Original Articles: Bladder Cancer: Long-Term Outcome Related to Epidermal Growth Factor Receptor Status in Bladder Cancer

0022-5347/95/1533-0919$03.00/0 JOURNAL OF

UROLOGY

Vol. 153,919-925, March 1995 Printed in U S A .

Copyright 0 1995 by AMERICANUROLOGICAL ASSOCIATION, INC.

BLADDER CANCER LONG-TERM OUTCOME RELATED TO EPIDERMAL GROWTH FACTOR RECEPTOR STATUS IN BLADDER CANCER KILIAN MELLON, CHRIS WRIGHT, PETER KELLY, C. H. WILSON HORNE

AND

DAVID E. NEAL

From the Department o f urOk?Y and University Department of Surgery, Freeman Hospital, Medical Statistics Department and University Department O f Pathology, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom

ABSTRACT

For bladder cancer we currently lack accurate methods of predicting outcome, although clinical stage and histological grade are broad determinants of prognosis. Preliminary data have indicated that assessment of epidermal growth factor receptor status is a method of further subclassifying bladder cancer. We assessed prospectively the clinical significance of determining epiderm a l growth factor receptor status in 212 patients with newly diagnosed bladder cancer who were followed for 1 to 96 months (mean 26.5). In multivariate analyses epidermal growth factor receptor w a s confirmed to be an independent predictor of survival (p = 0.004) a n d stage progression (p = 0.0004). Most importantly, epidermal growth factor receptor status w a s found to be 80% sensitive and 93%specific in predicting stage progression in T1, grade 3 bladder cancer. We conclude that epidermal growth factor receptor status is a useful molecular m a r k e r in patients with bladder cancer, especially those without infiltration of the detrusor muscle at presentation. KEY WORDS: bladder neoplasms; prognosis; immunohistochemistry;receptor, epidermal growth factor-urogastrone In transitional cell carcinoma of the bladder clinical stage (T category) and histopathological grade are undoubtedly strong determinants of prognosis. Based on T category, bladder cancer can be classified into the 2 broad categories of superficial (pTa/Tl) and muscle-invasive disease (T2 to 41, with quite distinct natural histories. The principal clinical problems encountered with superficial bladder cancer are a high rate of tumor recurrence (60 to 70%)but, more importantly, progression to muscle invasion or metastatic disease in 10 to 20%of patients. Risk factors for tumor recurrence are stage, grade, tumor size, tumor multiplicity and positive 3-month followup cystoscopy.lV2 For progression risk factors include stage, grade and the presence or absence of mucosal abnormalities elsewhere in the tumor-bearing bladder.Recently the basic classification of superficial bladder cancer has become less clinically relevant as it has become clear that, depending on the grade, T1 tumors frequently behave quite differently from Ta tumors. Unresolved clinical problems associated with muscle-invasive cancer are a variable predilection for metastasis and an unpredictable response to treatment. Currently, what we lack most are reliable methods of predicting which superficial tumors (especially T1) will progress and which tumors (especially T2 to 4 but also T1) will metastasize. The current upsurge in molecular biological studies of human solid tumors, including transitional cell tumors of the bladder, is at least partly attributable to the rapid accumulation of a significant amount of information concerning the role of growth factors, oncogenes, chromosomal losses and tumor suppressor genes. It is hoped that such information will assist in defining subgroups of poor prognosis and can be used t o design improved therapeutic strategies. We have been studying the role of the epidermal growth factor receptor in bladder cancer for almost a decade, and in 1990 we reported promising preliminary data from a mixed series of 101 patients with superficial and muscle-invasive bladder cancer, indicating that the assessment of epidermal growth

factor receptor status could assist in defining patient subgroups of poor prognosis.6 This study has now been extended to include more patients with longer clinical followup. PATIENTS AND METHODS

