Utility and Diagnostic Accuracy of Ureteroscopic Biopsy in Upper Tract Urothelial Carcinoma

Transcription

1 Utility and Diagnostic Accuracy of Ureteroscopic Biopsy in Upper Tract Urothelial Carcinoma Vishal Vashistha, BA; Ahmad Shabsigh, MD; Debra L. Zynger, MS, MD Context. Ureteroscopic biopsy is the gold standard for the histopathologic diagnosis of urothelial carcinoma of the upper urinary tract. Objective. To assess the accuracy of endoscopically obtained biopsy samples in diagnosing, grading, and staging urothelial carcinoma and correlate diagnostic findings to biopsy sample size. Design. We retrospectively reviewed endoscopic biopsies of the ureter, renal pelvis, and ureteropelvic junction from 2008 to Biopsy diagnoses that were discordant with follow-up pathology and/or ureteroscopic impression were rereviewed and samples were immunohistochemically analyzed. Results. Endoscopic biopsies (n ¼ 118) yielded a sensitivity of 85.4% for the ureter (n ¼ 79), 77.8% for the renal pelvis (n ¼ 37), and 100% for the ureteropelvic junction (n ¼ 2). A specificity of 100% for all locations and a diagnostic accuracy of 98.3% were identified. The median sample size was 0.3 cm for true positives, 0.3 cm for true negatives, and 0.2 cm for false negatives with no statistical significance. We found that 87.1% of tumors diagnosed on biopsy had concordant grade and 60.0% had concordant pt stage with follow-up surgical resections (n ¼ 43) and biopsies (n ¼ 24). Biopsy samples with concordant tumor grades (mean ¼ 0.6 cm) compared with follow-up resection were larger than biopsy samples with discordant grades (mean ¼ 0.3 cm) (P ¼.04). Conclusions. Though highly specific, endoscopic biopsy does provide a significant false-negative rate owing to both sampling and diagnostic errors when assessing the upper urinary tract for urothelial carcinoma. Tumor grading is accurate, particularly with larger tissue samples, but tumor staging is unreliable. (Arch Pathol Lab Med. 2013;137: ; doi: / arpa oa) Urothelial carcinoma comprises 5% of all urothelial that can be controlled with endoscopic ablation. 2 6 The malignancies and 10% of renal tumors. 1 The diagnosis presence of high-volume or high-grade urothelial carcinoma of upper urinary tract urothelial carcinoma is difficult. Historically, the presence of a filling defect on ureteropyelography and a positive cytology result established the diagnosis. The development of both better imaging techniques, may be an indication for neoadjuvant chemotherapy before resection. 7 Unfortunately, the small diameter of the ureteral lumen limits the types of instruments that can be used to obtain an including computed tomography urogram or adequate biopsy. This may yield suboptimal tissue for magnetic resonance urogram, and endoscopic instruments, accurately diagnosing, grading, and staging biopsy specimens such as flexible and digital ureteroscopes, improved the taken from the upper urinary tract Errors ability to identify and characterize malignancies. 2 Ureteroscopy provides excellent visualization of the tumor and with biopsy, has the potential to provide the histologic stemming from insufficient sampling or pathologic misdiagnosis may unnecessarily delay surgical intervention. Thus, determining the specificity and sensitivity of upper tract type, grade, and stage of a tumor. 2 This information is endoscopic biopsy for the histopathologic diagnosis of crucial toward determining the appropriate treatment. urothelial carcinoma is critical. However, only 1 publication Nephroureterectomy with bladder cuff excision or segmental ureterectomy using an open or laparoscopic technique remains the treatment of choice for upper urinary tract has reported a specificity and sensitivity for diagnosing tumor using ureteroscopic biopsy. In this report, the authors considered cases that had tumor visualized endoscopically malignances except for select patients who have either but were negative by histology as true positives. 8 compromised renal function or small, low-grade disease Specificity and sensitivity have been calculated for retrograde brush biopsies of the ureter and renal pelvis, but these values are not clinically relevant today as the forceps Accepted for publication May 25, approach is used more readily Lastly, the accuracy of From the Departments of Pathology (Dr Zynger and Mr Vashistha) tumor grading and staging has been evaluated in a few and Urology (Dr Shabsigh), The Ohio State University Medical articles, but no previous analysis has correlated the accuracy Center, Columbus, Ohio. of these factors with biopsy sample size. 10,12 15,19 The authors have no relevant financial interest in the products or The purpose of this investigation was to assess the companies described in this article. Reprints: Debra L. Zynger, MS, MD, The Ohio State University histopathologic diagnostic accuracy of specimens from the Medical Center, E-401 Doan Hall, 410 W 10th Ave, Columbus, OH ureter, renal pelvis, and ureteropelvic junction obtained via ( Debra.zynger@osumc.edu). endoscopic biopsy and to determine the specificity and 400 Arch Pathol Lab Med Vol 137, March 2013 Ureteroscopic Biopsy for Urothelial Carcinoma Vashistha et al

