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Ureterorenoscopic biopsy and urinary cytology according to the 2004 WHO classification underestimate tumor grading in upper urinary tract urothelial carcinoma
Urologic Oncology: Seminars and Original Investigations 31 (2013) 1166 –1170
Original article
Ureterorenoscopic biopsy and urinary cytology according to the 2004 WHO classification underestimate tumor grading in upper urinary tract urothelial carcinoma Julia Straub, M.D., Frank Strittmatter, M.D., Alexander Karl, M.D., Christian G. Stief, M.D., Stefan Tritschler, M.D.* Department of Urology, Grohadern University Hospital, Ludwig Maximilians University of Munich, Munich, Germany Received 22 October 2011; received in revised form 13 December 2011; accepted 28 December 2011
Abstract Objectives: To determine accuracy of upper tract cytology and ureteroscopic biopsy according to the 2004 World Health Organization (WHO) classification in predicting the correct tumor grade in patients with urothelial cancer of the upper urinary tract (UUT-UC). Methods: Pathology reports of 77 nephroureterectomy specimens were retrospectively analyzed for tumor grade and compared with preoperatively gained cytology and ureteroscopic biopsy results. For analysis, the 2004 WHO classification was used. Results: Overall sensitivity of cytology and biopsy in diagnosis of UUT-UC was 64% and 74%, respectively. Accuracy of cytology and biopsy in predicting high grade cancer was 53% and 58%, respectively. Combination of cytology and biopsy could improve sensitivity (84%) and accuracy (68%), but even for this combination, 15% of high grade tumors were misinterpreted as low grade cancer. Conclusion: Our results show only limited accuracy for preoperative cytology and ureterorenoscopically performed biopsies in the prediction of the correct tumor grading of an UUT-UC. Therefore, we suggest the use of additional diagnostic procedures before the decision for definitive surgical treatment in patients with UUT-UC is made. © 2013 Elsevier Inc. All rights reserved. Keywords: Upper tract urothelial carcinoma; Ureterorenoscopy; Urinary cytology; Grading
1. Introduction Urothelial carcinoma of the upper urinary tract (UUTUC) is an uncommon entity, accounting for 2–5% of all urothelial tumors. Standard therapy in patients with upper urinary tract urothelial carcinoma (UUT-UC) is nephroureterectomy (NU) with excision of the ureteric orifice [1]. This procedure has proven to provide optimal results in terms of oncologic outcome. However, NU seems to be an overtreatment in patients with well differentiated superficial tumors, especially with small pTa low grade tumors. The attempt of an organ-preserving approach is mandatory in patients with tumors in a solitary kidney. However an endoscopic management using resection, holmium:YAG or neodynium: YAG laser has been widely practiced even in select patients with low grade disease and normal contralateral kidney * Corresponding author. Tel.: ⫹49/89/7095– 0; fax: ⫹49/89/7095– 4745. E-mail address: [email protected] (S. Tritschler). 1078-1439/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.urolonc.2011.12.021
function [2– 4]. Furthermore, partial ureterectomy with ureteroneocystostomy seems to be appropriate for distal low grade ureteral tumors [2]. A basic requirement for such a conservative approach is the confirmation of a low grade and low volume tumor, since there is a strong correlation between grading and depth of tumor invasion [5]. Consequently, the prognostic power of pathologic grading is well established [2]. So the risk for the development of metastases and local progression of a high grade tumor would seem to vote against conservative management [6]. The confirmation of a low grade lesion is of utmost importance because simple inspection of a lesion has shown to predict the grade correctly only in 71% (low grade tumors) and 80% (high grade tumors) of cases [7]. Grading of upper urinary tract tumors is preoperatively determined either by cytology or by ureterorenoscopically performed biopsy. However, the limitation of cytology in determining the correct tumor grade is well established. Sensitivity of cytology in upper urinary tract tumors has proven to be very
J. Straub et al. / Urologic Oncology: Seminars and Original Investigations 31 (2013) 1166 –1170
poor with detection rates as low as 29% [8] because low grade disease is associated with very subtle microscopic changes [9,10]. In contrast, high grade lesions in the bladder are detected quite reliably by cytology [11]. But in UUTUC, even the use of fluorescent in situ hybridization (FISH) analysis does not reliably provide a high sensitivity [12]. Regarding ureteroscopic biopsy, recent pathologic studies demonstrate that in almost one of four renal pelvic/ ureteral biopsies, a definitive diagnosis cannot be made due to extraction of inadequate tissue. This is explained by the limited size of the sample, absence of papillary fronds, crush artifact, and distorted architecture [13]. The aim of the present study was the investigation of the capability of biopsy and cytology according to the 2004 WHO classification to determine the correct tumor grade in upper urinary tract tumors, thus discriminating those tumors that are favorable for conservative treatment from those that should be treated radically by NU.