Patients. Fresh tumor biopsies were collected from 212 patients with newly diagnosed bladder cancer. The study group comprised 2 subgroups, including 101 patients recruited to the study between 1984 and 1986, for whom individual patient and tumor details were known as well as the epidermal growth factor receptor status of the primary tumor, and 111 patients recruited between 1989 and 1990, from whom additional information concerning smoking habit and urothelial abnormalities elsewhere in the tumor-bearing bladder was gathered. There were 159 men and 53 women between 35 and 89 years old (mean age 69, standard deviation 9.7). Of the patients 39 smoked a n average of 4 to 50 cigarettes per day, 2 smoked a pipe, 18 had stopped smoking, 38 had never smoked cigarettes and smoking habit was unknown in 14. Histopathology. Tumors were staged by the tumor, node and metastasis system7 and graded histologically according to the system described by Bergkvist et a1.' A total of 99 patients had tumors infiltrating the muscle of the bladder wall (T2 to 4) and 113 had pTa or pT1 disease. Eight patients had grade 1 tumors, 102 grade 2 and 102 grade 3 (table 1). Of the 113 patients with superficial bladder cancer 74 (65%)had solitary tumors. Mean tumor size was 2.83 cm. for Ta (confidence interval 2.49 to 3.17), 4.0 cm. for T1 ( c o d dence interval 3.57 t o 4.43) and 4.61 cm. for muscle-invasive tumors (confidence interval 4.23 to 4.98). The majority of tumors were transitional cell carcinOmas but there were 5 pure squamous cell carcinomas and 1 pure adenocarcinoma. A further 30 tumors demonstrated a mixed histological pattern with transitional cell elements admixed with additional elements (squamous elements in 14, squamous and adenomatous in 1, squamous and sarcomatous in 2, adenomatous in 9, Accepted for publication August 19, 1994. Supported in art by a research grant from the North of England sarcomatous in 1, adenomatous and small cell in 2, and neuroendocrine in 1). Cancer ResearcR Campaign. 919

EPIDERMAL GROWTH FACTOR RECEPTOR STATUS IN BLADDER CANCER

920

T ~ L 1. E Epidermal growth factor receptor status and tumor stagelgrade (212 cases) Ta (70 cases) Grade

T1 (43 cases)

T2 (26 cases)

1

2

3

1

2

3

1

2

5

55

1

2

12

15

0

5

T3 (51 cases) 3

1

T4 (22 cases)

2

3

1

2

2

12

0

1

3

~

Epidermalgmwthfactorreceptorneg. Epidermal growth factnr receptor pos. Totals % Epidermal growth factor receptor

~

Q

5 13

6

s 4

1

~

3 33

1 2

0

~ 2

0

~

0 54

1

0

1

1

7

0

s

_

5

0 73

4

s

4

7

Q

0 64

z

3

7

3

1

9

WS.

TABLE2. First line treatment of patients with muscle-inuasiue disease systemic

Stage T2 T3 T4

&;i,"" ChemotheraDv

Radiotherapy

PartiabTotal Cvstectomv

14 7 7

4 6 2 18* 18* 9 6 6 3 Totals 28 28 30 14 * One patient received a combination of systemic chemotherapy and radiotherapy as primary treatment.

Primary bladder tumor biopsies obtained by resection and small mucosal biopsies (approximately 2 mm. in size) with flexible biopsy forceps and taken from normal-appearing bladder mucosa from an area of urothelium within 2 cm. of the tumor base (termed near biopsy) and from an area well away from the tumor (termed far biopsy) were examined for the presence of carcinoma in situ, dysplasia or other histological abnormality. Carcinoma in situ was detected in association with a concomitant bladder tumor in 14 of 111cases (13%)(6 stage T1 and 8 stage T2 to 4). Carcinoma in situ was most frequently detected in the primary tumor biopsy, and was found in only 1near biopsy and 2 far biopsies. Urothelial dysplasia was a more common finding in small biopsies of normal-appearing mucosa, and was present in 4 near and 5 far biopsies. Of significance was the finding of frank transitional cell tumor in 9 near and 2 far biopsies. Cystitis was reported in 28 near and 26 far biopsies, and 34 near and 41 far biopsies were reported as histologically normal (in 35 cases small biopsies were not taken). Treatment. Patients were recruited to the study during a 6-year period from the practices of 5 consultant urologists with inevitable minor variations in the exact management of individual patients. In addition, during the same period there were changes in the preferred chemotherapeutic agents used to treat superficial and muscle-invasive bladder cancer. All patients enlisted for the study underwent examination with anesthesia and cystoscopy to establish the precise diagnosis at which time appropriate biopsies were obtained. Superficial Tumors: Patients with pTa/Tl bladder cancers were treated with endoscopic resection and cystoscopy every 3 months during the first year after diagnosis, every 4

