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Review pathology in a diagnostic bladder cancer trial: Effect of patient risk category
ADULT UROLOGY
REVIEW PATHOLOGY IN A DIAGNOSTIC BLADDER CANCER TRIAL: EFFECT OF PATIENT RISK CATEGORY J. A. WITJES, P. M. J. MOONEN,
AND
A. G.
VAN DER
HEIJDEN
ABSTRACT Objectives. Bladder cancer pathologic features are a continuous spectrum from benign to invasive lesions, causing diagnostic difficulties. Review pathology might be an answer, but appears to be of limited value. We studied the effect of patients’ risk profile on the value of review pathology. Methods. We used three Phase III multicenter studies that assessed the value of hexaminolevulinate fluorescence cystoscopy on diagnosis and management. Two studies (Europe and United States) included patients at high risk of carcinoma in situ (CIS), the third study (Europe) included all patients at risk of bladder cancer. Tumors and biopsies were examined by a local and review pathologist. Results. The percentage of patients with CIS was high in the first two studies (20.6% and 15.9%) compared with the epidemiologic data (7.9%) and the third study (7.8%). The numbers of patients (specimens) in the three studies were 209 (927), 277 (986), and 142 (553). Overall conformity for both grade and stage was between 50.5% and 56.6%, comparable to published data. Although conformity was best in the high-risk study, this was predominantly because of the better conformity in low-risk tumors. Conformity in Stage T1, CIS, and invasive tumors was low. The results from Europe and the United States were comparable, although the local pathologist in the United States tended to overstage or overgrade. Conclusions. Although histologic conformity was greater in the high-risk patient population, this was mainly a result of pTa tumors. The diagnosis of pT1, CIS, and invasiveness appears difficult. Because these tumors significantly influence therapy, review pathology in patients at high risk or suspicious for high risk should be considered. UROLOGY 67: 751–755, 2006. © 2006 Elsevier Inc.
B
ladder cancer is a continuous spectrum of tumors, including benign lesions (inverted papilloma), superficial tumors, and invasive cancer. The difficulty with this continuous spectrum is reflected in the World Health Organization classification that is adapted regularly on the basis of discussion by experts and years of experience. This difficult diagnosis, however, might have implications for patient treatment and prognosis. A potential solution is review pathology. However, two reports on this topic clearly indicated the limitations of review pathology.1,2 The only practical advice came from a combined review of five European Organization for Research and Treatment of Cancer (EORTC) trials.2 The conclusion was that in T1G3 disease, the stage or grade often changed, so From the Department of Urology, University Medical Centre St. Radboud, Nijmegen, The Netherlands Reprint requests: J. A.Witjes, M.D., Ph.D., Department of Urology, University Medical Centre St. Radboud, Nijmegen, The Netherlands. E-mail: [email protected] Submitted: July 12, 2005, accepted (with revisions): October 14, 2005 © 2006 ELSEVIER INC. ALL RIGHTS RESERVED
that review pathology continued to be recommended for this subgroup. We speculated that a patient’s risk profile could have an impact on the value of review pathology. For example, in a study that included only high-risk patients, local and review pathology might correlate better. Therefore, we compared the results of three fluorescence cystoscopy studies with different risk profiles. MATERIAL AND METHODS The data sets used for the present comparison were from three fluorescence cystoscopy studies. All three studies were performed in large community hospitals or academic hospitals with experience in bladder cancer and bladder cancer trials. The methods and inclusion and exclusion criteria for the first study (PC-B301) have been previously described in detail.3 In this within-patients controlled multicenter Phase III study, the selection criteria were such that at least 20% of patients had carcinoma in situ (CIS) to determine the additional detection of CIS by hexaminolevulinate (HAL, Hexvix) fluorescence cystoscopy. The study was conducted in Europe. After 1 hour of intravesical Hexvix, the tumors were resected and the bladder was mapped with white light and with fluorescence cystoscopy (Karl Storz, Tuttlingen, Germany). The histologic results of the local pathologist were used for treatment deci0090-4295/06/$32.00 doi:10.1016/j.urology.2005.10.028 751
TABLE I. Local pathologic results in three studies per patient (P) and per specimen/biopsy (S/B) Study PC-B301 Missing Normal* pTaG1 pTaG2 pTaG3 pT1G1 pT1G2 pT1G3 CIS ⬎pT2 Total
PC-B302
PC-B303
Total
P
S/B
P
S/B
P
S/B
P
S/B
— 28 39 49 11 4 7 15 43 13 209
5 339 137 141 68 8 14 62 128 25 927
3 70 57 56 9 2 6 13 44 17 277
31 457 148 140 41 2 14 29 99 25 986
— 43 25 29 5 4 4 10 11 11 142
4 311 80 58 9 7 10 27 28 19 553
3 141 121 134 25 10 17 38 98 41 628
40 1107 365 339 118 17 38 118 255 69 2466
KEY: CIS ⫽ carcinoma in situ. * Normal included moderate dysplasia.
