Low biopsy volume in ureteroscopy does not affect tumor biopsy grading in upper tract urothelial carcinoma

Low biopsy volume in ureteroscopy does not affect tumor biopsy grading in upper tract urothelial carcinoma

Urologic Oncology: Seminars and Original Investigations 31 (2013) 1696 –1700 Original article Low biopsy volume in ureteroscopy does not affect tumo...

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Urologic Oncology: Seminars and Original Investigations 31 (2013) 1696 –1700

Original article

Low biopsy volume in ureteroscopy does not affect tumor biopsy grading in upper tract urothelial carcinoma Claudia P. Rojas, M.D.a,b, Scott M. Castle, M.D.c, Cesar A. Llanos, M.D., M.S.a,b, Janice A. Santos Cortes, M.D.c, Vincent Bird, M.D.c, Senen Rodriguez, M.D.a, Isildinha M. Reis, Ph.D.d,e, Wei Zhao, M.D., M.S.e, Carmen Gomez-Fernandez, M.D.a, Raymond J. Leveillee, M.D.c, Merce Jorda, M.D., Ph.D.a,* a

Department of Pathology, University of Miami, Miami Miller School of Medicine, Miami, FL 33136, USA b Department of Pathology, Jackson Memorial Hospital, Miami, FL 33136, USA c Department of Urology, University of Miami, Miami Miller School of Medicine, Miami, FL 33136, USA d Department of Epidemiology and Public Health, Division of Biostatistics, University of Miami, Miami Miller School of Medicine, Miami, FL 33136, USA e UM Sylvester Biostatistics and Bioinformatics Core, University of Miami, Miami Miller School of Medicine, Miami, FL 33136, USA Received 22 April 2012; received in revised form 20 May 2012; accepted 29 May 2012

Abstract Objectives: Urothelial carcinomas (UC) from the upper urinary tract represent 7%–10% of all kidney malignancies. With current ureteroscopic (URS) techniques, small tissue samples are usually the only available histopathologic material for evaluation, representing a diagnostic challenge. Precision in diagnosis is essential for treatment decision making. There has been much debate as to whether tumor grade and stage found on biopsy agree with final pathology. The purpose of this study is to evaluate whether URS biopsy volume affects tumor grading and staging agreement between biopsy and nephroureterectomy (NU) specimens. Materials and methods: We reviewed 137 URS biopsies in 81 patients with suspected upper urinary tract UC performed from April 2002 to April 2011. Of those, 54 patients had both the URS biopsy and NU performed at our institution and were available for review. Biopsy dimensions were recorded to calculate estimated ellipsoid volume, and 2 urological pathologists independently evaluated histologic grade (ISUP/WHO 2004), (based on pleomorphism and mitosis) and depth of invasion. Statistical analysis was performed to evaluate URS biopsy and NU specimen grade and stage concordance. In addition, univariable and multivariable analyses was performed to assess the effect of biopsy volume on agreement. Results: Of the 54 patients studied, low grade and high grade UC biopsy were found in 8 (15%) and 46 (85%), URS biopsies, respectively. Regarding biopsy stage, 51 (94%), 1 (2%), and 2 (4%) were stage Ta, T1, T2, respectively. Grade concordance was 92.6%, (95% CI: 82.4%–98.0%). Stage concordance was 43% (95% CI: 28.7%–55.9%). Multivariable analysis showed biopsy volume did not affect tumor assessment of grade (P ⫽ 0.81) or stage (P ⫽ 0.44). Conclusions: Histologic grade assigned on the URS biopsy sample accurately predicts histologic grade in the resected specimen (92.6%), even when the biopsy volume is small. Grading in URS biopsies provides sufficient information for clinical decision making that is independent of sample volume. © 2013 Published by Elsevier Inc. Keywords: Upper urinary tract; Urothelial carcinoma; Ureteroscopy; Nephroureterectomy

