Carcinoma in Situ of the Bladder

0022-5347/95/1533-0564$03.00/0 THE JOURNAL OF

Vol. 153,664472,March 1995 Printed in U.S.A.

UmmY

Copyright 0 1995 by

AMERICAN U R O ~ I CASS~CIATION, AL. INC.

Review Article CARCINOMA IN SITU OF THE BLADDER MLISS A. HUDSON

AND

HARRY W. HERR

From the Division of Urological Surgery, Washington University School of Medicine, St. Louis, Missouri and Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York

KEYWORDS: bladder neoplasms, carcinoma in situ HISTOLOGICAL FEATURES

NATURAL HISTORY

Carcinoma in situ was first described by Melicow in 1952 as areas of hyperplasia and anaplasia in grossly normalappearing mucosa of a tumor-bearing bladder.' Although clinically innocuous in appearance, Melicow and Hollowell emphasized the potentially invasive features of this lesion? Described as an intraepithelial cancer, the degree of invasiveness and rapidity of spread of carcinoma in situ were noted to vary considerably among patients. Weinstein et al suggested that carcinoma in situ exists in 2 forms: an aggressive variant that has the capacity to evolve into a solid, muscle invasive tumor and a less aggressive form (carcinoma paradoxicum)that lacks the capacity for invasion and metastasis.3 The majority (90%) of cases of carcinoma in situ are found in association with papillary or nodular bladder tumors. The likelihood of a muscle invasive cancer developing in such Only ~ approximately 10% of all cases patients is 42 to 8 3 2 . 4 ~ of carcinoma in situ occur as an isolated pathological finding. The likelihood of finding microinvasive carcinoma in these patients at cystectomy is 20 to 34%:~~A signiscant minority of carcinoma in situ patients with long-term followup never have invasive disease! Riddle et al found that the risk of invasion was only 8% in patients with focal carcinoma in situ, while those with diffuse disease had a 78% risk of subsequent invasion.' Malkowicz et al noted similar 5-year actuarial survival rates in patients with carcinoma in situ only, carcinoma in situ associated with stage T1 disease and carcinoma in situ associated with stage T2 disease treated by radical cystectomy.lo They also noted that carcinoma in situ was diagnosed before cystectomy in only 49 of 110 patients in whom it was found in the cystectomy specimen. While of'ten found in a bladder with high grade tumors that progress to muscle invasion or metastases, it is unclear whether carcinoma in situ is the earliest form of these aggressivetumors or only an innocent bystander, incapable of expressing an invasive or metastatic potential. This raises a clinically important question: can a low risk group and a high risk group with carcinoma in situ be defined and validated clinically?

Carcinoma in situ appears as flattened areas of epithelium composed of anaplastic cells with a disorderly pattern of growth without either extension into the bladder lumen or penetration of the basement membrane.3The cells are highly anaplastic with abundant mitotic figures and loss of cell cohesiveness. The number of cell layers may be normal or increased but without formation of papillary structures. The scattered areas or the entire thickness of the epithelium may be involved. Due to the loss of cell cohesiveness, occasionally only denuded connective tissue may be found in specimens when sloughing of the entire mucosal layer containing the carcinoma in situ has occurred. Pagetoid spread with single cells or clusters of malignant cells involving the deep layers of otherwise normal-appearing mucosa may occur. Involvement of von Brunn's nests is not uncommon. Carcinoma in situ has been found in all areas of the urothelium, including the renal pelves, ureters, bladder, and prostatic and anterior urethra. Rarely, carcinoma in situ has been found to involve the seminal vesicles, ejaculatory epithelium, urethral meatus and periurethral glands, and collecting ducts of the kidney.l2.l3 CYTOLOGICAL FEATURES

Criteria for the identification of malignant cells in cytological samples include increased cell-to-nuclearratio, markedly eccentric positioning of the nucleus, nuclear pleomorphism and irregularity, hyperchromatism, chromatin clumping, nuclear crowding and overlapping prominent nucleoli, mitotic figures, lack of cytoplasmic vacuolization and loss of cell cohe sion.14 Cytological examination of the urine has proved highly accurate in the diagnosis and monitoring of response to treatr ment in patients with carcinoma in situ of the bladder. More than 95% of the patients with biopsy proved carcinoma in situ have been reported to have a positive urine cytology resUlt.l6 Positive urine cytology findings may predate the development of discernible cancer by months to years.16 Persistently positive urine cytology studies during intravesical therapy17 or at the initial %month followup aRer intravesical therapy" have portended a worsened or poorer prognosis in patients with carcinoma in situ. Thus, classical histological and cytological features of carSIGNS AND SYMPTOMS cinoma in situ cannot be used at initial diagnosis to distinThe classical signs and symptoms of carcinoma in situ guish those cancers that will progress in invasion and those include dysuria, frequency and nocturia. Suprapubic fullness found to have an indolent course. Several new methodologies or pain, back or flank discomfort, lower abdominal pain or are currently being studied, however, and these may prove pelvidperineal pain are less frequent symptoms. Up to 25% useful in evaluating the invasive potential of carcinoma in situ. of patients with carcinoma in situ may be asymptomatic." Patients with focal carcinoma in situ may be more likely to be DEOXYRIBONUCLEIC ACID (DNA) PLOIDY asymptomatic, while those with diffuse disease are more likely to have irritative voiding symptoms. The vague signs DNA ploidy has been used as a prognostic factor in bladder and symptoms of carcinoma in situ have of'ten been confused cancer, with aneuploid tumors demonstrating a more aggreswith other disease processes and are not useful as prognostic sive clinical course. Most cases of carcinoma in situ demonfactors in individual patients with carcinoma in situ. strate an aneuploid DNA h i s t ~ g r a mas , ~do ~ most ~ ~ ~ deeply 564