2. Patients and methods Medical charts of patients who underwent NU between 2004 and 2011 at our institution for urothelial cancer of the upper urinary tract were reviewed. Patients who had undergone preoperative upper tract cytology and/or preoperative ureteroscopic biopsy due to hematuria or radiological suspicion of upper tract tumor were identified. Biopsies and cytology had been taken whenever UUT-UC was endoscopically suspected or clearly detected. In large tumors with good accessibility, multiple biopsies had been taken. Biopsies had been taken by 3F cup forceps or by a Dormia basket. The specimens had been fixed in formalin and sent for pathologic evaluation. Samples for cytologic analysis were obtained by ureteral catheterization and flushing with 2–5 mL of saline solution before administration of contrast Table 1 Pathologic examination of ureterorenoscopic and nephroureterectomy specimen Characteristics Ureteroscopic stage pT0 Papilloma PUNLMP pTa pT1 pTis pTx Definitive stage pT0 pTa pTis pT1 pT2 pT3 pT4
Number 14 1 3 26 13 3 9 1 18 4 14 10 28 2
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Table 2 Correlation of cytologic grading and surgical grading Surgical pathologic grade
High Low Benign
Cytology High
Low
Benign
Insufficient sample
24 2 0
6 5 0
15 6 1
14 4 0
medium. Papanicolaou staining was performed on the centrifuged samples. Grading of cytology, biopsy, and nephroureterectomy specimen was classified according to the 2004 WHO system. Biopsies and surgical specimens were staged according to the TNM system. Seven different boardcertified pathologists assessed the biopsies and NU specimens. NU was performed in case of high grade cancer in preoperative biopsies or in cases of bio-optically proven low grade tumors where endoscopic treatment was technically not feasible due to tumor size and/or location. Results of upper tract cytology and biopsy gained by preoperative ureterorenoscopy were analyzed and compared with histology of the specimen gained by NU. For further analysis, results of both methods have been combined and the correlation has been performed for the highest tumor grade of both investigations.
3. Results A total of 99 patients underwent nephroureterectomy within the observed time period, and 77 patients with a mean age of 68 years (47– 89) could be identified who met the inclusion criteria. All patients underwent nephroureterectomy for upper urinary tract urothelial cancer within the reviewed period. All patients had first diagnosis of UUTUC, no attempts of organ preserving surgery had been undertaken before; n ⫽ 14 and n ⫽ 8 patients had previous and metachronous bladder cancer with the necessity of transurethral resection of the bladder (TURB). Final pathologic stage was pT0 (n ⫽ 1), pTis (n ⫽ 4), pTa (n ⫽ 18), pT1 (n ⫽ 14), pT2 (n ⫽ 10), pT3 (n ⫽ 28), and pT4 (n ⫽ 2) (Table 1). Pathologic grade in these specimens was low grade (n ⫽ 17), high grade (n ⫽ 59), and benign (n ⫽ 1). Cancer was situated in the renal pelvis (n ⫽ 38), in the ureter (n ⫽ 27), or in both (n ⫽ 11), left-sided (n ⫽ 33) or right-sided (n ⫽ 34). Preoperative Table 3 Correlation of biopsy grading and surgical grading Surgical pathologic grade
High Low Benign
Biopsy High
Low
Benign
Insufficient sample
31 2 0
8 10 1
14 4 0
6 1 0
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J. Straub et al. / Urologic Oncology: Seminars and Original Investigations 31 (2013) 1166 –1170
Table 4 Correlation of combined cytology and biopsy grading and surgical grading Surgical pathologic grade
High Low Benign
Combination cytology ⫹ biopsy High
Low
Benign
Insufficient sample
40 3 0
9 12 0
10 2 1
0 0 0
ureterorenoscopic biopsy and upper tract cytology had been acquired in 70 and 59 patients, respectively; 51 patients underwent both procedures simultaneously. The pathologic and cytologic features of the specimens in correlation with the pathologic examination of the nephroureterectomy specimen are shown in Table 1, Table 2, Table 3, and Table 4. 3.1. Correlation of cytological grading and surgical grading (Table 2) Overall sensitivity of cytology was 64% (95% CI: 51%– 75%). Sensitivity of cytology for diagnosis of high grade carcinomas was 67% (95% CI: 52– 9); 13% of high grade carcinomas were misinterpreted by cytology as low grade tumors. Sensitivity for low grade tumors was 54% (95% CI: 29 –77). Two of the tumors (15%) were misinterpreted as high grade cancer. Accuracy in predicting high grade cancer was 53% (95% CI: 39 – 67). 3.2. Correlation of biopsy grading and surgical grading (Table 3) Overall sensitivity of biopsy was 74% (95% CI: 62– 83). Sensitivity of biopsy for detecting high grade tumors was 74% (95% CI: 60 – 84); 15% of high grade tumors were misinterpreted by biopsy as low grade cancer. Sensitivity of biopsy for detecting low grade tumors was 75 % (95%CI: 50 – 0). Two of the tumors were misinterpreted as high grade carcinoma (12%). Accuracy in predicting high grade cancer was 58% (95% CI: 45–70). 3.3. Correlation of combined cytology/biopsy grading and surgical grading (Table 4) Overall sensitivity of combined cytology/biopsy was 84% (95% CI: 74 –91). Sensitivity of combined cytology/ biopsy for detecting high grade tumors was 83% (95% CI: 71–90); 15% of high grade tumors were misinterpreted as low grade cancer. Sensitivity of biopsy for detecting low grade tumors was 88% (95% CI: 66 –97). Three of the tumors were misinterpreted as high grade carcinoma (18%). Accuracy in predicting high grade cancer was 68% (95% CI: 55–78).
