Inverted (Endophytic) Noninvasive Lesions and Neoplasms of the Urothelium: The Cinderella Group Has Yet to Be Fully Exploited

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EUROPEAN UROLOGY 59 (2011) 225 230 available at www.sciencedirect.com journal homepage: www.europeanurology.

Lopez-Beltran c, Marina Scarpelli a, Roberta Mazzucchelli a, Gregor Mikuz d, Ziya Kirkali e, Francesco Montorsi f a Section of Pathological Anatomy, Polytechnic University of the Marche Region,

1 EUROPEAN UROLOGY 59 (2011) available at journal homepage: Editorial Inverted (Endophytic) Noninvasive Lesions and Neoplasms of the Urothelium: The Cinderella Group Has Yet to Be Fully Exploited Rodolfo Montironi a, *, Liang Cheng b, Antonio Lopez-Beltran c, Marina Scarpelli a, Roberta Mazzucchelli a, Gregor Mikuz d, Ziya Kirkali e, Francesco Montorsi f a Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy b Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA c Department of Pathology, Reina Sofia University Hospital and Faculty of Medicine, Cordoba, Spain d Department of Pathology, University of Innsbruck School of Medicine, Innsbruck, Austria e Department of Urology, School of Medicine, Dokuz Eylül University, Izmir, Turkey f Department of Urology, University Vita-Salute San Raffaele, Scientific Institute H. San Raffaele, Milan, Italy 1. Introduction Noninvasive urothelial lesions and neoplasms can be flat (planophytic), papillary (exophytic), and inverted (endophytic), depending on their growth-pattern relationship with the surface of the surrounding urothelial mucosa [1]. Extensive clinicopathologic studies have been published related to the first two growth patterns. The clinical significance of the third has been dealt with in only a very limited extent. This is related to the fact that classification and terminology for the inverted lesions and neoplasms, consistent with those of the flat and papillary counterparts, are still lacking in the literature. 2. Flat (planophytic) lesions and neoplasms The 2004 World Health Organization (WHO) classification of the flat lesions includes flat hyperplasia (Fig. 1A and B), dysplasia, and carcinoma in situ (CIS). In addition, this classification also lists reactive atypia, secondary to inflammation, and atypia of unknown significance. 3. Flat urothelial hyperplasia Urothelial hyperplasia is characterized by markedly thickened urothelium with an increase in the number of cell layers, usually 10. The cells do not show cytologic abnormalities, although slight nuclear enlargement may be focally present. Morphologic evidence of maturation from base to surface is evident. Mitoses are absent. It has been described in association with inflammatory disorders as well as adjacent to low-grade papillary tumors [2]. Molecular analyses have shown that this lesion may be clonally related to the papillary tumors in bladder cancer patients and suggest a role in the pathogenesis of low-grade papillary urothelial carcinoma [3,4]. 4. Urothelial dysplasia Urothelial dysplasia is characterized by architectural distortion and a variable degree of atypia. The thickness is usually normal, and cytologic changes are restricted to the intermediate and basal cells. The nuclei are irregularly enlarged with loss of polarity and pleomorphism. Mitotic activity is scant, usually involving only the basal and intermediate cell layers. The features are those of a neoplastic atypia but fall short of the criteria for CIS. There is some evidence, largely genetic, that dysplasia shares some abnormalities with CIS and therefore likely represents a precursor lesion. One study indicates a 19% risk of developing cancer, with a mean follow-up of 4.9 yr [5]. 5. Urothelial carcinoma in situ CIS is characterized by architectural disorder and nuclear pleomorphism. There is loss of nuclear polarity, and the * Corresponding author. Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Via Conca 71, I Torrette, Ancona, Italy. address: r.montironi@univpm.it (R. Montironi) /$ see back matter # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

226 [()TD$FIG] EUROPEAN UROLOGY 59 (2011) 225 230 Fig.

2 226 [()TD$FIG] EUROPEAN UROLOGY 59 (2011) Fig. 1 Examples of a flat neoplasm (A: whole mount section of a bladder with a preoperative diagnosis of muscle invasive high-grade papillary carcinoma; B: urothelial dysplasia, from the specimen shown in Fig. 1A), a papillary neoplasm (C: the neoplasm grows exophytically into the lumen of the urinary system with a papillary configuration; D: low-grade papillary carcinoma, from the specimen shown in Fig. 1C), and an inverted neoplasm (E: the neoplasm, even though a polypoid appearance, is characterized by an epithelium that shows a noninfiltrative growth into the subepithelial connective tissue; F: Low-grade inverted urothelial carcinoma, from the specimen shown in Fig. 1E).