TABLE II. Total number of patients diagnosed by local pathologists per diagnosis (stage and grade) and per study, and percentage confirmed by review pathologist PC-B301 “Local” Diagnosis Normal* pTaG1 pTaG2 pTaG3 pT1G1 pT1G2 pT1G3 CIS ⬎pT2
PC-B302
PC-B303
Total
Total (n)
Confirmed (%)
Total (n)
Confirmed (%)
Total (n)
Confirmed (%)
Total
Confirmed % Total
28 39 49 11 4 7 15 43 13
50 53.9 55.1 27.3 0 42.9 26.7 81.4 84.6
70 57 56 9 2 6 13 44 17
68.6 64.9 14.3 22.2 0 0 38.5 65.9 64.7
43 25 29 5 4 4 10 11 11
81.4 68 20.7 20 0 0 30 45.5 100
141 121 134 25 10 17 38 98 41
68.8 62 30.6 24 0 17.7 31.6 70.4 80.5
KEY: CIS ⫽ carcinoma in situ. * Normal included moderate dysplasia.
sions. Review pathology was used for primary study analysis. In every study, one experienced uropathologist reviewed all slides. The lesions were staged according to the International Union Against Cancer/American Joint Committee on Cancer 1992 staging system.4 Flat lesions were graded according to the World Health Organization/International Society of Urological Pathologists 2001 consensus classification on urothelial neoplasms of the bladder.5 Papillary lesions were graded according to the World Health Organization 1973 criteria.6 Study PC-B302 had exactly the same inclusion criteria, endpoints, and methods, including review pathology for study analysis, and was conducted in North America. In the third study (PC-B303, conducted in Europe) management in patients with bladder cancer was compared. In this study, all patients with known or suspected bladder cancer, as diagnosed by cystoscopy or positive urine cytology, were included. Exclusions included gross hematuria and intravesical treatment within 3 months of inclusion.
RESULTS The results with regard to the primary diagnostic and safety endpoints of the three studies have been previously published.3,7–9 In brief, Hexvix fluores752
cence cystoscopy is safe, and it improves the detection of bladder tumors, especially CIS. Moreover, 22% of patients with bladder tumors receive a more appropriate treatment after blue light cystoscopy.9 The number of patients included in this histologic comparison was 209, 277, and 142 from the three studies. The total number of separate resections and biopsies was 927, 986 and 553. The local pathology results per patient and per “resection/ biopsy” are shown in Table I. As expected, the percentage of patients with CIS in the PC-B301 and PC-B302 studies was greater than in the PC-B303 study (20.6%, 15.9%, and 7.8%, respectively). The corresponding percentages of patients with grade 3 or Stage T1 or CIS tumors were 40.9%, 28.5%, and 25.6%. Pathologic T1G1 tumors were infrequent, even with local pathologic examination. Table II shows the total number of patients diagnosed by local pathology per stage and grade and per study, and the percentage was confirmed by review paUROLOGY 67 (4), 2006
TABLE III. Comparison of local and review pathology in absolute numbers and per stage/grade for three studies together Local Pathology Missing Normal* pTaG1 pTaG2 pTaG3 pT1G1 pT1G2 pT1G3 CIS ⬎pT2 Total (631)
Review Pathology Missing
Normal*
5 1 2 1
97 15 9 2 3
2 1 12
4 4 1 135
pTaG1 1 9 75 51 1 1 1 3 2 144
pTaG2
pTaG3
pT1G1
pT1G2
pT1G3 1
7 24 35 5 1 7
1 80
1 1
1 3 1 1 3 1 2
9
12
1 6
1 2 3
12 3 2 24
CIS 1 23 6 25 6 2 4 12 69 1 152
>pT2 3 1 1 2 1 8 14 33 63
KEY: CIS ⫽ carcinoma in situ. * Normal included moderate dysplasia.