2 sensitivity for ureteroscopic biopsy, based upon histopathologic findings. We further correlated both diagnosis and biopsy location with biopsy sample size. For patients who had follow-up pathology, tumor pt stage and grade were compared with the results of subsequent biopsy and resection specimens. MATERIALS AND METHODS We retrospectively reviewed procedural and pathology reports for endoscopic biopsies of the ureter, renal pelvis, or ureteropelvic junction from January 2008 to December 2011 at The Ohio State University Medical Center (Columbus, Ohio). Endoscopic impression and surgeon was noted from procedural reports. From pathology reports, clinical history, presence or absence of malignancy, location of biopsy, pathologic pt stage, histologic grade, results of follow-up biopsies and/or surgical resections, and the largest dimension of the tissue provided per the gross description was documented. Additional follow-up information via subsequent cytology reports and medical treatment was noted. Tumor grade was classified using the World Health Organization (WHO) criteria as high or low. 20 Tumor pt stage was classified by using the American Joint Committee on Cancer TNM criteria. 21 Endoscopic biopsies were done according to the surgeon s preference, with both semirigid and flexible ureteroscope used. Instruments used to obtain the biopsy samples included Piranha 3Fr ureteroscopic biopsy forceps (Boston Scientific, Natick, Massachusetts), BIGopsy biopsy forceps (Cook Medical, Bloomington, Indiana), and stone baskets from both manufacturers. Specificity, Sensitivity, Diagnostic Accuracy, and Sources of Error Specificity and sensitivity were calculated by comparing the initial biopsy diagnosis with the summation of the surgical impression and all follow-up pathology. True positives were cases with a neoplastic biopsy diagnosis and an endoscopic impression of neoplastic growth and/or follow-up pathology indicating malignancy. True negative cases had a nonneoplastic endoscopic impression and/or nonneoplastic follow-up pathology. False positives and false negatives reflected differences between biopsy pathologic diagnosis versus endoscopic appearance and follow-up pathology. One patient had neoadjuvant chemotherapy and was eliminated from calculations of specificity and sensitivity owing to possible alterations between initial biopsy and follow-up pathology. Slides from false-negative biopsies were rereviewed by a genitourinary surgical pathologist (D.L.Z.). Tissue from false-negative cases was further analyzed via immunohistochemistry using Ki-67 (1:400; clone MIB-1, Dako, Carpinteria, California), CD44s (1:200; clone DF1485, Leica Microsystems, Wetzlar, Germany), CK20 (1:200; clone K20.8, Dako), and p53 (1:1000; clone D0-7, Dako) to evaluate for diagnostic errors. A diagnostic accuracy was computed from rereview and immunohistochemical results. Grade and pt Stage Concordance for Biopsies With Follow-Up Pathology Concordance values for tumor pt stage and grade were calculated by comparing initial endoscopic biopsies with available follow-up resections. For patients who had multiple biopsies, separate pt stage and grade concordance values were calculated by comparing each initial biopsy to the later biopsy. Biopsy tissue size was tested for correlation between the accurate diagnosis of presence or absence of tumor, tumor grade, and tumor pt stage with the results of subsequent pathologic data. Lastly, the concordance values of invasive and noninvasive disease were also calculated to assess the accuracy of endoscopic biopsy toward predicting the extension of disease. Statistics Size correlations were tested by using analysis of variance for 3 or more groups of data and 2-tailed t tests for 2 groups of data. Analysis of variance calculations did not include variables with less than 4 data points. P values of.05 or less were considered significant. RESULTS Data from 93 patients with 118 endoscopic biopsies of the