3 EUROPEAN UROLOGY 59 (2011) cells show a high degree of atypia. Mitoses are generally frequent and may be seen at any level of the epithelium. Because the histologic criteria for distinguishing severe dysplasia from CIS are unreliable, it is recommended that they be combined into a single category, namely, CIS. The development of invasion is seen in 20 30% of the cases [6 11]. CIS with microinvasion (CISmic) of the urinary bladder is defined by invasion into the lamina propria to a depth of 5 mm from the basement membrane or, according to Lopez-Beltran et al, should not exceed 20 cells in the subepithelial connective tissue [12,13]. CISmic is a clinically relevant lesion, and 34% of totally embedded cystectomy specimens that contain extensive CIS (ie, involving at least 25% of the bladder) are found to contain microinvasion; 5.8% of patients have lymph node metastases and die of disease. 6. Papillary (exophytic) lesions and neoplasms The lesions and neoplasms of this group grow exophytically into the lumen of the urinary system with a papillary configuration (Fig. 1C). According to the 2004 WHO classification, this group includes urothelial papilloma, papillary urothelial hyperplasia, papillary urothelial neoplasm of low malignant potential (PUNLMP), low-grade papillary carcinoma, and high-grade papillary carcinoma. Urothelial papilloma is characterized by a few fine papillary fronds lined by normal urothelium and shows a very low recurrence rate. Papillary urothelial hyperplasia is defined as undulating urothelium arranged into thin mucosal papillary folds of varying heights occurring in a noninflamed setting [14]. The lack of cytologic atypia and fibrovascular cores characterize this lesion. Papillary urothelial hyperplasia appears to be a precursor lesion to papillary urothelial neoplasms, predominantly lower grade lesions [15]. PUNLMP, low-grade papillary carcinoma, and high-grade papillary carcinoma show a morphologic spectrum with similarities with flat hyperplasia, dysplasia, and CIS, respectively. 7. Papillary urothelial neoplasm of low malignant potential PUNLMP largely, though not completely, corresponds to grade 1 papillary carcinoma of the 1973 WHO system. The lesion consists of delicate papillae with little or no fusion. The covering urothelium shows minimal architectural irregularity. Nuclei lack significant nuclear hyperchromasia or pleomorphism. The chromatin is fine, and nucleoli are inconspicuous. Mitoses are infrequent and basally located. This tumor has a significantly lower rate of recurrence than either low- or high-grade papillary carcinomas and a very low rate of grade and stage progression. A review of published studies shows a mean tumor recurrence rate of 36% and a stage progression rate of 3.7% [4]. 8. Low-grade papillary carcinoma The majority of cases would have been considered as grade 2 in the 1973 WHO system. WHO grade 1 neoplasms showing slight cytologic atypia and mitoses are diagnosed in the 2004 WHO system as low-grade papillary urothelial carcinomas. At low magnification, there is a generally ordered appearance of the cells within the epithelium. The nuclei tend to be uniformly enlarged but retain the elongated to oval shape of normal urothelial cells. The chromatin remains fine with small nucleoli. Mitoses may be present but are few and remain basally located (Fig. 1D). These tumors have a significantly higher recurrence rate than PUNLMP. They also have a rate of stage progression that is significantly higher than PUNLMP but significantly lower than high-grade papillary carcinoma. A review of the literature reveals a mean recurrence rate of 50% and a mean stage progression rate of 10%. 9. High-grade papillary carcinoma High-grade papillary carcinoma corresponds to grade 3 papillary carcinoma in the 1973 WHO system. It includes WHO grade 2 lesions bordering on higher grade lesions, which in many institutions are called WHO grade 2 3. Individual cells are haphazardly arranged within the epithelium and generally lack cohesion. Nuclei are hyperchromatic and pleomorphic. The chromatin is dense, irregularly distributed, and often clumped. Nucleoli may be single or multiple and are often prominent. Mitoses are generally frequent and may be seen at any level of the epithelium. It is often associated with invasive disease at the time of diagnosis [16 23]. These tumors have not only a risk of invasion but also a significant risk of recurrence and progression. The overall progression rate (to invasive carcinoma) ranges from 15% to 40%. 10. Inverted (endophytic) lesions and neoplasms The lesions and neoplasms of this group are basically characterized by an epithelium that shows noninfiltrative growth into the subepithelial connective tissue, even though cystoscopically they might show a polypoid appearance (Fig. 1E). Von Brunn s nests and cystitis cystica and glandularis are the benign prototypes of inverted (endophytic) lesions. Von Brunn s nests refer to small groups of basal-like cells lying in the subepithelial connective tissue and attached the basal cell layer of the urothelium. Cystitis glandularis is composed of glands in the lamina propria that are lined by cuboidal or columnar cells surrounded by urothelial cells. Cystitis cystica is composed of cystically dilated von Brunn s nests acquiring a luminal space. Inverted urothelial papilloma, included in the 2004 WHO classification, shows a polypoid appearance and consists of thin anastomosing trabeculae of urothelial cells within the subepithelial connective tissue and covered by a normal or attenuated urothelium [24 26]. There is no nuclear

