Non-Invasive Urothelial Neoplasms: According to the Most Recent WHO Classification

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1 European Urology European Urology 46 (2004) Review Non-Invasive Urothelial Neoplasms: According to the Most Recent WHO Classification Antonio Lopez-Beltran a,1, Rodolfo Montironi b,* a Department of Pathology, Reina Sofia University Hospital and Cordoba University Medical School, Faculty of Medicine, Avda. Menendez Pidal S/N, Cordoba, Spain b Institute of Pathological Anatomy and Histopathology, Polytechnic University of the Marche Region (Ancona), School of Medicine, Azienda Ospedaliera Umberto I8, I Torrette, Ancona, Italy Accepted 19 March 2004 Available online 13 April 2004 Abstract The key points of the latest World Health Organization (WHO) classification of non-invasive urothelial tumors are: the description of the categories has been expanded in the current version to improve their recognition; one group (papillary urothelial neoplasm of low malignant potential) with particularly good prognosis does not carry the label of cancer ; it avoids use of ambiguous grading such as grade 1/2 or 2/3 (according to the WHO classification published in 1973, i.e., 1973 WHO classification); the group of non-invasive high grade carcinoma is large enough to contain virtually all those tumors that have biological properties (and a high level of genetic instability) similar to those seen in invasive urothelial carcinoma. This scheme is meant to replace the 1973 WHO classification. Changes in classification have their own inherent problems, tending to lead to confusion, at least for a period of time. From the practical point of view, the use of both the 1973 and the latest WHO classifications is recommended until the latter is sufficiently validated. # 2004 Elsevier B.V. All rights reserved. Keywords: Bladder cancer; Pathology; Genetics 1.Introduction From the morphological point of view, two basic diagnostic categories are identified on the basis of the pattern of growth of the intraepithelial lesions (flat and papillary), their clinical behavior being also related to the degree of architectural and cytological alteration of the urothelium [1]. Several classifications (including revisions and refinements) have been reported in the literature [2]. The latest World Health Organization classification of non-invasive urothelial tumors [3] is identical to The World Health Organization/ International Society of Urological Pathology Consensus Classification of 1998 (1998 WHO/ISUP * Corresponding author. Tel. þ ; Fax: þ addresses: em1lobea@uco.es (A. Lopez-Beltran), r.montironi@univpm.it (R. Montironi). 1 Co-corresponding author. Fax: þ classification). It is adopted in the book Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs, i.e., one of the Blue Books of the new series of World Health Organization Classification of Tumors. The contents of the book reflect the views of a Working Group made up of uropathologists that convened for an Editorial and Consensus Conference in Lyon, France, December 14 18, This review, based on presentations made in recent meetings, gives an overview on the latest WHO classification of non-invasive urothelial tumors. In this contribution it will be referred to as the 2004 WHO classification, based on the publication year (i.e., 2004) of the book. We are aware of the fact that others might refer or have referred to the year 2003 based of the original publication schedule of the book. Others have also used the acronym WHO(2003)/ISUP to indicate both the publication year schedule and /$ see front matter # 2004 Elsevier B.V. All rights reserved. doi: /j.eururo