CARCINOMA IN SITU OF BLADDER

565

invasive tumors. Koss believed that this demonstration of tion of cathepsin B33 and autocrine motility factor34have also aneuploidy confirms the relationship between carcinoma in correlated with the degree of bladder tumor invasiveness. situ and invasive cancer.21 Wijkstrom et a1 found bladder washings superior to voided urine samples for displaying PROLIFERATIVE ANTIGENS aneuploidy.22Therefore, flow cytometry bladder washings Flow cytometry studies of bladder cancer cell lines and may enhance detection of carcinoma in situ. Norming et al classified patients with carcinoma in situ into 3 groups based bladder tumors have suggested the nuclear antigens Ki67 on the DNA histogram: 1)carcinoma in situ with 1aneuploid and proliferating cell nuclear antigen, and the surface cell line at diagnosis that remains stable during observation, marker T43 provide information on the replicating potential 2) 1 aneuploid cell line at diagnosis that later changes to of these cells.3s Preliminary data also suggested a poorer multiple aneuploid cell lines and 3) multiple aneuploid cell prognosis in bladder cancer patients with T43 positive tu.~~ studies have shown a direct lines at diagnosis.20 Those carcinoma in situ patients with m o r ~ Immunohistochemical multiple aneuploid cell lines were at higher risk for the correlation between positive staining for Ki67 and bladder development of invasive or metastatic cancer compared to tumor grade?' SBnchez-Fernlndez found that carcinoma in those with only 1aneuploid cell line (76% compared to 19%, situ appeared immunohistochemicallyas an invasive bladder respectively). Hamano et a1 recently noted that 10% of the carcinoma.37Carcinoembryonic antigen staining was poor in histologically normal-appearing mucosa specimens from pa- normal urothelium and superficial tumors but progressively tients with bladder cancer showed DNA aneuploidy and, more positive in carcinoma in situ, as is also reported in thus, this finding may predict precancerous lesions before invasive carcinoma. Simple epithelium cytokeratin showed a recognizable carcinoma in situ or papillary tumors de~elop.'~ specific staining pattern in the basal layer of normal epitheFurther studies including a larger population of carcinoma in lium, which is lost in carcinoma in situ. situ patients are needed to verify these findings but DNA ABH(0) BLOOD GROUP ANTIGEN EXPRESSION ploidy shows promise as a prognostic indicator of the clinical course in patients with carcinoma in situ. The presence or absence of ABH(0) blood group surface antigens has previously been described as a prognostic factor in transitional cell carcinoma of the bladder.38 In patients CYTOGENETIC STUDIES Several chromosomal changes are associated with an in- known to express blood group antigens, a high degree of creased risk for tumor progression in patients with bladder correlation between the loss of cell surface blood group anticancer. Tyrkus et al noted in 17 patients with carcinoma in gens and the presence of muscle invasive bladder tumors had situ that tumors with a normal karyotype remained superfi- been documented in solid tumor specimens. Before 1986, cial and had a nonaggressive clinical course, whereas those most investigators did not recognize that approximately 20% with an abnormal karyotype ultimately became invasive.= of the population are nonsecretors (do not normally express Unlike papillary tumors, which are associated with 9q chro- ABH antigens) and, therefore, their results in carcinoma in mosomal deletion, carcinoma in situ uncommonly shows loss situ patients are questionable?' Cell surface blood group of 9q but instead expresses the more invasive genotype, antigens also have been studied more recently in patients loss of 17p. Deletions of 17p are rarely observed in superficial with carcinoma in situ. Loss of blood group antigens occurs more frequently in lesions with severe dysplasia and carcidisease except carcinoma in ~ i t u . ~ ~ - ' ~ p53 is a well known tumor suppressor gene that has been noma in situ than in those with mild to moderate dysplasia. associated with invasive tumors of several cell types, includ- Since blood group antigen expression is retained in low grade ing urothelial malignancies. The p53 gene is believed to be tumors and is lost in many high grade tumors,loss of ABH(0) associated with the 17p deletion in some cancers but p53 cell surface antigens may be a predictor of a more aggressive malignant potential leading to muscle invasion. Yamada et al mutations may also precede 17p allelic loss in other cases?' Sidransky et al first noted p53 gene mutations in the cells of demonstrated that ABH(0) antigen expression is retained in the urine sediment from 3 patients with metastatic bladder the severe dysplasia or carcinoma in situ associated with cancer.29 Melamed et al further demonstrated that expres- muscle invasive tumors but is lost in the invasive tumors sion of p53 gene mutation correlated with tumor progression themselves.& They suggested that intraepithelial lesions with a high malignant potential rapidly develop into invasive in patients with superficial bladder cancer, including carcinoma in sit^.^' In our study only 3 of 18 carcinoma in situ carcinoma losing the cell surface antigens. ABH(0)-positive patients (17%) with p53 mutation expression in less than intraepithelial lesions are not likely to progress. Tsujihashi 20% of the cells had progression to muscle invasion during et al were unable to demonstrate a relationship between associated invasive disease or risk of cancer-related death 10 years compared to 13 of 15 (87%) with p53 mutation and ABH(0) antigen expression in patients with carcinoma expression in more than 20% of the cells. Furthermore, in ~ i t u .Recently, ~l the National Institutes of Health Bladder p53 expression was the only independent variable in multiTumor Marker Network examined the relationship of ABH variate analysis for tumor progression (p = 0.004) and surantigenic expression and clinical outcome in a cohort of 131 vival (p = 0.01). Thus, chromosomal abnormalities and specific gene mutations also show promise as prognostic indicators patients with superficial bladder tumors. Loss of expression of ABH antigens was observed in 40% of tumors but did not in patients with carcinoma in situ. correlate with clinical progression. Other oncogenes and tumor suppressor genes have been Lewis" (LE")blood group antigen is expressed by urothelial implicated in bladder cancer. The H-ras mutation may be detected in as many as 40% of primary superficial bladder cancer cells but not by normal transitional epithelium?' This cancers. No apparent correlation between H-ras mutation is true even though histologically the mucosa may appear normal or dysplastic but not frankly malignant, as with and clinical prognosis has been ~bserved?~.~' The retinoblastoma gene may be associated with a poor prognosis.'6 nm23, carcinoma in situ. Figure 1demonstrates the staining with LE" antigen in cases of severe dysplasia, superficial cara suppressor of metastatic potential, has been suggested to the cinoma in situ and carcinoma in situ invading the lamina be helpful in assessing carcinoma in sit^.^' propria. All tumor cells were distinguished by staining with LE",which was not expressed by normal transitional cells. TUMOR CELL RECEPTORS AND PRODUCTS Thus, LE" may prove useful in early detection of carcinoma Increased expression of epidermal growth factor receptor in situ and may detect persistent tumor in trials of conseron superficial bladder tumors has been suggested to be a good vative management of carcinoma in situ. For example, of 56 predictor of progression to muscle invasive cancer?' Produc- patients who were disease-free 17 expressed LE' detected by