4 228 EUROPEAN UROLOGY 59 (2011) Table 1 Morphologic, immunologic, and molecular genetic features of inverted urothelial papilloma and urothelial carcinoma with inverted pattern Characteristic Inverted urothelial papilloma Urothelial carcinoma with inverted growth Surface Smooth, domed shaped, usually Usually exophytic papillary lesions present intact cytologically normal Growth pattern Endophytic, expansive, sharply Endophytic, lesional circumscription variable delineated, anastomosing cords and trabeculae Cytologic features Orderly polarized cells, some with Variable, nuclear pleomorphism and atypia present spindling and palisading at the periphery; no significant atypia, mitoses rare Immunohistochemistry Low p53 expression and Variable, usually high p53 and Ki-67 proliferation index Ki-67 proliferation index Molecular analysis Rare deletions at chromosome Frequent FGFR3 mutation, chromosome 9 and 17 deletions 9 or 17, rare FGFR3 mutations, low rate of LOH Biological potential Benign, rare recurrences * Recurrences and progression may occur LOH = loss of heterozygosity. * Rare recurrences related to incomplete excision Table 2 Urothelial carcinoma with inverted pattern: criteria for invasion Features Noninvasive Invasive Contours of neoplastic nests/cords Regular Irregular Size and shape of nests Similar, rounded edges Variable, irregular, and jagged edges Inflammatory and desmoplastic stroma Absent Present pleomorphism, and few mitoses can be seen. Inverted papilloma is associated with a low risk of recurrence (< 5%). Cases of synchronous inverted papilloma and papillary carcinoma are known. Reports of a noninvasive urothelial carcinoma with inverted growth pattern are found in the literature and mentioned in some recent books [2,27 29]. The endophytic growth pattern in this carcinoma has been described either as interanastomosing cords and columns of urothelium, often with a striking resemblance to inverted papilloma (inverted papilloma-like pattern), or as broad, pushing bulbous invaginations into the lamina propria (broad-front pattern) (Table 1). A diagnosis of invasion requires the unquestionable presence within the lamina propria of irregularly shaped nests or single cells that may have evoked a desmoplastic or inflammatory response. When a stromal response is absent, irregularity of the contours of the invasive nests, architectural complexity, and recognition of single-cell invasion are helpful (Table 2). 11. Morphologic spectrum of the noninvasive urothelial neoplasms with an inverted growth pattern to cutaneous and mucosal verrucous carcinoma and reminiscent of the growth pattern of the von Brunn s nests. The downward projection can be so pronounced that the base of the tumor lies on the muscularis propria. There is a wide range in the severity of cytologic atypia, such as nuclear pleomorphism, irregularities of nuclear borders and chromatin distribution, prominent nucleoli, and mitotic rate [30]. When diagnosing inverted urothelial neoplasms, pathologists have used a variety of terms, including inverted urothelial papilloma, inverted urothelial papilloma with atypia [30], inverted growth pattern of PUNLMP, and urothelial carcinoma with an inverted growth pattern, without any further specification to the degree of cellular anaplasia or even as invasive urothelial carcinoma [30]. Similar to the flat neoplasms, the overall cytologic changes range from hyperplasia to CIS. Similar to the papillary neoplasms and in agreement with the approach used in two books published very recently [30,31], three subgroups could be defined in such range: neoplasms that have the least degree of cytologic atypia, neoplasms with the most severe degrees of cytologic atypia, and those that lie in between: Morphologically the urothelial neoplasms with an inverted growth pattern (other than inverted urothelial papilloma) show a spectrum of architectural and cytologic features. In comparison with inverted urothelial papilloma, the architectural features favoring a diagnosis of a urothelial neoplasm with an inverted growth pattern include thick columns with irregularity in their width and transition into more solid areas. The characteristic orderly maturation, spindling, and peripheral palisading seen in inverted papilloma are generally absent or inconspicuous. The histologic appearance of urothelial neoplasms with a broad-front pattern is the pushing broad-front extension into the lamina propria, akin Inverted urothelial neoplasm of low malignant potential (IUNLMP) Low-grade inverted urothelial carcinoma (Fig. 1F) High-grade inverted urothelial carcinoma. 12. Conclusions The evaluation of the urothelial lesions and neoplasms with an inverted or endophytic growth pattern shows a morphologic spectrum similar to that seen in the flat and papillary counterparts (Table 3). This is not fully recognized in the current literature, in which, besides inverted