months during year 2 and annually thereafter provided the bladder remained free of tumor. When treatment of superficial bladder cancer by endoscopic means alone became difficult (because of multifocal disease or the detection of carcinoma in situ) the standard practice was for the patient to receive intravesical chemotherapy. During the study period 26 patients were given between 1 and 4 courses of intravesical chemotherapy using mitomycin, epirubicin or bacillus Calmette-Guerin. Invasive Tumors: The primary treatment of 99 patients with muscle-invasive bladder cancer is shown in table 2. Patients with muscle-invasive disease who had undergone resection alone were either unfit for alternative radical treatment (stage T3 in 5 cases), had incurable T4 tumors (7) or had suffcient initial treatment (stage T3 in 2 and T2 in 14). A total of 28 patients received systemic chemotherapy, containing cisplatin and methotrexate alone or in combination with doxorubicidvinblastine or epirubicin after transurethral resection. Of these patients 3 subsequently received radiotherapy (1 patient received chemotherapy and radiotherapy in combination as first line treatment). A total of 30 patients received either radical or palliative radiotherapy. After establishing a histological diagnosis 9 patients underwent radical cystectomy (1in combination with nephroureterectomy) and 5 recruited during the early years of the study underwent partial cystectomy. During clinical followup another 7 patients were treated by cystectomy 1 to 26 months after diagnosis, and a further planned cystectomy was abandoned after discovering pelvic lymph node involvement. Immunohistochemistry. A standard immunohistochemical method was used to stain sections of tumor as described p r e v i o u ~ l y . ~Briefly, *'~ frozen sections of tumor were stained using the monoclonal antibody epidermal growth factor receptor 1. Assessment of Staining: To assess staining the intensity of positive staining was considered together with the distribution of staining throughout the section. Intensity of staining was scored on a 5-point scale of zero, very weak, weak, moderately strong and very strong. A semiquantitative assessment of the extent of staining was made depending on the proportion of tumor cells positively stained: 0 to 25%, 25 to 50%, 50 to 75% and 75 to 100%. In the final analysis of the

TABLE3. Univariate and multivariate regression analysis of risk factors predictive of death due to bladder cancer in 212 patients Factor

Univariate Model Relative Risk

1.81 9.80 Stage 8.11 Grade Size 1.21 Multiple 0.52 Epidermal growth factor receptor status 5.99 1.21 Age 2.21 Ca in situ Metaplasia 5.96 Smoking 1.33 Near biopsy 0.32 Far biopsy 0.38 Papillary/solid 32.5 * p 20.1 and not included in the multivariate model. sex

Final Model

p Value

Relative Risk

p Value

0.025 <0.0001 <0.0001 0.0005 0.047 <0.0001 0.31 0.11 <0.0001 0.56 0.003 0.016 <0.0001

Not statistically significant* 3.36 2.97 Not statistically significant* Not statistically significant* 2.54 Not statistically significant'

Not statistically significant* 0.004 0.005 Not statistically significant* Not statistically significant* 0.004 Not statistically significant*

Not statistically significant:

Not statistically significant*

5

0

EPIDERMAL GROWTH FACTOR RECEPTOR STATUS IN BLADDER CANCER

921

EGFr- (n=l24)

P<0.0001

EGFr+ (11-88)

0.0

1

I

1

I

I

I

0

20

40

60

80

100

Time(mt hs) Noatrisk

0

1

2

3

4

5

6

7

Byr~

E G F ~neg. EGFr PO%.

I24 88

102 50

59 Z7

29

28 7

26 7

20 5

9 1

1 1

10

FIG. 1. Survival and epidermal growth factor receptor (EGFr)status (all patients). mths, months