2 A. Lopez-Beltran, R. Montironi / European Urology 46 (2004) the relationship of the current scheme to the 1998 WHO/ISUP classification. 2.Flat intraepithelial lesions The 2004 WHO classification of the flat lesions includes urothelial hyperplasia, reactive urothelial atypia, atypia of unknown significance, dysplasia and carcinoma in situ [3] (Table 1). This classification is very similar to that published recently by Lopez-Beltran et al. [4,5] Urothelial hyperplasia, reactive urothelial atypia and atypia of unknown significance Urothelial hyperplasia is defined as markedly thickened mucosa without cytological atypia. It may be seen adjacent to low grade urothelial papillary tumors. Within the spectrum of hyperplasia a papillary architecture may be present; most of these patients have concomitant papillary tumors [3,6]. When seen by itself, there is no evidence suggesting that it has a premalignant potential [5]. However, molecular analyses have shown that the lesion, at least in bladder cancer patients, may be clonally related to the papillary tumors [6]. Molecular alterations can also be seen in histologically normal appearing urothelium in bladders from cancer patients [7]. Reactive urothelial atypia has nuclear changes clearly ascribable to a reactive/regenerative process and occurs in acutely or chronically inflamed urothelium. Cells are uniformly enlarged with a single prominent nucleolus and evenly distributed vesicular chromatin. Mitotic activity may be brisk but without atypical forms. Inflammation may be present in the urothelium or in the subepithelial connective tissue (lamina propria). Atypia of unknown significance is a descriptive category (not adiagnostic entity) for cases in which the severity of reactive atypia appears out of proportion to the extent of inflammation such that dysplasia Table WHO classification of non-invasive urothelial neoplasia Hyperplasia (flat and papillary) Reactive atypia Atypia of unknown significance Urothelial dysplasia Urothelial carcinoma in situ Urothelial papilloma Urothelial papilloma, inverted type Papillary urothelial neoplasm of low malignant potential Non-invasive low grade papillary urothelial carcinoma Non-invasive high grade papillary urothelial carcinoma cannot be confidently excluded [3]. The use of the term atypia of unknown significance [8] was discouraged by Lopez-Beltran et al. [5] because it does not add any value in practice Urothelial dysplasia Dysplasia is an intra-urothelial lesion with appreciable cytologic and architectural changes felt to be preneoplastic but which fall short of carcinoma in situ (CIS). The morphology of dysplasia generally shows cohesive cells characterized by mild nuclear/nucleolar changes that focally include irregular nuclear crowding, and slight hyperchromasia. Nucleoli may be prominent and mitotic figures when present are generally basally located. The umbrella cells are usually present. Most cellular abnormalities in dysplasia are restricted to the basal and intermediate cell layers. There may be an increased number of cell layers. Nuclear and architectural features are considered most useful in distinguishing between reactive atypia and dysplasia [5]. Cytokeratin 20 may be of value in its recognition [9]. Alterations of p53 and allelic losses, particularly in chromosome 9, have been demonstrated to occur in dysplasia [9,10]. Dysplasia is most relevant in non-invasive papillary neoplasms, where its presence indicates urothelial instability and is a marker for recurrence or progression (true risk remains to be established). De novo dysplasia progresses to bladder neoplasia in 5 19% of cases [11] Urothelial carcinoma in situ CIS is a non-papillary, i.e. flat, lesion in which the surface epithelium contains cells that are cytologically malignant [4,5]. The morphological diagnosis of CIS requires the presence of severe cytological atypia (nuclear anaplasia). Full thickness-change is not essential, although it is usually present. Prominent disorganization of cells is characteristic, with loss of polarity and cohesiveness. The tumor cells tend to be large and pleomorphic, with moderate to abundant cytoplasm, although they are sometimes small with a high nucleus to cytoplasmic ratio. The chromatin tends to be coarse and clumped [4,5,12]. Nucleoli are usually large and prominent in at least some of the cells, and may be multiple. Mitotic figures are also seen also in the uppermost layers of the urothelium, and may be atypical [13,14]. Superficial (umbrella) cells may be present. Several patterns and/or variants have been described. Individual neoplastic cells may be seen scattered amidst normal urothelium (pagetoid pattern) [4,5]. Loss of intercellular cohesion of CIS may result in

