2004 World Health Organization Classification of the Noninvasive Urothelial Neoplasms: Inherent Problems and Clinical Reflections

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european urology supplements 8 (2009) 453 457 available at www.sciencedirect.com journal homepage: www.europeanurology.

a, Roberta Mazzucchelli a, Liang Cheng c a Section of Pathological Anatomy, School of Medicine, Polytechnic University of the Marche Region (Ancona), Ancona, Italy b Unit of Anatomic Pathology,

1 european urology supplements 8 (2009) available at journal homepage: World Health Organization Classification of the Noninvasive Urothelial Neoplasms: Inherent Problems and Clinical Reflections Rodolfo Montironi a, *, Antonio Lopez-Beltran b, Marina Scarpelli a, Roberta Mazzucchelli a, Liang Cheng c a Section of Pathological Anatomy, School of Medicine, Polytechnic University of the Marche Region (Ancona), Ancona, Italy b Unit of Anatomic Pathology, Cordoba University Medical School, Cordoba, Spain c Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA Article info Keywords: Bladder neoplasms Urothelial dysplasia Carcinoma in situ Urothelial papillary carcinoma Abstract Introduction, evidence acquisition and evidence synthesis: The 2004 World Health Organization (WHO) classification of tumors of the urinary system (ie, 2004 WHO classification) subdivides the noninvasive urothelial neoplasms into three major groups flat, endophytic and papillary depending on the relationship with the surface of the surrounding urothelial mucosa. Each lesion of these three groups is defined with strict morphologic criteria to provide more accurate information to urologists and oncologists in managing patients. Conclusions: There still is debate in the literature as to whether the 2004 WHO classification should be the only one used and whether the 1973 WHO system should be abandoned. Reporting both grades has been recommended. # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Section of Pathological Anatomy and Histopathology, Polytechnic University of the Marche Region (Ancona), School of Medicine, United Hospitals, I Torrette, Ancona, Italy. Fax: address: r.montironi@univpm.it (R. Montironi). 1. Introduction For more than 2 decades, the 1973 World Health Organization (WHO) classification of the urothelial neoplasms [1] has dominated. In the early 1990s, several factors emerged that resulted in the need to reevaluate this approach. 2. Evidence acquisition In 1998, a system of classifying noninvasive flat and papillary urothelial neoplasms of the urinary bladder was proposed by the International Society of Urologic Pathology (ISUP) in association with the WHO [2]; this system became known as the /$ see front matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eursup

454 european urology supplements 8 (2009) 453 457 Fig. 1 (a) Urothelial carcinoma in situ; (b) urothelial carcinoma with endophytic growth pattern; (c) noninvasive urothelial papillary carcinoma.

2 454 european urology supplements 8 (2009) Fig. 1 (a) Urothelial carcinoma in situ; (b) urothelial carcinoma with endophytic growth pattern; (c) noninvasive urothelial papillary carcinoma. ISUP/WHO classification system. In 2004, this classification system was adopted in Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs, one of a series of WHO Blue Books for the classification of tumors [3]; this version is known as the 2004 WHO classification. 3. Evidence synthesis 3.1. Subgroups of the 2004 WHO classification The classification of the noninvasive urothelial neoplasms is subdivided into three major subgroups flat, endophytic and papillary depending on the relationship with the surface of the surrounding urothelial mucosa [4] Flat lesions The flat lesions without cytologic atypia include flat hyperplasia, whereas those with cytological atypia include reactive (inflammatory) atypia, atypia of unknown significance, urothelial dysplasia, urothelial carcinoma in situ (CIS), and CIS with microinvasion (CISmic). The morphology and clinical significance of the flat lesions have been reviewed extensively in recent publications [4,5]. In this paper, we focus on urothelial dysplasia and CIS. Overall, the features of urothelial dysplasia are those of a neoplastic atypia but fall short of the criteria for CIS outlined below. There is some evidence, largely genetic, that dysplasia shares some abnormalities with CIS and, therefore, likely represents a precursor lesion; one study that applied the 1998 ISUP/WHO criteria indicated a 19% risk of developing cancer, with a mean follow-up of 4.9 yr [6]. The category of CIS includes lesions that were graded in the severe dysplasia category in previous systems (Fig. 1a). CIS is accepted as a direct precursor of invasive carcinoma. The development of invasion is seen in the follow-up in 20 30% of cases. CISmic of the urinary bladder is a clinically relevant lesion: 34% of totally embedded cystectomy specimens that contained extensive CIS (ie, involving at least 25% of the bladder) were found to contain microinvasion, and 5.8% of patients had lymph node metastases and died of disease [7,8] Endophytic urothelial lesions A series of urothelial lesions ranging from hyperplasia to carcinoma can have an exclusively endophytic pattern of growth, thus causing problems in differential diagnosis and evaluation of invasion. Similarly to the flat and exophytic lesions, the endophytic changes can be without atypia (von Brunn s nests and cystitis cystica and inverted urothelial papilloma) and with atypia (endophytic growth patterns in urothelial carcinoma) (Fig. 1b) [4]. The endophytic growth patterns in urothelial carcinoma have been dealt with by Amin and colleagues [9] and by Montironi et al [4] Papillary lesions Histologic grading is one of the most important prognostic factors in bladder cancer. The first widely accepted grading system for papillary urothelial neoplasms was the 1973 WHO classification system, which divided urothelial papillary tumors into four categories: papilloma, grade 1 carcinoma, grade 2 carcinoma, and grade 3 carcinoma [1]. Histologic grading is based on the degree of anaplasia. Grade 1 tumors have the least degree of anaplasia compatible with a diagnosis of malignancy, grade 3 tumors have the most severe degree of anaplasia, and grade 2 tumors have an intermediate degree of anaplasia. Anaplasia is defined by the authors of the 1973 WHO classification as increased cellularity, nuclear crowding, disturbed cellular polarity, failure of differentiation from the base to the surface, nuclear polymorphism, irregular cell size, variations in nuclear shape and chromatin pattern, displaced or abnormal mitotic figures, and giant cells [1].

