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Year : 2015  |  Volume : 58  |  Issue : 1  |  Page : 59-61
Study of the reproducibility of the 2004 World Health Organization classification of urothelial neoplasms

1 Department of Pathology, Melaka Manipal Medical College, Manipal University, Mangalore, Karnataka, India
2 Department of Pathology, Kasturba Medical College, Manipal University, Mangalore, Karnataka, India

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Date of Web Publication11-Feb-2015


The aim of the study was to evaluate urinary bladder biopsies showing papillary urothelial neoplastic lesions based on the 2004 WHO/ISUP classification of Urothelial Neoplasms of the Urinary Bladder, to assess the reproducibility of the bladder carcinoma grade. Fifty consecutive transurethral tumor resection biopsies were evaluated by four pathologists independently. The final diagnoses of each pathologist were subjected to statistical analysis to assess the degree of interobserver variability and reproducibility of this classification. Significant interobserver variation was found in the reporting of urothelial neoplasms. In 22 instances there was difference in opinion between PUNLMP and low-grade carcinoma, and in 59 instances between low and high grade carcinoma. The 4 observers never unanimously agreed on the diagnosis of PUNLMP.

Keywords: Histologic grading, urinary bladder, World Health Organization/International Society of Urological Pathology classification

How to cite this article:
Sharma P, Kini H, Pai RR, Sahu KK, Kini J. Study of the reproducibility of the 2004 World Health Organization classification of urothelial neoplasms. Indian J Pathol Microbiol 2015;58:59-61

How to cite this URL:
Sharma P, Kini H, Pai RR, Sahu KK, Kini J. Study of the reproducibility of the 2004 World Health Organization classification of urothelial neoplasms. Indian J Pathol Microbiol [serial online] 2015 [cited 2021 Jul 25];58:59-61. Available from: https://www.ijpmonline.org/text.asp?2015/58/1/59/151189

   Introduction Top

Noninvasive papillary urothelial neoplasms are the most common type of bladder tumors. For decades, the terminology applied to the various reactive, preneoplastic and neoplastic lesions of the urinary bladder have been confusing. Under-treatment or overtreatment could result from the actions based on the wording employed by a pathologist. In addition to the potential for problems with clinical management, disparity in the nomenclature of bladder lesions rendered inter-institutional research problematic, collection of accurate cancer statistics difficult, and caused difficulties in interpreting the urological literature at the local level. As the evidence mounted linking the grade of flat and papillary urothelial lesions with prognosis, it became apparent that a consensus classification scheme for the reactive, preneoplastic and neoplastic lesions of the bladder with easy reproducibility amongst pathologists, facilitating the use of a common nomenclature, was a necessity. [1]

   Subjects and Methods Top

In the present study, 50 consecutive cases received at the Department of Pathology, Kasturba Medical College, Mangalore, Karnataka, India were studied. The samples included transurethral tumor resections and bladder biopsies.

The World Health Organization (WHO)/International Society of Urological Pathology (ISUP) consensus 2004 classification of urothelial (transitional cell) neoplasms of the urinary bladder [2] was used to grade the papillary urothelial neoplasms [Table 1].
Table 1: Histologic criteria used in WHO/ISUP 1998 classification [2]

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These papillary urothelial neoplasms were evaluated by four pathologists independently. Each of the pathologists had at least 20 years of experience in histopathology reporting. All histopathologic slides of a particular case were supplied to each pathologist, along with educational material on the WHO/ISUP 2004 classification. Relevant patient history, ultrasonography and cystoscopy findings, along with urine analysis and cytology reports were also provided. Each pathologist evaluated every case based on the eight architectural and cytologic criteria as laid out in the WHO/ISUP 2004 classification. The independent final diagnoses of each pathologist were subjected to statistical analysis to assess the degree of interobserver variability and reproducibility of this classification.

