversion has usually involved drainage of ureters into an isolated intestinal segment (ileal conduit, colonic conduit, cecal conduit,.jejunal conduit) (Figs 12 and 13). 248 If no prior radiation therapy has been administered, drainage into nonisolated intestine (ureterosigmoidostomy), or into an isolated segment of large intestine, and transanal pull-through have also been performed. 265

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....................

Fig 13.--Colon conduit in urinary diversion. A segment of descending colon is isolated and brought inferolateral to the remaining bowel; one should take care to preserve the mesenteric vasculature of each. The proximal end is closed and the ureters are anastomosed in an antireflux staggered fashion to bowel segment at level of teniae coil (Courtesy of Skinner D.G., Richie J.P., in Harrison J.H., et at. (eds.): Campbell's Urology. Philadelphia: W.B. Saunders Co., 1979. Used by permission.)

Postoperative mortality with ileal conduit, the most commonly used form of diversion, has ranged from 2% to 12%. 24~ Early complications, consisting of urinary leakage and pyelonephritis, and late complications, consisting of urolithiasis, impairment of renal function, pyelonephritis, ureteroileal stenosis, and stomal stenosis, have occurred in 15-20% of patients. 214'24~ Use of colon has permitted the introduction of antireflux anastomoses between ureters and bowel and has led to fewer associated stomal problems or metabolic disturbances. 5' 247 The increased use of colon reflects the fewer apparent long-term complications than those with the use of small bowel. Implantation of urete~:s into nonisolated intestine (ureterosigmoidostomy), once the commonest form of urinary diversion, is again popular for selected patients (those without bowel disease, fecal incontinence, previously damaged kidneys, or high-dose pelvic radiation therapy). 4~ Late complications with an incidence of 2% to 20% have included pyelonephritis, calculi, hyperchloremic acidosis, and ureterosigmoid stenosis. 246 Careful follow-up of all patients with urinary diversion is mandatory to detect potential complications early. 214'24~ Staged procedures (diversion followed by irradiation and later cystectomy) have proved neither necessary nor effective and only seem to complicate irradiation, performance of the subsequent operation, and the need for patients to undergo two hospitalizations and two operations. ADJUVANT SYSTEMIC CHEMOTHERAPY.--It is conceivable that attempts to cure truly invasive disease are doomed to failure at 266

the outset because the disease is already metastatic. There is certainly a great deal of evidence to support this possibility, for lymph nodes are positive in at least 50% of patients 1~9(see Table 4) and the vesical vasculature has been shown to have been penetrated in 55% of patients with invasive disease. 1~9'212 In one recent report, for example, 78% of 50 patients were found to have developed metastases that were ~clinically evident in one year; over 70% of these patients were found to have metastases outside of the soft tissues of the pelvis. 1~9 This has prompted several proposals for the introduction of adjuvant systemic chemotherapy when cystectomy is contemplated. Presently, clinical trials of adjuvant chemotherapy are under way. Their goal is to determine whether failures due to distant metastases not clinically evident at the time of cystectomy can be avoided. 159Whether these protocols will be effective, or whether the actual need is to recognize and treat patients with aggressive disease at an earlier phase, when tumor is still superficial and possibly still confined to the bladder, remains to be determined. CHEMOTHERAPY FOR ADVANCED DISEASE

Many cytotoxic agents have been used either singly or in combination in attempts to control metastatic disease associated with transitional cell cancer of the bladder. 3~ 4s No agent o r regimen, however, has been singularly effective against either regional metastatic disease or disseminated disease. Among the more effective agents have been adriamycin, which has given an overall partial response rate of between 24% and 55%245; cyclophosphamide (Cytoxan), which has given an overall response of approximately25% 142'245 and most recently, Cis-platinum, which has led to a response rate of 20-~35%. 32"244 Other agents have been used with variable success. 5-Fluorouracil has shown an overall response rate of 35%, 4s but in at least one a t t e m p t to use this agent as an adjuvant with radiation therapy and cystectomy, patients had better results when treated with placebo. TM Methotrexate has produced symptomatic and objective signs of tumor regression in 3 6 - 5 6 % of patients but requires additional evaluation with higher doses and the use of citrovorum factor rescue. 216 Mitomycin C as a systemic antitumor antibiotic has been reported to have a response ranging from 16% to 33%, but its toxic effects have outweighed its clinical usefulness. ~2 Results with double or triple combinations of these agents have not been any more promising than results seen with the use of these agents individually, s~ When a response is seen, it is usually rapid, b u t is then often of short duration. ~98 Moreover, the use of combination chemotherapy is limited by the cumula267

rive toxicities of the individual agents employed. In sum, we need an agent effective against advanced disease and usable as an adjuvant to operation. CONCLUSIONS