data only tumors that were unequivocally positive, that is graded as moderately strong or very strong to any extent, were considered positive and the others were considered negative. All sections were assessed by 2 independent observers. Interobserver Error: Of 111tumors 95 (86%) were graded similarly in regard to staining intensity by the 2 observers following the initial independent assessment of epidermal growth factor receptor status. As might be expected, there was some variability between the 2 observers in the exact interpretation of diffise weakly positive staining of tumor sections. Such sections accounted for 12 of 16 tumors in which the initial independent assessments were different but by 1grade only. In 4 sections the initial grades differed by 2 points on the grading system. In these discordant cases a consensus view was reached by reviewing the sections jointly. Statistical methods. Descriptive statistical analysis of data is reported as means with standard deviations or 95% confidence intervals of the means as appropriate. The rate of tumor recurrence was defined as the number of followup cystoscopies in which recurrent tumor was found per month of clinical followup multiplied by Stage progression was defined as later detection of tumor of higher stage or the development of metastases. Differences between grouped data were analyzed using the Mann-Whitney test, chi-square test or Kruskal-Wallis nonparametric test for comparing more than 2 groups, adjusted for ties. To assess which parameters influence survival, tumor recurrence and stage progression, proportional hazards regression" was used. These analyses examined the relative importance of the potential prognostic factors of sex, stage, grade, tumor size, multiplicity, age, smoking habit, presence of metaplasia, carcinoma in situ, dysplasidcarcinoma in sit& tumor in near and far biopsies, pedunculatedsessile tumor morphology, papillary compared with solid tumor architec-

ture and epidermal growth factor receptor status. Initially, each factor was treated as independent and its relative risk was calculated together with the significance level of that factor (p value). Age was divided into 10-year intervals of less than 50, 50 to 60, 60 to 70 and greater than 70 years. The data for sex, stage, grade, tumor size, multiplicity, age and epidermal growth factor receptor status were then analyzed using Cox's proportional regression with a forward stepwise procedure. Clearly, there will be several strong associations between some of the independent factors. Hence, once a particular factor is selected for the multivariate model, other factors that are associated with it will not be adding new information to the model and, therefore, seemingly significant factors in the univariate sense may not actually be included in the multivariate model. The number of parameters that could be included in the multivariate analyses was dictated by the size of the study g r ~ u p . ' ~ In survival models the data from patients who died of causes other than bladder cancer and who were free of tumor at the time were treated as censored data. The data were analyzed using statistical software. RESULTS

Clinical course. The clinical course of each patient was charted and all significant events were recorded. Mean period of followup was 26.5 months (standard deviation 23.6, range 1 to 96). For those patients with superficial tumors mean followup was 34 months (range 2 to 96) and for those with infiltrative tumors it was 17.6 months (range 1 to 89). Only 17 patients (15%)with superficial disease had less than 12 months of clinical followup. Death. During the study period 87 patients (41%) died, including 62 (29%) of bladder cancer. The causes of death

922

EPIDERMAL GROWTH FACTOR RECEPTOR STATUS IN BLADDER CANCER

P10.06 O0g24 \

0.0

EGFr+ (n-65)

;

I

I

I

I

1

0

18

36

54

72

90

Time (mt hs) Noatrisk EGFr neg. PoS*

0

1

2

3

4

5

6

7

8 F

34

12 17

5 6

5 6

5

3 1

2 1

2 1

2

2

65

1

FIG.2. Survival and epidermal growth factor receptor (EGFr) status (muscle-invasive tumors only). mths, months

other than bladder cancer were myocardial infarct in 6 cases, cerebrovascular accident in 5,pulmonary embolus in 1,bronchogenic carcinoma in 5, complicated chronic obstructive airway disease in 2, colonic carcinoma in 1, renal failure secondary to papillary necrosis in 1 and unknown in 4. The death rate due to bladder cancer in superficial tumors was 8.8% (10of 113 patients) and for those with muscle-invasive tumors it was 52% (52of 99). Tumor recurrence. Of 113 superficial tumors 82 (73%) recurred, including 48 of 70 stage Ta (69%) and 34 of 43 stage T1(79%). T1 tumors had a significantly greater mean recurrence rate (14.2per 100 patient-months, confidence interval 11.1 to 17.4)compared to Ta tumors (9.3per 100 patientmonths, confidence interval 7.0 to 11.6,p = 0.03). Stage progression. Stage progression occurred in 19 of 113 pTdpT1 tumors, including 8 of 70 stage Ta (11%) and 11 of 43 stage T1 (26%)(chi-square 3.82,p = 0.05).Five Ta tumors