CARCINOMA IN SITU OF BLADDER

566

FIG. 1. A, normal histolo 'cally appearing mucosa. Left half stained brown with Le" by immunofluorescenceshows severe atypia but not frank carcinoma in situ. Regced from ~200. B, carcinoma in situ cells, stained with Le" scattered throughout mucosa. Poor cellular cohesion is evident. Reduced from x 100. C , carcinoma in situ cells stained with Le" invading lamina propria and undermining overlying normal mucosa illustrates insidious progression of carcinoma in situ in some cases with normal biopsy. Reduced from X 100.

immunocytology of voided urine samples and all had recurrent carcinoma in situ or papillary tumor within a mean of 8.4 months. Of the 39 LE" negative patients, 8 had a clinical recurrence (p = 0.001).43LE" antigen has been present in the majority of invasive tumors studied and may prove useful as a prognostic factor for the development of invasive tumors.44 Further studies are needed to determine if blood group antigens will prove useful in predicting the natural history of carcinoma in situ. TUMOR ASSOCIATED ANTIGENS

A number of monoclonal antibodies have been produced to transitional cell carcinoma. The M344 is a high molecular weight, mucin-like antigen expressed on approximately 60% of stages Ta and T1 tumors but only 15% of invasive tumors. The 19A211 antigen is a sialo-glycoprotein, which is expressed by 70% of stages Ta and T1 bladder tumor cells, and occasionally superficial umbrella cells. Loss of M344 and/or 19A211 is seen more commonly in carcinoma in situ than papillary tumors.32 T138 is a marker of progression expressed in approximately 15%of superficial tumors and more than 60% of invasive tumors. I t has proved particularly useful in stratifying invasive cancer between those with and without progression. Its usefulness in carcinoma in situ patients remains to be determined. MANAGEMENT