thology. The review pathologists did not confirm many pT1 tumors, as was the case with pTaG2 tumors in the PC-B302 and PC-B303 studies, in which conformity with a fair number of patients was also less than 50%. More details are given in Table III, which shows a comparison of the local and review pathologic findings in absolute numbers and per stage/grade for the three studies together. The overall conformity for grade and stage was between 50.5% and 56.6% (Table IV). COMMENT As indicated previously, bladder cancer is a continuous spectrum. The result is that it is not always easy to differentiate between two stages or grades. Therefore, the details of bladder cancer stage and grade have been regularly adapted to improve the value of the classification. However, interobserver and intraobserver variability in histologic assessment of superficial bladder tumors is significant. A potential solution for this problem is review pathology. In a study with 254 pTa and 133 pT1 tumors and 50 patients with CIS, local and review pathologic results were analyzed with regard to treatment and a prognostic factor analysis.1 The conformity between local and review pathology was 79.3% for stage, 70.2% for grade, and 59.7% for both. However, the risks of recurrence in the separate groups remained similar after changing the pathologic results. A multivariate prognostic factor analysis for recurrence also hardly changed after correction for review pathology. Only the prognostic relevance of tumor stage increased after the pathology change. The investigators concluded that although review pathology caused considerable changes, this did not affect the treatment results and hardly altered the prognostic factor analysis. Local and review UROLOGY 67 (4), 2006
pathology were also compared in 1400 patients with Stage Ta-T1 bladder cancer treated in five randomized Phase III EORTC trials.2 Considerable variations in stage and grade were found, but differences in the prognosis according to the local and review pathologic results were limited. However, these investigators advised review for T1G3 disease, because changes are frequent and have great impact on patient management. In all, these two reports have clearly shown the limitations of review pathology. The present study compared local and review pathology in three studies, two of which selected only high-risk patients to include at least 20% of patients with CIS. On the basis of the local pathologic results (Table I), the percentage of patients with CIS was 20.6% and 15.9% in the PC-B301 and PC-B302 studies, greater than in the PC-B303 study (7.8%) and a random bladder cancer population (7.9%).10 The PC-B301 study also included more patients with grade 3 or Stage T1 or CIS (40.9%) compared with the PC-B302 (28.5%) and PC-B303 (25.6%) studies. Thus, PC-B302 and, especially, PC-B301 had a high-risk superficial bladder cancer population, and PC-B303 reflected an average patient population much more. If one then considers the effect of review pathology on patient level in these three studies, several points deserve attention. T1G1 remains a rare diagnosis.1 Local pathology diagnosed this tumor in 10 patients (1.6%) and 17 specimens, of which only 2 specimens were confirmed after review. The overall conformity, in which both grade and stage were confirmed, was between 50.5% and 56.6% in these three studies compared with approximately 60% in published data (Table IV). However, in most studies, conformity was largely a re753
TABLE IV. Conformity of stage or grade or both: comparison of three studies and with published data Study PC-B301 PC-B302 PC-B303 Witjes et al.1 Van Der Meijden et al.2
Stage and Grade (%)
Ta (%)
T1 (%)
All Grades (%)
CIS (%)
56.5 50.5 50.7 59.8 62.1
90.5 82.4 59.6 81.5 68.7
61.5 40 37.5 77.4 77.1
61.9 50.4 41.8 69.5 57.3
53.8 44.6 22.7 94 —
KEY: CIS ⫽ carcinoma in situ.
sult of low-stage tumors. The better conformity in PC-B301, the study with the highest risk patient population, was also a result of the low-risk patients. PC-B302, which also had a high-risk population, had similar overall results as PC-B303, with an average patient risk population. This also suggests that the effect of the risk classification is limited. This observation also illustrates that North American and European pathologists do not seem to differ in their classification. However, in both European studies, discrepancies were mostly caused by a lower stage or grade being given by the local pathologists. In the PC-B301 study, the disease of 58 patients were upstaged or upgraded after review and 31 were downstaged or downgraded. In PCB303, the corresponding numbers were 44 and 23. In contrast, in the North American study, the corresponding numbers were 59 and 68. Although the number of T1 tumors in this study was limited, the results for conformity in patients with Stage T1 and CIS appeared lower than those in published studies. The EORTC analysis showed that 53% of T1 tumors were reclassified as Ta tumors, with agreement in only 50% of Stage T1G3 cases. Also, of Stage T1G3 tumors, 10% were upstaged as muscle-invasive disease.2 Because the determination of T1 tumors is important for patient treatment, standard review pathology or perhaps standard repeat resection in these patients should be considered,11 as it is obvious that for these tumors, histologic examination has limitations. However, review pathology cannot compensate for inadequate resection or repeat resection and vice versa. The same might be true for patients with CIS. The conformity in these three studies was 23% to 54%. Moreover, many of the discrepancies were in patients with CIS on review and no or low-grade/ low-stage tumor on local pathologic examination. Fortunately, the results in published studies have been better.1 Furthermore, triggered by abnormal cytologic findings, which are very common in CIS, and guided by fluorescence cystoscopy, the diagnosis of CIS will improve in the future.12 Finally, a surprising problem was found with pT2 tumors, for which conformity was 50% in 754