1. Introduction

The authors declare no conflict of interest. * Corresponding author. Tel.: ⫹1-305-243-6500; fax: ⫹1-305-689-5899. E-mail address: [email protected] (M. Jorda). 1078-1439/$ – see front matter © 2013 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.urolonc.2012.05.010

Upper tract urothelial carcinoma (UC) is estimated to represent ⬍10% of renal tumors and accounts for 5% of all UC [1]. Recent evidence indicates that the frequency of upper urinary tract malignancies is increasing [2]. Historically, radiographic imaging has been used to evaluate upper urinary tract lesions, including contrasted CT

C.P. Rojas et al. / Urologic Oncology: Seminars and Original Investigations 31 (2013) 1696 –1700

scan, and intravenous and retrograde pyelography. However, direct inspection of the urinary tract via ureteroscopy (URS) with concomitant biopsy has proven to have the highest diagnostic sensitivity [3]. The URS approach is typically the least invasive surgical treatment option, and the best initial method for procuring an adequate tissue sample for diagnosis and grading [4]. Nephroureterectomy (NU) remains the gold standard for treatment of upper tract UC, and produces an improved survival for those patients [5,6]. However, for those patients with low grade UC of the distal ureter, distal ureterectomy and ureteroneocystostomy may be performed. Histologic grade and tumor stage are well established prognostic factors of UC [4,5,7]. The histologic grade is determined by cellular pleomorphism and the presence of mitosis. In addition, histologic grade has been closely associated with tumor stage [4,7,8]. Lymphovascular invasion has also been identified as a poor prognostic factor but is difficult to evaluate in biopsy samples [7,9]. Based on these histologic results, treatment modalities may vary from observation, endoscopic management, or nephroureterectomy (NU). There has been current debate on whether URS biopsy provides an accurate diagnosis for upper tract UC grade [10 –12]. A potential pitfall of the URS biopsy is insufficient tissue sampling. Small volume of biopsy material may display a limited number of malignant cells, potentially compromising an accurate histologic grade. Furthermore, a reliable full thickness sample may not be available to accurately diagnose the presence of muscle invasion. This is due to the relatively thin ureteral wall and the associated risk of perforation if deep biopsies are attempted. Also, the diameter of the working channel of current ureteroscopes is ⬍1/3 mm, making biopsy forceps delicate and small in diameter. Therefore, the volume of the tissue samples obtained may be limited, becoming a challenge for the pathologist when assessing histologic grade and depth of invasion. Additionally, for some lesion locations, it may be difficult to obtain a biopsy; therefore, URS biopsy of all suspected upper tract UC is not ubiquitous among urologists, and NU may be performed without a tissue diagnosis. However, there is an inherent risk of end-stage renal disease in these patients undergoing kidney removal, and a risk of increased comorbidity and mortality [13]. Therefore, pathologic diagnosis is of utmost importance to appropriately treat patients while preserving renal function if possible. We wished to investigate whether the URS biopsy volume of upper tract UC lesion affected the agreement between URS biopsy and NU specimens in terms of tumor stage, grade, and histopathologic parameters. Our goal is to determine whether URS biopsies should be attempted in lesions that may result in small volume samples, and whether this will affect the pathologist’s ability to grade and stage the tumor. To our knowledge, there are no studies that correlate the biopsy sample size with the final pathology of NU specimens.