   Results Top

Statistical analyses to assess interobserver/rater agreement in World Health Organization/International Society of Urological Pathology classification

Multiple comparisons by Wilcoxon test show that the difference is being observed with rater 2 in comparison with the others [Table 2]. From the table, we can understand that wherever observer 2 is being compared with the rest of the observers, P value is significant, that is, <0.005.
Table 2: Determination of Wilcoxon signed ranks test P value

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Calculation of intraclass correlation coefficient for all raters

Intraclass correlation coefficient (I.C.C) is 0.853 with the confidence interval 0.771-0.910, which is good agreement among all the 4 pathologists taken together.

When observer 1 and 2 are taken for assessing the level of agreement, I.C.C value is 0.710 with the confidence interval 0.478-0.837, which is again a good agreement between rater 1 and 2 [Table 3].
Table 3: Comparison of observer 1 and 2

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Alternatively, we can calculate the percentage of agreement between observer 1 and 2. Both the observers agree on 35 out of 50 diagnoses that is, they agree in 70% of the cases.

Similarly, the interobserver agreement is good when observers 2 and 3; 2 and 4; 3 and 1; 1 and 4; 3 and 4 are compared. The percentages of agreement between them are 64%, 72%, 78%, 80% and 72%, respectively.

[Table 4] shows that the 4 observers never unanimously agreed on the diagnosis of papillary urothelial neoplasm of low malignant potential (PUNLMP). In nine cases, all the observers agreed on the low-grade carcinoma and in 17 instances they concurred on the diagnosis of high-grade carcinoma. Similarly, 3 out of 4 pathologists also never concurred on the diagnosis of PUNLMP.
Table 4: Interobserver agreement between all 4 pathologists

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   Discussion Top

Currently, the recommended scheme is the WHO/ISUP 2004 classification for grading of bladder tumors.

Holmang et al.[3] found that sub-classification of WHO Grade I tumors into PUNLMP and low-grade carcinoma added valuable prognostic information. The recurrence rate was 35% in patients with PUNLMP compared with 71% in those with low-grade papillary urothelial carcinoma. None of the patients with PUNLMP had progression compared to 6 with low-grade papillary urothelial carcinoma.

On the other hand, Liu and Cheng, [4] held a different opinion that although PUNLMP was considered as low-grade urothelial tumor with a purported low incidence of recurrence and progression, the published rates were conflicting. The tumor recurrence rate after PUNLMP resection was reported to be 35% in the study by Holmang et al.[3] and 47% in the study by Pich et al.[5] With a median follow-up of 56 months, the WHO (1973) Grade I tumors had a progression rate of 11%, whereas the WHO (2004) PUNLMP had a progression rate of 8%. [6] Taken together, this data indicated that patients with PUNLMP do not have a benign neoplasm, but instead have a low, but significant risk of tumor recurrence and disease progression. At least, 80% of PUNLMP have allelic losses in putative tumor suppressor genes at multiple chromosome loci comparable to those found in urothelial carcinoma. Point mutations in the FGFR3 gene were found in 85% of PUNLMP tumors and in 88% of low-grade carcinoma. [4]

In our interobserver variation study, there was no concurrence among the 4 pathologists on the diagnosis of PUNLMP. It was observed that even 3 pathologists did not concur even once on the diagnosis of PUNLMP.

As in our case, despite provision of detailed histologic criteria for the diagnostic categories in the WHO (2004) system, improvement in intra and interobserver variability as compared with the WHO (1973) system has not been documented in the literature. Certain studies demonstrated that interobserver agreement was higher using the WHO (1973) than when using either the WHO (2004) or WHO/ISUP (1999) systems. [4] Murphy, Takezawa, and Maruniak recorded a 50% discrepancy rate among pathologists attempting to distinguish between PUNLMP and low-grade papillary urothelial carcinoma after a period of structured pathologist education. [7]

The 2004 WHO classification provides clearly defined histologic criteria for each of its diagnostic categories; however urothelial neoplasms frequently demonstrate features of more than one grade. In our study, we observed that some observers chose to grade a tumor based on predominant morphology. Hence, minor areas of high-grade morphology were ignored and the lesion was passed off as a low-grade tumor. The grading of papillary urothelial tumors, however, is typically based on the worst grade present. Cheng et al. as well as subsequent studies have suggested that a combined scoring system based on primary and secondary patterns of tumor growth like the Gleason scoring system of prostate may be a better prognostic indicator in the grading of bladder tumors. [6]

Additional difficulties in the interpretation of bladder tumors are posed due to errors resulting from thicker sections, improper orientation of transurethral resection of bladder tumour specimens, tangential cutting, and fixation artefacts.

