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RECURRENCE AND PROGRESSION IN LOW GRADE PAPILLARY UROTHELIAL TUMORS
0022-5347/99/1623-0702/0 THEJ O ~ N A OFLUROLOCY Copyright Q 1999 by AMERICAN UROLOGIC& ASSOCIATION,I N C .
Val. 162,702-707, September 1999 Printed in U.S.A.
RECURRENCE AND PROGRESSION IN LOW GRADE PAPILLARY UROTHELIAL TUMORS STEN H O L W G , HANS HEDELIN, C m S ANDERSTROM, ERIK HOLMBERG, CHRISTER BUSCH AND SONNY L. JOHANSSON From the Department of Urology and Oncological Centre, Sahlgrenska University Hospital, Gdteborg, Department of urology, Ktirnsjukhuset, Skovde, Sureden, Department of Pathology, University Hospital, Tromso, Norway, and Department of Pathology and Microbiology, Eppley Institute of Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska
ABSTRACT
Purpose: We report long-term followup data on patients with World Health Organization (WHO) grade I bladder tumors, and determine whether histopathological subgrouping as papillary neoplasm of low malignant potential and low grade papillary carcinoma is of clinical value. Materials and Methods: All 680 patients in western Sweden with first diagnosis of bladder carcinoma in 1987 to 1988 were registered and followed for at least 5 years. Of the tumors 255 (37.5%)were stage Ta, WHO grade I. Tumors were further classified as papillary neoplasm of low malignant potential in 95 patients and low grade papillary carcinoma in 160 according to WHO and the International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the bladder. Results: Mean age of patients a t first diagnosis of low grade papillary carcinoma was 69.2 years, which was 4.6 years higher than those with papillary neoplasm of low malignant potential (p <0.005). During a mean observation time of 60 months our 255 patients underwent 577 operations for recurrences and had 1,858 negative cystoscopies. The risk of recurrence was significantly lower in patients with papillary neoplasm of low malignant potential compared to those with low grade papillary carcinoma (35 versus 71%, p <0.001). The risk of recurrence was higher in patients with multiple tumors a t first diagnosis a s well as those with recurrence at the first followup after 3 to 4 months. Stage progressed in 6 patients (2.4%), all with low grade papillary carcinoma a t diagnosis. Conclusions: More than 90% of patients with stage Ta, WHO grade I have a benign form of bladder neoplasm, and few have truly malignant tumors. Future research should focus on reducing the number of recurrences and followup cystoscopies, and finding methods to identify malignant tumors so that pertinent treatment can be instituted. Subgrouping of WHO grade I bladder tumors a s papillary neoplasm of low malignant potential and low grade papillary carcinoma seems to add valuable prognostic information. KEY WORDS:bladder, bladder neoplasms, World Health Organization,recurrence, prognosis
Noninvasive World Health Organization (WHO) grade I bladder tumors account for 25 to 38% of all bladder carcinoMost patients with this form of bladder cancer are treated at local hospitals and are rarely referred t o larger hospitals or tertiary care facilities for treatment. There are few reports dealing with this specific We report on 255 patients with stage Ta, WHO grade I bladder tumor from a large geographical region (population 1.6 million), the majority of whom were treated at local hospitals and followed for at least 5 years. The most common grading systems for bladder cancer are the WHO, Bergkvist and modified Bergkvist sy~tems.”~Recently a new consensus for bladder tumors was adopted by WHO and International Society for Urologic Pathology (ISuP).8 Papillary lesions were categorized as papilloma, papillary urothelial neoplasm of low malignant potential, low grade papillary carcinoma or high grade papillary carcinoma. We determined whether subgrouping 255 stage Ta, WHO grade I tumors (modified Bergkvist grade 1 and grade 2A) as papillary neoplasm of low malignant potential and low grade papillary carcinoma would be of prognostic significance. Accepted for publication April 1. 1999. Supported by the Western Sweden Oncological Center and Kommunalforbundet Vastra Gotaland.
PATIENTS AND METHODS
Western Sweden Health Care District. The counties of avsborg, Skaraborg, Bohusliin and Halland (northern part), and the city of Gijteborg form the Western Sweden Health Care District. In 1987 this area had a population of 1.6 million. Sahlgrenska University Hospital, Ostra Hospital and Lundby Hospital serve the largest city, Goteborg, and its 430,000inhabitants. Outside of Gijteborg there are 15 hospitals each with catchment areas of 30,000 to 150,000 inhabitants. There is only 1 small private hospital in the region. Transurethral resections of the bladder for diagnosis and treatment of bladder carcinomas were performed a t all 19 hospitals during the study period. A bladder cancer treatment program was designed in 1986’ which was accepted and adopted by the urologists and surgeons in the area. A decision was made to treat noninvasive WHO grades I and I1 carcinomas with transurethral resection and followup cystoscopy every 4 to 6 months. When the patient had been recurrence-free for 2 years, cystoscopy was recommended once or twice a year. A prospective registration of all newly diagnosed bladder tumors was performed as part of the treatment program. The registration of bladder tumors began February 1,1987 and ended January 31,1989. The surgeodurologist completed a form which included patient name, date of birth, gender, clinical stage and his-
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RECURRENCE AND PROGRESSION IN LOW GRADE PAPILLARY UROTHELIAL TUMORS
topathological findings. The register was compared to the Swedish Cancer Registry and found to be identical. Grading, staging and followup. All histopathological material from the primary tumors was reviewed by one of us (S. L. J.). Nearly 40 pathologists from 7 different pathology departments and 2 private laboratories were involved in the initial classification of cases. The tumors were graded according to the WHO7 and modified B e r g k ~ i s t systems, ~.~ and the WHO/ISUP consensus classification.8 The latter classification stratifies papillary urothelial neoplasms as papilloma, papillary urothelial neoplasm of low malignant potential, low grade papillary urothelial carcinoma and high grade papillary urothelial carcinoma (fig. 1).The Appendix shows the translation of the modified Bergkvist system into the WHO/ ISUP consensus classification. The modified Bergkvist grading system is based on pattern analysis (fig. 2). A general rule is that the pattern should be judged in areas of the section where papillae are sectioned perpendicular to the surface and basement membrane and, thus, include the fibrovascular stalk. Obliquely or longitudinally cut areas should be avoided. Furthermore, the tumors were staged according to the TNM system. lo Routine blood tests, a plain chest x-ray and excretory urography were performed before diagnostic transurethral resection of the bladder. All original patient records were reviewed in 1994 to 1996 by one of us (S. H.) resulting in at least 5 years of followup. Individual followup was calculated as the number of months from the date of the diagnostic surgical procedure (usually radical transurethral resection of the bladder) to the date of the most recent cystoscopy. A recurrence was defined as a tumor which was fulgurated (no histopathological material) or resected (with histological examination which displays urothelial malignancy). Progression in stage was defined as a recurrence with at least deep lamina propria invasion (stage pTlb) or development of metastatic disease. The chi-square test was used for comparisons between groups. The probability of recurrence was calculated using