2. Materials and methods We reviewed all URS biopsies performed from April 2002 through April 2011 for suspected upper tract UC. A total of 137 biopsies were performed in 81 patients (multiple biopsies in some patients). Of those 81 patients, 54 underwent both their URS biopsy and NU at our institution and had histopathology available for review from both specimens. Tissues from both procedures were evaluated. If the patient had multiple biopsies at different times, only the biopsy directly preceeding NU was evaluated since the decision to perform NU was based most strongly on this biopsy result. At our institution, URS biopsy is recommended to all patients with an upper tract mass suspicious for UC with no prior histopathologic diagnosis. NU is offered to all patients with an upper tract urothelial tumor, and recommended to patients with high grade invasive disease or low grade tumors that are multifocal, high volume, or rapidly recurring. Endoscopic management is recommended to patients with low grade, low-stage disease. Pathologic diagnosis from URS biopsy is factored into therapy choice (observation, endoscopic management, or NU) along with the risks of chronic kidney disease and patient comorbidities. Ultimately, patients make the decision whether to receive NU based on recommendations provided by the surgeon. 2.1. Ureteroscopic biopsy All URS biopsies were performed by 2 experienced, fellowship trained endourologists. Retrograde pyelograms were routinely evaluated before URS to further delineate the anatomy. Piranha forceps (Boston Scientific Corp., Natick, MA) and/or Segura basket (Boston Scientific, Corp., Spencer, IN) were commonly used through a flexible or semirigid ureteroscope. For those tumors unable to be accessed via rigid or semirigid URS, a flexible ureteroscope was used along with a ureteral access sheath to facilitate reintroduction of the ureteroscope. Specimens were placed in formalin and immediately sent to the pathology laboratory. 2.2. Tissue processing and sample evaluation Before tissue sectioning, 3 measurements of each sample (length, width, height) were recorded and used to approximate tissue volume using an elliptic formula (4/3 ⫻ ␲ ⫻ a ⫻ b ⫻ c, a ⫽ length, b ⫽ width, c ⫽ height). Hematoxylineosin (H and E) staining was performed on formalin fixedparaffin embedded tissue from URS biopsies and corresponding NU specimens. Two urological pathologists independently evaluated the following disease characteristics: histologic grade (pleomorphism, mitosis, according to WHO 2004 criteria), depth of invasion, and lymphovascular invasion (LVI) in both URS biopsies and NU specimens. In the case of disagreement between pathologists (2 cases), a


C.P. Rojas et al. / Urologic Oncology: Seminars and Original Investigations 31 (2013) 1696 –1700

third uropathologist evaluated the slide. Pathologists were blinded to clinical information of each patient. 2.3. Statistical analysis All analyses were performed using SPSS 18 (SPSS, Inc, Chicago, IL). Comparison of proportions was done using Fisher’s exact test. Comparison of continuous variables was performed using Mann-Whitney U test. Binomial logistic regression was performed for multivariable analysis.

3. Results We evaluated a total of 54 patients undergoing URS biopsy and NU. Patient and tumor demographics are listed in Table 1. In 13 (24%) cases, a ureteral access sheath was used since biopsy was unable to be obtained using unaided rigid or flexible URS due to tumor location or difficult anatomy. Table 2 lists URS biopsy and NU specimen characteristics. Eight URS biopsies (15%) were considered low grade UC and 46 cases (85%) were high-grade UC according to WHO 2004 classification. Fifty-nine percent of URS biopsies contained subepithelial connective tissue (SCT), and in most biopsies (53/54) LVI could not be proven. Lymph node sampling was not performed during the NU. Table 3 displays concordance for URS biopsy and NU. Tumor grade concordance occurred in 50 (92.7%, 95% CI 82.4%–98.0%) cases. However, stage concordance was only 43% (95% CI 28.7%–55.9%). Univariable and multivariable analysis are shown in Table 4. Multivariate analysis for tumor grade showed that none of the evaluated factors influence the agreement between URS biopsy and NU specimen, including biopsy volume (P ⫽ 0.81). Only the presence of SCT in the biopsy specimen affected agreement between tested samples (P ⫽ 0.002, OR 6.4, 95% CI 1.9 – 21). Biopsies containing SCT were more likely to have disagreement with regard to detection of invasion.

Table 1 Patient and biopsy demographics Value Median age (years, IQR) Male (n, %) Right-sided (n, %) Ureteral access states of health used for biopsy (n, %) Median biopsy volume (cm3, IQR) Median nephroureterectomy tumor volume (cm3, IQR) Median biopsy-nephroureterectomy interval (days, IQR) IQR ⫽ inner quartile range.