4. Discussion In a recent study, biopsy grade and urinary cytology helped to improve the prediction of upper tract urothelial cancer stage [14]. Keeley et al. could show a high correlation between the ureterorenoscopic biopsy grade and the pathologic grade in a series of 51 cases of upper urinary tract tumors [15]. These data suggest a reliable agreement between cytology and biopsy grade and grading of the surgical specimen. But high recurrence rates are reported in series with endourologically treated low grade tumors [2] as well as significant rates of stage and grade progression with the necessity of delayed NU [16]. This is in contrast to the widely accepted progression rate of low grade urothelial cancer, which is not higher than 10% [17]. These facts raise the question, if the “upgraded” and “upstaged” patients were graded and staged correctly before the endoscopic treatment. Other studies using the 1973 WHO classification presented a significant percentage of underreported grading by ureterorenoscopic biopsy and upper tract cytology [18,19]. Accuracy rates in predicting exact grades were 78% and 67% in these studies. These findings coincide with our data in the current study: Using the 2004 WHO classification, accuracy of cytology and biopsy in predicting high grade tumors was 53% and 58%, respectively, and the combination of both methods provided an accuracy of 68%. In our study overall sensitivity of urinary cytology was relatively higher (63%) in comparison to former studies (40%– 48%) [18,20]. Sensitivity of ureteroscopic biopsy was 74%. This is in the range of a relation of correct to incorrect pathologic diagnoses of one to four, which has been described before [13]. These findings underline the difficulties pathologists have to cope with in the diagnosis of UUT-UC using upper tract biopsies. However, the observed overall sensitivity of both methods is acceptable because diagnosis of UUT-UC always has to be confirmed by different modalities like ureterorenoscopy, retrograde pyelography, computed tomography, cytology, and biopsy [1]. But accuracy of cytology and biopsy are not adequate to discriminate reliably between low and high grade cancers. Even the combination of cytology and biopsy did not achieve an accuracy of more than 68% in detection of high grade cancer. Thus our data show a high proportion— up to one third— of high grade UUT-UC that are either overlooked or misinterpreted as low grade tumors. This diagnostic uncertainty may have two distinct causes: First, it may be due to technical difficulties during ureteroscopy (either sampling error in tumors with a grade heterogeneity, or crush artifacts of the tiny biopsies). Second, it may be the result of the rather subjective nature of cytopathologic diagnosis. In a recent study, ureteroscopic biopsies underwent a pathologic expert review, and both causes contributed to discrepancies between primary and review diagnosis [13]. In approximately one-fourth of the cases, a definitive diagnosis could not be made because of inade-
J. Straub et al. / Urologic Oncology: Seminars and Original Investigations 31 (2013) 1166 –1170
quate tissue. In further 10%, a diagnosis could be made; however, the histopathologic diagnosis was revised by the expert, indicating an inter-observer variability. In the present study, we have not established pathological review process as we aimed to evaluate the reliability of bio-optical diagnosis as a base for the decision on further clinical management. However, our findings have a significant impact on the decision, whether an endoscopic therapeutic approach may be safe and feasible, or if NU should be performed. Local recurrence after endoscopic treatment has to be suspected in 25%–93% [2], and in a study with patients undergoing endoscopic treatment of UUT-UC, the tumor grade has been identified as an independent prognostic factor with regard to tumor recurrence and abandonment of endoscopic therapy [21]. So the risk of local progression and subsequent metastatic disease should be high in cases of overlooked high grade tumors. This presumption is supported by the finding that cancer-specific survival is poor in patients with an imperative indication for organ preserving approach because in these patients high grade cancer intentionally has not been excluded [22]. These findings have led to the general accepted opinion that in patients with high grade UUT-UC and normal contralateral kidney, nephroureterectomy should be recommended to achieve cancer cure, and endoscopic treatment should be reserved only for those patients with absolute indications (solitary kidney or tumor in both renal units). In contrast, in patients with low grade tumors, sparing nephrons may be given the priority so that endoscopic treatment, if technically feasible, may be performed safely even in patients with a normal contralateral kidney [23]. However, according to our present findings, the preoperative identification of high grade tumors is not reliably possible in fact. Skolarikos et al. found in upper tract biopsies a high uncertainty especially in the assessment of G2 tumors, and urinary cytology improved the predictive power of biopsy G2 disease for high risk specimen grade [18]. This situation is one of the reasons why the WHO classification grading system has been revised in 2004: inter-observer-variability should be improved and the ambiguous G2 category should be avoided. Thus the pathologist should be forced to decide whether a tumor is high grade or low grade. But there is no clear consensus whether the 2004 WHO classification is superior to the 1973 classification for predicting clinical outcomes in patients with urothelial cancer [24,25]. Consequently, in the present study we used the 2004 classification, but in comparison to other studies using the 1973 classification, there was no improvement of accuracy in predicting high grade cancer by cytology or biopsy. Regarding the different methods (cytology vs. biopsy vs. combined cytology/biopsy), there were clear differences in overall sensitivity with the highest for combined cytology/ biopsy. But the rate of high grade tumors that were misinterpreted as low grade disease was constantly 13%–15% irrespective of which method has been used. This may be due to tumors with portions of both high grade and low grade cancer. In these tumors it may be difficult to gain
1169
biopsies and cells for cytologic examination reliably from areas of the high grade cancer. One way to avoid these problems may be the attempt to gain multiple biopsies. A recent study proposed the use of access sheaths to facilitate and improve the acquisition of multiple biopsy specimens for adequate histopathologic evaluation [26]. In this study, in 90% of cases biopsies yielded adequate specimens. However, the authors reported on 35 renal units that had to be removed after ureteroscopic biopsy, and in these cases there was an under- and overgrading in 11% as well.