703
Kaplan-Meier estimates and compared with the log rank test. RESULTS
Mean age of all 680 patients was 70.5 years and 25% of the patients were women. Mean age plus or minus standard deviation of 95 patients with papillary urothelial neoplasm of low malignant potential was 64.6 2 13.9 years (range 29 to 94) and of 160 with low grade papillary urothelial carcinoma it was 69.2 t 11.7 (range 28 to go), which was statistically significant (p <0.005). Of the patients with papillary urothelial neoplasm of low malignant potential 17 (17.9%) and of those with low grade papillary urothelial carcinoma 41 (25.6%)were women (difference not statistically significant). Total followup for the 255 patients was 15,203 months (average 59.6 per patient) and there was no difference in followup between the groups. The diagnostic operation was performed a t the university hospital in 54 patients and a t local hospitals in 201. During followup only 1patient was referred to the university hospital for additional treatment. The primary surgical pathology report was classified as WHO grade I or papilloma in 81% of patients with papillary urothelial neoplasm of low malignant potential and as WHO grades I to I1 or I1 in 19%.Of the cases with low grade papillary urothelial carcinoma 39%were initially reported as WHO grade I, 11%as WHO grade I to I1 and 43% as WHO grade 11. Of the cases 9 initially classified as pTaGIII, pTlGII or pTlGIII were reclassified by the reviewer as noninvasive WHO grade I (low grade papillary urothelial carcinoma). On the other hand, 5 cases initially classified as pTaGl were reclassified as pTaGIII, pTlGII or pTlGIII and, thus, not included in this report. The primary tumor was removed during 1 transurethral resection in all but 6 patients. In 5 cases a second resection was necessary. One patient had a bladder filled with tumor and was treated with cystectomy after initial diagnostic transurethral resection. Three patients 81 to 90 years old died within 30 days after diagnostic transurethral resection of the bladder. Their general condition was poor even before I I the operation and, although there were no recorded postopUrothelial neoplasm erative complications, it cannot be completely ruled out that Grade? transurethral resection of the bladder contributed to premature death. A fourth patient had considerable perioperative bleeding during resection of a large recurrence and died postoperatively from a myocardial infarction, which was considered a treatment related death. Predominant Multiple primary tumors were slightly more common among order patients with low grade papillary urothelial carcinoma (difference not statistically sigmfxant, table 1). Patients with multiGrade 1,2A1 ple primary tumors had a higher risk of future recurrences but those with a single primary tumor accounted for the majority of recurrences (table 2). During followup 143patients (58%)had at least 1 recurrence. Of 93 patients with papillary urothelial neoplasm of low malignant potential who underwent followup cystoscopy 33 (35%) had recurrences during the observation Variation period compared to 110 of 154 (71%)with low grade papillary readily seen ? urothelial carcinoma (p <0.001, fig. 3). Recurrences were 3 times more common (p <0.001) at the 4-month cystoscopy in patients with low grade papillary urothelial carcinoma than those with an initial papillary urothelial neoplasm of low malignant potential (table 3). A total of 647 transurethral operations were performed during followup. The tumor(s) were fulgurated (no histological examination) in 298 of the 647 operations. Histopathological material was obtained at 349 operations and a urothe(HGPUC I lial tumor was verified in 279. For 70 transurethral resections no urothelial tumor could be identified histopathoFIG. 1. Flow chart of subjective malignancy grading of urothelial logically. Instead, the findings were those of normal mucosa, carcinoma. PUNLMP, papillary neoplasm of low malignant Potential. LGPUC, low $ade. papillary carcinoma. HGPUC, high grade artifacts or chronic inflammation. A total of 1,858negative cystoscopies were performed during the observation period. Papillary urothelia carcmoma.
I
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RECURRENCE AND PROGRESSION IN LOW O
E PAPILLARY UROTHELIAL TUMORS
FIG. 2. A, papillary urothelial neoplasm of low malignant potential (modified Bergkvist grade 1). B , low grade papillary urothelial carcinoma (modified Bergkvist grade 2A). H & E, reduced from X560. TABLE3. Relationship between a negative or positive 4-month cystoscopy and subsequent recurrences in WHO grade I tumors NO.NO4-MOS. NO.4-Mos.
TABLE1. Correlation between tumor grade and number of tumors at initial presentation No. Tumors 1
2-3
4 or More
Recurrence (%)
Recurrence (%)
Papillary neoplasm of low malignant potential (93 pts.):* No. papillary neoplasms of low 81 (85) lO(11) 4 (4) 82 (88) 11 (12) No. pts. malignant potential (S) 5 0 No. low grade papillary Ca (lo) 124 (78) -23 (14) _ 13 (8) _ No followup ~ No yr. 1 recurrence 70 (91) 5 (46)f Totals 205 (80) 33 (13) 17 (7) Yr. 1 recurrence 7 (9) 6 (55): Low grade papillary Ca (154 pts.):8 TABLE2 . Relationship between the number of tumors at initial No. pts. 97 (63) 57 (37) No fbllowup 4 presentation and frequency of recurrences among 247 patients with No yr. 1 recurrence 76 (82) WHO grade I bladder tumors Yr. 1 recurrence 17 (18) No. Tumors at Initial Diagnosis * No followup in 2 patients. f No recurrence in addition to 4-month recurrence. 1 2-3 4orMore Total $ Additional year 1 recurrences. 8 No followup in 6 patients. No. recurrence: 0 91 11 2 104 1 32 4 2 38 2 19 3 1 23 3 14 2 1 17 vation period. Bacillus Calmette-Guerin (BCG) was given to 4 14 20 2 4 11 patients and chemotherapy, mainly doxorubicin, to an5 or More 3 11 45 6 other 10. No recurrence was noted in 8 patients (38%) after Totals 198 33 16 247 the start of intravesical therapy. Radical cystectomy was Total No. recurrence 401 102 74 577 performed in 1 patient with a bladder filled with tumor, and Ratio (No. recurrencdpt.) 2.0 3.1 4.6 2.3 1 with multiple recurrences and a distal ureteral tumor. No Of 255 patients 8 did not undergo followup V diagnostic - CY . S ~ ~ S C.O .P after resection. patient was treated with external beam radiotherapy.