Transurethral surgery. Transurethral resection and fulguration of visible lesions and associated papillary tumors are the initial treatment for carcinoma in situ. Visible, focal lesions should be widely resected or fulgurated after appropriate biopsies are obtained. Postoperative urine cytology should also be performed to assess the presence of residual disease. Because carcinoma in situ may not be visible endoscopically and it may be too extensive to resect, and because the visible lesions have ill-defined margins transurethral resection is rarely definitive treatment for this disease. Utz et a1 noted among 62 patients with carcinoma in situ usually treated with electrofulguration that 51 (82%) had recurrences, 37 (60%)had invasive cancer and 24 (39%)died of the disease within 5 years.45 Whitmore reported a tumor progression rate of 50 to 80% in carcinoma in situ patients treated with transurethral resection alone.46In the series by Herr e t a1 none of the patients undergoing transurethral resection alone was cured of the disease and 17 (65%) required cystectomy for muscle invasive tumors or intractable carcinoma in sit^.^^ Melamed et a1 followed a select group of 25 patients with carcinoma in situ without invasive carcinoma primarily treated with transurethral resection and fulguration with or without radiation therapy.48 None of the 8 patients subsequently undergoing cystectomy died of bladder cancer. Of the patients who did not undergo cystectomy invasive cancer developed in 8 after a median of 26 months (range 8 to 67) and 2 had metastatic disease. Only 2 patients treated with transurethral resection appeared to be cured of

cancer. R o u t et al, however, noted that only 2 of 7 carcinoma in situ patients treated with transurethral resection alone had a superficial recurrence and none of these patients had progres~ion.~'Lamm summarized the natural history of carcinoma in situ in 382 patients as showing an average incidence of subsequent invasive disease of 54%.7 While these series do not define the extent of carcinoma in situ, such results suggest that transurethral resection is not definitive treatment for the majority of patients. Transurethral resection may be curative in a minority of patients who are able to retain normal bladder function. Immediate cystectomy. Because carcinoma in situ is associated with invasive disease in the majority of patients, radical cystectomy was deemed the most appropriate treatment for carcinoma in situ by urologists from the 1960s to the mid 1980s. Tsujihasi et a1 performed immediate cystectomy in 21 The 5-year actuarial patients with carcinoma in situ survival rates were 71%, 67% and 83% for patients with primary and secondary carcinoma in situ, and carcinoma in situ concomitant with papillary tumors, respectively. Tumor invaded the bladder, prostate, ureter or lymph nodes in 9 patients (43%).Dixon et a1 reported involvement of the distal ureters or prostatic urethra in 60% of cystectomy specimens with carcinoma in ~ i t u . ~ They ' also suggested a worse prognosis for patients with initial carcinoma in situ than those in whom it subsequently developed. As many as 10% of patients with carcinoma in situ have unsuspected lymph node or systemic metastases a t clinical diagnosis of the disease.50 Such patients are unlikely to be cured despite early, aggressive surgery. Farrow et al compared primary immediate cystectomy in 15 patients to delayed cystectomy in 14 and none in either group died of bladder cancer.6 The results of immediate cystectomy, as noted by Lamm et al, have never proved superior to cystectomy performed promptly after failure of intravesical therapyF1 The 5-year actuarial survival rates as reported by Malkowicz et a1 were 85% for pure carcinoma in situ, 78% for carcinoma in situ associated with stage T1 disease and 87% for carcinoma in situ associated with stage T2 disease in patients treated initially with repeated transurethral resection, intravesical chemotherapy or immunotherapy and later by cystectomy." Thus, even early aggressive surgery does not cure every patient with carcinoma in situ, nor does a trial of intravesical therapy appear to have a negative impact on subsequent survival. Zntrauesical therapies. Carcinoma in situ is the optimal target for intravesical therapy. Close contact between agent and tumor cells occurs, and the tumor burden is low. The impact of intravesical therapies on the natural history of carcinoma in situ can be made by comparing the risk of progression with transurethral resection alone to treatment with transurethral resection plus intravesical therapy. Figure 2 shows results among 86 patients with multifocd stages Ta and T1 papillary tumors followed for more than 10 years who were initially randomized to undergo transurethral resection alone or with bacillus Calmette-Guerin

CARCINOMA IN SITU OF BLADDER

A

PROGRESSION GROUP = BCG

567

PROGRESSION GROUP = TUR

-! f

z

I I

I

I

mOnmS

lllmlhs

FIG. 2. Progression-free survival in patients with papillary Ta or T1 disease with or without associated diffise carcinoma in situ (2'1s).A, treated with transurethral resection and intravesical BCG therapy. Of 24 patients without carcinoma in situ 15 (60%)had pro ession-free survival compared to 28 of 46 (64%)with carcinoma in situ in this treatment grou B, treated with transurethral resection (T&) alone. Of 24 patients (56%)without carcinoma in situ 16 (56%)had progression-free survivarcompared to 27 of 36 (33%)with carcinoma in situ in this treatment group.