5. Conclusion There is a high uncertainty of preoperative cytology and ureteroscopic biopsy in predicting correct tumor grading in UUT-UC. This implicates the importance of additional diagnostic techniques like multiple biopsies or ureteroscopic inspection before the decision if organ preserving procedures are suitable for patients with UUT-UC. However, in cases of doubt, nephroureterectomy should be given priority due to the risk of preoperative undergrading.
References [1] Roupret M, Zigeuner R, Palou J, et al. European Guidelines for the Diagnosis and Management of Upper Urinary Tract Urothelial Cell Carcinomas: 2011 Update. Eur Urol 2011;59:584 –94. [2] Zigeuner R, Pummer K. Urothelial carcinoma of the upper urinary tract: Surgical approach and prognostic factors. Eur Urol 2008;53: 720 –31. [3] Painter DJ, Denton K, Timoney AG, et al. Ureteroscopic management of upper-tract urothelial cancer: An exciting nephron-sparing option or an unacceptable risk? J Endourol 2008; 22:1237–9. [4] Borkowski A, Malouf D. The endourological management of upper urinary tract tumors. BJU Int 1999;83:369 –77. [5] Olgac S, Mazumdar M, Dalbagni G, et al. Urothelial carcinoma of the renal pelvis: A clinicopathologic study of 130 cases. Am J Surg Pathol 2004;28:1545–52. [6] Walton TJ, Novara G, Matsumoto K, et al. Oncological outcomes after laparoscopic and open radical nephroureterectomy: Results from an international cohort. BJU Int 2011;108:406 –12. [7] El-Hakim A, Weiss GH, Lee BR, et al. Correlation of ureteroscopic appearance with histologic grade of upper tract transitional cell carcinoma. Urology 2004;63:647–50, Discussion 50. [8] Siemens DR, Morales A, Johnston B, et al. A comparative analysis of rapid urine tests for the diagnosis of upper urinary tract malignancy. Can J Urol 2003;10:1754 – 8. [9] Hughes JH, Raab SS, Cohen MB. The cytologic diagnosis of lowgrade transitional cell carcinoma. Am J Clin Pathol 2000;114(Suppl): S59 – 67. [10] Tritschler S, Karl A, Sommer ML, et al. Influence of clinical information on the interpretation of urinary cytology in bladder cancer: How suggestible is a cytologist? BJU Int 2010;106:1165– 8. [11] Lodde M, Mian C, Wiener H, et al. Detection of upper urinary tract transitional cell carcinoma with ImmunoCyt: A preliminary report. Urology 2001;58:362– 6. [12] Johannes JR, Nelson E, Bibbo M, et al. Voided urine fluorescence in situ hybridization testing for upper tract urothelial carcinoma surveillance. J Urol 2010;184:879 – 82.
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[13] Tavora F, Fajardo DA, Lee TK, et al. Small endoscopic biopsies of the ureter and renal pelvis: Pathologic pitfalls. Am J Surg Pathol 2009;33:1540 – 6. [14] Brien JC, Shariat SF, Herman MP, et al. Preoperative hydronephrosis, ureteroscopic biopsy grade, and urinary cytology can improve prediction of advanced upper tract urothelial carcinoma. J Urol 2010; 184:69 –73. [15] Keeley FX, Kulp DA, Bibbo M, et al. Diagnostic accuracy of ureteroscopic biopsy in upper tract transitional cell carcinoma. J Urol 1997;157:33–7. [16] Lucas SM, Svatek RS, Olgin G, et al. Conservative management in selected patients with upper tract urothelial carcinoma compares favorably with early radical surgery. BJU Int 2008;102:172– 6. [17] Lopez-Beltran A, Montironi R. Non-invasive urothelial neoplasms: According to the most recent WHO classification. Eur Urol 2004;46: 170 – 6. [18] Skolarikos A, Griffiths TR, Powell PH, et al. Cytologic analysis of ureteral washings is informative in patients with grade 2 upper tract TCC considering endoscopic treatment. Urology 2003;61:1146 –50. [19] Guarnizo E, Pavlovich CP, Seiba M, et al. Ureteroscopic biopsy of upper tract urothelial carcinoma: Improved diagnostic accuracy and histopathologic considerations using a multi-biopsy approach. J Urol 2000;163:52–5.
[20] Dodd LG, Johnston WW, Robertson CN, et al. Endoscopic brush cytology of the upper urinary tract. Evaluation of its efficacy and potential limitations in diagnosis. Acta Cytol 1997;41:377– 84. [21] Suh RS, Faerber GJ, Wolf JS Jr. Predictive factors for applicability and success with endoscopic treatment of upper tract urothelial carcinoma. J Urol 2003;170(6 Pt 1):2209 –16. [22] Krambeck AE, Thompson RH, Lohse CM, et al. Imperative indications for conservative management of upper tract transitional cell carcinoma. J Urol 2007;178(3 Pt 1):792– 6, Discussion 6 –7. [23] Wolf JS Jr. Are we underutilizing minimally invasive approaches for upper tract urothelial carcinoma? Urol Oncol 2009;27:75– 80. [24] Otto W, Denzinger S, Fritsche HM, et al. The WHO classification of 1973 is more suitable than the WHO classification of 2004 for predicting survival in pT1 urothelial bladder cancer. BJU Int 2011; 107:404 – 8. [25] Cao D, Vollmer RT, Luly J, et al. Comparison of 2004 and 1973 World Health Organization grading systems and their relationship to pathologic staging for predicting long-term prognosis in patients with urothelial carcinoma. Urology 2010;76:593–9. [26] Gorin MA, Santos Cortes JA, Kyle CC, et al. Initial clinical experience with use of ureteral access sheaths in the diagnosis and treatment of upper tract urothelial carcinoma. Urology 2011;78:523–7.
