Evaluation of Second-Look Transurethral Resection in Restaging of Patients with Nonmuscle-Invasive Bladder Cancer

Abstract

Purpose:

Evaluation of second-look transurethral resection (TUR) in avoidance of staging errors, and determination of risk factors of upstaging in patients with nonmuscle invasive bladder cancer.

Patients and Methods:

An analytic prospective cohort study included 91 patients with stage T₁ and T_a bladder cancer. All patients underwent second-look TUR within 2 to 6 weeks after the initial resection. Histopathologic findings of the second TUR of bladder tumor (TURBT) were compared with those of the initial one.

Results:

Specimens obtained during the second TURBT showed no tumor in 38 (41.7%) patients; 22 (24.2%) patients had residual cancer of the same stage, 9 (14.8%) patients of PT₁ had a lower stage, and 22 (24.2%) had a higher stage. Upstaging had changed treatment strategy in 22 (24.2%) cases. Appearance, size, grade, and stage of the tumor at the initial resection are all considered independent risk factors for upstaging detected at second-look TURBT.

Conclusions:

Second TURBT is a valuable procedure for accurate staging of nonmuscle-invasive bladder cancer. It changed the treatment strategy of a significant proportion of our patients. Second TURBT is indicated in T₁, high grade, large size (>3 cm), and nodular tumors because of the significant risk of detecting muscle-invasive disease.

Introduction

B ladder cancer is the most common cancer of the genitourinary tract in Egypt.¹ Approximately 75% to 85% of patients with bladder cancer present with nonmuscle invasive bladder cancer (NMIBC).² Transurethral resection of bladder tumor (TURBT) is the cornerstone of diagnosis, and it is the gold standard treatment for patients with NMIBC. Without an adequate resection, with good quality of the underlying detrusor muscle, the pathologist will not be able to fully differentiate between T_a, T₁, and T₂ bladder tumor.³ The histopathologic diagnosis may be compromised by fulguration of the specimen, incomplete resection of the tumor, the pathologist's expertise, and the difficult orientation of multiple fragmented pieces of tissue that may lead to staging error.⁴ Moreover, different patterns of invasion in cases of T₁ tumors (broad-front or tentacular invasion) may contribute in these staging errors.⁵ At the first resection, underestimation of pathologic stage occurs in 9% to 49% of patients with NMIBC.⁶

The fact that local tumor control and accurate tumor staging depend on a complete TURBT and reevaluation of the tumor base suggests that a second restaging TURBT may be of value in evaluating patients with bladder tumors.⁵

A second TUR may change treatment strategy in patients with a diagnosis of NMIBC at initial TUR. In cases of upstaging to muscle infiltrating tumor (T₂) detected at the second TUR, cystectomy or one of the bladder preservation protocols should be performed.⁷

The objectives of this prospective analysis are: Evaluation of a second-look TUR in avoidance of staging errors, possibility of changing treatment strategy, and determination of risk factors of upstaging in patients with a diagnosis of nonmuscle invasive urinary bladder cancer.

Patients and Methods

From May 2008 to December 2009, 91 patients underwent a second-look TUR in our institution within 2 to 6 weeks after the initial resection of bladder tumor. All patients included in this study had a diagnosis of NMIBC in the initial TURBT. Patients with a muscle-invasive disease diagnosis in the initial TURBT were excluded. The mean age was 59 years; 65 patients were men and 26 were women. Complete preoperative clinical evaluation including history and full physical examination; laboratory and radiologic investigations were performed for all patients.

At the initial TURBT, the procedure was performed by both senior staff and residents in our department, without any special assignment. All visible tumors were completely resected, with a deep muscular sample taken from the tumor base as well as the tumor margins. All samples were taken as separate specimens and sent for histopathologic assessment. Tumors were staged according to Tumor-Node-Metastasis classification and graded according to the new World Health Organization/International Society of Urologic Pathology (ISUP) classification.⁸ Patients with any pathologic types rather than transitional-cell carcinoma (TCC) were excluded from the study.