(BCG).47,52More than half of the patients in each arm had TABLE1. Effect of intravesical chemotherapy on recurrence in associated diffuse (3lesions or more) carcinoma in situ. Propatients with carcinoma in situ gression is defined as subsequent muscle invasion. Of the No, pts. No. Complete Reference Response (96) Fol'ormp patients undergoing transurethral resection alone 56% with carcinoma in situ had progression versus 33% of those Thiotepa without carcinoma in situ (p = 0.0065,fig. 2,B ) . Progression Koontz et alS5 20 11 (55) 2 yrs. was not documented beyond 48 months because those with 5 1 (20) h u t et a149 4 yrs. carcinoma in situ were crossed over to the BCG arm at that 26 mos. 24 6 (25) Stanisic et 27 mos. 16 (40) 3 hut% point and, therefore, were censored. In the BCG arm the 89 34 (38) Totals influence of carcinoma in situ on disease progression is obscured by the effects of BCG (fig. 2, A). This is excellent Mitornycin C confirmation that BCG is highly effective against carcinoma 12 wks. Harrison et alS7 6 6 (100) in situ and is significantly better than transurethral resec12 mos. Issel et dS8 14 4 (29) 58 mos. 3 (60) 5 B O ~ ~ ~ ~ O U X ~ ~ tion alone, since this study was established in a prospective, 28 mos. 12 5 (42) &lowayG0 stratified, randomized trial. 12 wks. 20 9 (45) h n t z et a161 As reviewed by Lamm, the long-term tumor-free response 27 mos. 11 Jauhiainen et a16* 9 (82) rate for intravesical chemotherapy was only 20% for 49 thio28 mos. 12 5 (42) Cant et d" 22 mos. 5 4 (80) Lucem and Wise= tepa treated carcinoma in situ patients followed more than 4 4 4 (100) 19 mos. Hetherington et alM years and 34% for 51 doxorubicin treated carcinoma in situ 15 (79) 21 mos. 19 et alS3 patients followed more than 5 years (table 1).7,18*51*53-70 Stricker 0 7 Stanisic et alM Multicenter studies have shown that thiotepa and doxorubi40 mos. 2 &loway= cin are inferior to BCG in preventing tumor r e c u ~ ~ e n c eAs . ~ ~ Totals 71 (52) 136 direct comparison of intravesical BCG to doxorubicin in paDoxorubicin tients with carcinoma in situ showed a complete response in 24 mos. 7 (88) 8 Edsmyr and AnderssonGs 74% of those treated with BCG (median disease-free interval 30 20 (67) 26 mos. Edsmyr et a16' 48 months) compared to 42% treated with doxorubicin (me15 10 (67) 12 mos. Jaske et al" 12 rnos. 55 36 (64) ~i~hans9 dian disease-free interval 5.9 months).72 In studies compar27 mo8. 22 Ek et a l " 2 (9) ing mitomycin C and BCG, initial tumor-free response rates 0 6 Stanisic et dS4 are comparable for the 2 agents, with some studies suggest65 mos. 67 23 (34) Lamm et al" ing a n advantage for BCG therapy.73374Approximately 42% Totals 203 98 (48) of carcinoma in situ patients treated with mitomycin C1s,53 Reprinted with permission.' have a long-term tumor-free response. Fukui et a1 used a combination of intravesical mitomycin C and doxorubicin for treatment of carcinoma in sit^.^^ Of 40 patients 25 (62.5%) had a n initial complete response, 12 of 23 with long-term west Oncology Group reported a n 82% tumor-free response in followup had recurrence, 4 had invasive or metastatic disease patients with carcinoma in situ followed 48 months. Primary carcinoma in situ (no previous transitional cell carcinoma), and 2 required cystectomy. The highest tumor-free success rates have been reported secondary carcinoma in situ (that occurring after previous BCG is transitional cell carcinoma) and concurrent carcinoma in situ after intravesical BCG therapy (table 2).7*51,76-88 recommended as first line treatment for carcinoma in situ (that associated with superficial transitional cell carcinoma) and has been approved by the Food and Drug Administra- respond similarly to BCG treatment.g0 Multiple investigation. Results of multiple studies suggest a n overall complete tors have now recommended intravesical BCG therapy response rate of 70% in patents with carcinoma in situ rather than cystectomy as the most appropriate initial treattreated by intravesical BCG, 64% of whom had a durable ment for carcinoma in situ. Carcinoma in situ present aRer initial BCG therapy may Coplen et a1 response of 5 years or longer (table 3).7*76*89 noted 19 of 32 carcinoma in situ patients (59%) to be tumor- have a more ominous prognosis than previously untreated free with a mean followup of 46 ? 5 months after intravesical carcinoma in situ. Herr et algl found an increased risk of BCG therapy:' while Brosman noted 27 of 33 such patients tumor progression for patients with carcinoma in situ and a rendered free of disease with a mean followup of 5.25years.76 positive urine cytology result at the initial 3-month followup Using a more optimal regimen of BCG therapy, the South- visit. The overall risk of progression was 95% at 5 years for

CARCINOMA IN SITU OF BLADDER

568

TABLE2. Response to BCG in patients with carcinoma in situ N ~pts. .