-
Clinical data for 6 patients (2.4%)with progression in stage during the observation period are listed in table 4. Of the 6 patients 3 had multiple and frequent recurrences of WHO grade I tumors, and 2 had carcinoma in situ diagnosed during year 1. No patient with papillary urothelial neoplasm of low malignant potential had progression in stage but 1 had extensive and noninvasive uncontrollable disease at the last cystoscopy. Status at the last followup examination is seen in table 5. A renal pelvic tumor was diagnosed concomitantly with the bladder tumor in 1 patient. During followup 3 patients had distal ureteral tumors diagnosed on cystoscopy. Of the 6 patients with low grade papillary urothelial carcinoma at initial presentation who died of disease 5 had progression in stage and 1 died of treatment complications.
'u
._ -
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I
D
n
e
a 0.25-
o.oo-(
I
0
12
24 36 Time (months)
48
60
DISCUSSION
We studied 255 patients with WHO grade I7 urothelial tumors and subclassified them as grades 1 and 2A according FIG.3. Relationship between pa illary neoplasm of low malignant to the modified Bergkvist and as papillary neopotential (PUNLMP) and low g a l e papillary carcinoma (LGPUC), plasm of low malignant potential and low grade papillary and interval to fist recurrence. carcinoma according to the WHO/ISUP classification.' This subclassification seemed to add valuable prognostic information. The recurrence rate was 35% in patients with papillary One course of intravesical therapy was given to 2 of 252 pa- urothelial neoplasm of low malignant potential compared to tients (0.8%)after the primary operation and 4 additional 71%in those with low grade papillary urothelial carcinoma patients (1.6%)were treated similarly during the first 24 (p <0.001). None of the patients with papillary urothelial months of followup. Another 15 patients (6%)were treated neoplasm of low malignant potential had progression comwith intravesical therapy during the remainder of the obser- pared to 6 with low grade papillary urothelial carcinoma.
705
RECURRENCE AND PROGRESSION IN LOW GRADE PAPILLARY UROTHELIAL TUMORS TABLE5 . Clinical status at last followup
TABLE4. Clinical information on the 6 patients with progression in stage Pt. -Age - Sex Clinical History (mos.)
No.
1-
46 - M
2- 83 -M
3-
79 - M
4-
77 -M
Bladder filled with tumor, cystedomy after diagnostic transurethral resection, no invasive tumor identified in cystectomy specimen, liver metastases (12, no histological documentation). 2 Primary tumors, small recurrence (3). 7 transurethral resections for recurrences (total 31 tumors, low grade Ca), intravesical chemotherapy (31), detrusor muscle invasion (high grade papillary Ca, 33). Small solitary primary tumor, malignant cytology (9, Ca in situ (131, BCG instillations (29), recurrent Ca in situ (43), deep lamina propria invasion (57, high grade papillary Ca). Moderate sized primary tumor, negative cystoscopy (4), 13 transurethral resections for recurrence (total 38 tumors, low grade papillary tumor), intravesical chemotherapy (59). prostatic invasion (63, high grade papillary Ca). 3 Primary tumors, Ca in situ (3), intravesical BCG a t 12 mos., detrusor muscle invasion (WHO grade not stated), lung metastases a t 19 mos. Small primary tumor, small recurrence a t 4 rnos., 8 transurethral resections for recurrence (total25 tumors, low grade papillary Ca), intravesical BCG (30), 7 transurethral resections for recurrences (low grade papillary Ca every time), skeletal metastases (80).
-
No. Papillary Neoplasms of Low Malignant Potential (%)
75 (79) Uive without bladder tumor* 3 (3) Uive with bladder tumor? 14 (15) lead, no bladder tumor at last followup 1 (1) Dead, with bladder tumor a t last followup Dead of bladder Ca$ 0 Dead,notexaminedafterdiagnosis Totals 95 * Followup less than 48 months in 16 patients. t Followup less than 48 months in 1 patient. One patient died of treatment complications.
No. Low Grade Total No. Papillary Ca WHO I (%)
91 (57) 16(10) 31 (19)
166 ( 6 5 ) 19 (8) 45 (18)
10 ( 6 )
11 (4)
6 (4) 6 (4) 160
6 (2) 8 (3) 255
~~
*
treated with sterile water only.16 The economic consequences of this reduction has not been determined. For example, it cannot be ruled out that the reduction in recurrences mainly affected small papillary tumors, which are often fulgurated 6- 67 - F with the patient under local anesthesia in an outpatient setting. In that case routine administration of a single instillation of a cytostatic drug after transurethral resection for bladder cancer may actually increase total treatment costs. Long-term instillations of a cytostatic drug are not significantly superior to a single in~tillationl~ but would increase Mean age of our patients at diagnosis was 67.5 years, costs significantly. which was 7.5 years lower than the mean age of those in the A major future goal must be to reduce the large number of same cohort with muscle invasive disease in Western negative cystoscopies which are costly and produce patient Sweden." A similar age difference was reported by others2 discomfort. Many have noted that patients with a negative and may be explained by longer exposure time to carcinogens cystoscopy at 3 months have a good p r o g n o ~ i s land ~ * ~it~has or a weakened immune system in elderly patients.12 "he been suggested that such patients should undergo the next significant age difference among patients with noninvasive followup evaluation 9 months later.Ig Morris et a1 noted that papillary urothelial neoplasm of low malignant potential and patients with a negative cystoscopy at 3 months rarely had low grade papillary urothelial carcinoma was an unexpected recurrences and, if they did, these recurrences had a low finding and may also be explained by the same factors. malignant potential and were easily fulgurated. As a rule In addition to the histopathological distinctions between intravesical therapy was not indicated in such patients." papillary urothelial neoplasm of low malignant potential and Our results confirm these findings, lending support for a low grade papillary urothelial carcinoma, all papillary change in endoscopic followup routines. It remains to be urothelial neoplasms of low malignant potential are strictly determined whether voided urine cytology or simple bladder near diploid. Low grade papillary carcinomas are predomi- tumor tests, such as the BTA* test, will be of value if followup nantly near diploid, a few (approximately 10%)are tetraploid routines are changed." but none is aneup10id.l~However, mitosis frequency did not Traditionally, intravesical therapy has been infrequently differ between grades 1 and 2A tumors corresponding to used in western Sweden. Only 8% of our patients were papillary urothelial neoplasm of low malignant potential and treated with intravesical therapy compared to 21% in a simlow grade papillary urothelial car~inoma.'~ In morphometric ilar study from the Netherlands2and 31% in a study from the studies the distinction between papillary urothelial neo- National Bladder Cancer Group? Only 38% of our patients plasm of low malignant potential and low grade papillary had no tumors after the start of such treatment which may be urothelial carcinoma was above all related to variation pa- explained by the fact that almost all had multiple recurrameters.l4The morphometric discrimination between mod- rences of multifocal tumor before treatment. A major concluified Bergkvist tumors grades 1and 2 combined, and 2b and sion of our study is that the majority of patients with W H O 3 combined was more accurate than that between grades 1 grade I tumors do not benefit from intravesical treatment. and 2A, respectively, and between 2b and 3, respecti~e1y.l~ The problem is to identify the rare cases that need additional Multiple tumors at initial diagnosis are associated with an therapy to reduce the number of recurrences and if possible increased recurrence rate.15 With a mean followup of 5 years the rate of progression. The size of the primary tumor and our patients with 4 or more tumors a t initial presentation also of the recurrences is probably of prognostic importance had more than twice as many recurrences compared to those but, unfortunately, was not recorded in our study. Whether