At the second-look TURBT, the bladder was reassessed for detection of any residual tumors or missed lesions. Resection from the base of the previously resected tumor was performed for restaging. All data obtained from the first and second TURBT were recorded on a cystoscopic sheet by the surgeon immediately after the operation, including size, number, appearance, and location of the tumor. Histopathologic staging and grading results in the second TUR were compared with those of the initial TUR.

Statistical analysis

The data were analyzed using Statistical Package for Social Sciences, version11 (SPSS, Chicago, IL). Analytic statistics were obtained using the chi-square test, the Fisher exact test, and the differences were significant if P < 0.05. Multivariate logistic regression analysis (binary regression) was used to assess the different risk factors of upstaging and presence of residual tumors in patients with a diagnosis of NMIBC.

Results

The second TUR was negative in 38 (41.7%) patients. Residual malignant tissue was found in the same site of the previous resection in 37 (40.6%) patients, while missed lesions were found in another site far from the previous resection in 11 (12.1%) patients; five (5.5%) patients had concurrent residual and missed lesions in their second TUR. Table 1 describes the rate of residual tumors and missed lesions in the second TUR. Among the 53 patients with residual cancer or missed lesion, 22 (41.5%) had an identical pathologic stage as in the first TUR, while 31 (58.5%) had either a lower stage (n = 9; 17%) or a higher stage (n = 22; 41.5%).

Table 1.

Rate of Residual and Missed Tumors Found in Second-Look Transurethral Resection

Second TUR findings	No. of patients	Rate (%)
Residual^a	37	40.7
Missed^b	11	12.1
Concurrent missed and residual	5	5.5
Tumor free	38	41.7
Total	91	100

Residual tumor is one in the same site as the first resection.

Missed lesion is a tumor in another site away from the first resection.

TUR = transurethral resection.

Of the 30 patients with stage pT_a at the initial TUR, only 6 (20%) had a higher stage pT₁ at the second-look TURBT (Table 2).

Table 2.

Second Transurethral Resection Results of Original pT_a

	First TUR findings
Histopathologic	pT_a
Findings at second TUR	N = 30 (33%)
No tumor	18 (60%)
Same stage (pT_a)	6 (20%)
Higher stage (pT₁)	6 (20%)

TUR = transurethral resection.

On the other hand, of the 61 patients with stage pT₁, 16 (26.2%) patients had a higher stage (pT₂), while 9 (14.8%) patients were downstaged to stage T_a (Table 3). The second TUR results changed treatment strategy for 22 (24.2%) of 91 patients. Six patients, upstaged from T_a to T₁, received maintenance intravesical bacille Calmette-Guérin (BCG), because the second TUR showed that they had T₁ high-grade tumors. Of 16 patients upstaged from T₁ to muscle-invasive disease, 5 were referred to a bladder preservation protocol, while the other 11 had radical cystectomy.

Table 3.

Second Transurethral Resection Results of Original pT₁

	First TUR findings
Histopathologic	pT₁
Findings at second TUR	N = 61 (67%)
No tumor	20 (32.8%)
Same stage (pT₁)	16 (26.2%)
Higher stage (pT₂)	16 (26.2%)
Downstage (pT_a)	9 (14.8%)

TUR = transurethral resection.

Of these 16 patients upstaged to muscle-invasive disease, 13 had pT₁ high-grade tumor at the initial resection. Table 4 shows the strong relation between high-grade pT₁ bladder tumors and the probability of upstaging at the second TURBT (P ≤ 0.05). Univariate analysis of the different histopathologic and morphologic risk factors at the initial TURBT (Table 5) reveals that there is a significant statistical relation between upstaging to muscle-invasive disease and presence of T₁, high grade, large size (>3 cm), nodular tumor detected at the initial resection (P ≤ 0.05).

Table 4.

Second-Look Transurethral Resection Results of Original pT₁, High Grade

Histopathologic findings at second TUR	Results of original pT₁ high grade in second TUR
	n = 30	P value
No tumor	3 (10%)	^a0.03
T_a (downstage)	5 (16.7%)
T₁ (same stage)	9 (30%)
T₂ (upstage)	13 (43.3%)

Significant P value ≤0.05.

TUR = transurethral resection.