Reference

7 47 14 33 12 6 19 9 59 10 40 16 153 64

Morales7' He@ Lamm" Brosman" Kelley e t ale* Schellhammer e t al" deKernion e t a17* Soloway and Perry77 Kavoussi e t a P Rintala et alss Brosmanse Prescott et als7 ReitsmaSouthwest Oncology Group 8216" Southwest Oncology Group 8507': 6 wk. 6 + 3 Totals Reprinted with p e r m i s ~ i o n . ~

78

2 639

No. Complete Response (%) 5 (71) 34 (72) l1 (79) 21 (82) 8 (67) 6 (100) 13 (66)

Followup 23 mos. 18 mas. l4 mas.

zs.

12 mos. 15 mos. 16mos. 24 mos. 21 mas. 35 mos. 24 mos. l8 mas. 39 mos.

(56) 23 (39) (40) 28 (70) 14 (88)

lo7 (70) 45 (70)

55 (70) 49 (82) 434 (68)

48 mos. 481110s.

TABLE3. Carcinoma in situ: risk ofprogression by response to BCG Response Complete

No. b. 105

Type of

Overall Local

T2+ Incomplete

75

Metastasis Overall Loeal

T2+ Metastasis

Probability of Progression (70)

Yr. 2 1 1

0 23 20 3 0

yrs. 11 7 3 1 60 43 15 2

yrs. 19 11 7

95 65 25 5

therapy. Soloway and Perry reported a tumor-free response in 5 of 9 carcinoma in situ patents treated with BCG who had previously failed thiotepa or mitomycin C therapy.77Only 2 of the complete responders remained disease-free but none required cystectomy. deKernion et a1 reported a 68% tumorfree response in 19 carcinoma in situ patients, of whom half had previously failed thiotepa treatment^.^' Stanisic et al studied 26 patients with carcinoma in situ with and without papillary tumors treated by secondary intravesical agents.54 Therapy was successful in 6 of 24 patients treated with thiotepa, 0 of 7 treated with mitomycin C, 0 of 6 treated with doxorubicin and 3 of 8 treated with BCG, while 7 (27%) had progression to muscle invasive disease. Sarosdy (persona1 communication) recently reported a 69% short-term response to oral bropirimine in 13 patients with carcinoma in situ failing intravesical BCG therapy. Williams et a1 reported a complete response to recombinant interferon-crab in 2 of 5 patients failing BCG therapy.96 Klein et a1 reported on 41 patients who failed an initial 6-week course of BCG, of whom 19 failed with pure carcinoma in situ and 13 had carcinoma in situ in association with stage Ta or T1 disease.97 No significant difference in survival was noted in 10 patients undergoing prompt cystectomy after failure of 1course of BCG compared to 11requiring delayed cystectomy after additional intravesical therapy. Although the number of patients with refractoly carcinoma in situ treated by alternative intravesical agents is small, there are patients who appear to respond to second lines of treatment and avoid cystectomy. However, consideration of early, aggressive surgery should not be abandoned in all patients with carcinoma in situ. Recently, several studies have suggested improved survival rates for patients with high grade, lamina propria invasive disease treated with immediate cystectomy when compared to repeated transurethral r e s e c t i ~ n . ~ ~Cookson .~' and Sarosdy have shown a n impressive tumor-free response in patients with stage T1 tumors treated with intravesical BCG therapy." The association of carcinoma in situ and high grade, lamina propria invasive disease has a substantial risk for disease progression and may be a n indication for early aggressive surgery in the hands of many urologists. The presence of this form of disease after initial intravesical therapy warrants strong consideration of prompt cystectomy. Other alternative therapies should only be performed after a thorough discussion of the potential risk of progression with the motivated and reliable patient.