3 172 A. Lopez-Beltran, R. Montironi / European Urology 46 (2004) the so-called denuding cystitis or in residual neoplastic cells attached to the surface ( clinging pattern). Small and large cells variants have been described. CIS cells may involve Von Brunn s nests and cystitis cystica. CIS may be focal or diffuse. Cytokeratin 20 is abnormally expressed in CIS. Abnormal expression of p53 and RB protein may correlate with progression of CIS or response to BCG therapy [9,15]. The nuclear matrix protein NMP22 is present. Cytogenetically CIS shows close similarities to invasive tumors [16,17]. Primary (de novo) CIS accounts for 1 3% of urothelial neoplasms and is most commonly seen in the bladder. The distal ureters are involved in 6 60%, the prostatic urethra in 20 67%, and the prostate ducts and acini in up to 40% [5]. CIS patients are usually in their fifties and present with irritative symptoms or hematuria; they may also be asymptomatic. At cystoscopy, the mucosa may be unremarkable or erythematous and edematous. Primary CIS is less likely to progress to invasive disease than secondary CIS [5]. Patients with CIS and concomitant invasive tumors die in 45 65% compared to 7 15% of patients with CIS and concomitant papillary tumor. CIS with multiple aneuploid cell lines appears to be at high risk of progression. Extensive lesions associated with marked symptoms have a guarded prognosis. 3.Non-invasive papillary urothelial lesions It distinguishes papilloma, inverted papilloma, papillary urothelial neoplasm of low malignant potential, as well as non-invasive low grade and high grade papillary urothelial carcinoma [8] (Table 1) Urothelial papilloma Urothelial papilloma is a benign exophytic neoplasia composed of a delicate fibrovascular core covered by normal looking urothelium [18]. The superficial cells are often prominent. Mitoses are absent to rare and, if present, are located in the basal cell layer. The stroma may show edema and/or inflammatory cells. Diffuse papillomatosis applies when the mucosa is extensively involved. Papillomas are diploid with low proliferation, uncommon p53 expression, and frequent (75%) FGFR3 mutation [19]. Cytokeratin 20 expression is limited to the superficial (umbrella) cells. The incidence is below 1% of all bladder tumors and the male-to-female ratio is 1.9:1 [18]. Hematuria is common. Most papillomas are single and occur in younger patients (mean age, 46 years), close to the ureteric orifices in most cases [18]. Urothelial papilloma may recur; however, it does not progress [1,3] Inverted papilloma Benign urothelial tumor that has an inverted growth pattern with normal to minimal cytologic atypia of the cells [20]. Most cases are solitary polypoid lesions, smaller than 3 cm, and arise in the bladder trigone but can also be found in ureter, renal pelvis or urethra [20]. At histology, inverted papilloma has a smooth surface covered by normal urothelium, and endophytic cords of urothelial cells invaginating extensively from the surface urothelium into the subadjacent lamina propria but not into the muscular bladder wall. Trabecular and glandular have been described. Foci of non-keratinizing squamous metaplasia and neuroendocrine differentiation have been reported. Focal minor cytological atypia may be present but mitotic figures are rare. Inverted papilloma may coexist with carcinoma [20]. The male:female ratio is 4 5:1. The age of the patients range from 10 to 94 years. Hematuria or obstructive symptoms are common symptoms. Recurrent lesions have been observed in less than 1% of cases [20] Papillary urothelial neoplasm of low malignant potential (PUNLMP) A non-invasive papillary urothelial tumor which resembles the exophytic urothelial papilloma but shows increased cellularity exceeding the thickness of normal urothelium [21,22]. At cystoscopy, most cases are solitary, 1 2 cm in diameter and located in the lateral or posterior wall, close to the ureteric orifices [22]. The papillae are slender without fusion and lined by multilayered urothelium with minimal to absent