3 european urology supplements 8 (2009) The 1973 WHO histologic grading of bladder cancer is one of most successful grading systems among all organ sites and has been validated since its introduction 3 decades ago. It has been accepted by pathologists, urologists, oncologists, and cancer registrars in Europe and elsewhere. An enormous amount of data have been accumulated using this system in studies of the morphologic properties, clinical behavior, treatment, and follow-up of urothelial tumors. Because of its relative simplicity and its well-documented powerful predictive value, it has been well accepted by urologists and used globally for several decades in making clinical decisions for management of patients with urothelial cancer Histologic grading according to the 2004 WHO classification According to proponents, the following factors are key points of the 2004 WHO classification of the noninvasive urothelial tumors [3]: The description of the categories has been expanded to improve recognition; one group (papillary urothelial neoplasm of low malignant potential [PUNLMP]) with particularly good prognosis does not carry the label of cancer. It avoids the use of ambiguous grading, such as grade 1/2 or 2/3. The group of noninvasive high-grade carcinoma is large enough to contain virtually all of those tumors that have biologic properties (and a high level of genetic instability) similar to those seen in invasive urothelial carcinoma Papillary urothelial neoplasm of low malignant potential Morphologically, PUNLMP largely, though not completely, corresponds with grade 1 papillary carcinoma in the old WHO system. These tumors have a significantly lower rate of recurrence than either low- or high-grade papillary carcinomas and have a very low rate of grade and stage progression [10 17]. In a review of published studies, Lopez-Beltran and Montironi [18] found the mean tumor recurrence rate to be 36% and the mean stage progression rate to be 3.7% Papillary urothelial carcinoma, low grade In the 1973 WHO system, this classification would include the lower half of grade 2 papillary carcinoma. These tumors have a significantly higher recurrence rate than PUNLMP and a similar rate to high-grade papillary carcinomas. They also have a significantly higher rate of stage progression than PUNLMP but a significantly lower rate than highgrade papillary carcinoma [10,15 17]. A review of the literature revealed a mean recurrence rate of 50% and a mean stage progression rate of 10% [18] Papillary urothelial carcinoma, high grade This category contains grade 3 and the upper half of grade 2 papillary carcinoma based on the 1973 WHO system (Fig. 1c). These tumors not only have a risk of invasion but have a significant risk of recurrence and progression. The overall progression rate (to invasive carcinoma) ranges from 15% to 40% [19,20]. These tumors, when noninvasive (pta), likely all require additional intravesical therapy. Heterogeneity of grade is recognized in papillary lesions [21], and the consensus is that tumors should be graded on the worst part Relation of 1973 and 2004 WHO classifications A major misconception is that there is a one-to-one translation between the 1973 and 2004 WHO classifications. Only at the extremes of grades in the 1973 WHO classification does this correlation hold true [4,22]. Lesions called papilloma in the 1973 WHO classification system would also be called papilloma in the 2004 WHO system. At the other end of the grading extreme, lesions called WHO grade 3 are, by definition, high-grade carcinoma in the 2004 WHO system; however, for WHO grades 1 and 2, there is no direct translation to the 2004 WHO system. Some lesions that are classified as WHO grade 1 in the 1973 system and that show, on review, no cytologic atypia, some nuclear enlargement, and merely thickened urothelium are PUNLMP in the 2004 WHO system. Yet other WHO grade 1 lesions that show slight cytologic atypia and mitoses are diagnosed in the 2004 WHO classification as low-grade papillary urothelial carcinomas. WHO grade 2 is a very broad category. It includes lesions that are relatively bland, which in some places are diagnosed as WHO grade 1/2; in the 2004 WHO classification, these lesions would be called low-grade papillary urothelial carcinoma. In other cases, WHO grade 2 lesions border on higher grade lesions, which in many institutions are called WHO grade 2/3; in the 2004 WHO classification, these lesions would be called high-grade papillary urothelial carcinoma [4,22] Has the 2004 WHO classification system facilitated changes in clinical management of papillary urothelial neoplasms? In the past few decades, it has been and still is well understood by most practicing urologists and