carcinoma in situ patients with a n incomplete response to BCG therapy but only 19% in those with an initial complete response (table 3hS2Coplen et a1 found that patients with carcinoma in situ failing an initial 6-week course of intravesical BCG therapy were more likely to have muscle invasive disease despite further intravesical therapy." Harland et a1 noted that 48% of BCG failures had progression to muscle invasive disease, compared to only 10% of patients with an initial complete response to BCG therapy.93 Treatment of carcinoma in situ refractory to initial intraLONG-TERM RESPONSES TO INTRAVESICAL THERAPY vesical therapy. Many investigators reserve intravesical therapy for the high risk patient. Therefore, failure of intravesiAre patients with carcinoma in situ ever really cured? Herr cal therapy may select the patients at highest risk for tumor et a1 suggested that BCG therapy may only delay tumor progression. These data suggest that this premise is true. progression in patients with superficial bladder cancer, inDroller and Walsh reported dire outcomes in 7 of 8 patients cluding carcinoma in situ.lo0In their report with a 10-year treated with prolonged intravesical therapy and persistently followup in 44 patients with carcinoma in situ and coexistent positive cytology ~ t u d i e s . 'Of ~ these 7 patients who eventu- papillary tumors, they noted a 31% long-term tumor-free ally underwent cystectomy 3 had pelvic lymph node metas- response rate. Of these patients 16 (36%) subsequently had tases and 4 died of distant disease. Failure to clear the tumor progression: 5 had progression to metastatic disease, bladder of other forms of high grade tumors (stage T1) within while 11 underwent cystectomy for muscle invasive tumor. 1 year have also demonstrated poorer survival rates with Although other studies report a higher complete response delayed cystectomy compared to immediate c y ~ t e c t o m y . ~ ~rate, * ~ ~these are usually determined after only short-term folPrompt cystectomy, therefore, is often recommended for pa- lowup (less than 5 years). On the other hand, Lamm et a1 tients failing 1 intravesical agent. suggested that BCG therapy may decrease the need for CYSThis, then, presents a difficult dilemma: are other forms of tectomy in up to 75% of carcinoma in situ patient^.^' Nadler alternative therapy reasonable for carcinoma in situ refrac- et a1 recently updated our series of 104 patients treated with tory to an initial intravesical agent? Clearly, many patients intravesical BCG therapy with a mean followup of 74 with a relatively asymptomatic form of carcinoma in situ months.lol More than half of these patients have remained prefer to maintain normal bladder function. Only patients disease-free. Of the original 32 patients with carcinoma in situ who are willing to assume an additional risk for the devel- 8 ultimately required cystectomy for invasive disease, 4 of opment of invasive or metastatic disease should be consid- whom were cured by cystectomy and 4 died of metastatic disered for alternative therapies. Alternative therapies have ease. Also, 4 patients had progression to mesectable disease proved effective for some patients failing initial intravesical without undergoing cystectomy and died of metastasis, while 1

CARCINOMA IN SITU OF BLADDER

with known persistent carcinoma in situ committed suicide. Of these 13 failures 5 occurred more than 2 years after apparent mccessful treatment with BCG and 2 recurrences appeared more than 5 years after BCG therapy. Clearly careful, longterm surveillance is required in all patients with carcinoma in mtu. The natural history of treated carcinoma in situ is still being defined. Although patients with residual carcinoma in mtu after intravesical treatment are at increased risk for tumor progression, this progression usually occurs after 2 years and second line intravesical therapies may be attempted with reaeonable safety9* However, carcinoma in situ should be treated as a disease requiring lifetime followup for the patient since late or extravesical recurrences are being observed more frequently. EXTRAVESICAL DISEASE

The pan-urothelial nature of carcinoma in situ is emphasized by the fact that the upper urinary tract remains at risk for "new" tumor development, especially among patients whose bladder is preserved by successful intravesical treatment. Of 128 patients with bladder carcinoma in situ treated with BCG and followed for more than 5 years 26 (20%)had upper tract tumors involving the distal ureters (19) or pelvid i c e a l system (7).'02 The median interval to upper collecting system tumor was 38 months (range 6 to 81). Of note, these tumors were clinically silent despite 9 (35%) being invasive. Klein et a1 noted 10 of 41 patients (24%) with superficial bladder tumors who failed intravesical BCG therapy and suffered upper tract disease.71 Schwartz et a1 found carcinoma in situ to be the only predictive variable in the 3% of 638 superficial bladder cancer patients treated with intravesical agents who ultimately had a n upper tract tumor.lo3 In patients followed after treatment for bladder carcinoma in situ an annual excretory urogram is necessary for at least 10 years and perhaps for a lifetime. Carcinoma in situ patients undergoing radical cystoprostatectomy without urethrectomy are at risk for the development of a urethral recurrence and should be monitored with urethral washings.lo4 Takashi e t a1 reported that 20% of carcinoma in situ patients undergoing radical cystoprostatectomy without urethrectomy died of subsequent urethral recurrence. Wishnow and Ro reported that 23 men undergoing radical cystoprostatectomy for multifocal carcinoma in situ also had transitional cell carcinoma of the prostatic ducts.lo6 Metastases developed in 11%of patients with transitional cell carcinoma limited to the ductal epithelium, whereas 100%of those with prostatic stromal invasion had metastases despite radical surgery. Schellhammer et al, in their classical review of 38 patients with transitional cell carcinoma involving the prostate, found that 42%had carcinoma in situ of the bladder.lffi The prognosis of these patients, all of whom underwent radical cystoprostatectomy, was more closely related to the depth of prostatic invasion rather than bladder involvement by tumor. Upper tract and prostatic urethral tumors are notoriously difficult to monitor by standard radiological and endoscopic techniques. The Gologist must be ever vigilant to investigate abnormal urinary cytology results and rigorously assess changes in the upper tract imaging studies with retrograde pyelograms, brush biopsies and ureteroscopy."' SUMMARY