73 (64–81) 35 (65%) 20 (36%) 13 (24%) 0.008 (0.003–0.033) 1.70 (0.43–12.9) 46 (28–69)

Table 2 Ureteroscopic biopsy and nephroureterectomy specimen characteristics

0–5 mitoses n (%) 6–10 mitoses n (%) ⬎10 mitoses n (%) Low pleomorphism n (%) High pleomorphism n (%) Low grade n (%) High grade n (%) SCT present in biopsy, n (%) Stage Ta, n (%) Tis, n (%) T1, n (%) T2, n (%) T3, n (%) LVI, n (%)

Biopsy specimen

Nephroureterectomy specimen

31 (57%) 20 (37%) 3 (6%) 11 (20%) 43 (80%) 8 (15%) 46 (85%) 32 (59%)

22 (41%) 20 (37%) 12 (22%) 5 (9%) 49 (91%) 6 (11%) 48 (89%) NA

51 (94%) 0 (0%) 1 (2%) 2 (4%) 0 (0%) 1 (1.9%)

22 (41%) 1 (2%) 12 (22%) 3 (6%) 16 (30%) 7 (13%)

SCT ⫽ subepithelial connective tissue; LVI ⫽ lymphovascular invasion. Grading from WHO classification 2004, Standardized TNM stage was used.

4. Discussion NU is currently the gold standard for upper urinary tract UC [6], and tumor grade, stage, and appearance [14] guide whether to observe, endoscopically manage, or perform NU. Grading and staging are prognostic factors in patient survival [7,15]. Given the improved survivability of patients undergoing NU [5], and the comorbidity of end-stage renal disease [13], providing an accurate tumor grade and stage at the time of the biopsy are of utmost importance to help improve patient survival since some selected patients can safely benefit from repeated endoscopic management [16]. Due to technologic developments in recent years, we are now able to directly visualize upper urinary tract lesions through URS techniques, providing a more sensitive approach for a feasible and reliable diagnosis. However, despite new technology, the ability to obtain tissue is still limited by different variables. The small caliber channels available to introduce instruments can be a limitation. Some studies will note that several factors affect the accuracy of diagnosis in URS biopsies, including the biopsy size [17]. Table 3 Agreement and disagreement of biopsy and NU specimens

Tumor grading Upgraded Downgraded Grade concordance Tumor staging Upstaged Downstaged Stage concordance Pleomorphism concordance Mitoses concordance

n (%)

95% CI

3 (5.6%) 1 (1.9%) 50 (92.6%)


31 (57%) 0 (0%) 23 (43%) 47 (87%) 33 (61%)

28.7–55.9 73.3–93.5 45.9–73.0

C.P. Rojas et al. / Urologic Oncology: Seminars and Original Investigations 31 (2013) 1696 –1700


Table 4 Univariable and multivariable analysis Tumor grade SCT in biopsy sample, n (%) Use of ureteral access states of health, n (%) Right laterality, n (%) Biopsy volume (median cm3, IQR) Age (median years, IQR) Biopsy-NU interval (median days, IQR) Tumor stage SCT in biopsy sample, n (%) Use of ureteral access States of Health, n (%) Laterality, n (%) Biopsy volume (median cm3, IQR) Age (median years, IQR) Biopsy-NU interval (median days, IQR)

Agreement n ⫽ 50

Disagreement n⫽4

31 (62%) 13 (24.0%)

1 (25%) 0 (0%)

31 (38.0%) 0.008 (0.002–0.037) 73 (64–81) 48 (28–69)

0 (0%) 0.012 (0.004–0.099) 67 (60.8–74.5) 81 (36.5–140)

Agreement n ⫽ 23

Disagreement n ⫽ 31

8 (34.8%) 5 (21.7%) 15 (65%) 0.017 (0.005–0.037) 74 (64–82) 49 (33–81)

24 (77.4%) 8 (25.8%) 20 (64.5%) 0.006 (0.002–0.046) 73 (64–79) 38.5 (25.3–68)