these series and 36.2% and even 0% in published data. Most were understaged by the local pathologist as pT1G3 lesions. Apparently, the recognition of detrusor muscle in transurethral resection material is difficult, or, worse, no detrusor muscle was present as a result of an insufficient resection. In other cases, the local and review pathologists might have received different parts of the resected tissue in which the detrusor was not always present. Why is the histologic diagnosis of bladder cancer so difficult? Because stage and grade are among the most important prognostic factors, a correct diagnosis in superficial bladder cancer is probably more important than the use of intravesical therapy, which only marginally influences the natural course of the disease. The pathologist can only do a proper job with good tissue samples, representative of the index tumor. Simple methods to improve transurethral resection (TUR) are standard operating procedures, such as the use of a bladder diagram or video-assisted TUR, proper TUR techniques, proper orientation and labeling of tissue, and biopsies on good indications.11 Important standard operating procedures include the careful use of cautery. Also, in the case of suspected CIS, contact between the instrument and the mucosal surface should be limited to avoid mucosal denudation. Whether a grading system with only low and high-grade tumors would improve reproducibility remains unclear. Considering our figures, this might be so for pTa tumors, for which many discrepancies were found in the grade 2 group. However, for pT1, pT2, and CIS tumors, which are mostly high grade, the effect of a new grading system would probably be limited. Therefore, the limited reproducibility of bladder cancer histologic examination is a mutual problem for the pathologist and urologist that can only be solved by good interactions between both. One might wonder whether the “prediction” of histologic type during TUR by an experienced urologist is not better than an insufficient resection or histologic classification. Herr et al.13 correlated cystoscopy and histologic findings in recurrent papillary tumors and found that 93% of Ta tumors UROLOGY 67 (4), 2006
were predicted correctly, as were 99% of grade 3 or T1 tumors.13 For biopsy judgment, the same was found by Cina et al.14 Benign and malignant lesions of the bladder were predicted with 100% sensitivity and specificity. In contrast, in the same study, discrimination between low and high-grade tumors, as well as the determination of microscopic invasion was inaccurate. In all, endoscopic examination can be an important aid in discriminating good and bad tumors. CONCLUSIONS Histologic examination of superficial bladder cancer remains difficult. The overall conformity is only between 50% and 60%, which limits its prognostic value. Although in this study, the conformity was best in the study with the patient population at highest risk, this was predominantly caused by the better conformity in low-stage tumors. T1 tumors, although the number in this study was limited, CIS, and even invasive tumors remain a diagnostic challenge. Because it is most important to differentiate these tumors for decisions regarding aggressive or conservative therapy, review pathology of these tumors, or if they are suspected, should be considered. Proper TUR and careful tissue handling will without doubt help to improve the value of bladder cancer histologic examination. Whether a standard second resection can add to the correct diagnosis remains to be seen. The difference in conformity between the North American and European studies was limited. The local pathologist in North America tended to overstage or overgrade. REFERENCES 1. Witjes JA, Kiemeney LA, Schaafsma HE, et al: The influence of review pathology on study outcome of a randomized multicentre superficial bladder cancer trial. Br J Urol 73: 172–176, 1994.
UROLOGY 67 (4), 2006
2. Van Der Meijden A, Sylvester R, Collette L, et al: The role and impact of pathology review on stage and grade assessment of stages Ta and T1 bladder tumors: a combined analysis of 5 European Organization for Research and Treatment of Cancer Trials. J Urol 164: 1533–1537, 2000. 3. Schmidbauer J, Witjes F, Schmeller N, et al: Improved detection of urothelial carcinoma in situ with hexaminolevulinate fluorescence cystoscopy. J Urol 171: 135–138, 2004. 4. Hermanek J, and Sobin J: UICC TNBM Classification of Malignant Tumours, 4th ed. Berlin, Springer Verlag, 1992. 5. Epstein JI, Amin MB, Reuter VR, et al, for the Bladder Consensus Conference Committee: The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Am J Surg Pathol 22: 1435–1448, 1998. 6. Mostofi FK, Sobin LH, and Torloni H: Histopathological typing of urinary bladder tumours, in International Histological Classification of Tumours. Geneva, World Health Organisation, 1973. 7. Grossman HB, Gomella LG, Fradet Y, et al: The use of Hexvix and fluorescence cystoscopy as an adjunct in the diagnosis of stage Ta/T1 urothelial cancer in the urinary bladder (abstract). J Urol 171: 69, 2004. 8. Gomella LG, Grossman HB, Presti JC Jr, et al: The use of Hexvix and fluorescence cystoscopy as an adjunct in the diagnosis of carcinoma in situ of the urinary bladder (abstract). J Urol 171: 69, 2004. 9. Jocham D, Witjes F, Wagner S, et al: Improved detection and treatment of bladder cancer using Hexvix imaging: a prospective phase III multi-centre study. J Urol 174: 862– 866, 2005. 10. Kiemeney LALM, Witjes JA, Verbeek ALM, et al: The clinical epidemiology of superficial bladder cancer. Br J Cancer 67: 806 – 812, 1993. 11. Jakse G, Algaba F, Malmstrom PU, et al: A second-look TUR in T1 transitional cell carcinoma: why? Eur Urol 45: 539 –546, 2004. 12. Witjes JA: Bladder CIS in 2003, state of the art. Eur Urol 45: 142–146, 2004. 13. Herr HW, Donat SM, and Dalbagni G: Correlation of cystoscopy with histology of recurrent papillary tumors of the bladder. J Urol 168: 978 –980, 2002. 14. Cina SJ, Epstein JI, Endrizzi JM, et al: Correlation of cystoscopic impression with histologic diagnosis of biopsy specimens of the bladder. Hum Pathol 32: 630 – 637, 2001.