ureter (n ¼ 79), renal pelvis (n ¼ 37), and/or ureteropelvic junction (n ¼ 2) were collected. Twelve cases used biopsy slides submitted from outside institutions for patients undergoing further care at our hospital, with the remainder of specimens obtained from procedures performed at our institution. Clinicopathologic characteristics are shown in the Table. Clinical indication for endoscopic biopsy included bladder tumor (n ¼ 36), ureteral tumor (n ¼ 21), nephrolithiasis (n ¼ 13), renal tumor (n ¼ 13), hydronephrosis (n ¼ 12), hematuria (n ¼ 11), ureteropelvic junction obstruction (n ¼ 4), ureteral stricture (n ¼ 2), and ureteral obstruction (n ¼ 2), with a few cases in which an indication was not provided (n ¼ 4). Whereas 42.3% (50 of 118) of diagnoses were nonneoplastic, 57.6% (68 of 118) were neoplastic (Figure 1, A) with 56.0% (66 of 118) urothelial carcinoma (Figure 1, B) and 1.7% (2 of 118) nonurothelial (colonic adenocarcinoma and primary clear cell adenocarcinoma) (Figure 1, C and D). Urothelial carcinoma was diagnosed in 57% (45 of 79) of biopsies from the ureter, 56.8% (21 of 37) from the renal pelvis, and 0% (0 of 2) from the ureteropelvic junction. Of the urothelial tumors, 48.5% (32 of 66) were high grade, 45.4% (30 of 66) were low grade, and 6.1% (4 of 66) were not graded. Urothelial carcinoma was staged as ptis or pta: 74.2% (49 of 66); pt1 (Figure 1, E): 9.1% (6 of 66); and pt2 (Figure 1, F): 6.1% (4 of 66), while 10.6% (7 of 66) were unstaged. Specificity, Sensitivity, Diagnostic Accuracy, and Sources of Error The overall specificity was 100% and the sensitivity was 83.0% for endoscopic biopsy diagnoses, inclusive of both sampling and diagnostic errors. Regarding only biopsies of the ureter, the specificity was 100%; sensitivity, 85.4%; and false-negative rate, 10.4% (8 of 79). In the renal pelvis, the specificity was 100%; sensitivity, 77.8%; and false-negative rate, 16.2% (6 of 37). For endoscopic biopsies, 57.6% (68 of 118) were true positives with no false positives identified. Of the 50 nonneoplastic diagnoses, 72.0% (36 of 50) were true negatives (Figure 2, G) and 28% (14 of 50) were considered false negatives. Thirteen of the 14 false-negative cases had slides available for rereview and immunohistochemical testing. The initial pathology report described the specimen in 85.7% (12 of 14) of the false negatives as inadequate via terminology such as scant, denuded, or as not containing urothelial tissue. For the 2 reports that did not document poor tissue, both were inadequate upon rereview. In 84.6% (11 of 13) of the falsenegative cases, the rereview and immunostains did not reveal evidence of malignancy. However, for 2 specimens, rereview was suggestive of urothelial carcinoma. One biopsy specimen (Figure 2, H) showed carcinoma in situ (confirmed by surgical resection) and 1 biopsy specimen (Figure 2, I) contained a minute focus of low-grade noninvasive papillary urothelial carcinoma (confirmed by endoscopic impression). Immunohistochemical results in these 2 cases were equivocal. Considering these cases as 2 diagnostic errors yielded an endoscopic pathologic diagnostic accuracy of 98.3% (116 of 118). Arch Pathol Lab Med Vol 137, March 2013 Ureteroscopic Biopsy for Urothelial Carcinoma Vashistha et al 401

3 Figure 1. A through F, Photomicrographs of upper tract endoscopic biopsies. A, Reactive urothelium with underlying acute and chronic inflammation. The endoscopic impression showed ureteral stricture and follow-up biopsy also showed reactive urothelium (ureter). B, Low-grade noninvasive papillary urothelial carcinoma with minute intact papillary core. The tumor was low grade and noninvasive upon resection (ureter). C, Colonic adenocarcinoma (ureter). D, Clear cell adenocarcinoma with a large tumor at the ureteral orifice (ureter). E, Cords and single cells of highgrade urothelial carcinoma invading the lamina propria (pt1) (ureter). F, High-grade urothelial carcinoma invading the muscularis propria (pt2) (ureter) (hematoxylin-eosin, original magnifications 320 [A, B, D, and F] and 340 [C and E]). 402 Arch Pathol Lab Med Vol 137, March 2013 Ureteroscopic Biopsy for Urothelial Carcinoma Vashistha et al