with a solitary tumor at initial diagnosis. It remains to be other markers, such as p53 and retinoblastoma gene product, seen whether this difference will increase with extended in the primary tumor could identify patients at high risk for followup. It seems logical to treat patients with 4 or more recurrence and progression is not known but should be exprimary tumors with a series of intravesical instillations plored. Lamm et a1 suggested that intravesical chemotherapy (BCG or chemotherapeutic agents) after diagnostic resection. may reduce the number of recurrences but does not prevent Yet, even if such treatment was 100% successful, the total progression.21If this was the case, BCG would be the drug of number of recurrences in the entire group would be reduced choice also for W H O grade I tumors. by only 13% since patients with solitary tumor at initial Few patients had progression in stage during the observadiagnosis have 70% of recurrences. Instillation of epirubicin tion period and, thus, no firm conclusions can be drawn within hours postoperatively has been tried to reduce the regarding what kind of patients are destined to have p r o m s number of recurrences among patients with single primary sion. However, it seems that multiple and large tumors at tumors. Tumor recurred developed in 29% of patients treated *Bard Diagnostics, Redmond, Washingtmn. with epirubicin during a 32-month followup compared to 41% 5- 69 -M
706
RECURRENCE AND PROGRESSION IN LOW GRADE PAPILLARY UROTHELIAL TUMORS
every cystoscopy are an ominous sign. In such cases progression may come suddenly after many years. Other patients may have carcinoma in situ and progression without development of exophytic lesions. In retrospect, progression was not surprising in any of our cases. Critical evaluation indicates that they were treated too late and with too few instillations. Thus, it seems important to identify these cases early and to treat them with intravesical BCG. If a high tumor formation persists despite BCG, radical cystectomy is probably necessary. Studies with followup as long as 10 to 20 years revealed that progression occurred more than 5 years after initial diagnosis in the majority of patients initially .~~ diagnosed with WHO grade I c a r c i n ~ m a . ~It. ~is~ likely that some of our 19 patients who were alive with recurrent tumor 5 to 7 years after initial diagnosis will have stage progression and possibly die of bladder carcinoma. Others may have progression after a long tumor-free interval but there is insufficient information available to decide how long followup cystoscopies should continue. Thompson et a1 identified 7 patients, all heavy smokers, with initial grade I carcinomas who were tumor-free at least 5 years and later had a muscle invasive rec~rrence.’~They suggested that heavy smokers should be followed yearly until death because of a higher progression rate. The WHO grading system for bladder carcinomas is the most widely accepted grading system but a sharp demarcation between different grades cannot be obtained, resulting in considerable interobserver ~ariability.’~ Some have suggested a grading system with only low and high grade tumors.22.25Our results indicate that such a grading system is too simple since WHO grade I carcinomas can be divided in 2 groups of papillary urothelial neoplasm of low malignant potential and low grade papillary urothelial carcinoma, each
with somewhat different clinical behavior. Clearly the overwhelming majority of WHO grade I tumors are benign and should not be labeled as carcinoma. Nearly 40 uropathologists overwhelmingly agreed to use the term “papillary neoplasm of low malignant potential” for such lesions according to the WHO/ISUPs and the new WHO systems. “Urothelial carcinoma, low grade”” is identical t o the forthcoming new WHO grade I. CONCLUSIONS
WHO grade I tumors are benign in more than 90% of cases, with the main clinical problem being recurrence. Future research should focus on reducing the number of recurrences and followup cystoscopies. A small number of patients have truly malignant tumors which should be identified and treated aggressively as early as possible. Subdivision of WHO grade I tumors as papillary neoplasm of low malignant potential and low grade papillary carcinoma demonstrated that the incidence of recurrence was significantly higher in patients with low grade papillary carcinoma. No patient with papillary urothelial neoplasm of low malignant potential had progression. The Departments of Urology, Surgery, Pathology and Oncology staff a t the Sahlgrenska University Hospital, Ostra, Carlanderska, Lundby, Molndal, Kungalv, Uddevalla, Lysekil, Stromstad, N&, Saffle, Kungsbacka, Varberg, Halmstad, Borls, Skene, Alingsbs, Skovde, Lidkoping and Falkoping contributed to the study. Ulla-Britt Wallgren, Oncological Center and Karin Karlsson, Department of Pathology, Sahlgrenska University Hospital, provided assistance.
APPENDIX: CORRELATION AMONG THE OLD AND NEW WHO CLASSIFICATION SYSTEMS, MODIFIED BERGKVIST SYSTEM AND THE WHOlISUP CONSENSUS CLASSIFICATION
Modified Bergkvist Papilloma grade 0 Papilloma grade 1 Ca made 2A Ca b a d e 2B Ca grade 3 I
WHO 1972 Papilloma grade 0 Transitional cell Ca grade Transitional cell Ca made Transitional cell Ca b a d e Transitional cell Ca grade
1 1 2 3
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RECURRENCE AND PROGRESSION IN LOW GRADE PAPILLARY UROTHELIAL TUMORS and 2). The importance of recurrence pattern following initial resection. J. Urol., 135: 920, 1986. 16. Oosterlinck, W., Kurth, K. H., Schroder, F., Bultinck, J., Hanlmond, B., Sylvester, R. and Members of the European Organization for Research and Treatment of Cancer Genitourinary Group: A prospective European Organization for Research and Treatment of Cancer Genitourinary Group randomized trial comparing transurethral resection followed by a single intravesical instillation of epirubicin or water in single stage Ta, T1 papillary carcinoma of the bladder. J . Urol., 1 4 9 749. 1993. 17. Riihhen, H., Lutzeyer, W., Fischer, N., Deutz, F., Lagrange, W., Giani, G. and Members of the registry for urinary tract tumors: Rheinisch Westfalische Technische Hochschule, Aachen. Natural history and treatment of low and high risk superficial bladder tumors. J . Urol., 1 3 9 283, 1988. 18. Morris, S. B., Shearer, R. J., Gordon, E. M. and Woodhouse, C. R. J.: Superficial bladder cancer: timing of check cystoscopies in the first year. Brit. J. Urol., 7 2 446, 1993. 19. Hall, R. R., Parmar, M. K., Richards, A. B. and Smith, P. H.: Proposal for changes in cystoscopic follow up of patients with bladder cancer and adjuvant intravesical chemotherapy. Brit. Med. J., 308 257, 1994. 20. Murphy, W. M., Rivera-Ramirez, I., Medina, C. A., Wright, N. J . and Wajsman, Z.: The bladder tumor antigen (BTA) test com-
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pared to voided urine cytology in the detection of bladder neoplasms. J . Urol., 1 5 8 2102, 1997. 21. Lamm, D. L., Riggs, D. R., Traynelis, C. L. and Nseyo, U. 0.: Apparent failure of current intravesical chemotherapy prophylaxis to influence the long-term course of superficial transitional cell carcinoma of the bladder. J. Urol., 1 5 3 1444, 1995. 22. Jordan, A. M., Weingarten, J . and Murphy, W. M.: Transitional cell neoplasms of the urinary bladder. Can biologic potential be predicted from histologic grading? Cancer, 6 0 2766, 1987. 23. Holmang, S., Hedelin, H., Anderstrom, C. and Johansson, S. L.: The relationship among multiple recurrences, progression and prognosis of patients with stages Ta and T1 transitional cell cancer of the bladder followed for at least 20 years. J . Urol., 1 5 3 1823, 1995. 24. Thompson, R. A,, Jr., Campbell, E. W., Jr., Kramer, H. C., Jacobs, S. C. and Naslund, M. J.: Late invasive recurrence despite long-term surveillance for superficial bladder cancer. J . Urol., 149 1010, 1993. 25. Schapers, R. F. M., Pauwels, R. P. E., Wijnen, J . Th. M., Arends, J. W., Thunnissen, F. B. J. M., Coebergh, J . W. W., Smeets, A. W. G. B. and Bosman, F. T.: A simplified grading method of transitional cell carcinoma of the urinary bladder; reproducibility, clinical significance and comparison with other prognostic parameters. Brit. J . Urol., 7 3 625, 1994.