Univariable P value

Multivariable P value


95% CI

0.290 0.320

0.147 0.242

— —

— —

0.285 0.99 0.336 0.99

0.126 0.810 0.315 0.891

— — — —

— — — —

Univariable P value

Multivariable P value


95% CI

0.002 0.494

0.002 0.549

6.4 —

1.9–21 —

0.594 0.169 0.289 0.409

0.896 0.438 0.674 0.505

— — — —

— — — —

IQR ⫽ inner quartile range; NU ⫽ nephroureterectomy; SCT ⫽ ubepithelial connective tissue.

There has been recent debate as to whether URS biopsy correlates to final tissue diagnosis [10 –12,14]. Brien et al. [18] reported that tumor grade predicted whether disease was organ confined (HR 3.9, P ⬍ 0.001). Clements et al. [10] reported a positive predictive value of 92% for high grade URS biopsies. Additionally, they reported statistically significant (P ⬍ 0.0001) relationship of high grade biopsy agreement with final pathology specimen grade, but not stage. Williams et al. [14] reported a 75% agreement between biopsy and NU grade. Straub et al. [11] reported 15% of biopsies being upgraded. Wang et al. [12]; reported a significant amount of upgrading (96% for grade I biopsy results, 40% for grade II biopsy results) of upper tract tumor biopsies. In reviewing these studies there appears to be some discrepancy of the accuracy of upper tract UC tumor grading via URS biopsy. Our study confirms the results of Clements [10] and Williams [14], showing concordance between tumor grading (92.6%, 95% CI 82.4 –98.0), but poor stage concordance (43%, 95% CI 28.7–55.9), despite 59% of our biopsies having SCT. It is not surprising that there was poor stage concordance since URS biopsy is unable to obtain deep tissue sample due to the small biopsy forceps, and the risk of perforation. Additionally, 5.6% were upgraded, and 57% were upstaged in our study. Pleomorphism concordance and concordance of number of mitoses were 87% (95% CI 73.3%–93.5%) and 61% (95% CI 45.9%–73.0%), respectively. The goal of our study was to determine whether biopsy volume affected grade and stage concordance as previously suggested [17]. The univariate and multivariate analysis showed no correlation of biopsy volume to agreement between biopsy and NU specimen grade (P ⫽ 0.81) or stage (P ⫽ 0.44). Based on our data, it does not appear that biopsy volume affects agreement between biopsy and final pathol-

ogy of upper tract UC tumors. It did appear that presence of SCT in URS biopsy did correlate with increased disagreement in specimen stage (P ⫽ 0.002, OR 6.4, 95% CI 1.9 –21). The significance or cause of this finding is unclear. There is likely some inherent bias to those patients which have SCT on their biopsy specimens that cannot be evaluated in the retrospective nature performed here. There are limitations to this study. First, the retrospective nature and small sample size limit the applicability of the conclusion and, further, prospective studies of much larger populations are needed to truly evaluate the effect of volume biopsy on tumor staging. Additionally, there is inherent selection bias in this study since those patients who undergo NU are more likely to have advanced disease. Therefore, our cohort consists largely of high grade biopsies. However, NU is often performed in those patients with low grade disease that have multiple tumors, rapidly recurring disease, or high volume of disease. Even though NU is required to confirm pathologic diagnoses, it is unethical to pursue NU in every patient for the sake of research and, therefore, we cannot confirm biopsy specimens in patients without indications for NU. Lastly, we did not perform lymph node dissection in these patients. This may have limited tumor staging evaluation. With NU remaining the gold standard in treatment of upper tract UC, clinicians have a duty to reserve this treatment for those patients who truly need extirpation and should pursue all information to aid in decision making. Based on the results of this study, URS biopsy volume does not affect tumor grading. Despite URS biopsy being a poor predictor of tumor stage, clinicians should understand that tumor grade appears to be accurate, and biopsy should be pursued in all patients with suspected upper tract UC. This