Original article
Ureterorenoscopic biopsy and urinary cytology according to the 2004 WHO classification underestimate tumor grading in upper urinary tract urothelial carcinoma Julia Straub, M.D., Frank Strittmatter, M.D., Alexander Karl, M.D., Christian G. Stief, M.D., Stefan Tritschler, M.D.* Department of Urology, Grohadern University Hospital, Ludwig Maximilians University of Munich, Munich, Germany Received 22 October 2011; received in revised form 13 December 2011; accepted 28 December 2011
Abstract Objectives: To determine accuracy of upper tract cytology and ureteroscopic biopsy according to the 2004 World Health Organization (WHO) classification in predicting the correct tumor grade in patients with urothelial cancer of the upper urinary tract (UUT-UC). Methods: Pathology reports of 77 nephroureterectomy specimens were retrospectively analyzed for tumor grade and compared with preoperatively gained cytology and ureteroscopic biopsy results. For analysis, the 2004 WHO classification was used. Results: Overall sensitivity of cytology and biopsy in diagnosis of UUT-UC was 64% and 74%, respectively. Accuracy of cytology and biopsy in predicting high grade cancer was 53% and 58%, respectively. Combination of cytology and biopsy could improve sensitivity (84%) and accuracy (68%), but even for this combination, 15% of high grade tumors were misinterpreted as low grade cancer. Conclusion: Our results show only limited accuracy for preoperative cytology and ureterorenoscopically performed biopsies in the prediction of the correct tumor grading of an UUT-UC. Therefore, we suggest the use of additional diagnostic procedures before the decision for definitive surgical treatment in patients with UUT-UC is made. © 2013 Elsevier Inc. All rights reserved. Keywords: Upper tract urothelial carcinoma; Ureterorenoscopy; Urinary cytology; Grading
1. Introduction Urothelial carcinoma of the upper urinary tract (UUTUC) is an uncommon entity, accounting for 2–5% of all urothelial tumors. Standard therapy in patients with upper urinary tract urothelial carcinoma (UUT-UC) is nephroureterectomy (NU) with excision of the ureteric orifice [1]. This procedure has proven to provide optimal results in terms of oncologic outcome. However, NU seems to be an overtreatment in patients with well differentiated superficial tumors, especially with small pTa low grade tumors. The attempt of an organ-preserving approach is mandatory in patients with tumors in a solitary kidney. However an endoscopic management using resection, holmium:YAG or neodynium: YAG laser has been widely practiced even in select patients with low grade disease and normal contralateral kidney * Corresponding author. Tel.: ⫹49/89/7095– 0; fax: ⫹49/89/7095– 4745. E-mail address: [email protected] (S. Tritschler). 1078-1439/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.urolonc.2011.12.021
function [2– 4]. Furthermore, partial ureterectomy with ureteroneocystostomy seems to be appropriate for distal low grade ureteral tumors [2]. A basic requirement for such a conservative approach is the confirmation of a low grade and low volume tumor, since there is a strong correlation between grading and depth of tumor invasion [5]. Consequently, the prognostic power of pathologic grading is well established [2]. So the risk for the development of metastases and local progression of a high grade tumor would seem to vote against conservative management [6]. The confirmation of a low grade lesion is of utmost importance because simple inspection of a lesion has shown to predict the grade correctly only in 71% (low grade tumors) and 80% (high grade tumors) of cases [7]. Grading of upper urinary tract tumors is preoperatively determined either by cytology or by ureterorenoscopically performed biopsy. However, the limitation of cytology in determining the correct tumor grade is well established. Sensitivity of cytology in upper urinary tract tumors has proven to be very
J. Straub et al. / Urologic Oncology: Seminars and Original Investigations 31 (2013) 1166 –1170
poor with detection rates as low as 29% [8] because low grade disease is associated with very subtle microscopic changes [9,10]. In contrast, high grade lesions in the bladder are detected quite reliably by cytology [11]. But in UUTUC, even the use of fluorescent in situ hybridization (FISH) analysis does not reliably provide a high sensitivity [12]. Regarding ureteroscopic biopsy, recent pathologic studies demonstrate that in almost one of four renal pelvic/ ureteral biopsies, a definitive diagnosis cannot be made due to extraction of inadequate tissue. This is explained by the limited size of the sample, absence of papillary fronds, crush artifact, and distorted architecture [13]. The aim of the present study was the investigation of the capability of biopsy and cytology according to the 2004 WHO classification to determine the correct tumor grade in upper urinary tract tumors, thus discriminating those tumors that are favorable for conservative treatment from those that should be treated radically by NU.