Val. 162,702-707, September 1999 Printed in U.S.A.
RECURRENCE AND PROGRESSION IN LOW GRADE PAPILLARY UROTHELIAL TUMORS STEN H O L W G , HANS HEDELIN, C m S ANDERSTROM, ERIK HOLMBERG, CHRISTER BUSCH AND SONNY L. JOHANSSON From the Department of Urology and Oncological Centre, Sahlgrenska University Hospital, Gdteborg, Department of urology, Ktirnsjukhuset, Skovde, Sureden, Department of Pathology, University Hospital, Tromso, Norway, and Department of Pathology and Microbiology, Eppley Institute of Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska
ABSTRACT
Purpose: We report long-term followup data on patients with World Health Organization (WHO) grade I bladder tumors, and determine whether histopathological subgrouping as papillary neoplasm of low malignant potential and low grade papillary carcinoma is of clinical value. Materials and Methods: All 680 patients in western Sweden with first diagnosis of bladder carcinoma in 1987 to 1988 were registered and followed for at least 5 years. Of the tumors 255 (37.5%)were stage Ta, WHO grade I. Tumors were further classified as papillary neoplasm of low malignant potential in 95 patients and low grade papillary carcinoma in 160 according to WHO and the International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the bladder. Results: Mean age of patients a t first diagnosis of low grade papillary carcinoma was 69.2 years, which was 4.6 years higher than those with papillary neoplasm of low malignant potential (p <0.005). During a mean observation time of 60 months our 255 patients underwent 577 operations for recurrences and had 1,858 negative cystoscopies. The risk of recurrence was significantly lower in patients with papillary neoplasm of low malignant potential compared to those with low grade papillary carcinoma (35 versus 71%, p <0.001). The risk of recurrence was higher in patients with multiple tumors a t first diagnosis a s well as those with recurrence at the first followup after 3 to 4 months. Stage progressed in 6 patients (2.4%), all with low grade papillary carcinoma a t diagnosis. Conclusions: More than 90% of patients with stage Ta, WHO grade I have a benign form of bladder neoplasm, and few have truly malignant tumors. Future research should focus on reducing the number of recurrences and followup cystoscopies, and finding methods to identify malignant tumors so that pertinent treatment can be instituted. Subgrouping of WHO grade I bladder tumors a s papillary neoplasm of low malignant potential and low grade papillary carcinoma seems to add valuable prognostic information. KEY WORDS:bladder, bladder neoplasms, World Health Organization,recurrence, prognosis
Noninvasive World Health Organization (WHO) grade I bladder tumors account for 25 to 38% of all bladder carcinoMost patients with this form of bladder cancer are treated at local hospitals and are rarely referred t o larger hospitals or tertiary care facilities for treatment. There are few reports dealing with this specific We report on 255 patients with stage Ta, WHO grade I bladder tumor from a large geographical region (population 1.6 million), the majority of whom were treated at local hospitals and followed for at least 5 years. The most common grading systems for bladder cancer are the WHO, Bergkvist and modified Bergkvist sy~tems.”~Recently a new consensus for bladder tumors was adopted by WHO and International Society for Urologic Pathology (ISuP).8 Papillary lesions were categorized as papilloma, papillary urothelial neoplasm of low malignant potential, low grade papillary carcinoma or high grade papillary carcinoma. We determined whether subgrouping 255 stage Ta, WHO grade I tumors (modified Bergkvist grade 1 and grade 2A) as papillary neoplasm of low malignant potential and low grade papillary carcinoma would be of prognostic significance. Accepted for publication April 1. 1999. Supported by the Western Sweden Oncological Center and Kommunalforbundet Vastra Gotaland.