progressed to T1 (in 1 patient muscle-invasive disease also developed with metastases and 1 patient later presented with metastatic disease). In 2 patients with initially Ta tumors muscle-invasive disease developed and another patient presented with evidence of metastatic urothelial cancer after only having Ta disease in the bladder. Of those T1 tumors that later progressed 10 became muscle-invasive (1 with evidence of metastatic disease) and 1 metastasized. Bladder cancer prognosis related to epidermal growth factor receptor status. Overall, 88 of 212 tumors (42%) were epidermal growth factor receptor positive (table 1). A strong association was confirmed between epidermal growth factor receptor positivity and high tumor stage (chi-square 50.6,p <0.0001)and high tumor grade (chi-square 23.5,p
TABLE4. Univariate and multivariate regression analysis of risk factors predictive of time to recurrence in 113 patients with superficial bladder cancer Factor

Sex stage

Grade Size Multiple Epidermal growth factor receptor status Age Ca in situ Smoking Near biopsy Far biopsy Pedunculated/sessile

Univariate Model

Final Model

Relative Risk

p Value

Relative Risk

p Value

1.14 1.59 1.42 1.20

0.63 0.04 0.19 0.004 0.14 0.06 0.44 0.04 0.58 0.75 0.96 0.02

Not statistically significant Not statistically significant Not statistically significant 1.20 Not statistically significant Not statistically significant Not statistically significant

Not statistically significant Not statistically significant Not statistically significant

1.07

1.62 1.13 2.04 0.83 0.92 1.01 0.40

co.01

Not statistically significant Not statistically significant Not statistically significant

EPIDERMAL GROWTH FACTOR RECEPTOR STATUS IN BLADDER CANCER

Om8

Ii

923

P10.036

Time(mths1 Noatrisk

0

1

2

3

4

5

6

7

8yrS

E G F ~neg. EGFr POS.

90

38

25

5 1

1

2

8 2

5

4

12 2

7

23

1

1

2

FIG.3. Recurrence and epidermal growth factor receptor (EGFr) status (pTa and pT1 tumors). mths, months

with epidermal growth factor receptor positivity, with those positive being larger (4.56cm., confidence interval 4.12 to 4.99)than those negative (3.43cm., confidence interval 3.15 to 3.71,p
opsies, and solid tumor architecture. In the final model the factors that were significant were stage (p = 0.004),grade (p = 0.005)and epidermal growth factor receptor status (p = 0.004,fig. 1).The difference in survival for epidermal growth factor receptor positive and negative tumors failed to reach statistical significance when the data from patients with muscle-invasive tumors were analyzed separately (p = 0.06, fig. 2). Recurrence and epidermal growth factor receptor status. For Ta tumors the mean recurrence rate was significantly higher for those that were epidermal growth factor receptor positive (18.1per 100 patient-months, confidence interval 8.4 to 28,9 cases) compared to those that were epidermal growth factor receptor negative (7.6per 100 patient-months, confidence interval 5.4to 9.8,61cases, p = 0.012).The recurrence rate of pT1 tumors was similar regardless of epidermal growth factor receptor status. The mean recurrence rate of 14 epidermal growth factor receptor positive T1 tumors was 16.6

TABLE5 . Univariate and multivariate regression analysis of risk factors predictive of time to progression in 113 patients with superficial bladder cancer Univariate Model Factor

Relative Risk

p Value

Final Model Relative Risk

Sex 1.91 0.19 Not statistically significant Stage 3.36 0.007 Not Statistically significant Grade 2.97 0.03 Not statistically significant Size 1.46 0.0006 1.40 Multiple 2.53 0.007 Not statistically significant Epidermal growth factor receptor status 6.15
p Value Not statistically sigdicant Not statistically sigdicant Not statistically significant 0.004 Not statistically significant O.OOO4

Not statistically significant

924

EPIDERMAL GROWTH FACTOR RECEPTOR STATUS IN BLADDER CANCER

P
0.o 0

40

20

60

80

100

Time(mths) Noatrisk0 EGFr neg. 90 EGFrPoS.23

I

2

3

4

5

81 18

52 9

25

24 6

6

6

7

8yrs

23

18

3

7 1

1

6

I

FIG.4. Progression and epidermal growth factor receptor (EGFr)status (pTa and pT1 tumors). mths, months