4 Figure 2. G through K, Photomicrographs of upper tract endoscopic biopsies. G, Blood with scant clusters of nonneoplastic urothelium, potentially mimicking papillae. A repeated biopsy also yielded a nonneoplastic diagnosis (ureter). H, Nest of urothelial cells showing atypia consistent with carcinoma in situ in which a nonneoplastic diagnosis was originally rendered. The arrow directs attention to a mitotic figure. Nephroureterectomy contained high-grade urothelial carcinoma invasive into the periureteral soft tissue (ureter). I, Noninvasive papillary urothelial carcinoma with focal papillary cores in which a nonneoplastic diagnosis was originally rendered. Ureteroscopy revealed minute papillary lesions (ureter). J, High-grade noninvasive papillary urothelial carcinoma. Nephroureterectomy confirmed noninvasive high-grade tumor (renal pelvis). K, Papillary urothelial carcinoma with detached fragmented cores, which was ungraded and unstaged at diagnosis. The tumor was high grade and invasive in the ureterectomy specimen (ureter) (hematoxylin-eosin, original magnifications 340 [G, H, I, and J] and 320 [K]). Arch Pathol Lab Med Vol 137, March 2013 Ureteroscopic Biopsy for Urothelial Carcinoma Vashistha et al 403

5 Histopathologic Characteristics of Upper Urinary Tract Endoscopic Biopsies All Locations Ureter Renal Pelvis Ureteropelvic Junction No. of biopsies Mean age, y Sex (M:F) 58:35 39:23 19:11 1:1 Median tissue size, cm Malignant biopsy diagnoses, No. (%) 68/118 (57.6) 47/79 (59.5) 21/37 (56.8) 0/2 (0) Urothelial 66/118 (56.0) 45/79 (57.0) 21/37 (56.8) 0/2 (0) Nonurothelial 2/118 (1.7) 2/79 (2.5) 0/37 (0) 0/2 (0) Specificity, % Sensitivity, % NA Grade a, No. (%) High 32/66 (48.5) 21/45 (46.7) 11/21 (52.3) NA Low 30/66 (45.4) 22/45 (46.8) 8/21 (38.0) NA Grade not evaluated 4/66 (6.1) 2/45 (4.4) 2/21 (9.5) NA Grade concordance, b No. (%) 34/39 (87.1) 23/27 (85.1) 11/12 (91.7) NA pt stage c, No. (%) ptis/pta 49/66 (74.2) 35/45 (77.8) 14/21 (66.7) NA pt1 6/66 (9.1) 4/45 (8.9) 2/21 (9.5) NA pt2 4/66 (6.1) 3/45 (6.7) 1/21 (4.8) NA Stage not evaluated 7/66 (10.6) 3/45 (6.7) 4/21 (19.0) NA pt stage concordance, b No. (%) 21/35 (60.0) 16/27 (59.3) 5/8 (62.5) NA Invasiveness concordance, No. (%) Noninvasive concordance d 14/21 (66.7) 12/17 (70.6) 2/4 (50.0) NA Invasive concordance d 8/8 (100.0) 5/5 (100.0) 3/3 (100.0) NA Abbreviation: NA, not applicable. a Tumor grade only included urothelial carcinoma. b Tumor grade and stage concordance values included initial biopsies compared to all follow-up pathology (further resections and biopsies). c pt stage included primary upper tract carcinoma. d Noninvasive concordance reflects the percentage of patients with noninvasive disease upon biopsy that was subsequently noninvasive upon resection; invasive concordance reflects the percentage of patients with invasive disease upon biopsy that was subsequently invasive upon resection. Tissue size was available for 113 of the 118 ureteroscopic cases with 5 sizes from outside cases not available. The median biopsy sample size was 0.3 cm (mean, 0.7 cm; range, cm) with a median size of 0.3 cm for the ureter (mean, 0.7 cm; range, cm), 0.2 cm for the renal pelvis (mean, 0.5 cm; range, cm), and 0.7 cm for the ureteropelvic junction (mean, 0.8 cm; range, cm) (P ¼.10). Based on diagnosis, the median size was 0.3 cm for true positives (mean, 0.7 cm; range, cm), 0.3 cm for true negatives (mean, 0.5; range, cm), and 0.2 cm for false negatives (mean, 0.6 cm; range, cm) (P ¼.50). No significant difference in tissue size was found between the 6 surgeons who performed at least 4 procedures (P ¼.56). Grade and pt Stage Concordance for Biopsies With Follow-Up Pathology Forty-three initial biopsies had subsequent surgical resections (nephroureterectomy, n ¼ 36; ureterectomy, n ¼ 5; nephrectomy, n ¼ 2). The average duration between biopsy and resection was 62.3 days (range, days). Thirty-two of the 43 corresponding initial biopsies were diagnosed as malignant and all 32 of these resections (100%) contained urothelial carcinoma. Eleven cases were negative upon initial biopsy, and 10 of these were found to be malignant upon resection and are included in the 14 aforementioned false negatives. One true negative was identified in a patient with a nonneoplastic biopsy followed by a resection performed for pyelonephritis. The median sample size for biopsies that had concordant diagnoses of urothelial carcinoma with follow-up resection was 0.3 cm (mean, 0.6 cm), whereas discordant biopsies had a median sample size of 0.2 cm (mean, 0.5 cm), (P ¼.71). Twenty-seven of the 31 resections (87.1%) with urothelial carcinoma had concordant grade between biopsy and surgical resection (high grade, n ¼ 15; low grade, n ¼ 12) (Figure 2, J), with 1 biopsy sample ungraded owing to insufficient intact tumor cells to evaluate for pleomorphism, thus precluding assessment of grade (Figure 2, K). Considering the resection as the gold standard, 3 biopsy samples were