PATIENTS AND METHODS
Western Sweden Health Care District. The counties of avsborg, Skaraborg, Bohusliin and Halland (northern part), and the city of Gijteborg form the Western Sweden Health Care District. In 1987 this area had a population of 1.6 million. Sahlgrenska University Hospital, Ostra Hospital and Lundby Hospital serve the largest city, Goteborg, and its 430,000inhabitants. Outside of Gijteborg there are 15 hospitals each with catchment areas of 30,000 to 150,000 inhabitants. There is only 1 small private hospital in the region. Transurethral resections of the bladder for diagnosis and treatment of bladder carcinomas were performed a t all 19 hospitals during the study period. A bladder cancer treatment program was designed in 1986’ which was accepted and adopted by the urologists and surgeons in the area. A decision was made to treat noninvasive WHO grades I and I1 carcinomas with transurethral resection and followup cystoscopy every 4 to 6 months. When the patient had been recurrence-free for 2 years, cystoscopy was recommended once or twice a year. A prospective registration of all newly diagnosed bladder tumors was performed as part of the treatment program. The registration of bladder tumors began February 1,1987 and ended January 31,1989. The surgeodurologist completed a form which included patient name, date of birth, gender, clinical stage and his-
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RECURRENCE AND PROGRESSION IN LOW GRADE PAPILLARY UROTHELIAL TUMORS
topathological findings. The register was compared to the Swedish Cancer Registry and found to be identical. Grading, staging and followup. All histopathological material from the primary tumors was reviewed by one of us (S. L. J.). Nearly 40 pathologists from 7 different pathology departments and 2 private laboratories were involved in the initial classification of cases. The tumors were graded according to the WHO7 and modified B e r g k ~ i s t systems, ~.~ and the WHO/ISUP consensus classification.8 The latter classification stratifies papillary urothelial neoplasms as papilloma, papillary urothelial neoplasm of low malignant potential, low grade papillary urothelial carcinoma and high grade papillary urothelial carcinoma (fig. 1).The Appendix shows the translation of the modified Bergkvist system into the WHO/ ISUP consensus classification. The modified Bergkvist grading system is based on pattern analysis (fig. 2). A general rule is that the pattern should be judged in areas of the section where papillae are sectioned perpendicular to the surface and basement membrane and, thus, include the fibrovascular stalk. Obliquely or longitudinally cut areas should be avoided. Furthermore, the tumors were staged according to the TNM system. lo Routine blood tests, a plain chest x-ray and excretory urography were performed before diagnostic transurethral resection of the bladder. All original patient records were reviewed in 1994 to 1996 by one of us (S. H.) resulting in at least 5 years of followup. Individual followup was calculated as the number of months from the date of the diagnostic surgical procedure (usually radical transurethral resection of the bladder) to the date of the most recent cystoscopy. A recurrence was defined as a tumor which was fulgurated (no histopathological material) or resected (with histological examination which displays urothelial malignancy). Progression in stage was defined as a recurrence with at least deep lamina propria invasion (stage pTlb) or development of metastatic disease. The chi-square test was used for comparisons between groups. The probability of recurrence was calculated using
703
Kaplan-Meier estimates and compared with the log rank test. RESULTS
Mean age of all 680 patients was 70.5 years and 25% of the patients were women. Mean age plus or minus standard deviation of 95 patients with papillary urothelial neoplasm of low malignant potential was 64.6 2 13.9 years (range 29 to 94) and of 160 with low grade papillary urothelial carcinoma it was 69.2 t 11.7 (range 28 to go), which was statistically significant (p <0.005). Of the patients with papillary urothelial neoplasm of low malignant potential 17 (17.9%) and of those with low grade papillary urothelial carcinoma 41 (25.6%)were women (difference not statistically significant). Total followup for the 255 patients was 15,203 months (average 59.6 per patient) and there was no difference in followup between the groups. The diagnostic operation was performed a t the university hospital in 54 patients and a t local hospitals in 201. During followup only 1patient was referred to the university hospital for additional treatment. The primary surgical pathology report was classified as WHO grade I or papilloma in 81% of patients with papillary urothelial neoplasm of low malignant potential and as WHO grades I to I1 or I1 in 19%.Of the cases with low grade papillary urothelial carcinoma 39%were initially reported as WHO grade I, 11%as WHO grade I to I1 and 43% as WHO grade 11. Of the cases 9 initially classified as pTaGIII, pTlGII or pTlGIII were reclassified by the reviewer as noninvasive WHO grade I (low grade papillary urothelial carcinoma). On the other hand, 5 cases initially classified as pTaGl were reclassified as pTaGIII, pTlGII or pTlGIII and, thus, not included in this report. The primary tumor was removed during 1 transurethral resection in all but 6 patients. In 5 cases a second resection was necessary. One patient had a bladder filled with tumor and was treated with cystectomy after initial diagnostic transurethral resection. Three patients 81 to 90 years old died within 30 days after diagnostic transurethral resection of the bladder. Their general condition was poor even before I I the operation and, although there were no recorded postopUrothelial neoplasm erative complications, it cannot be completely ruled out that Grade? transurethral resection of the bladder contributed to premature death. A fourth patient had considerable perioperative bleeding during resection of a large recurrence and died postoperatively from a myocardial infarction, which was considered a treatment related death. Predominant Multiple primary tumors were slightly more common among order patients with low grade papillary urothelial carcinoma (difference not statistically sigmfxant, table 1). Patients with multiGrade 1,2A1 ple primary tumors had a higher risk of future recurrences but those with a single primary tumor accounted for the majority of recurrences (table 2). During followup 143patients (58%)had at least 1 recurrence. Of 93 patients with papillary urothelial neoplasm of low malignant potential who underwent followup cystoscopy 33 (35%) had recurrences during the observation Variation period compared to 110 of 154 (71%)with low grade papillary readily seen ? urothelial carcinoma (p <0.001, fig. 3). Recurrences were 3 times more common (p <0.001) at the 4-month cystoscopy in patients with low grade papillary urothelial carcinoma than those with an initial papillary urothelial neoplasm of low malignant potential (table 3). A total of 647 transurethral operations were performed during followup. The tumor(s) were fulgurated (no histological examination) in 298 of the 647 operations. Histopathological material was obtained at 349 operations and a urothe(HGPUC I lial tumor was verified in 279. For 70 transurethral resections no urothelial tumor could be identified histopathoFIG. 1. Flow chart of subjective malignancy grading of urothelial logically. Instead, the findings were those of normal mucosa, carcinoma. PUNLMP, papillary neoplasm of low malignant Potential. LGPUC, low $ade. papillary carcinoma. HGPUC, high grade artifacts or chronic inflammation. A total of 1,858negative cystoscopies were performed during the observation period. Papillary urothelia carcmoma.
I
704
RECURRENCE AND PROGRESSION IN LOW O
E PAPILLARY UROTHELIAL TUMORS
FIG. 2. A, papillary urothelial neoplasm of low malignant potential (modified Bergkvist grade 1). B , low grade papillary urothelial carcinoma (modified Bergkvist grade 2A). H & E, reduced from X560. TABLE3. Relationship between a negative or positive 4-month cystoscopy and subsequent recurrences in WHO grade I tumors NO.NO4-MOS. NO.4-Mos.