per 100 patient-months (confidence interval 10.5 to 22.5) compared to 13.1per 100 patient-months (confidenceinterval 9.2 to 17.0) for 29 epidermal growth factor receptor negative T 1 tumors (p = 0.35). The mean time to first recurrence was not significantly different for epidermal growth factor receptor positive superficial tumors (4.50 months, confidence interval 2.85 to 6.15, 20 cases) compared to epidermal growth factor receptor negative tumors (6.01 months, confidence interval 4.20 to 7.82, 62 cases, p = 0.64). Table 4 shows the results of univariate and multivariate regression analyses of factors in predicting time to recurrence in patients with superficial bladder cancer. In the univariate model the factors that had a significant effect were stage, size, sessile morphology and the presence of concomitant carcinoma in situ. Epidermal growth factor receptor status was not a significant factor (p = 0.06, fig. 3). In the final multivariate analysis the only factor that was significant was tumor size (p <0.01). Progression and epidermal growth factor receptor status. Stage progression occurred in 19 of 113 pTdpT1 tumors and was more likely in epidermal growth factor receptor positive tumors (10 of 23) compared with epidermal growth factor receptor negative tumors (9 of 90) (chi-square 14.7, p <0.001). Progression occurred in 3 of 8 epidermal growth factor receptor positive Ta tumors compared with 6 of 62 epidermal growth factor receptor negative Ta tumors (p = 0.06) and in 7 of 11epidermal growth factor receptor positive T1 tumors compared with 7 of 32 epidermal growth factor receptor negative T1 tumors (p = 0.009). Of 20 T1, grade 3 tumors 5 progressed, of which 4 were epidermal growth factor receptor positive (sensitivity 80%), and only 1 of the remaining 15 was epidermal growth factor receptor positive (specificity 93%). Table 5 indicates the results of univariate and multivariate regression analyses of factors in predicting

time to stage progression in patients with superficial bladder cancer. In the univariate model the factors that had a significant effect were stage, grade, size, metaplasia, multiplicity and epidermal growth factor receptor status. In the final multivariate analysis the only factors that were significant were size (p = 0.004) and epidermal growth factor receptor status (p = 0.004, fig. 4). DISCUSSION

In the management of patients with bladder cancer certain prognostic parameters are well established. The difference in the clinical behavior of high stage muscle-invasive tumors compared with low stage noninvasive tumors is striking with regard to patient survival and has led some authors to suggest that such tumors are fundamentally different in terms of biological makeup. In this series the importance of tumor stage as a strong predictor of recurrence, progression and survival is confirmed. Histological grade has been shown to be a n independent predictor of survival in this series but, in agreement with the previous study and many others, it failed to predict independently recurrence and progression. There was a surprisingly low number of cases in which carcinoma in situ was detected in the small mucosal biopsies and a surprisingly high number of such biopsies in which franktransitional cell tumor was detected. Positive near and far biopsies, defined as biopsies exhibiting dysplasia, carcinoma in situ or frank tumor, were significant in the univariate analysis of risk factors for death due t o bladder cancer, and carcinoma in situ similarly had an effect on the risk of future tumor recurrence. The acquisition of data relating to smoking habit was not influential in any of the 3 main analvses. " As previously noted by us several characteristics of the ~~