2. Patients and methods Medical charts of patients who underwent NU between 2004 and 2011 at our institution for urothelial cancer of the upper urinary tract were reviewed. Patients who had undergone preoperative upper tract cytology and/or preoperative ureteroscopic biopsy due to hematuria or radiological suspicion of upper tract tumor were identified. Biopsies and cytology had been taken whenever UUT-UC was endoscopically suspected or clearly detected. In large tumors with good accessibility, multiple biopsies had been taken. Biopsies had been taken by 3F cup forceps or by a Dormia basket. The specimens had been fixed in formalin and sent for pathologic evaluation. Samples for cytologic analysis were obtained by ureteral catheterization and flushing with 2–5 mL of saline solution before administration of contrast Table 1 Pathologic examination of ureterorenoscopic and nephroureterectomy specimen Characteristics Ureteroscopic stage pT0 Papilloma PUNLMP pTa pT1 pTis pTx Definitive stage pT0 pTa pTis pT1 pT2 pT3 pT4
Number 14 1 3 26 13 3 9 1 18 4 14 10 28 2
1167
Table 2 Correlation of cytologic grading and surgical grading Surgical pathologic grade
High Low Benign
Cytology High
Low
Benign
Insufficient sample
24 2 0
6 5 0
15 6 1
14 4 0
medium. Papanicolaou staining was performed on the centrifuged samples. Grading of cytology, biopsy, and nephroureterectomy specimen was classified according to the 2004 WHO system. Biopsies and surgical specimens were staged according to the TNM system. Seven different boardcertified pathologists assessed the biopsies and NU specimens. NU was performed in case of high grade cancer in preoperative biopsies or in cases of bio-optically proven low grade tumors where endoscopic treatment was technically not feasible due to tumor size and/or location. Results of upper tract cytology and biopsy gained by preoperative ureterorenoscopy were analyzed and compared with histology of the specimen gained by NU. For further analysis, results of both methods have been combined and the correlation has been performed for the highest tumor grade of both investigations.
3. Results A total of 99 patients underwent nephroureterectomy within the observed time period, and 77 patients with a mean age of 68 years (47– 89) could be identified who met the inclusion criteria. All patients underwent nephroureterectomy for upper urinary tract urothelial cancer within the reviewed period. All patients had first diagnosis of UUTUC, no attempts of organ preserving surgery had been undertaken before; n ⫽ 14 and n ⫽ 8 patients had previous and metachronous bladder cancer with the necessity of transurethral resection of the bladder (TURB). Final pathologic stage was pT0 (n ⫽ 1), pTis (n ⫽ 4), pTa (n ⫽ 18), pT1 (n ⫽ 14), pT2 (n ⫽ 10), pT3 (n ⫽ 28), and pT4 (n ⫽ 2) (Table 1). Pathologic grade in these specimens was low grade (n ⫽ 17), high grade (n ⫽ 59), and benign (n ⫽ 1). Cancer was situated in the renal pelvis (n ⫽ 38), in the ureter (n ⫽ 27), or in both (n ⫽ 11), left-sided (n ⫽ 33) or right-sided (n ⫽ 34). Preoperative Table 3 Correlation of biopsy grading and surgical grading Surgical pathologic grade
High Low Benign
Biopsy High
Low
Benign
Insufficient sample
31 2 0
8 10 1
14 4 0
6 1 0
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J. Straub et al. / Urologic Oncology: Seminars and Original Investigations 31 (2013) 1166 –1170
Table 4 Correlation of combined cytology and biopsy grading and surgical grading Surgical pathologic grade
High Low Benign
Combination cytology ⫹ biopsy High
Low
Benign
Insufficient sample
40 3 0
9 12 0
10 2 1
0 0 0
ureterorenoscopic biopsy and upper tract cytology had been acquired in 70 and 59 patients, respectively; 51 patients underwent both procedures simultaneously. The pathologic and cytologic features of the specimens in correlation with the pathologic examination of the nephroureterectomy specimen are shown in Table 1, Table 2, Table 3, and Table 4. 3.1. Correlation of cytological grading and surgical grading (Table 2) Overall sensitivity of cytology was 64% (95% CI: 51%– 75%). Sensitivity of cytology for diagnosis of high grade carcinomas was 67% (95% CI: 52– 9); 13% of high grade carcinomas were misinterpreted by cytology as low grade tumors. Sensitivity for low grade tumors was 54% (95% CI: 29 –77). Two of the tumors (15%) were misinterpreted as high grade cancer. Accuracy in predicting high grade cancer was 53% (95% CI: 39 – 67). 3.2. Correlation of biopsy grading and surgical grading (Table 3) Overall sensitivity of biopsy was 74% (95% CI: 62– 83). Sensitivity of biopsy for detecting high grade tumors was 74% (95% CI: 60 – 84); 15% of high grade tumors were misinterpreted by biopsy as low grade cancer. Sensitivity of biopsy for detecting low grade tumors was 75 % (95%CI: 50 – 0). Two of the tumors were misinterpreted as high grade carcinoma (12%). Accuracy in predicting high grade cancer was 58% (95% CI: 45–70). 3.3. Correlation of combined cytology/biopsy grading and surgical grading (Table 4) Overall sensitivity of combined cytology/biopsy was 84% (95% CI: 74 –91). Sensitivity of combined cytology/ biopsy for detecting high grade tumors was 83% (95% CI: 71–90); 15% of high grade tumors were misinterpreted as low grade cancer. Sensitivity of biopsy for detecting low grade tumors was 88% (95% CI: 66 –97). Three of the tumors were misinterpreted as high grade carcinoma (18%). Accuracy in predicting high grade cancer was 68% (95% CI: 55–78).