TABLE1. Correlation between tumor grade and number of tumors at initial presentation No. Tumors 1
2-3
4 or More
Recurrence (%)
Recurrence (%)
Papillary neoplasm of low malignant potential (93 pts.):* No. papillary neoplasms of low 81 (85) lO(11) 4 (4) 82 (88) 11 (12) No. pts. malignant potential (S) 5 0 No. low grade papillary Ca (lo) 124 (78) -23 (14) _ 13 (8) _ No followup ~ No yr. 1 recurrence 70 (91) 5 (46)f Totals 205 (80) 33 (13) 17 (7) Yr. 1 recurrence 7 (9) 6 (55): Low grade papillary Ca (154 pts.):8 TABLE2 . Relationship between the number of tumors at initial No. pts. 97 (63) 57 (37) No fbllowup 4 presentation and frequency of recurrences among 247 patients with No yr. 1 recurrence 76 (82) WHO grade I bladder tumors Yr. 1 recurrence 17 (18) No. Tumors at Initial Diagnosis * No followup in 2 patients. f No recurrence in addition to 4-month recurrence. 1 2-3 4orMore Total $ Additional year 1 recurrences. 8 No followup in 6 patients. No. recurrence: 0 91 11 2 104 1 32 4 2 38 2 19 3 1 23 3 14 2 1 17 vation period. Bacillus Calmette-Guerin (BCG) was given to 4 14 20 2 4 11 patients and chemotherapy, mainly doxorubicin, to an5 or More 3 11 45 6 other 10. No recurrence was noted in 8 patients (38%) after Totals 198 33 16 247 the start of intravesical therapy. Radical cystectomy was Total No. recurrence 401 102 74 577 performed in 1 patient with a bladder filled with tumor, and Ratio (No. recurrencdpt.) 2.0 3.1 4.6 2.3 1 with multiple recurrences and a distal ureteral tumor. No Of 255 patients 8 did not undergo followup V diagnostic - CY . S ~ ~ S C.O .P after resection. patient was treated with external beam radiotherapy.
-
Clinical data for 6 patients (2.4%)with progression in stage during the observation period are listed in table 4. Of the 6 patients 3 had multiple and frequent recurrences of WHO grade I tumors, and 2 had carcinoma in situ diagnosed during year 1. No patient with papillary urothelial neoplasm of low malignant potential had progression in stage but 1 had extensive and noninvasive uncontrollable disease at the last cystoscopy. Status at the last followup examination is seen in table 5. A renal pelvic tumor was diagnosed concomitantly with the bladder tumor in 1 patient. During followup 3 patients had distal ureteral tumors diagnosed on cystoscopy. Of the 6 patients with low grade papillary urothelial carcinoma at initial presentation who died of disease 5 had progression in stage and 1 died of treatment complications.
'u
._ -
0.50-
I
D
n
e
a 0.25-
o.oo-(
I
0
12
24 36 Time (months)
48
60
DISCUSSION
We studied 255 patients with WHO grade I7 urothelial tumors and subclassified them as grades 1 and 2A according FIG.3. Relationship between pa illary neoplasm of low malignant to the modified Bergkvist and as papillary neopotential (PUNLMP) and low g a l e papillary carcinoma (LGPUC), plasm of low malignant potential and low grade papillary and interval to fist recurrence. carcinoma according to the WHO/ISUP classification.' This subclassification seemed to add valuable prognostic information. The recurrence rate was 35% in patients with papillary One course of intravesical therapy was given to 2 of 252 pa- urothelial neoplasm of low malignant potential compared to tients (0.8%)after the primary operation and 4 additional 71%in those with low grade papillary urothelial carcinoma patients (1.6%)were treated similarly during the first 24 (p <0.001). None of the patients with papillary urothelial months of followup. Another 15 patients (6%)were treated neoplasm of low malignant potential had progression comwith intravesical therapy during the remainder of the obser- pared to 6 with low grade papillary urothelial carcinoma.
705
RECURRENCE AND PROGRESSION IN LOW GRADE PAPILLARY UROTHELIAL TUMORS TABLE5 . Clinical status at last followup
TABLE4. Clinical information on the 6 patients with progression in stage Pt. -Age - Sex Clinical History (mos.)
No.
1-
46 - M
2- 83 -M
3-
79 - M
4-
77 -M
Bladder filled with tumor, cystedomy after diagnostic transurethral resection, no invasive tumor identified in cystectomy specimen, liver metastases (12, no histological documentation). 2 Primary tumors, small recurrence (3). 7 transurethral resections for recurrences (total 31 tumors, low grade Ca), intravesical chemotherapy (31), detrusor muscle invasion (high grade papillary Ca, 33). Small solitary primary tumor, malignant cytology (9, Ca in situ (131, BCG instillations (29), recurrent Ca in situ (43), deep lamina propria invasion (57, high grade papillary Ca). Moderate sized primary tumor, negative cystoscopy (4), 13 transurethral resections for recurrence (total 38 tumors, low grade papillary tumor), intravesical chemotherapy (59). prostatic invasion (63, high grade papillary Ca). 3 Primary tumors, Ca in situ (3), intravesical BCG a t 12 mos., detrusor muscle invasion (WHO grade not stated), lung metastases a t 19 mos. Small primary tumor, small recurrence a t 4 rnos., 8 transurethral resections for recurrence (total25 tumors, low grade papillary Ca), intravesical BCG (30), 7 transurethral resections for recurrences (low grade papillary Ca every time), skeletal metastases (80).
-
No. Papillary Neoplasms of Low Malignant Potential (%)
75 (79) Uive without bladder tumor* 3 (3) Uive with bladder tumor? 14 (15) lead, no bladder tumor at last followup 1 (1) Dead, with bladder tumor a t last followup Dead of bladder Ca$ 0 Dead,notexaminedafterdiagnosis Totals 95 * Followup less than 48 months in 16 patients. t Followup less than 48 months in 1 patient. One patient died of treatment complications.