cytological atypia. The cell polarity is preserved and there is an impression of predominant order with minimal variation in the architecture. The nuclei are slightly enlarged. The basal layers may show palisading and the superficial cell layer is often preserved. Mitoses are rare and have a basal location. These architectural and cytological features should be evaluated in non-tangentially cut areas of the neoplasm. These tumors are predominantly diploid with low a proliferation rate, and FGFR3 mutation and allelic loss in 85% and 80% of cases, respectively [19,23,24]. Gross or microscopic hematuria is frequent [25]. The male:female ratio is 5:1 and the mean age at diagnosis is 65 years (range years) [21]. Tumor recurrence, stage progression and tumor-related mortality occur in approximately 35%, 4% and in less than 2% of

4 A. Lopez-Beltran, R. Montironi / European Urology 46 (2004) Table 2 Follow-up studies on papillary urothelial neoplasm of low malignant potential Reference N Tumor recurrence Stage progression Tumor related mortality [21] % 0.00% 0.00% [23] % 3.57% 2.67% [25] 50 60% 8.00% 0.00% [26] % 0.00% 0.00% [27] % NA NA [28] % 3.90% 3.90% [29] 29 NA 8.00% NA [30] % 2.58% 0.86% [31] % NA NA Mean percentage (range) (25 47) 3.72 (0 8) 1.23 (0 3.90) N: Number of cases; NA: Not available. patients, respectively (Table 2) [23,26 31]. 68% of patients that are tumor free at the first follow-up cystoscopy remain tumor free during a follow-up period of at least 5 years [22] Non-invasive low grade papillary urothelial carcinoma A neoplasm of urothelium lining papillary fronds which shows an orderly appearance, but easily recognizable variations in architecture and cytologic features [22,28]. At histology, the tumor shows slender papillae with frequent branching, minimal fusion and variations in nuclear polarity, size, shape, and chromatin pattern and with presence of nucleoli. Mitoses may occur at any level. Focal high grade areas may be present and in these cases the tumor should be classified as a high grade carcinoma. Altered expression of cytokeratin 20, CD44, p53 and p63 is frequent, some tumors being diploid [21,26,27]. The male:female ratio is 2.9:1 and the mean age is 70 years (range years) [30]. Most patients present with hematuria, have a single tumor in the posterior or lateral wall but 22% of them have two or more tumors [21,22]. Tumor recurrence, stage progression and tumor-related mortality is approximately 50%, 10% and 5%, respectively [26 28,30,31] (Table 3) Non-invasive high grade papillary urothelial carcinoma A neoplasm of urothelium lining papillary fronds which shows a predominant pattern of disorder with moderate-to-marked architectural and cytologic atypia. At histology, the papillae are frequently fused. It shows a predominant pattern of disorder with easily recognizable variations in architectural and cytologic features even at scanning power. The nuclei are often pleomorphic with prominent nucleoli and altered polarity. Mitoses are frequent. The thickness of the urothelium varies considerably. Within this category there is a spectrum of atypia, the highest of which show marked and diffuse nuclear pleomorphism (identical to that seen in Grade 3 (G3) tumors in the 1973 WHO classification) and pathologists have the option of recording the level of anaplasia in a comment [8]. Carcinoma in situ is frequent in the adjacent mucosa. Changes in cytokeratin 20, p53, p63 expression and aneuploidy are more frequent than in previous categories [32]. Molecular alterations in these tumors show a frequency of p53, HER2 or EGFR overexpression and p21 or p27 loss comparable to that seen in invasive cancers [16]. Genetically, high grade non-invasive lesions (pta G3) resemble invasively growing tumors. A comparative genomic hybridization-based study Table 3 Follow-up studies on non-invasive low grade papillary urothelial carcinoma Reference N Tumor recurrence Stage progression Tumor related mortality [26] % 10.50% 5.30% [27] % NA NA [28] % 11.60% NA [29] 29 NA 13.00% NA [30] % 3.53% 3.54% [31] % NA NA Mean percentage (range) ( ) 9.65 ( ) 4.42 ( ) N: Number of cases; NA: Not available.