undergraded and 1 was overgraded. The median size for biopsy samples with and without grade concordance with resection was 0.3 cm (mean ¼ 0.6 and 0.3 cm, respectively) (P ¼.04). Only 58.6% (17 of 29) of the resections had concordant pt stages with initial biopsies (pta, n ¼ 14; pt1, n ¼ 3), with 4 biopsies unstaged owing to a lack of subepithelial tissue or severely fragmented/disrupted tissue precluding assessment of invasion through the basement membrane. Twelve biopsies had a lower pt stage than the resected specimen as follows: 7 pta/ptis at biopsy were found to be pt1 (n ¼ 1), pt2 (n ¼ 3), and pt3 (n ¼ 3) upon resection; 2 pt1 biopsies were pt3 at resection, and 3 pt2 biopsies were pt3 at resection. All resections that were staged pt2 or pt3 were understaged at biopsy. Biopsies with and without concordant pt stage both had a median biopsy sample size of 0.3 cm (mean ¼ 0.5 and 0.8 cm, respectively) (P ¼.27). Of patients who had a biopsy diagnosis of noninvasive disease, 66.7% (14 of 21) had noninvasive disease upon resection. All patients (100%; 8 of 8) who had a diagnosis of invasive disease had invasive disease upon resection. Biopsies showing concordant invasive disease with resection, concordant noninvasive disease with resection, and discordance of disease invasion with resection all had a median sample size of 0.3 cm (mean ¼ 0.5, 0.5, and 0.7 cm, respectively) (P ¼.81). 404 Arch Pathol Lab Med Vol 137, March 2013 Ureteroscopic Biopsy for Urothelial Carcinoma Vashistha et al

6 Twenty-four initial biopsies had corresponding subsequent endoscopic biopsies. The average duration between biopsies was 87 days (range, days), and 66.7% (16 of 24) had concordant diagnoses. Three patients had 3 consecutive biopsies, and the first and second biopsies were compared independently to the third biopsy to calculate pt stage and grade concordance. Upon first biopsy diagnosis, 20.8% (5 of 24) of the cases were malignant but were nonneoplastic upon follow-up biopsy, whereas 12.5% (3 of 24) of the initial biopsies were nonneoplastic upon first biopsy diagnosis but were diagnosed as malignant upon follow-up biopsy. Of the 8 patients who were found to have malignancy in both biopsies, 87.5% (7 of 8) had concordant grade; 3 of these concordant grades were high and 4 were low. The lone discordant grade had a higher grade on initial biopsy. Of the biopsy pairs, 66.6% (4 of 6) had concordant pt stage, with 1 follow-up biopsy unstaged owing to inadequate tissue. One discordant biopsy pair had a higher stage and 1 had a lower stage upon initial biopsy. Of the biopsies diagnosed as noninvasive, 66.7% (4 of 6) were noninvasive upon follow-up biopsy. COMMENT Ureteroscopic evaluation with biopsy is currently the gold standard for both visualizing and diagnosing tumors of the upper urinary tract. 2 Therefore, assessing the sensitivity, specificity, and the stage and grade concordances of endoscopic biopsy are important toward determining the proper treatment for patients with urothelial carcinoma of the ureter, renal pelvis, or ureteropelvic junction. Tumor staging is currently of particular interest because of the higher rates of mortality associated with invasive disease and reports of endoscopic biopsy and imaging staging inadequacies. 4,12 15,22 24 Although most ureteroscopic biopsies in our study were conducted to evaluate the upper urinary tract in patients with suspected tumor, other prevalent clinical indications included nephrolithiasis and hydronephrosis. Endoscopic biopsies achieved a specificity of 100%, which suggests that a biopsy diagnosed with urothelial carcinoma reliably reflects malignancy. Contrarily, Hara et al 8 reported a specificity of 88% for patients undergoing ureteropyeloscopy following indeterminate results from urine cytology and radiology. Because these cases involved only patients with equivocal evidence for disease, the results of the study may not be comparable to routine clinical use. The authors 8 reported 3 false positives diagnosed as urothelial carcinoma upon biopsy. Following surgical resection, the authors concluded that the misdiagnosis of 2 of the biopsy samples was due to overinterpretation of epithelial hyperplasia, while information regarding the follow-up resection for the last sample was unavailable. Other studies 9,10 did not calculate specificity but did describe false positives. Tavora et al 9 examined ureter and renal pelvis biopsies that were submitted by an outside pathologist for expert pathology consultation. Comparing the originating pathologist impression with the expert pathology review