4. Discussion In a recent study, biopsy grade and urinary cytology helped to improve the prediction of upper tract urothelial cancer stage [14]. Keeley et al. could show a high correlation between the ureterorenoscopic biopsy grade and the pathologic grade in a series of 51 cases of upper urinary tract tumors [15]. These data suggest a reliable agreement between cytology and biopsy grade and grading of the surgical specimen. But high recurrence rates are reported in series with endourologically treated low grade tumors [2] as well as significant rates of stage and grade progression with the necessity of delayed NU [16]. This is in contrast to the widely accepted progression rate of low grade urothelial cancer, which is not higher than 10% [17]. These facts raise the question, if the “upgraded” and “upstaged” patients were graded and staged correctly before the endoscopic treatment. Other studies using the 1973 WHO classification presented a significant percentage of underreported grading by ureterorenoscopic biopsy and upper tract cytology [18,19]. Accuracy rates in predicting exact grades were 78% and 67% in these studies. These findings coincide with our data in the current study: Using the 2004 WHO classification, accuracy of cytology and biopsy in predicting high grade tumors was 53% and 58%, respectively, and the combination of both methods provided an accuracy of 68%. In our study overall sensitivity of urinary cytology was relatively higher (63%) in comparison to former studies (40%– 48%) [18,20]. Sensitivity of ureteroscopic biopsy was 74%. This is in the range of a relation of correct to incorrect pathologic diagnoses of one to four, which has been described before [13]. These findings underline the difficulties pathologists have to cope with in the diagnosis of UUT-UC using upper tract biopsies. However, the observed overall sensitivity of both methods is acceptable because diagnosis of UUT-UC always has to be confirmed by different modalities like ureterorenoscopy, retrograde pyelography, computed tomography, cytology, and biopsy [1]. But accuracy of cytology and biopsy are not adequate to discriminate reliably between low and high grade cancers. Even the combination of cytology and biopsy did not achieve an accuracy of more than 68% in detection of high grade cancer. Thus our data show a high proportion— up to one third— of high grade UUT-UC that are either overlooked or misinterpreted as low grade tumors. This diagnostic uncertainty may have two distinct causes: First, it may be due to technical difficulties during ureteroscopy (either sampling error in tumors with a grade heterogeneity, or crush artifacts of the tiny biopsies). Second, it may be the result of the rather subjective nature of cytopathologic diagnosis. In a recent study, ureteroscopic biopsies underwent a pathologic expert review, and both causes contributed to discrepancies between primary and review diagnosis [13]. In approximately one-fourth of the cases, a definitive diagnosis could not be made because of inade-
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quate tissue. In further 10%, a diagnosis could be made; however, the histopathologic diagnosis was revised by the expert, indicating an inter-observer variability. In the present study, we have not established pathological review process as we aimed to evaluate the reliability of bio-optical diagnosis as a base for the decision on further clinical management. However, our findings have a significant impact on the decision, whether an endoscopic therapeutic approach may be safe and feasible, or if NU should be performed. Local recurrence after endoscopic treatment has to be suspected in 25%–93% [2], and in a study with patients undergoing endoscopic treatment of UUT-UC, the tumor grade has been identified as an independent prognostic factor with regard to tumor recurrence and abandonment of endoscopic therapy [21]. So the risk of local progression and subsequent metastatic disease should be high in cases of overlooked high grade tumors. This presumption is supported by the finding that cancer-specific survival is poor in patients with an imperative indication for organ preserving approach because in these patients high grade cancer intentionally has not been excluded [22]. These findings have led to the general accepted opinion that in patients with high grade UUT-UC and normal contralateral kidney, nephroureterectomy should be recommended to achieve cancer cure, and endoscopic treatment should be reserved only for those patients with absolute indications (solitary kidney or tumor in both renal units). In contrast, in patients with low grade tumors, sparing nephrons may be given the priority so that endoscopic treatment, if technically feasible, may be performed safely even in patients with a normal contralateral kidney [23]. However, according to our present findings, the preoperative identification of high grade tumors is not reliably possible in fact. Skolarikos et al. found in upper tract biopsies a high uncertainty especially in the assessment of G2 tumors, and urinary cytology improved the predictive power of biopsy G2 disease for high risk specimen grade [18]. This situation is one of the reasons why the WHO classification grading system has been revised in 2004: inter-observer-variability should be improved and the ambiguous G2 category should be avoided. Thus the pathologist should be forced to decide whether a tumor is high grade or low grade. But there is no clear consensus whether the 2004 WHO classification is superior to the 1973 classification for predicting clinical outcomes in patients with urothelial cancer [24,25]. Consequently, in the present study we used the 2004 classification, but in comparison to other studies using the 1973 classification, there was no improvement of accuracy in predicting high grade cancer by cytology or biopsy. Regarding the different methods (cytology vs. biopsy vs. combined cytology/biopsy), there were clear differences in overall sensitivity with the highest for combined cytology/ biopsy. But the rate of high grade tumors that were misinterpreted as low grade disease was constantly 13%–15% irrespective of which method has been used. This may be due to tumors with portions of both high grade and low grade cancer. In these tumors it may be difficult to gain
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biopsies and cells for cytologic examination reliably from areas of the high grade cancer. One way to avoid these problems may be the attempt to gain multiple biopsies. A recent study proposed the use of access sheaths to facilitate and improve the acquisition of multiple biopsy specimens for adequate histopathologic evaluation [26]. In this study, in 90% of cases biopsies yielded adequate specimens. However, the authors reported on 35 renal units that had to be removed after ureteroscopic biopsy, and in these cases there was an under- and overgrading in 11% as well.
5. Conclusion There is a high uncertainty of preoperative cytology and ureteroscopic biopsy in predicting correct tumor grading in UUT-UC. This implicates the importance of additional diagnostic techniques like multiple biopsies or ureteroscopic inspection before the decision if organ preserving procedures are suitable for patients with UUT-UC. However, in cases of doubt, nephroureterectomy should be given priority due to the risk of preoperative undergrading.