5 EUROPEAN UROLOGY 59 (2011) Table 3 Proposed subgrouping of the noninvasive urothelial neoplasms Group No 1., Flat Urothelial hyperplasia Urothelial dysplasia Urothelial carcinoma in situ Group No 2., Papillary Papillary urothelial neoplasm Low-grade papillary carcinoma High-grade papillary carcinoma of low malignant potential Group No 3., Inverted Inverted urothelial neoplasm of low malignant potential Low-grade inverted urothelial carcinoma High-grade inverted urothelial carcinoma urothelial papilloma, only one form of neoplasms is reported, namely, urothelial carcinoma with an inverted growth pattern. Scant molecular and clinical studies on the urothelial carcinoma with an inverted growth pattern have been published [28], and those that have focus mainly on differences with the inverted urothelial papilloma. Classification and terminology consistent with those of flat and papillary urothelial lesions and neoplasms should be adopted. Conflicts of interest: The authors have nothing to disclose. References [1] Montironi R, Mazzucchelli R, Scarpelli M, Lopez-Beltran A, Cheng L. Morphological diagnosis of urothelial neoplasms. J Clin Pathol 2008;61:3 10. [2] 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: [3] Hodges KB, Lopez-Beltran A, Davidson DD, Montironi R, Cheng L. Urothelial dysplasia and other flat lesions of the urinary bladder: clinicopathologic and molecular features. Hum Pathol 2010;41: [4] Montironi R, Lopez-Beltran A, Scarpelli M, Mazzucchelli R, Cheng L. Morphological classification and definition of benign, preneoplastic and non-invasive neoplastic lesions of the urinary bladder. Histopathology 2008;53: [5] Cheng L, Cheville JC, Neumann RM, Bostwick DG. Natural history of urothelial dysplasia of the bladder. Am J Surg Pathol 1999;23: [6] Birkhahn M, Mitra AP, Williams AJ, et al. Predicting recurrence and progression of noninvasive papillary bladder cancer at initial presentation based on quantitative gene expression profiles. Eur Urol 2010;57: [7] Burger M. Editorial comment on: prognostic accuracy of individual uropathologists in noninvasive urinary bladder carcinoma: a multicentre study comparing the 1973 and 2004 World Health Organisation classifications. Eur Urol 2010;57:858. [8] Guey LT, García-Closas M, Murta-Nascimento C, et al. Genetic susceptibility to distinct bladder cancer subphenotypes. Eur Urol 2010;57: [9] May M, Brookman-Amissah S, Roigas J, et al. Prognostic accuracy of individual uropathologists in noninvasive urinary bladder carcinoma: a multicentre study comparing the 1973 and 2004 World Health Organisation classifications. Eur Urol 2010;57: [10] van Rhijn BWG, Burger M, Lotan Y, et al. Recurrence and progression of disease in non-muscle-invasive bladder cancer: from epidemiology to treatment strategy. Eur Urol 2009;56: [11] Yorukoglu K, Tuna B, Kirkali Z, Re: Matthias May, Sabine Brookman- Amissah, Jan Roigas, et al. Prognostic accuracy of individual uropathologists in noninvasive urinary bladder carcinoma: a multicentre study comparing the 1973 and 2004 World Health Organisation classifications. Eur Urol 2010;58:e7. [12] Cheng L, Montironi R, Davidson DD, Lopez-Beltran A. Staging and reporting of urothelial carcinoma of the urinary bladder. Mod Pathol 2009;22(Suppl 2):S [13] Lopez-Beltran A, Cheng L, Andersson L, et al. Preneoplastic nonpapillary lesions and conditions of the urinary bladder: an update based on the Ancona International Consultation. Virchows Arch 2002;440:3 11. [14] Taylor DC, Bhagavan BS, Larsen MP, Cox JA, Epstein JI. Papillary urothelial hyperplasia. A precursor to papillary neoplasms. Am J Surg Pathol 1996;20: [15] Readal N, Epstein JI. Papillary urothelial hyperplasia: relationship to urothelial neoplasms. Pathology 2010;42: [16] Babjuk M. Second resection for non-muscle-invasive bladder carcinoma: current role and future perspectives. Eur Urol 2010;58: [17] Dalbagni G, Vora K, Kaag M, et al. Clinical outcome in a contemporary series of restaged patients with clinical T1 bladder cancer. Eur Urol 2009;56: [18] Divrik RT, Şahin AF, Ergör G. Reply from authors re: Marko Babjuk. Second resection for non-muscle-invasive bladder carcinoma: current role and future perspectives. Eur Urol 2010;58:191 2 and Giacomo Novara, Vincenzo Ficarra. Does routine second transurethral resection affect the long-term outcome of patients with T1 bladder cancer? Why a flawed randomized controlled trial cannot address the issue. Eur Urol 2010;58: Eur Urol 2010;58: [19] Divrik RT, Şahin AF, Yildirim Ü, Altok M, Zorlu F. Impact of routine second transurethral resection on the long-term outcome of patients with newly diagnosed pt1 urothelial carcinoma with respect to recurrence, progression rate, and disease-specific survival: a prospective randomised clinical trial. Eur Urol 2010;58: [20] Fritsche H-M, Burger M, Svatek RS, et al. Characteristics and outcomes of patients with clinical T1 grade 3 urothelial carcinoma treated with radical cystectomy: results from an international cohort. Eur Urol 2010;57: [21] Kulkarni GS, Hakenberg OW, Gschwend JE, et al. An updated critical analysis of the treatment strategy for newly diagnosed high-grade T1 (previously T1G3) bladdercancer.eururol2010; 57: [22] Novara G, Ficarra V. Does routine second transurethral resection affect the long-term outcome of patients with T1 bladder cancer? Why a flawed randomized controlled trial cannot address the issue. Eur Urol 2010;58: [23] van Rhijn BWG, Zuiverloon TCM, Vis AN, et al. Molecular grade (FGFR3/MIB-1) and EORTC risk scores are predictive in primary non-muscle-invasive bladder cancer. Eur Urol 2010;58: [24] Cheng L, Bostwick DG. Overdiagnosis of bladder carcinoma. Anal Quant Cytol Histol 2008;30: [25] Lott S, Wang M, Zhang S, et al. FGFR3 and TP53 mutation analysis in inverted urothelial papilloma: incidence and etiological considerations. Mod Pathol 2009;22: [26] Sung MT, Maclennan GT, Lopez-Beltran A, Montironi R, Cheng L. Natural history of urothelial inverted papilloma. Cancer 2006;107: [27] Cheng L, Lopez-Beltran A, MacLennan GT, Montironi R, Bostwick DG. Neoplasms of the urinary bladder. In: Bostwick DG, Cheng L, editors. Urologic Surgical Pathology. ed. 2. Philadelphia, PA, USA: Mosby/Elsevier; p