EPIDERMAL GROWTH FACTOR RECEPTOR STATUS IN BLADDER CANCER

925

study population differ from those expected if dealing with a prognostic factors should be an indication for more radical randomly selected group of patients with newly diagnosed local treatment in the form of cystectomy. bladder cancer. There was a relatively high proportion of R. Hall, P. Ramsden, P. Powell and D. Essenhigh helped muscle-invasive tumors in the study group overall, and the recruit patients to this study. It is rate of tumor progression for Ta tumors was high (11%). possible that these anomalies resulted because only tumors that were sufficiently large to provide samples for routine REFERENCES histopathology and snap freezing were included in the study. 1. Anderstriim, C., Johansson, S.and Nilsson, S.: The significance The small number of grade 1 tumors is a reflection of the of lamina propria invasion on the prognosis of patients with grading system used by the pathologist. The Bergkvist sysbladder tumors. J. Urol., 124: 23, 1980. tem of grading differs from the World Health Organization 2. Parmar, M. K B., Freedman, L. S., Hargreave, T. B. and Tolley, system and allows for essentially no abnormality of cellular D. A.: Prognostic factors for recurrence and followup policies in differentiation in the grade 1category. The mean followup of the treatment of superficial bladder cancer: report fmm the British Medical Research Council Subgroup on Superficial 26.5 months in a study that began 8 years ago is a reflection Bladder Cancer (Urological Cancer Working Party). J. Urol., of combining 2 patient cohorts and is also influenced by the 142: 284,1989. relatively short survival of a significant proportion of pa3. Althausen, A. F., Prout, G. R., Jr. and Daly, J. J.: Non-invasive tients with muscle-invasive disease. papillary carcinoma of the bladder associated with carcinoma Epidermal growth factor receptor status in bladder cancer in situ. J. Urol., 116 575, 1976. has been assessed by others. Messing determined the distri- 4. Smith, G., Elton, R. A, Beynon, L. L., Newsam, J. E., Chisholm, bution of epidermal growth factor receptor in neoplastic and G. D. and Hargreave, T. B.: Prognostic significance of biopsy nonneoplastic urothelium. l3 He reported that epidermal results of normal-looking mucosa in cases of superficial bladgrowth factor receptors are detected only in the basal layer of der cancer. Brit. J. Urol., 55: 665, 1983. 5. Jakse, G., h i d l , W., Seeber, G. and Hofstiidter. F.: Stage T1, epithelial cells in most normal urothelial specimens and in grade 3 transitional cell carcinoma of the bladder: an unfavorall pathological specimens without urothelial malignancy. able tumor? J. Urol., 137: 39, 1987. On the other hand, 92% of low grade superficial tumors and 6. Neal, D. E., Sharples, L., Smith, K, Fennelly, J., Hall, R. R. and 100% of high grade tumors had epidermal growth factor Harris, A. L.: The epidermal growth factor receptor and the receptor richly expressed by superficial as well as deeper prognosis of bladder cancer. Cancer, 65:1619, 1990. layers of urothelium. This latter pattern of distribution of 7. Hermanek, P. and Sobin, L. H.: TNM classification of malignant epidermal growth factor receptor was also found in all cases tumours, 4th ed. International Union Against Cancer. Heidelof endoscopically normal-appearing urothelium from tumor berg: Springer Verlag, p. 133, 1987. 8. Bergkvist, A, Ljungqvist, A. and Moberger, G.: Classificationof bearing bladders. It is likely, as indicated by Messing, that bladder tumours based on the cellular pattern. Preliminary methodological differences account for the discrepancies bereport of a clinical-pathological study of 300 cases with a tween his results and ours, especially in relation to the minimum follow-up of eight years. Ada Chir. Scand., 130:371, greater percentage of superficial, low grade tumors found by 1965. Messing to have abnormal epidermal growth factor receptor 9. Neal, D. E., Marsh, C., Bennett, M. K., Abel, P. D., Hall, R. R., expression. Sainsbury, J. R. C. and Harris, A. L.: Epidermal-growth-faetor Our study confrms that epidermal growth factor receptor receptors in human bladder cancer: comparison of invasive status is a strong independent predictor of survival and stage and superficial tumours. Lancet, 1 6 366,1985. progression in bladder cancer. Unlike our earlier study, epi- 10. Wright, C., Mellon, K, Johnston, P., Lane, D. P., Harris, A L., Horne, C. H. W. and Neal, D. E.: Expression of mutant p53, dermal growth factor receptor has not been shown to provide c-erbB-2 and the epidermal growth faetor receptor in transiindependent prognostic information in predicting tumor retional cell carcinoma of the human urinarv bladder. Brit. J. currence. Over expression of epidermal growth factor recepCancer, 63:967,1991. tor in bladder tumors has been shown in this study to be associated with an adverse prognosis. The importance of this 11. Cox. D. R.: Remssion models and life tables (with discussion). J. Rby. Stat. &c. B., 34:187, 1972. h d i n g relates to the management of superficial tumors that 12. Altman, D. G.: Statistim for Medical Research. London: Chapman are at risk of recurrence and more importantly of stage proand Hall, 1991. gression. It could be argued that the finding of epidermal 13. Messing, E. M.: Clinical implications of the expression of epidergrowth factor receptor over expression by a tumor with invamal growth faetor receptors in human transitional cell carcinoma. Cancer Res., M). 2530,1990. sion of the lamina propria and in association with other poor