The interobserver discrepancy in our study is certainly disturbing. Interobserver agreement among all the 4 observers was for low-grade carcinomas, and there was no agreement on PUNLMP. It was satisfactory only for high-grade carcinomas. This means whenever a pathologist has called a certain lesion as PUNLMP, the other 3 have never agreed and have reported it as low-grade carcinoma. Even 3 pathologists have never concurred on a diagnosis of PUNLMP.

   Conclusion Top

The results of this study showed significant interobserver differences in grading urothelial carcinoma, and this variability had strong implications for the patients. Before radical therapy is administered to the patient a consensus diagnosis (second and preferentially a third pathologist) of stage and grade should be made unless alternative, additional, and more accurate prognostic markers are available. However, obtaining multiple opinions might sometimes be practically difficult. In view of the intrinsic subjective problems with interpreting hematoxylin and eosin sections regarding invasion and grade, there is a strong need for new, easily reproducible prognostic indicators that are independent of stage and grade. [8]

   References Top

Cina JS, Milord RA, Epstein JI. An introduction to the WHO/ISUP consensus classification of the urothelial lesions of the urinary bladder. In: Foster CS, Ross JS, editors. Pathology of the urinary bladder - Major problems in pathology.1 st ed. Philadelphia: Saunders; 2004. p. 103-4.  Back to cited text no. 1
Montironi R, Lopez -Beltran A, Scarpelli M, Mazzucchelli R, Cheng L. Morphological classification and definition of benign, preneoplastic and noninvasive neoplastic lesions of the urinary bladder. Histopathology 2008;53:621-33.  Back to cited text no. 2
Holmang S, Hedelin H, Anderstrom C, Holmberg E, Busch C, Johannson SL. Recurrence and progression in low grade papillary urothelial tumors. J Urol 1999;162:702-7.  Back to cited text no. 3
Lina Liu, Liang Cheng. Grade 1 Urothelial Carcinoma versus PUNLMP Current Status. Pathology Case Reviews 2008;13;144-153.  Back to cited text no. 4
Pich A, Chiusa L, Formiconi A, Galliano D, Bortolin P, Navone R. Biologic differences between noninvasive papillary urothelial neoplasms of low malignant potential and low grade (grade 1) papillary carcinomas of the urinary bladder. Am J Surg Pathol 2001;25:1528-33.  Back to cited text no. 5
Cheng L, Lopez A-Beltran, Mac Lennan GT, Montironi R, Bostwick DG. Neoplasms of the urinary bladder. In: Bostwick DG, Cheng L, editors. Urologic surgical pathology,2 nd edition. St. Louis: Mosby;2008. p. 259-352.  Back to cited text no. 6
Murphy WM, Takezawa K, Maruniak NA. Interobserver discrepancy using the 1998 WHO/ISUP classification of urothelial neoplasms: Practical choices for patient care. J Urol 2002;168:968-72.   Back to cited text no. 7
Tosoni I, Wagner U, Sauter G, Egloff M, Knönagel H, Alund G et al. Clinical significance of interobserver differences in the staging and grading of superficial bladder cancer. Br J Urol 2000;85:48-53.  Back to cited text no. 8

Correspondence Address:
Dr. Pallavi Sharma
Department of Pathology, Melaka Manipal Medical College, Manipal - 576 104, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.151189

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  [Table 1], [Table 2], [Table 3], [Table 4]

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