identified 7 false-positive diagnoses out of 76 submitted cases. The authors suggested that the biopsy samples were incorrectly diagnosed as low-grade papillary urothelial neoplasms owing to detached pieces of urothelium imitating papillary formation, urothelium displaying pseudopapillary formation, or von Brunn nest proliferations. It is difficult to compare this false-positive rate, as the investigation only included cases that required expert consultation. Our study included all cases obtained at a tertiary care academic center in which there was a clinical history of tumor in 48.3%; therefore, it should be emphasized that false positives may occur when diagnosing or managing nephrolithiasis with endoscopic biopsy, and we may have found a higher specificity for testing for neoplasia because our patients had a higher pretest probability for neoplastic disease. Williams et al 10 reported 2 false positives out of 30 biopsies in which surgical resections were negative for malignancy. However, rereview of these 2 biopsies unequivocally showed urothelial carcinoma, and therefore, these biopsies were not actually falsely positives. The authors noted that these tumors were most likely completely resected upon biopsy. Our review of ureteroscopic biopsies yielded a sensitivity of 83.0%. The sensitivity in the ureter (85.4%) was slightly higher than for the renal pelvis (77.8%). This small difference may be due to the difficulty in obtaining adequate biopsy samples in some locations in the renal pelvis, such as the inferior pole calyces where the biopsy is done with retroflection of the ureteroscope. Because only 2 endoscopic biopsies were conducted in the ureteropelvic junction, the results from these procedures offer little notable value, particularly since both were true-negative diagnoses. Greater than one-quarter of all endoscopic biopsies negative for malignancy were false negatives, mainly due to tissue sampling rather than diagnostic errors. As such, for upper tract biopsies, a nonneoplastic diagnosis should be interpreted with caution. Hara et al 8 reported a sensitivity of 92.0%, but as the ureteroscopic impression of a tumor was used in combination with biopsy to designate a case as a true positive, the actual number of true positives, and hence the sensitivity calculated, may have been inflated when compared to our data. The 2 identified false negatives were due to sampling errors. 8 To our knowledge, we are the first to report a histopathologic sensitivity for upper tract endoscopic biopsy. Only 2 of the false negatives we identified were shown to be diagnostic errors, yielding a very high diagnostic accuracy (98.3%). Rereview showed urothelial carcinoma in situ and a small focus of low-grade papillary urothelial carcinoma, confirmed with follow-up resection and endoscopic impression, respectively. Immunostaining (Ki-67, p53, CD44s, CK20) of the false-negative cases, including the 2 diagnostic errors, failed to confirm or refute the presence of malignancy, and thus may not be helpful in difficult cases with minute amounts of tissue. Shiraishi et al 11 reported 5 falsenegative biopsies in 23 patients with resections, although the authors did not detail a rereview of the biopsy slides. The findings upon resection of the false-negative cases were urothelial carcinoma, with the authors attributing the discrepancy to tissue sampling error. Our study achieved a grade concordance of 87.1% for biopsies in which a grade was given, compared to follow-up specimens. Almost all biopsies were graded (97.5%). In the few discordances, there was more frequent undergrading than overgrading (60.0% and 40.0%, respectively) with a short median interval between procedures, suggesting that discordance due purely to tumor growth was unlikely. Renal pelvic biopsies (91.7%) had a slightly higher grade concordance than those of the ureter (85.1%). Overall grade concordance was within the range of previous results (72% 90.4%). 10,12 15 Smith et al 12 demonstrated a grade concordance of 72% with similar methodology. All of the Arch Pathol Lab Med Vol 137, March 2013 Ureteroscopic Biopsy for Urothelial Carcinoma Vashistha et al 405