Table 5.

Relation of Various Histopathologic and Morphologic Prognostic Factors with Patients Upstaged to Muscle Invasive Transitional-Cell Carcinoma (T₂) in Second-Look Transurethral Resection

		Upstaged patients (T₂) N = 6 (18.2%)
Prognostic histopathologic and morphologic factors in initial TUR		No.	%	P value
Stage	Ta	(n=30)	0 (0%)	^a0.05
	T1	(n=61)	16 (26.2%)
Grade	Low grade	(n=59)	3 (5 %)	^a0.01
	High grade	(n=32)	12 (37.5%)
Size	< 3 cm	(n=65)	3 (4.6%)	^a0.004
	> 3 cm	(n=26)	12 (46.1%)
Appearance	papillary	(n=80)	8 (10%)	^a0.002
	nodular	(n=11)	8 (72.7%)
Number	Single	(n=72)	14 (19.4%)	0.5
	Multiple	(n=19)	2 (10.5%)
Associated CIS	+ ve	(n=3)	1 (33%)	0.6
	− ve	(n=88)	15 (17%)

Significant P value ≤0.05.

TUR = transurethral resection; CIS = carcinoma in situ.

Using a multivariate logistic regression analysis (Table 6), our results showed that appearance, size, grade, and stage of the tumor are all considered independent risk factors for upstaging detected at second-look TURBT.

Table 6.

Logistic Regression Analysis of the Different Histopathologic and Morphologic Risk Factors for Upstaging to Muscle-Invasive Disease in Second-Look Transurethral Resection

Logistic regression table	Odds ratio	P value
Variables
Appearance (nodular)	9.878	0.002^a
Size (>3 cm)	8.250	0.004^a
Grade (high)	5.930	0.015^a
Stage (pT₁)	4.188	0.05^a
Number	.416	.519
Associated CIS	.229	.632
Overall statistics	12.866	0.045

CIS = carcinoma in situ.

Significant p value ≤ 0.05.

Discussion

It is well established that early recurrence (less than 3 months) is one of the most important prognostic factors in patients with NMIBC. Evidence is emerging, however, that a substantial number of so-called early recurrences simply constitute residual cancer rather than a true recurrence.⁹ Benefits of second-look TURBT of NMIBC include not only complete resection of residual tumor, but also avoiding staging errors. Several studies reported that staging errors after initial TUR range between 9% and 49% of patients with NMIBC.^6,10,11

A second therapeutic TUR also appears to improve the short-term response to BCG therapy because it can reduce tumor burden. Herr¹² performed a study of patients with high-risk NMIBC (high-grade T_a and T₁ tumors associated with carcinoma in situ [CIS]); 132 patients underwent a single TUR and 215 patients underwent restaging TUR before receiving six weekly intravesical BCG treatments. The patients were evaluated for response to BCG. Herr found that 57% of patients who underwent a single TUR before BCG therapy had residual or recurrent tumor at the first cystoscopy and 34% had progression. On the other hand, only 29% of patients who underwent restaging TUR had residual or recurrent tumors and 7% had progression. The author concluded that restaging TUR of high-risk superficial bladder cancer improves the initial response rate to BCG therapy, reduces the frequency of subsequent tumor recurrence, and appears to delay early tumor progression.

An international consensus panel on the management of T₁ tumors of the bladder mentioned that the risk of residual tumors after a textbook initial TURB has been reported to be as high as 60%. They also stated that the result of a second-look TURB changed the treatment in 33% of patients with T₁ tumors.¹³

In the present study, residual malignant tissue was found in the same site of the previous resection in 40.6%, while missed lesions were found in other sites far from the previous resection in 12.1%; concurrent residual and missed lesions were found in 5.5% of patients on re-TUR. The overall rate of residual tumors in the second resection is 58.2% in our patients. Our results were similar to those reported by Herr¹⁴ in 1999. He reported that the overall rate of residual tumors in the second resection was 75%.