755
REVIEW PATHOLOGY IN A DIAGNOSTIC BLADDER CANCER TRIAL: EFFECT OF PATIENT RISK CATEGORY J. A. WITJES, P. M. J. MOONEN,
AND
A. G.
VAN DER
HEIJDEN
ABSTRACT Objectives. Bladder cancer pathologic features are a continuous spectrum from benign to invasive lesions, causing diagnostic difficulties. Review pathology might be an answer, but appears to be of limited value. We studied the effect of patients’ risk profile on the value of review pathology. Methods. We used three Phase III multicenter studies that assessed the value of hexaminolevulinate fluorescence cystoscopy on diagnosis and management. Two studies (Europe and United States) included patients at high risk of carcinoma in situ (CIS), the third study (Europe) included all patients at risk of bladder cancer. Tumors and biopsies were examined by a local and review pathologist. Results. The percentage of patients with CIS was high in the first two studies (20.6% and 15.9%) compared with the epidemiologic data (7.9%) and the third study (7.8%). The numbers of patients (specimens) in the three studies were 209 (927), 277 (986), and 142 (553). Overall conformity for both grade and stage was between 50.5% and 56.6%, comparable to published data. Although conformity was best in the high-risk study, this was predominantly because of the better conformity in low-risk tumors. Conformity in Stage T1, CIS, and invasive tumors was low. The results from Europe and the United States were comparable, although the local pathologist in the United States tended to overstage or overgrade. Conclusions. Although histologic conformity was greater in the high-risk patient population, this was mainly a result of pTa tumors. The diagnosis of pT1, CIS, and invasiveness appears difficult. Because these tumors significantly influence therapy, review pathology in patients at high risk or suspicious for high risk should be considered. UROLOGY 67: 751–755, 2006. © 2006 Elsevier Inc.
B
ladder cancer is a continuous spectrum of tumors, including benign lesions (inverted papilloma), superficial tumors, and invasive cancer. The difficulty with this continuous spectrum is reflected in the World Health Organization classification that is adapted regularly on the basis of discussion by experts and years of experience. This difficult diagnosis, however, might have implications for patient treatment and prognosis. A potential solution is review pathology. However, two reports on this topic clearly indicated the limitations of review pathology.1,2 The only practical advice came from a combined review of five European Organization for Research and Treatment of Cancer (EORTC) trials.2 The conclusion was that in T1G3 disease, the stage or grade often changed, so From the Department of Urology, University Medical Centre St. Radboud, Nijmegen, The Netherlands Reprint requests: J. A.Witjes, M.D., Ph.D., Department of Urology, University Medical Centre St. Radboud, Nijmegen, The Netherlands. E-mail: [email protected] Submitted: July 12, 2005, accepted (with revisions): October 14, 2005 © 2006 ELSEVIER INC. ALL RIGHTS RESERVED
that review pathology continued to be recommended for this subgroup. We speculated that a patient’s risk profile could have an impact on the value of review pathology. For example, in a study that included only high-risk patients, local and review pathology might correlate better. Therefore, we compared the results of three fluorescence cystoscopy studies with different risk profiles. MATERIAL AND METHODS The data sets used for the present comparison were from three fluorescence cystoscopy studies. All three studies were performed in large community hospitals or academic hospitals with experience in bladder cancer and bladder cancer trials. The methods and inclusion and exclusion criteria for the first study (PC-B301) have been previously described in detail.3 In this within-patients controlled multicenter Phase III study, the selection criteria were such that at least 20% of patients had carcinoma in situ (CIS) to determine the additional detection of CIS by hexaminolevulinate (HAL, Hexvix) fluorescence cystoscopy. The study was conducted in Europe. After 1 hour of intravesical Hexvix, the tumors were resected and the bladder was mapped with white light and with fluorescence cystoscopy (Karl Storz, Tuttlingen, Germany). The histologic results of the local pathologist were used for treatment deci0090-4295/06/$32.00 doi:10.1016/j.urology.2005.10.028 751
TABLE I. Local pathologic results in three studies per patient (P) and per specimen/biopsy (S/B) Study PC-B301 Missing Normal* pTaG1 pTaG2 pTaG3 pT1G1 pT1G2 pT1G3 CIS ⬎pT2 Total
PC-B302
PC-B303
Total
P
S/B
P
S/B
P
S/B
P
S/B
— 28 39 49 11 4 7 15 43 13 209
5 339 137 141 68 8 14 62 128 25 927
3 70 57 56 9 2 6 13 44 17 277
31 457 148 140 41 2 14 29 99 25 986
— 43 25 29 5 4 4 10 11 11 142
4 311 80 58 9 7 10 27 28 19 553
3 141 121 134 25 10 17 38 98 41 628
40 1107 365 339 118 17 38 118 255 69 2466
KEY: CIS ⫽ carcinoma in situ. * Normal included moderate dysplasia.