5 174 A. Lopez-Beltran, R. Montironi / European Urology 46 (2004) showed deletions at 2q, 5q, 10q, and 18q as well as gains at 5p and 20q [16]. Hematuria is common and the endoscopic appearance varies from papillary to nodular/solid single or multiple tumors [16]. Progression in terms of stage and death due to disease can be observed in as many as 65% of patients [3]. 4.Genetics The genetic studies so far published have used tumors classified according to 1973 WHO scheme and further studies are needed to link available genetic information to the 2004 WHO classification [16]. Current data suggest two genetic subtypes/pathways that correspond to morphologically defined entities [15,16,33,34] (Fig. 1). The genetically stable category includes low grade non-invasive papillary tumors (pta, G1 and G2). The genetically unstable category contains high grade (including pta G3 and CIS) and invasively growing carcinomas (stage pt1 4). Noninvasive low grade bladder neoplasms have only few genomic alterations and are therefore viewed as genetically stable [33]. Invasively growing and high grade neoplasia appear to be genetically unstable and have several chromosomal aberrations. 5.Translation between 1973 and 2004 WHO systems Fig. 2. Relationship of 1973 WHO classification to 2004 WHO classification (1998 WHO/ISUP) of papillary urothelial tumors. Some controversies followed the introduction of the 1998 WHO/ISUP classification of bladder tumors [8,35,36], mainly because of lack of validation, reproducibility and translation studies. In particular, no sound translation scheme comparing the 1973 with the 1998 (and 2004) classifications has been put forward. Basically, grade 1 (G1) (WHO 1973 classification) tumors should be subdivided into PUNLMP and low grade carcinomas, whereas most grade 2 (G2) and all grade 3 (G3) cases are defined as high grade carcinomas, grade 2 tumors, whose morphology borders with that of grade 1, becoming low grade carcinomas [8] (Fig. 2). Some authors [35,36] think that 1998 WHO/ISUP proposal represents only a change in terminology and that PUNLMP should include all grade 1 carcinomas, and low grade and high grade carcinomas all grade 2 and all grade 3 lesions of the 1973 WHO classification, respectively. This approach corresponds to the proposal made in 1987 by Montironi et al. according to which non-invasive G1 papillary carcinoma shows morphometrically the architectural and cytological features of a dysplastic lesion rather than of a carcinoma [37]. This group of authors proposed the term of papillary dysplasia, which seems to be much better than PUNLMP. The 1973 WHO classification is still preferred by some authors [35] with minor modifications for international use to allow valid comparison of results between different clinical centers. This is due to the fact the WHO 1973 standard for classification and grading of bladder tumours is a robust clinically proven, widely-used, time-tested, and reasonably-reproducible method for pathologic reporting, and is recommended with minor modifications. 6.Controversies on the best contemporary classification Fig. 1. Current genetic data suggests two major subtypes/pathways of bladder urothelial tumors (See text). The WHO classification introduced in 1999 (WHO 1999 classification) scheme is almost identical to the

6 A. Lopez-Beltran, R. Montironi / European Urology 46 (2004) WHO/ISUP classification, the difference being that the former subdivides the low and high grade spectrum into three grades (grade I, II, and III) [38,39]. The topic of the best contemporary classification of the papillary neoplasia has been debated in several recent meetings, including the Ancona International Consultation on the Diagnosis of Non-Invasive Urothelial Neoplasms (May 11 12, 2001). The discussion was basically around the WHO 1973 scheme vs. the WHO/ ISUP 1998 (now the 2004 WHO classification) and WHO 1999 classifications. Full consensus on which classification should be used by practicing pathologists and followed by the urologists and oncologists was not reached. Drs Bostwick and Mikuz [35] represented the majority opinion: the WHO 1973 classification for papillary urothelial neoplasms was still superior to all existing alternatives (including WHO/ISUP 1998 and WHO 1999), although some refinement of diagnostic criteria would be useful. Drs C. Busch and F. Algaba [36] advocated the contemporary role of the WHO/ISUP 1998 and WHO 1999 classifications in the pathology and urology practice. From the practical point of view, the use of both the 1973 and 2004 WHO classifications is recommended until the latter is sufficiently validated [38]. 