4 456 european urology supplements 8 (2009) oncologists that noninvasive papillary urothelial tumors of all 1973 WHO grades require follow-up to detect recurrence or progression, despite the fact that grade 1 tumors are characteristically associated with an excellent prognosis. The length of clinical follow-up, the frequency of surveillance cystoscopy, and the adjunctive use of intravesical instillations of bacillus Calmette-Guérin (BCG) or a variety of chemotherapeutic agents are influenced by many factors, including histologic grade, tumor size, tumor multiplicity, depth of tumor invasion, recurrence history, and apparent grade migration with recurrence. Currently, both in North America and Europe, there is no uniformity in the clinical management of patients with noninvasive papillary urothelial tumors diagnosed according to the 2004 WHO grading system. Patients with PUNLMP and noninvasive lowgrade carcinoma are typically treated by transurethral resection of their tumors and are subsequently monitored for recurrence or progression by regular cystoscopy. Low-grade noninvasive carcinoma was found to have a significantly higher progression rate than PUNLMP in the study by Samaratunga et al (8% for PUNLMP vs 13% for low-grade noninvasive urothelial carcinoma) [23]; however, the reported high incidences of recurrence (up to 60%) [24] and progression (up to 8%) [23,24] for PUNLMP suggest that it is prudent to follow patients with a diagnosis of PUNLMP in an identical manner to patients with a diagnosis of low-grade noninvasive carcinoma [14]. Indeed, investigators studying the recurrence and progression rate of PUNLMP have recommended long-term clinical follow-up for patients with these lesions [12,16,23 25]. To our knowledge, there has not been a published recommended surveillance protocol for PUNLMP tumors that differs significantly from the standard surveillance for low-grade noninvasive urothelial carcinomas. In terms of clinical management of patients with noninvasive papillary urothelial neoplasms, those who are charged with following these lesions appear to have gained minimal benefit from the new grading system in terms of surveillance or intravesical therapy protocols [26]. 4. Conclusions There is still debate as to whether the 2004 WHO classification should be the only one used. We do not know of any published recommendations for following noninvasive urothelial tumors diagnosed according to the 2004 WHO grading system or for the use of intravesical therapy that vary significantly from the traditions long established for following comparable lesions diagnosed according to the 1973 WHO grading system. Conflicts of interest The authors have nothing to disclose. Funding support None. References [1] Mostofi FK, Sobin LH. Histologic typing of urinary bladder tumors. Geneva, Switzerland: World Health Organization; [2] Epstein JI, Amin MB, Reuter VR, Mostofi FK. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol 1998;22: [3] Sauter G, Algaba F, Amin MB, et al. Non-invasive urothelial tumours. In: Eble JN, Sauter G, Epstein JI, Sesterhenn IA, editors. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Urinary System and Male Genital Organ. Lyon, France: IARC Press; p [4] Montironi R, Mazzucchelli R, Scarpelli M, Lopez-Beltran A, Cheng L. Morphological diagnosis of urothelial neoplasms. J Clin Pathol 2008;61:3 10. [5] Montironi R, Lopez-Beltran A, Scarpelli M, Mazzucchelli R, Cheng L. Morphological classification and definition of the benign, preneoplastic and non-invasive neoplastic lesions of the urinary bladder. Histopathology 2008;53: [6] Cheng L, Cheville JC, Neumann RM, Bostwick DG. Natural history of urothelial dysplasia of the bladder. Am J Surg Pathol 1999;23: [7] Farrow GM, Utz DC. Observations on microinvasive transitional cell carcinoma of the urinary bladder. Clin Oncol 1982;1: [8] Farrow GM, Utz DC, Rife CC, Greene LF. Clinical observations on sixty-nine cases of in situ carcinoma of the urinary bladder. Cancer Res 1977;37: [9] Amin MB, Gómez JA, Young RH. Urothelial transitional cell carcinoma with endophytic growth patterns: a discussion of patterns of invasion and problems associated with assessment of invasion in 18 cases. Am J Surg Pathol 1997;21: [10] Alvarez Kindelán J, López Beltrán A, Anglada Curado F, et al. Clinico-pathologic differences between bladder neoplasm with low malignant potential and low-grade carcinoma. Actas Urol Esp 2001;25:

5 european urology supplements 8 (2009) [11] Campbell PA, Conrad RJ, Campbell CM, Nicol DL, MacTaggart P. Papillary urothelial neoplasm of low malignant potential: reliability of diagnosis and outcome. BJU Int 2004;93: [12] Cheng L, Neumann RM, Bostwick DG. Papillary urothelial neoplasms of low malignant potential. Clinical and biologic implications. Cancer 1999;86: [13] Holmäng S, Andius P, Hedelin H, Wester K, Busch C, Johansson SL. Stage progression in Ta papillary urothelial tumors: relationship to grade, immunohistochemical expression of tumor markers, mitotic frequency and DNA ploidy. J Urol 2001;165: [14] Jones TD, Cheng L. Papillary urothelial neoplasms of low malignant potential: evolving terminology and concepts. J Urol 2006;175: [15] Malmström PU, Busch C, Norlén BJ. Recurrence, progression and survival in bladder cancer. A retrospective analysis of 232 patients with greater than or equal to 5-year follow-up. Scand J Urol Nephrol 1987;21: [16] Oosterhuis JW, Schapers RF, Janssen-Heijnen ML, Pauwels RP, Newling DW, ten Kate F. Histological grading of papillary urothelial carcinoma of the bladder: prognostic value of the 1998 WHO/ISUP classification system and comparison with conventional grading systems. J Clin Pathol 2002;55: [17] Yin H, Leong AS. Histologic grading of noninvasive papillary urothelial tumors: validation of the 1998 WHO/ISUP system by immunophenotyping and follow-up. Am J Clin Pathol 2004;121: [18] Lopez-Beltran A, Montironi R. Non-invasive urothelial neoplasms: according to the most recent WHO classification. Eur Urol 2004;46: [19] Herr HW. Tumor progression and survival of patients with high grade, noninvasive papillary (TaG3) bladder tumors: 15-year outcome. J Urol 2000;163:60 1. [20] Saika T, Tsushima T, Nasu Y, et al. Clinical study of G3 superficial bladder cancer without concomitant CIS treated with conservative therapy. Jpn J Clin Oncol 2002; 32: [21] Cheng L, Neumann RM, Nehra A, Spotts BE, Weaver AL, Bostwick DG. Cancer heterogeneity and its biologic implications in the grading of urothelial carcinoma. Cancer 2000;88: [22] Montironi R, Lopez-Beltran A. The 2004 WHO classification of bladder tumors: a summary and commentary. Int J Surg Pathol 2005;13: [23] Samaratunga H, Makarov DV, Epstein JI. Comparison of WHO/ISUP and WHO classification of noninvasive papillary urothelial neoplasms for risk of progression. Urology 2002;60: [24] Fujii Y, Kawakami S, Koga F, Nemoto T, Kihara K. Longterm outcome of bladder papillary urothelial neoplasms of low malignant potential. BJU Int 2003;92: [25] Holmäng S, Hedelin H, Anderström C, Holmberg E, Busch C, Johansson SL. Recurrence and progression in low grade papillary urothelial tumors. J Urol 1999;162: [26] MacLennan GT, Kirkali Z, Cheng L. Histologic grading of noninvasive papillary urothelial neoplasms. Eur Urol 2007;51:

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