TABLE II. Total number of patients diagnosed by local pathologists per diagnosis (stage and grade) and per study, and percentage confirmed by review pathologist PC-B301 “Local” Diagnosis Normal* pTaG1 pTaG2 pTaG3 pT1G1 pT1G2 pT1G3 CIS ⬎pT2
PC-B302
PC-B303
Total
Total (n)
Confirmed (%)
Total (n)
Confirmed (%)
Total (n)
Confirmed (%)
Total
Confirmed % Total
28 39 49 11 4 7 15 43 13
50 53.9 55.1 27.3 0 42.9 26.7 81.4 84.6
70 57 56 9 2 6 13 44 17
68.6 64.9 14.3 22.2 0 0 38.5 65.9 64.7
43 25 29 5 4 4 10 11 11
81.4 68 20.7 20 0 0 30 45.5 100
141 121 134 25 10 17 38 98 41
68.8 62 30.6 24 0 17.7 31.6 70.4 80.5
KEY: CIS ⫽ carcinoma in situ. * Normal included moderate dysplasia.
sions. Review pathology was used for primary study analysis. In every study, one experienced uropathologist reviewed all slides. The lesions were staged according to the International Union Against Cancer/American Joint Committee on Cancer 1992 staging system.4 Flat lesions were graded according to the World Health Organization/International Society of Urological Pathologists 2001 consensus classification on urothelial neoplasms of the bladder.5 Papillary lesions were graded according to the World Health Organization 1973 criteria.6 Study PC-B302 had exactly the same inclusion criteria, endpoints, and methods, including review pathology for study analysis, and was conducted in North America. In the third study (PC-B303, conducted in Europe) management in patients with bladder cancer was compared. In this study, all patients with known or suspected bladder cancer, as diagnosed by cystoscopy or positive urine cytology, were included. Exclusions included gross hematuria and intravesical treatment within 3 months of inclusion.
RESULTS The results with regard to the primary diagnostic and safety endpoints of the three studies have been previously published.3,7–9 In brief, Hexvix fluores752
cence cystoscopy is safe, and it improves the detection of bladder tumors, especially CIS. Moreover, 22% of patients with bladder tumors receive a more appropriate treatment after blue light cystoscopy.9 The number of patients included in this histologic comparison was 209, 277, and 142 from the three studies. The total number of separate resections and biopsies was 927, 986 and 553. The local pathology results per patient and per “resection/ biopsy” are shown in Table I. As expected, the percentage of patients with CIS in the PC-B301 and PC-B302 studies was greater than in the PC-B303 study (20.6%, 15.9%, and 7.8%, respectively). The corresponding percentages of patients with grade 3 or Stage T1 or CIS tumors were 40.9%, 28.5%, and 25.6%. Pathologic T1G1 tumors were infrequent, even with local pathologic examination. Table II shows the total number of patients diagnosed by local pathology per stage and grade and per study, and the percentage was confirmed by review paUROLOGY 67 (4), 2006
TABLE III. Comparison of local and review pathology in absolute numbers and per stage/grade for three studies together Local Pathology Missing Normal* pTaG1 pTaG2 pTaG3 pT1G1 pT1G2 pT1G3 CIS ⬎pT2 Total (631)
Review Pathology Missing
Normal*
5 1 2 1
97 15 9 2 3
2 1 12
4 4 1 135
pTaG1 1 9 75 51 1 1 1 3 2 144
pTaG2
pTaG3
pT1G1
pT1G2
pT1G3 1
7 24 35 5 1 7
1 80
1 1
1 3 1 1 3 1 2
9
12
1 6
1 2 3
12 3 2 24
CIS 1 23 6 25 6 2 4 12 69 1 152
>pT2 3 1 1 2 1 8 14 33 63
KEY: CIS ⫽ carcinoma in situ. * Normal included moderate dysplasia.