7.Conclusions The consistent use of the 2004 WHO classification of non-invasive urothelial tumors should result in the uniform diagnosis of tumors, stratified according to risk potential, and will facilitate comparative clinical studies, incorporation of molecular data and identification of aggressive, genetically unstable neoplasms. Molecular pathology could have a role in the further refinements of the classification system. Until the 2004 WHO system is fully validated from the clinical and prognostic point of view, tumor should be graded according to both the 2004 WHO scheme and the 1973 WHO system. Changes in classification have their own inherent problems, tending to lead to confusion, at least for a period of time. Acknowledgements This contribution has been supported by the Grant FIS03/0952 (Madrid, Spain) (ALB) and a grant from the Italian Ministry of University and Scientific Research (MIUR 2003) (RM). References [1] Montironi R, Lopez-Beltran A, Mazzucchelli R, Bostwick DG. Classification and grading of the non-invasive urothelial neoplasms: recent advances and controversies. J Clin Pathol 2003;56:91 5. [2] Montironi R, Scarpelli M, Mazzucchelli R, Hamilton PW, Thompson D, Ranger-Moore J, et al. Subvisual changes in chromatin organization state are detected by karyometry in the histologically normal urothelium in patients with synchronous papillary carcinoma. Hum Pathol 2003;34: [3] Sauter G, Algaba F, Amin M, Busch C, Cheville J, Gasser T, et al. Non-Invasive Urothelial Neoplasias. WHO Classification of Non Invasive Papillary Urothelial Tumors. In: Eble JN, Sauter G, Epstein JI, Sesterhenn I, editors. World Health Organization Classification of Tumors. Pathology and Genetics: Tumors of the Urinary System and Male Genital Organs. Lyon: IARCC Press; [4] Lopez-Beltran A, Luque RJ, Moreno A, Bollito E, Carmona E, Montironi R. The pagetoid variant of bladder urothelial carcinoma in situ A clinico-pathological study of 11 cases. Virchows Arch 2002; 441: [5] Lopez-Beltran A, Cheng L, Andersson L, Brausi M, de Matteis A, Montironi R, et al. Preneoplastic non-papillary lesions and conditions of the urinary bladder: an update based on the Ancona International Consultation. Virchows Arch 2002;440:3 11. [6] Hartmann A, Moser K, Kriegmair M, Hofstetter A, Hofstaedter F, Knuechel R. Frequent genetic alterations in simple urothelial hyperplasias of the bladder in patients with papillary urothelial carcinoma. Am J Pathol 1999;154: [7] Muto S, Horie S, Takahashi S, Tomita K, Kitamura T. Genetic and epigenetic alterations in normal bladder epithelium in patients with metachronous bladder cancer. Cancer Res 2000;60: [8] 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. Am J Surg Pathol 1998;22: [9] Harnden P, Eardley I, Joyce AD, Southgate J. Cytokeratin 20 as an objective marker of urothelial dysplasia. Br J Urol 1996;78: [10] Hartmann A, Schlake G, Zaak D, Hungerhuber E, Hofstetter A, Hofstaedter F, et al. Occurrence of chromosome 9 and p53 alterations in multifocal dysplasia and carcinoma in situ of human urinary bladder. Cancer Res 2002;62: [11] Cheng L, Cheville JC, Neumann RM, Bostwick DG. Natural history of urothelial dysplasia of the bladder. Am J Surg Pathol 1999; 23: [12] McKenney JK, Gomez JA, Desai S, Lee MW, Amin MB. Morphologic expressions of urothelial carcinoma in situ: a detailed evaluation of its histologic patterns with emphasis on carcinoma in situ with microinvasion. Am J Surg Pathol 2001;25: [13] Helpap B, Kollermann J. Assessment of basal cell status and proliferative patterns in flat and papillary urothelial lesions: a contribution to the new WHO classification of the urothelial tumors of the urinary bladder. Hum Pathol 2000;31: [14] Bostwick DG, Ramnani D, Cheng L. Diagnosis and grading of bladder cancer and associated lesions. Urol Clin North Am 1999;26: [15] Cordon-Cardo C, Cote RJ, Sauter G. Genetic and molecular markers of urothelial premalignancy and malignancy. Scand J Urol Nephrol Suppl 2000: [16] Waldman FM, Jones PA, Knowles MA, Sidransky D, Cordon-Cardo C, Simon R, et al. Molecular genetics of non invasive urothelial neoplasias. In: Eble JN, Sauter G, Epstein JI, Sesterhenn I, editors. World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of the Urinary System and Male Genital Organs. Lyon: IARCC Press; 2004.