Mersdorf and associates¹⁵ believed that a second TUR is a must. Among 94 cases with T_a and T₁ tumors, about 80% of the cases had residual cancer on re-TURBT.¹⁵ Other authors, however, reported a rather lower rate of residual tumors in their studies. This rate could be explained by the quality of the initial TUR in these studies.^16,17 Variation in residual tumor rates may be because of factors associated with individual surgeons such as different techniques and experience of the resectionists.

Regarding the staging error reported in our study including upstaging and downstaging with a change in the treatment strategy in our population: In our study, among the 53 patients with residual cancer or missed lesion, 22 (41.5%) had an identical pathologic stage as in the first TUR, while 31 (58.5%) had either a lower stage (n = 9; 17%) or a higher stage (n = 22; 41.5%). Of 30 patients with stage pT_a in re-TUR, 6 (20%) patients had a higher stage (pT₁), while of the 61 patients with stage pT₁, 16 patients (26.2%) had a higher stage (pT₂) and 9 (14.8%) downstaged to stage T_a tumors. The second TUR results changed treatment strategy for 22 (24.2%) of 91 patients. Six patients, upstaged from T_a to T₁, received maintenance intravesical BCG, because the second TUR showed that they had T₁ high grade. Of 16 patients upstaged from T₁ to muscle-invasive disease, 5 were referred to bladder preservation protocol, while the other 11 had radical cystectomy.

Postoperative pathologic examination of these radical cystectomy specimens revealed that those patients had pT₂ tumors. The second TUR in our series resulted in a change of treatment strategy for 22 (24.2%) of 91 patients.

Our study results were comparable with the published results regarding correction of the staging errors. Herr¹⁴ reported that of 38 cases with T_a disease, 23% had lamina propria invasion (pT₁) and 7.8% were upstaged to a muscle-invasive (pT₂) tumor; among the 58 cases with T₁ tumor, 27.5% were upstaged to muscle-invasive disease (pT₂) tumor. In Herr's study, second resection of those patients changed treatment in 28 (29%) cases upstaged from noninvasive to invasive tumor. Our results demonstrated that patients with T₁, high-grade tumors are at high risk for presence of residual muscle-invasive bladder cancer at re-TUR.

Brauers and colleagues³ studied 42 patients with moderately or poorly differentiated T₁ bladder tumor; 64% had residual tumors in their second resection and 24% were upstaged to muscle-invasive disease. Sanseverino and coworkers¹⁸ concluded that a second-look TURBT in cases of a primary diagnosis of pT₁G3 bladder tumor allows restaging correctly in about 21% of cases, with great impact on appropriate surgical treatment of the disease. They reported that of 72 patients with T₁G3 TCC, residual malignant tissue was found in about 45% of cases; histologic findings after the second TURB showed upstaging to pT₂ tumors in 20.84% of patients.

Univariate analysis of the different histopathologic and morphologic risk factors at the initial TURBT reveals that there is a significant statistical relation between upstaging to muscle-invasive disease and presence of T₁, high grade, large size (>3 cm), nodular tumor detected at the initial resection (P ≤ 0.05). Furthermore, we used a multivariate logistic regression analysis to determine the independent prognostic or high-risk factors of NMIBC for upstaging to muscle-invasive disease at the second-look TURBT. We found that the risk of upstaging to muscle-invasive disease increases in patients with T₁, high-grade, large size (>3 cm), and nodular tumor. In our study, only three patients had associated CIS in their first TUR result; this number is too small. Therefore, we cannot draw any definitive conclusions about associated CIS and its impact on finding residual tumor in the second TURBT.

The fact that local tumor control and accurate tumor staging depend on a complete TUR and reevaluation of the tumor base suggests that a second restaging TUR may be of value in evaluating patients with bladder tumors. Another TUR reduces the uncertainty of depth of tumor invasion, better controls the primary tumor, and provides additional pathologic information that may help to select appropriate treatment.^4,5

Conclusions

Second TURBT is a valuable procedure for accurate staging of NMIBC. It changed the treatment strategy of a significant proportion of our patients. Second TURBT is indicated in T₁, high-grade, large size (>3 cm), and nodular tumors because of the significant risk of detecting muscle-invasive disease.

Footnotes

Disclosure Statement

No competing financial interests exist.

Abbreviations Used

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