thology. The review pathologists did not confirm many pT1 tumors, as was the case with pTaG2 tumors in the PC-B302 and PC-B303 studies, in which conformity with a fair number of patients was also less than 50%. More details are given in Table III, which shows a comparison of the local and review pathologic findings in absolute numbers and per stage/grade for the three studies together. The overall conformity for grade and stage was between 50.5% and 56.6% (Table IV). COMMENT As indicated previously, bladder cancer is a continuous spectrum. The result is that it is not always easy to differentiate between two stages or grades. Therefore, the details of bladder cancer stage and grade have been regularly adapted to improve the value of the classification. However, interobserver and intraobserver variability in histologic assessment of superficial bladder tumors is significant. A potential solution for this problem is review pathology. In a study with 254 pTa and 133 pT1 tumors and 50 patients with CIS, local and review pathologic results were analyzed with regard to treatment and a prognostic factor analysis.1 The conformity between local and review pathology was 79.3% for stage, 70.2% for grade, and 59.7% for both. However, the risks of recurrence in the separate groups remained similar after changing the pathologic results. A multivariate prognostic factor analysis for recurrence also hardly changed after correction for review pathology. Only the prognostic relevance of tumor stage increased after the pathology change. The investigators concluded that although review pathology caused considerable changes, this did not affect the treatment results and hardly altered the prognostic factor analysis. Local and review UROLOGY 67 (4), 2006
pathology were also compared in 1400 patients with Stage Ta-T1 bladder cancer treated in five randomized Phase III EORTC trials.2 Considerable variations in stage and grade were found, but differences in the prognosis according to the local and review pathologic results were limited. However, these investigators advised review for T1G3 disease, because changes are frequent and have great impact on patient management. In all, these two reports have clearly shown the limitations of review pathology. The present study compared local and review pathology in three studies, two of which selected only high-risk patients to include at least 20% of patients with CIS. On the basis of the local pathologic results (Table I), the percentage of patients with CIS was 20.6% and 15.9% in the PC-B301 and PC-B302 studies, greater than in the PC-B303 study (7.8%) and a random bladder cancer population (7.9%).10 The PC-B301 study also included more patients with grade 3 or Stage T1 or CIS (40.9%) compared with the PC-B302 (28.5%) and PC-B303 (25.6%) studies. Thus, PC-B302 and, especially, PC-B301 had a high-risk superficial bladder cancer population, and PC-B303 reflected an average patient population much more. If one then considers the effect of review pathology on patient level in these three studies, several points deserve attention. T1G1 remains a rare diagnosis.1 Local pathology diagnosed this tumor in 10 patients (1.6%) and 17 specimens, of which only 2 specimens were confirmed after review. The overall conformity, in which both grade and stage were confirmed, was between 50.5% and 56.6% in these three studies compared with approximately 60% in published data (Table IV). However, in most studies, conformity was largely a re753
TABLE IV. Conformity of stage or grade or both: comparison of three studies and with published data Study PC-B301 PC-B302 PC-B303 Witjes et al.1 Van Der Meijden et al.2
Stage and Grade (%)
Ta (%)
T1 (%)
All Grades (%)
CIS (%)
56.5 50.5 50.7 59.8 62.1
90.5 82.4 59.6 81.5 68.7
61.5 40 37.5 77.4 77.1
61.9 50.4 41.8 69.5 57.3
53.8 44.6 22.7 94 —
KEY: CIS ⫽ carcinoma in situ.
sult of low-stage tumors. The better conformity in PC-B301, the study with the highest risk patient population, was also a result of the low-risk patients. PC-B302, which also had a high-risk population, had similar overall results as PC-B303, with an average patient risk population. This also suggests that the effect of the risk classification is limited. This observation also illustrates that North American and European pathologists do not seem to differ in their classification. However, in both European studies, discrepancies were mostly caused by a lower stage or grade being given by the local pathologists. In the PC-B301 study, the disease of 58 patients were upstaged or upgraded after review and 31 were downstaged or downgraded. In PCB303, the corresponding numbers were 44 and 23. In contrast, in the North American study, the corresponding numbers were 59 and 68. Although the number of T1 tumors in this study was limited, the results for conformity in patients with Stage T1 and CIS appeared lower than those in published studies. The EORTC analysis showed that 53% of T1 tumors were reclassified as Ta tumors, with agreement in only 50% of Stage T1G3 cases. Also, of Stage T1G3 tumors, 10% were upstaged as muscle-invasive disease.2 Because the determination of T1 tumors is important for patient treatment, standard review pathology or perhaps standard repeat resection in these patients should be considered,11 as it is obvious that for these tumors, histologic examination has limitations. However, review pathology cannot compensate for inadequate resection or repeat resection and vice versa. The same might be true for patients with CIS. The conformity in these three studies was 23% to 54%. Moreover, many of the discrepancies were in patients with CIS on review and no or low-grade/ low-stage tumor on local pathologic examination. Fortunately, the results in published studies have been better.1 Furthermore, triggered by abnormal cytologic findings, which are very common in CIS, and guided by fluorescence cystoscopy, the diagnosis of CIS will improve in the future.12 Finally, a surprising problem was found with pT2 tumors, for which conformity was 50% in 754