7 176 A. Lopez-Beltran, R. Montironi / European Urology 46 (2004) [17] Stampfer DS, Carpinito GA, Rodriguez-Villanueva J, Willsey LW, Dinney CP, Grossman HB, et al. Evaluation of NMP22 in the detection of transitional cell carcinoma of the bladder. J Urol 1998; 159: [18] McKenney JK, Amin MB, Young RH. Urothelial (transitional cell) papilloma of the urinary bladder: a clinicopathologic study of 26 cases. Mod Pathol 2003;16: [19] van Rhijn BW, Montironi R, Zwarthoff EC, Jobsis AC, van der Kwast TH. Frequent FGFR3 mutations in urothelial papilloma. J Pathol 2002;198: [20] Sauter G. Inverted papilloma. WHO Classification of Non-invasive Papillary Urothelial Tumors. In: Eble JN, Sauter G, Epstein JI, Sesterhenn I, editors. World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of the Urinary System and Male Genital Organs. Lyon: IARCC Press; [21] Holmang 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;165:1124 8, discussion [22] Holmang S, Johansson SL. Stage Ta-T1 bladder cancer: the relationship between findings at first follow-up cystoscopy and subsequent recurrence and progression. J Urol 2002;167: [23] Cheng L, Neumann RM, Bostwick DG. Papillary urothelial neoplasms of low malignant potential. Clinical and biologic implications. Cancer 1999;86: [24] Cheng L, Zhang S, Ulbright T, Bostwick DG, MacLennan T, Eble J. Genetic analysis of papillary urothelial neoplasm of low malignant potential. Mod Pathol 2002;15:158A. [25] Fujii Y, Kawakami S, Koga F, Nemoto T, Kihara K. Long-term outcome of bladder papillary urothelial neoplasms of low malignant potential. BJU Int 2003;92: [26] Desai S, Lim SD, Jimenez RE, Chun T, Keane TE, McKenney JK, et al. Relationship of cytokeratin 20 and CD44 protein expression with WHO/ISUP grade in pta and pt1 papillary urothelial neoplasia. Mod Pathol 2000;13: [27] Alsheikh A, Mohamedali Z, Jones E, Masterson J, Gilks CB. Comparison of the WHO/ISUP classification and cytokeratin 20 expression in predicting the behavior of low-grade papillary urothelial tumors. World/Health Organization/International Society of Urologic Pathology. Mod Pathol 2001;14: [28] Alvarez Kindelan J, Lopez Beltran A, Anglada Curado F, Moreno Arcas P, Carazo JL, Regueiro Lopez JC, et al. Clinico-pathologic differences between bladder neoplasm with low malignant potential and low-grade carcinoma. Actas Urol Esp 2001;25: [29] 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: [30] 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: [31] 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 bladder. Am J Surg Pathol 2001;25: [32] Schmitz-Drager BJ, van Roeyen CR, Grimm MO, Gerharz CD, Decken K, Schulz WA, et al. P53 accumulation in precursor lesions and early stages of bladder cancer. World J Urol 1994;12: [33] Richter J, Jiang F, Gorog JP, Sartorius G, Egenter C, Gasser TC, et al. Marked genetic differences between stage pta and stage pt1 papillary bladder cancer detected by comparative genomic hybridization. Cancer Res 1997;57: [34] Richter J, Wagner U, Schraml P, Maurer R, Alund G, Knonagel H, et al. Chromosomal imbalances are associated with a high risk of progression in early invasive (pt1) urinary bladder cancer. Cancer Res 1999;59: [35] Bostwick DG, Mikuz G. Urothelial papillary (exophytic) neoplasms. Virchows Arch 2002;441: [36] Busch C, Algaba F. The WHO/ISUP 1998 and WHO 1999 systems for malignancy grading of bladder cancer. Scientific foundation and translation to one another and previous systems. Virchows Arch 2002;441: [37] Montironi R, Scarpelli M, Sisti S, et al. Quantitative analysis and malignancy progression of the papillary neoplasia of urinary bladder. Pathol Res Pract 1987;182: [38] Lopez-Beltran A, Bassi PF, Pavone-Macaluso M, Montironi R. Handling and pathology reporting of specimens with carcinoma of the urinary bladder, ureter, and renal pelvis. Eur Urol 2004;45: [39] Mostofi FK, Davis CJ, Sesterhenn IA. Histological typing of urinary bladder tumours. World Health Organization, International Histological Classification of Tumours, 2nd ed. Berlin: Springer-Verlag; 1999.