Of transitional cell neoplasms 80% are initially papillary, while 20% arise as nodular growths. Carcinoma in situ is likely the precursor to solid tumors. Carcinoma in situ is a Bpectnun between preneoplastic or precursor lesions and frank penetration of the basement membrane. Diagnosis is subjective and descriptive only. Preneoplastic lesions can be defined by molecular markers, such as LE" and p53, and are targets for chemo-prevention strategies, just as carcinoma in mtu is a suitable target for intravesical therapies.

569

It seems clear that carcinoma in situ may have a long or a short in situ phase before progressing to invasion. The duration of a long in situ phase may be years. However, carcinoma in situ is inexorably progressive and will become invasive in 1or more areas if uncontrolled and given enough time. Carcinoma in situ does not regress but is characterized by indolent transmural growth involving bladder and eventually extravesical transitional urothelium. To date, no study has attempted to stratify carcinoma in situ patients into high and low risk groups prospectively, nor to recommend treatment options based on clinical or pathological features of carcinoma in situ. Based on our review of the literature, we suggest several studies be used in the diagnosis and monitoring of patients with carcinoma in situ for correlation with subsequent treatment outcome. Patients should undergo bladder mapping studies and be stratified into those with focal (1 site) or diffuse (more than 1 site) involvement, and with or without prostatic urethral disease. DNA ploidy will be determined and patients stratified as to the presence of only 1or multiple aneuploid cell lines. Monoclonal antibody techniques may prove highly useful in determining the invasivelmetastatic potential of carcinoma in situ. Those that appear most promising to date include over expression of p53 gene mutation, cell surface receptors, tumor associated antigens and proliferative antigens. With the information currently available, it appears that 2 forms of carcinoma in situ exist. Our educated guess would be that patients with focal carcinoma in situ, a single aneuploid cell line by DNA histogram, lack of over expression of p53, cell surface receptors, tumor associated or proliferative antigens and expression of normal urothelial antigens would predict a low risk with the best overall prognosis. Responsiveness of low risk carcinoma in situ patients to intravesical agents could proceed with a reasonable assumption of a low risk of metastases even if 1 or more intravesical therapies fail. Monitoring of these parameters during intravesical therapy and detection of a change may predict an increased risk in the malignant potential of carcinoma in situ. Such patients may then be reclassified into the high risk group. High risk factors, such as diffuse carcinoma in situ and prostatic urethral involvement, over expression of p53, cell surface receptors, tumor associated or proliferative antigens, or loss of normally expressed antigens, may predict patients in whom early, aggressive management is necessary. Either immediate cystectomy or a 3-month trial of intravesical BCG therapy followed by prompt cystectomy if BCG proves ineffective would be reasonable for high risk patients with carcinoma in situ. Clinical symptoms do not appear useful for disease stratification, although the severely symptomatic patient may elect early cystectomy to control vesical irritability. We realize that much work must be accomplished before parameters are clearly defined and accepted for classifying carcinoma in situ patients into high and low risk categories but we ~ believe the circumstantial evidence continues to S U D D O ~the theory that carcinoma in situ exists in 2 forms of-differing invasivelmetastatic potential. We urge our colleagues to stratlfy patients with carcinoma in situ by these and other new parameters to determine if we can better predict the natural history and most appropriate treatment for the individual with carcinoma in situ. Until these parameters are assessed for usefulness in predicting the likelihood of invasive or metastatic disease, and the interval during which this may occur in the individual with carcinoma in situ, treatment recommendations must remain tentative. The likelihood of invasive disease developing during the initial 6 months a h r diagnosis is low and it appears safe for the majority of patients to be treated with conservative measures within this period. Of the patients who fail conservative therapies, the majority who suffer muscle invasive disease will do so within 5 years after diagnosis but for some disease persists beyond 10 years. Carcinoma in

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situ appears to be a lifelong disease and even those cured of the bladder component must be followed indefinitely since thev are at risk for the develoDment of extravesical carcinoma. Future efforts must be -directed toward identifying risk factors in the individual before the development of invasive or metastatic disease so that appropriate aggressive local therapy and chemo-preventivestrategies can be applied effectively.

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