No. Low Grade Total No. Papillary Ca WHO I (%)
91 (57) 16(10) 31 (19)
166 ( 6 5 ) 19 (8) 45 (18)
10 ( 6 )
11 (4)
6 (4) 6 (4) 160
6 (2) 8 (3) 255
~~
*
treated with sterile water only.16 The economic consequences of this reduction has not been determined. For example, it cannot be ruled out that the reduction in recurrences mainly affected small papillary tumors, which are often fulgurated 6- 67 - F with the patient under local anesthesia in an outpatient setting. In that case routine administration of a single instillation of a cytostatic drug after transurethral resection for bladder cancer may actually increase total treatment costs. Long-term instillations of a cytostatic drug are not significantly superior to a single in~tillationl~ but would increase Mean age of our patients at diagnosis was 67.5 years, costs significantly. which was 7.5 years lower than the mean age of those in the A major future goal must be to reduce the large number of same cohort with muscle invasive disease in Western negative cystoscopies which are costly and produce patient Sweden." A similar age difference was reported by others2 discomfort. Many have noted that patients with a negative and may be explained by longer exposure time to carcinogens cystoscopy at 3 months have a good p r o g n o ~ i s land ~ * ~it~has or a weakened immune system in elderly patients.12 "he been suggested that such patients should undergo the next significant age difference among patients with noninvasive followup evaluation 9 months later.Ig Morris et a1 noted that papillary urothelial neoplasm of low malignant potential and patients with a negative cystoscopy at 3 months rarely had low grade papillary urothelial carcinoma was an unexpected recurrences and, if they did, these recurrences had a low finding and may also be explained by the same factors. malignant potential and were easily fulgurated. As a rule In addition to the histopathological distinctions between intravesical therapy was not indicated in such patients." papillary urothelial neoplasm of low malignant potential and Our results confirm these findings, lending support for a low grade papillary urothelial carcinoma, all papillary change in endoscopic followup routines. It remains to be urothelial neoplasms of low malignant potential are strictly determined whether voided urine cytology or simple bladder near diploid. Low grade papillary carcinomas are predomi- tumor tests, such as the BTA* test, will be of value if followup nantly near diploid, a few (approximately 10%)are tetraploid routines are changed." but none is aneup10id.l~However, mitosis frequency did not Traditionally, intravesical therapy has been infrequently differ between grades 1 and 2A tumors corresponding to used in western Sweden. Only 8% of our patients were papillary urothelial neoplasm of low malignant potential and treated with intravesical therapy compared to 21% in a simlow grade papillary urothelial car~inoma.'~ In morphometric ilar study from the Netherlands2and 31% in a study from the studies the distinction between papillary urothelial neo- National Bladder Cancer Group? Only 38% of our patients plasm of low malignant potential and low grade papillary had no tumors after the start of such treatment which may be urothelial carcinoma was above all related to variation pa- explained by the fact that almost all had multiple recurrameters.l4The morphometric discrimination between mod- rences of multifocal tumor before treatment. A major concluified Bergkvist tumors grades 1and 2 combined, and 2b and sion of our study is that the majority of patients with W H O 3 combined was more accurate than that between grades 1 grade I tumors do not benefit from intravesical treatment. and 2A, respectively, and between 2b and 3, respecti~e1y.l~ The problem is to identify the rare cases that need additional Multiple tumors at initial diagnosis are associated with an therapy to reduce the number of recurrences and if possible increased recurrence rate.15 With a mean followup of 5 years the rate of progression. The size of the primary tumor and our patients with 4 or more tumors a t initial presentation also of the recurrences is probably of prognostic importance had more than twice as many recurrences compared to those but, unfortunately, was not recorded in our study. Whether with a solitary tumor at initial diagnosis. It remains to be other markers, such as p53 and retinoblastoma gene product, seen whether this difference will increase with extended in the primary tumor could identify patients at high risk for followup. It seems logical to treat patients with 4 or more recurrence and progression is not known but should be exprimary tumors with a series of intravesical instillations plored. Lamm et a1 suggested that intravesical chemotherapy (BCG or chemotherapeutic agents) after diagnostic resection. may reduce the number of recurrences but does not prevent Yet, even if such treatment was 100% successful, the total progression.21If this was the case, BCG would be the drug of number of recurrences in the entire group would be reduced choice also for W H O grade I tumors. by only 13% since patients with solitary tumor at initial Few patients had progression in stage during the observadiagnosis have 70% of recurrences. Instillation of epirubicin tion period and, thus, no firm conclusions can be drawn within hours postoperatively has been tried to reduce the regarding what kind of patients are destined to have p r o m s number of recurrences among patients with single primary sion. However, it seems that multiple and large tumors at tumors. Tumor recurred developed in 29% of patients treated *Bard Diagnostics, Redmond, Washingtmn. with epirubicin during a 32-month followup compared to 41% 5- 69 -M
706
RECURRENCE AND PROGRESSION IN LOW GRADE PAPILLARY UROTHELIAL TUMORS
every cystoscopy are an ominous sign. In such cases progression may come suddenly after many years. Other patients may have carcinoma in situ and progression without development of exophytic lesions. In retrospect, progression was not surprising in any of our cases. Critical evaluation indicates that they were treated too late and with too few instillations. Thus, it seems important to identify these cases early and to treat them with intravesical BCG. If a high tumor formation persists despite BCG, radical cystectomy is probably necessary. Studies with followup as long as 10 to 20 years revealed that progression occurred more than 5 years after initial diagnosis in the majority of patients initially .~~ diagnosed with WHO grade I c a r c i n ~ m a . ~It. ~is~ likely that some of our 19 patients who were alive with recurrent tumor 5 to 7 years after initial diagnosis will have stage progression and possibly die of bladder carcinoma. Others may have progression after a long tumor-free interval but there is insufficient information available to decide how long followup cystoscopies should continue. Thompson et a1 identified 7 patients, all heavy smokers, with initial grade I carcinomas who were tumor-free at least 5 years and later had a muscle invasive rec~rrence.’~They suggested that heavy smokers should be followed yearly until death because of a higher progression rate. The WHO grading system for bladder carcinomas is the most widely accepted grading system but a sharp demarcation between different grades cannot be obtained, resulting in considerable interobserver ~ariability.’~ Some have suggested a grading system with only low and high grade tumors.22.25Our results indicate that such a grading system is too simple since WHO grade I carcinomas can be divided in 2 groups of papillary urothelial neoplasm of low malignant potential and low grade papillary urothelial carcinoma, each
with somewhat different clinical behavior. Clearly the overwhelming majority of WHO grade I tumors are benign and should not be labeled as carcinoma. Nearly 40 uropathologists overwhelmingly agreed to use the term “papillary neoplasm of low malignant potential” for such lesions according to the WHO/ISUPs and the new WHO systems. “Urothelial carcinoma, low grade”” is identical t o the forthcoming new WHO grade I. CONCLUSIONS
WHO grade I tumors are benign in more than 90% of cases, with the main clinical problem being recurrence. Future research should focus on reducing the number of recurrences and followup cystoscopies. A small number of patients have truly malignant tumors which should be identified and treated aggressively as early as possible. Subdivision of WHO grade I tumors as papillary neoplasm of low malignant potential and low grade papillary carcinoma demonstrated that the incidence of recurrence was significantly higher in patients with low grade papillary carcinoma. No patient with papillary urothelial neoplasm of low malignant potential had progression. The Departments of Urology, Surgery, Pathology and Oncology staff a t the Sahlgrenska University Hospital, Ostra, Carlanderska, Lundby, Molndal, Kungalv, Uddevalla, Lysekil, Stromstad, N&, Saffle, Kungsbacka, Varberg, Halmstad, Borls, Skene, Alingsbs, Skovde, Lidkoping and Falkoping contributed to the study. Ulla-Britt Wallgren, Oncological Center and Karin Karlsson, Department of Pathology, Sahlgrenska University Hospital, provided assistance.
APPENDIX: CORRELATION AMONG THE OLD AND NEW WHO CLASSIFICATION SYSTEMS, MODIFIED BERGKVIST SYSTEM AND THE WHOlISUP CONSENSUS CLASSIFICATION
Modified Bergkvist Papilloma grade 0 Papilloma grade 1 Ca made 2A Ca b a d e 2B Ca grade 3 I
WHO 1972 Papilloma grade 0 Transitional cell Ca grade Transitional cell Ca made Transitional cell Ca b a d e Transitional cell Ca grade
1 1 2 3
REFERENCES
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