References [1] Roupret M, Zigeuner R, Palou J, et al. European Guidelines for the Diagnosis and Management of Upper Urinary Tract Urothelial Cell Carcinomas: 2011 Update. Eur Urol 2011;59:584 –94. [2] Zigeuner R, Pummer K. Urothelial carcinoma of the upper urinary tract: Surgical approach and prognostic factors. Eur Urol 2008;53: 720 –31. [3] Painter DJ, Denton K, Timoney AG, et al. Ureteroscopic management of upper-tract urothelial cancer: An exciting nephron-sparing option or an unacceptable risk? J Endourol 2008; 22:1237–9. [4] Borkowski A, Malouf D. The endourological management of upper urinary tract tumors. BJU Int 1999;83:369 –77. [5] Olgac S, Mazumdar M, Dalbagni G, et al. Urothelial carcinoma of the renal pelvis: A clinicopathologic study of 130 cases. Am J Surg Pathol 2004;28:1545–52. [6] Walton TJ, Novara G, Matsumoto K, et al. Oncological outcomes after laparoscopic and open radical nephroureterectomy: Results from an international cohort. BJU Int 2011;108:406 –12. [7] El-Hakim A, Weiss GH, Lee BR, et al. Correlation of ureteroscopic appearance with histologic grade of upper tract transitional cell carcinoma. Urology 2004;63:647–50, Discussion 50. [8] Siemens DR, Morales A, Johnston B, et al. A comparative analysis of rapid urine tests for the diagnosis of upper urinary tract malignancy. Can J Urol 2003;10:1754 – 8. [9] Hughes JH, Raab SS, Cohen MB. The cytologic diagnosis of lowgrade transitional cell carcinoma. Am J Clin Pathol 2000;114(Suppl): S59 – 67. [10] Tritschler S, Karl A, Sommer ML, et al. Influence of clinical information on the interpretation of urinary cytology in bladder cancer: How suggestible is a cytologist? BJU Int 2010;106:1165– 8. [11] Lodde M, Mian C, Wiener H, et al. Detection of upper urinary tract transitional cell carcinoma with ImmunoCyt: A preliminary report. Urology 2001;58:362– 6. [12] Johannes JR, Nelson E, Bibbo M, et al. Voided urine fluorescence in situ hybridization testing for upper tract urothelial carcinoma surveillance. J Urol 2010;184:879 – 82.
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[13] Tavora F, Fajardo DA, Lee TK, et al. Small endoscopic biopsies of the ureter and renal pelvis: Pathologic pitfalls. Am J Surg Pathol 2009;33:1540 – 6. [14] Brien JC, Shariat SF, Herman MP, et al. Preoperative hydronephrosis, ureteroscopic biopsy grade, and urinary cytology can improve prediction of advanced upper tract urothelial carcinoma. J Urol 2010; 184:69 –73. [15] Keeley FX, Kulp DA, Bibbo M, et al. Diagnostic accuracy of ureteroscopic biopsy in upper tract transitional cell carcinoma. J Urol 1997;157:33–7. [16] Lucas SM, Svatek RS, Olgin G, et al. Conservative management in selected patients with upper tract urothelial carcinoma compares favorably with early radical surgery. BJU Int 2008;102:172– 6. [17] Lopez-Beltran A, Montironi R. Non-invasive urothelial neoplasms: According to the most recent WHO classification. Eur Urol 2004;46: 170 – 6. [18] Skolarikos A, Griffiths TR, Powell PH, et al. Cytologic analysis of ureteral washings is informative in patients with grade 2 upper tract TCC considering endoscopic treatment. Urology 2003;61:1146 –50. [19] Guarnizo E, Pavlovich CP, Seiba M, et al. Ureteroscopic biopsy of upper tract urothelial carcinoma: Improved diagnostic accuracy and histopathologic considerations using a multi-biopsy approach. J Urol 2000;163:52–5.
[20] Dodd LG, Johnston WW, Robertson CN, et al. Endoscopic brush cytology of the upper urinary tract. Evaluation of its efficacy and potential limitations in diagnosis. Acta Cytol 1997;41:377– 84. [21] Suh RS, Faerber GJ, Wolf JS Jr. Predictive factors for applicability and success with endoscopic treatment of upper tract urothelial carcinoma. J Urol 2003;170(6 Pt 1):2209 –16. [22] Krambeck AE, Thompson RH, Lohse CM, et al. Imperative indications for conservative management of upper tract transitional cell carcinoma. J Urol 2007;178(3 Pt 1):792– 6, Discussion 6 –7. [23] Wolf JS Jr. Are we underutilizing minimally invasive approaches for upper tract urothelial carcinoma? Urol Oncol 2009;27:75– 80. [24] Otto W, Denzinger S, Fritsche HM, et al. The WHO classification of 1973 is more suitable than the WHO classification of 2004 for predicting survival in pT1 urothelial bladder cancer. BJU Int 2011; 107:404 – 8. [25] Cao D, Vollmer RT, Luly J, et al. Comparison of 2004 and 1973 World Health Organization grading systems and their relationship to pathologic staging for predicting long-term prognosis in patients with urothelial carcinoma. Urology 2010;76:593–9. [26] Gorin MA, Santos Cortes JA, Kyle CC, et al. Initial clinical experience with use of ureteral access sheaths in the diagnosis and treatment of upper tract urothelial carcinoma. Urology 2011;78:523–7.