7 discordant cases (100%) were undergraded with all cases graded. Brien et al 19 reported a strong correlation between high grade diagnosed at biopsy and high grade on surgical resection. Biopsy grade was not associated with tumor site (ureter, renal pelvis, or multifocal). For older investigations, 10,13,15 the WHO 3-tiered grading classification was used, with Williams et al 10 and Keeley et al 13 deeming grade 1 to be equivalent to grade 2 for concordance calculations. Using this method, Williams et al 10 found a grade concordance rate of 75%. Most discordant biopsies were undergraded and all cases were graded. Keeley et al 13 reported a grade concordance rate of 90.4% with equal overgrading and undergrading. Albeit Keeley et al 13 described the highest reported grade concordance, the study had a high percentage of biopsies that were not graded (17.6%). Skolarikos et al 15 did not combine grade 1 tumors with grade 2 tumors and calculated a concordance rate of 80.4%. Most discrepancies were due to undergrading. Similar to Keeley et al, 13 a high percentage of cases were not graded (17.7%). 15 As conveyed by our data and that of other reported grade concordance values, pathologists should recognize that grade assessment based on histopathology is often correct, and therefore, it is worthwhile to grade most upper tract biopsy specimens. We identified a pt stage concordance of 60% for biopsies in which a stage was designated. A pt classification was not given in 10.6% of cases. The ureter (59.3%) and renal pelvis (62.5%) had similar pt stage concordance for biopsies that had sufficient tissue for staging. However, including unstaged biopsies, pt stage concordance was only 52.5%, with a greater concordance in the ureter (57.1%) than in the renal pelvis (41.7%). Almost all ureter biopsies were pt staged (93.3%) as compared to biopsies taken from the renal pelvis (81%). The large number of unstaged renal pelvis biopsies may reflect the difficulty in extracting optimal tissue using the ureteroscope in the renal pelvis. All discrepancies were due to understaging; 33.3% of biopsies initially diagnosed as noninvasive urothelial carcinoma ultimately showed invasive tumor upon follow-up pathology. Similar concordance rates (45.5% 68%) have been found in previous studies, although the percentage of unstaged biopsies (17.7% 32.5%) has varied or has not been specified. 12,14 15 Smith et al 12 reported a stage concordance of 68% with all discordant cases reclassified from noninvasive to invasive disease. However, the authors only included specimens if a nonfragmented base of the lesion was present. 12 Skolarikos et al 15 identified a stage concordance of 49%, and all discordant biopsies were understaged, compared to followup. Both data from our institution as well as from other investigations demonstrate that stage diagnosed on endoscopic biopsy is often inaccurate owing to understaging. However, all diagnosed invasive disease (pt1-pt3) has been found to be invasive upon follow-up. Additionally, biopsies of the renal pelvis may be less likely to have adequate tissue for staging. To our knowledge, we are the first to test for correlations between histopathologic findings and ureteroscopic biopsy sample size. Although sizes from true positives and ureter biopsies were slightly larger, the differences were not statistically significant. Size was equivalent regardless of the diagnosis of invasive or noninvasive disease. Biopsy sample size differences between surgeons conducting the endoscopic procedures were minimal. Biopsy samples with concordant grades, compared to surgical resections, were significantly larger than those with discordant grades. Although Smith et al 12 did not examine biopsy tissue size versus stage concordance, the authors did confirm that tumor size was not significantly different between the concordant grade/stage and the discordant grade/stage groups. It appears that biopsy sample and tumor size are not predictors of presence of tumor or pt stage concordance, but may impact grade concordance. Tissue size may be a limitation of the procedure instrumentation and the location of the tumor rather than the amount or absence of tumor. Endoscopic biopsy of the upper urinary tract offers an exceptional diagnostic accuracy for patients reported to have urothelial carcinoma; however, pathologists and urologists should approach accepting negative biopsy results with caution, particularly for biopsies with scant tissue. Grade concordance is high between ureteroscopic biopsies and surgical resections, especially for larger tissue samples. Tumor pt staging is not accurate regardless of tissue size. References 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, CA Cancer J Clin. 2008;58(2): Kirkali Z, Tuzel E. Transitional cell carcinoma of the ureter and renal pelvis. Crit Rev Oncol Hematol. 