C.P. Rojas et al. / Urologic Oncology: Seminars and Original Investigations 31 (2013) 1696 –1700

information is obtainable by the pathologist even in the case of samples with small volume biopsies. 5. Conclusions NU is the gold standard in the treatment of upper tract UC. Although it has been shown to improve survival in select patients, it also carries significant comorbidity. Therefore, URS biopsy plays a significant role in determining which patients are candidates for NU. There has been significant debate as to whether tumor grading and staging is accurate, and as to whether low biopsy volume may be a potential reason for disagreements between biopsy and NU specimens. The results of this study show that there is 92.6% concordance between tumor grading, but only 43% concordance for tumor stage. Low biopsy volume does not affect tumor grading or staging. Larger prospective studies are required to assess this in the future. References [1] Jemal A, Murray T, Ward E, et al. Cancer statistics. CA Cancer J Clin 2005;2005:10 –30. [2] Siegel R, Naishadham D, Jemal A. Cancer statistics. CA Cancer J Clin 2012;2012:10 –29. [3] Hara I, Hara S, Miyake H, et al. Usefulness of ureteropyeloscopy for diagnosis of upper urinary tract tumors. J Endourol 2001;15:601–5. [4] 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. [5] Grasso M, Fishman AI, Cohen J, et al. Ureteroscopic and extirpative treatment of upper urinary tract urothelial carcinoma: A 15-year comprehensive review of 160 consecutive patients. BJU Int 2012, in press, available online March 28, 2012. DOI:10.1111/j1464-410x. 2012.11066x. [6] Koukourakis G, Zacharias G, Koukourakis M, et al. Comprehensive management of upper tract urothelial carcinoma. Adv Urol 2009: 656521.

[7] Langner C, Hutterer G, Chromecki T, et al. Pt classification, grade, and vascular invasion as prognostic indicators in urothelial carcinoma of the upper urinary tract. Mod Pathol 2006;19:272–9. [8] Margulis V, Shariat SF, Matin SF, et al. Outcomes of radical nephroureterectomy: A series from the upper tract urothelial carcinoma collaboration. Cancer 2009;115:1224 –33. [9] Kikuchi E, Horiguchi Y, Nakashima J, et al. Lymphovascular invasion independently predicts increased disease specific survival in patients with transitional cell carcinoma of the upper urinary tract. J Urol 2005;174:2120 –3, Discussion 2124. [10] Clements T, Messer JC, Terrell JD, et al. High-grade ureteroscopic biopsy is associated with advanced pathology of upper-tract urothelial carcinoma tumors at definitive surgical resection. J Endourol 2012; 26:398 – 402. [11] Straub J, Strittmatter F, Karl A, et al. Ureterorenoscopic biopsy and urinary cytology according to the 2004 who classification underestimate tumor grading in upper urinary tract urothelial carcinoma. Urol Oncol 2012, in press, available online January 31, 2012. DOI:10. 1016/jurologic.204.12.021. [12] Wang JK, Tollefson MK, Krambeck AE, et al. High rate of pathologic upgrading at nephroureterectomy for upper tract urothelial carcinoma. Urology 2012;79:615–9. [13] Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296 –305. [14] Williams SK, Denton KJ, Minervini A, et al. Correlation of uppertract cytology, retrograde pyelography, ureteroscopic appearance, and ureteroscopic biopsy with histologic examination of upper-tract transitional cell carcinoma. J Endourol 2008;22:71– 6. [15] Huben RP, Mounzer AM, Murphy GP. Tumor grade and stage as prognostic variables in upper tract urothelial tumors. Cancer 1988; 62:2016 –20. [16] Cutress ML, Stewart GD, Zakikhani P, et al. Ureteroscopic and percutaneous management of upper tract urothelial carcinoma (UTUC): Systematic review. BJU Int 2012, in press, available online April 3, 2012. DOI:10.1111/j.1464-410x.2012.11068x. [17] 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. [18] 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.