Bladder cancer, according to our present understanding, appears to be comprised of two general forms: a superficial, usually recurrent form that does not appear to jeopardize the patient, is by far the more common form, and may ultimately be entirely controllable by intravesical chemotherapy, and an aggressive form that occurs in 10-30% of patients and may lead rapidly to death regardless of therapeutic interventions. Although the two forms may represent different phases in a spectrum of a single disease process and its progression, they may also reflect separate neoplastic processes and occur independently of each other. Based on our present knowledge of the natural history of bladder cancer and on therapeutic options, several overall objectives appear to be of overriding importance in the assessment and management of transitional cell carcinoma: 1. Identification and characterization of features of superficial lesions that predict recurrence and permit definition of the likelihood of progression. 2. Establishment of a reliable means by which recurrent superficial tumors can be prevented. 3. Characterization of treatment regimens that permit control of advanced disease still confined to the bladder. 4. Identification of treatments effective against disease no longer confined to the bladder and possibly then applicable adjunctively in the management of disease thought to be confined to the bladder but subclinically metastatic. Finally, epidemiologic studies have identified factors that strongly influence the development of a substantial proportion of cases of transitional cell carcinoma of the bladder. Undoubtedly, further studies and epidemiologic observations will focus attention on additional factors that play an important role in the induction of bladder cancer. As etiologic factors are identified, steps must be taken to minimize or eliminate them. BIBLIOGRAPHY 1. Albarran J.: Les Tumeurs de la Vessie. Paris: G. Steinheil, 1892, p 41. 2. AIIegra S.R., Broderick P.A., Corvese N.L.: Cytologic and histogenetic observations in well-differentiated transitional cell carcinoma of the bladder. J. t i r o l 107:777, 1972. 3. Alroy J., Banner B.F., Pauli B.U., et al.: Alterations of intercellular junctions in acinic ceil'carcinomas of the canine pancreas. Virchows Archiv. [Cel[ Pathol.] 28:21, 1978. 4, Althausen A.F., Prout G.R. Jr., Daly J.J.: Noninvasive papillary carcinoma of the bladder associated with carcinoma in situ. J. Urol. 116:575, 1976. 268

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SELF-ASSESSMENT ANSWERS l.d 2. False 3. False. The majority of patients do not progress. 4. False. It is not a reliable indicator in the presence of lowgrade and low-stage disease. 5. False. The major presenting symptom of transitional cell carcinoma, it may be recognized as either~gross hematuria or microscopic hematuria with similar significance. 6. False. Continual surveillance is important because the occurrence of broad field changes in the urethelium that may not be endoscopically visible may lead to the recurrence of tumors later on. 7. e. Intravenous pyelogram is unreliable in detecting tumors in the bladder per se. 8. d. To determine the depth of penetration of the tumor. 9. False. Radiation therapy is not useful in the treatment of superficial disease and may only be useful in an adjuvant fashion in the treatment of invasive disease. 10. False. Segmental cystectomy can only be applied in highly selected patients in the management of invasive cancer, and in this setting, total cystectomy is to be preferred. 11. False. The carcinoma in situ may assume a prolonged course and does not necessarily lead to invasive disease; its association with grossly visible tumor is the clinical setting that might require early cystectomy. Its presence by itself may signal the need for topical chemotherapy, but conservative treatment may be quite appropriate. 12. False. A substantial number of tumors that have been found to invade only the lamina propria have also been found to be metastatic. 13. False. Those tumors that may only be superficially invasive may be the manifestation of a less aggressive neoplastic diathesis, and tumors that have penetrated deeply may reflect a more aggressive potential tumor behavior. 14. False. The use of the ileum has been found to lead to excellent results with a complication rate of only approximately 10%. 15. e 16. e

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