2003;47(2): Lam JS, Gupta M. Ureteroscopic management of upper tract transitional cell carcinoma. Urol Clin North Am. 2004;31(1): Thompson RH, Krambeck AE, Lohse CM, Elliott DS, Patterson DE, Blute ML. Endoscopic management of upper tract transitional cell carcinoma in patients with normal contralateral kidneys. Urology. 2008;71(4): Elliott DS, Segura JW, Lightner D, Patterson DE, Blute ML. Is nephroureterectomy necessary in all cases of upper tract transitional cell carcinoma: longterm results of conservative endourologic management of upper tract transitional cell carcinoma in individuals with a normal contralateral kidney. Urology. 2001; 58(2): Iborra I, Solsona E, Casanova J, Ricós JV, Rubio J, Climent MA. Conservative elective treatment of upper urinary tract tumors: a multivariate analysis of prognostic factors for recurrence and progression. J Urol. 2003;169(1): O Donnell PH, Stadler WM. The role of chemotherapy in upper tract urothelial carcinoma [published online ahead of print January 26, 2009]. Adv Urol. 2009: doi: /2009/ Hara I, Hara S, Miyake H, et al. Usefulness of Ureteropyeloscopy for diagnosis of upper urinary tract tumors. J Endourol. 2001;15(6): 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(10): Williams SK, Denton KJ, Minervini A, et al. Correlation of upper-tract cytology, retrograde pyelography, ureteroscopic appearance, and ureteroscopic biopsy with histologic examination of upper-tract transitional cell carcinoma. J Endourol. 2008;22(1): Shiraishi K, Eguchi S, Mohri J, Kamiryo Y. Role of ureteroscopic biopsy in the management of upper urinary tract malignancy. Int J Urol. 2003;10(12): Smith AK, Stephenson AJ, Lane BR, et al. Inadequacy of biopsy for diagnosis of upper tract urothelial carcinoma: implications for conservative management. Urology. 2011;78(1): Keeley FX, Kulp DA, Bibbo M, McCue PA, Bagley DH. Diagnostic accuracy of ureteroscopic biopsy in upper tract transitional cell carcinoma. J Urol. 1997;157(1): Guarnizo E, Pavlovich CP, Seiba M, Carlson DL, Vaughan ED Jr, Sosa RE. Ureteroscopic biopsy of upper tract urothelial carcinoma: improved diagnostic accuracy and histopathological considerations using a multi-biopsy approach. J Urol. 2000;163(1): Skolarikos A, Griffiths TR, Powell PH, Thomas DJ, Neal DE, Kelly JD. Cytologic analysis of ureteral washings is informative in patients with grade 2 upper tract TCC considering endoscopic treatment. Urology. 2003;61(6): Sheline M, Amendola MA, Pollack HM, Banner MP, de las Morenas A, Wein AJ. Fluoroscopically guided retrograde brush biopsy in the diagnosis of transitional cell carcinoma of the upper urinary tract: results in 45 patients. AJR Am J Roentgenol. 1989;153(2): Dodd LG, Johnston WW, Robertson CN, Layfield LJ. Endoscopic brush cytology of the upper urinary tract: evaluation of its efficacy and potential limitations in diagnosis. Acta Cytol. 1997;41(2): Blute RD Jr, Gittes RR, Gittes RF. Renal brush biopsy: survey of indications, techniques and results. J Urol. 1981;126(2): 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(1): Arch Pathol Lab Med Vol 137, March 2013 Ureteroscopic Biopsy for Urothelial Carcinoma Vashistha et al

8 20. Eble JN, Sauter G, Epstein JI, Sesterhenn IA. Pathology and Genetics of Tumors of the Urinary System and Male Genital Organs. Tumours of the Urinary System. 3rd ed. Lyon, France: IARC Press; 2004:90. World Health Organization Classification of Tumours; vol Edge SB, Byrd DR, Compton CC, et al. Renal pelvis and ureter. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer Publishing; 2010: Nielsen K, Ostri P. Primary tumors of the renal pelvis: evaluation of clinical and pathological features in a consecutive series of 10 years. J Urol. 1988;140(1): Browne RF, Meehan CP, Colville J, Power R, Torreggiani WC. Transitional cell carcinoma of the upper urinary tract: spectrum of imaging findings. Radiographics. 2005;25(6): Charbit L, Gendreau MC, Mee S, Cukier J. Tumors of the upper urinary tract: 10 years of experience. J Urol. 1991;146(5): CAP 13 Abstract Program Accepting Submissions Abstract and case study submissions will be accepted beginning Monday, February 4, 2013 for the College of American Pathologists (CAP) 2013 meeting. CAP 13 will be held October 13 through the 16th in Orlando, Florida. Submissions for the CAP 13 Abstract Program will be accepted through Monday, April 1, Accepted submissions will appear in the October 2013 issue of the Archives of Pathology & Laboratory Medicine. Visit the CAP 13 Website at for a link to the abstract submission site and additional abstract program information as it becomes available. Arch Pathol Lab Med Vol 137, March 2013 Ureteroscopic Biopsy for Urothelial Carcinoma Vashistha et al 407