these series and 36.2% and even 0% in published data. Most were understaged by the local pathologist as pT1G3 lesions. Apparently, the recognition of detrusor muscle in transurethral resection material is difficult, or, worse, no detrusor muscle was present as a result of an insufficient resection. In other cases, the local and review pathologists might have received different parts of the resected tissue in which the detrusor was not always present. Why is the histologic diagnosis of bladder cancer so difficult? Because stage and grade are among the most important prognostic factors, a correct diagnosis in superficial bladder cancer is probably more important than the use of intravesical therapy, which only marginally influences the natural course of the disease. The pathologist can only do a proper job with good tissue samples, representative of the index tumor. Simple methods to improve transurethral resection (TUR) are standard operating procedures, such as the use of a bladder diagram or video-assisted TUR, proper TUR techniques, proper orientation and labeling of tissue, and biopsies on good indications.11 Important standard operating procedures include the careful use of cautery. Also, in the case of suspected CIS, contact between the instrument and the mucosal surface should be limited to avoid mucosal denudation. Whether a grading system with only low and high-grade tumors would improve reproducibility remains unclear. Considering our figures, this might be so for pTa tumors, for which many discrepancies were found in the grade 2 group. However, for pT1, pT2, and CIS tumors, which are mostly high grade, the effect of a new grading system would probably be limited. Therefore, the limited reproducibility of bladder cancer histologic examination is a mutual problem for the pathologist and urologist that can only be solved by good interactions between both. One might wonder whether the “prediction” of histologic type during TUR by an experienced urologist is not better than an insufficient resection or histologic classification. Herr et al.13 correlated cystoscopy and histologic findings in recurrent papillary tumors and found that 93% of Ta tumors UROLOGY 67 (4), 2006
were predicted correctly, as were 99% of grade 3 or T1 tumors.13 For biopsy judgment, the same was found by Cina et al.14 Benign and malignant lesions of the bladder were predicted with 100% sensitivity and specificity. In contrast, in the same study, discrimination between low and high-grade tumors, as well as the determination of microscopic invasion was inaccurate. In all, endoscopic examination can be an important aid in discriminating good and bad tumors. CONCLUSIONS Histologic examination of superficial bladder cancer remains difficult. The overall conformity is only between 50% and 60%, which limits its prognostic value. Although in this study, the conformity was best in the study with the patient population at highest risk, this was predominantly caused by the better conformity in low-stage tumors. T1 tumors, although the number in this study was limited, CIS, and even invasive tumors remain a diagnostic challenge. Because it is most important to differentiate these tumors for decisions regarding aggressive or conservative therapy, review pathology of these tumors, or if they are suspected, should be considered. Proper TUR and careful tissue handling will without doubt help to improve the value of bladder cancer histologic examination. Whether a standard second resection can add to the correct diagnosis remains to be seen. The difference in conformity between the North American and European studies was limited. The local pathologist in North America tended to overstage or overgrade. REFERENCES 1. Witjes JA, Kiemeney LA, Schaafsma HE, et al: The influence of review pathology on study outcome of a randomized multicentre superficial bladder cancer trial. Br J Urol 73: 172–176, 1994.
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2. Van Der Meijden A, Sylvester R, Collette L, et al: The role and impact of pathology review on stage and grade assessment of stages Ta and T1 bladder tumors: a combined analysis of 5 European Organization for Research and Treatment of Cancer Trials. J Urol 164: 1533–1537, 2000. 3. Schmidbauer J, Witjes F, Schmeller N, et al: Improved detection of urothelial carcinoma in situ with hexaminolevulinate fluorescence cystoscopy. J Urol 171: 135–138, 2004. 4. Hermanek J, and Sobin J: UICC TNBM Classification of Malignant Tumours, 4th ed. Berlin, Springer Verlag, 1992. 5. Epstein JI, Amin MB, Reuter VR, et al, for the Bladder Consensus Conference Committee: The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Am J Surg Pathol 22: 1435–1448, 1998. 6. Mostofi FK, Sobin LH, and Torloni H: Histopathological typing of urinary bladder tumours, in International Histological Classification of Tumours. Geneva, World Health Organisation, 1973. 7. Grossman HB, Gomella LG, Fradet Y, et al: The use of Hexvix and fluorescence cystoscopy as an adjunct in the diagnosis of stage Ta/T1 urothelial cancer in the urinary bladder (abstract). J Urol 171: 69, 2004. 8. Gomella LG, Grossman HB, Presti JC Jr, et al: The use of Hexvix and fluorescence cystoscopy as an adjunct in the diagnosis of carcinoma in situ of the urinary bladder (abstract). J Urol 171: 69, 2004. 9. Jocham D, Witjes F, Wagner S, et al: Improved detection and treatment of bladder cancer using Hexvix imaging: a prospective phase III multi-centre study. J Urol 174: 862– 866, 2005. 10. Kiemeney LALM, Witjes JA, Verbeek ALM, et al: The clinical epidemiology of superficial bladder cancer. Br J Cancer 67: 806 – 812, 1993. 11. Jakse G, Algaba F, Malmstrom PU, et al: A second-look TUR in T1 transitional cell carcinoma: why? Eur Urol 45: 539 –546, 2004. 12. Witjes JA: Bladder CIS in 2003, state of the art. Eur Urol 45: 142–146, 2004. 13. Herr HW, Donat SM, and Dalbagni G: Correlation of cystoscopy with histology of recurrent papillary tumors of the bladder. J Urol 168: 978 –980, 2002. 14. Cina SJ, Epstein JI, Endrizzi JM, et al: Correlation of cystoscopic impression with histologic diagnosis of biopsy specimens of the bladder. Hum Pathol 32: 630 – 637, 2001.
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