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6 230 EUROPEAN UROLOGY 59 (2011) [28] Hodges KB, Lopez-Beltran A, MacLennan GT, Montironi R, Cheng L. Urothelial lesions with inverted growth patterns: histogenesis, molecular genetic findings, differential diagnosis and clinical management. BJU Int. In press. doi: /j x x. [29] Jones TD, Zhang S, Lopez-Beltran A, et al. Urothelial carcinoma with an inverted growth pattern can be distinguished from inverted papilloma by fluorescence in situ hybridization, immunohistochemistry, and morphologic analysis. Am J Surg Pathol 2007;31: [30] Epstein JI, Amin MB. Urothelial neoplasms with inverted growth patterns. In: Epstein JI, Amin MB, editors. Biopsy Interpretation of the Bladder. ed. 2. Philadelphia, PA, USA: Lippincot Williams & Wilkins; p [31] McKenney JK, Vankalakunti M. Overview of urinary bladder neoplasms. In: Amin MB, editor. Diagnostic Pathology: Genitourinary. ed. 1 Manitoba, Canada: AMIRSYS; p. 50.

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

european urology supplements 8 (2009) 453 457 available at www.sciencedirect.com journal homepage: www.europeanurology.com 2004 World Health Organization Classification of the Noninvasive Urothelial Neoplasms: