Section 2 -

Papillary Urothelial Neoplasms Mahul B. Amin, MD Jesse K. McKenney, MD

Case 1 History: 47 year-old man who presented with microscopic hematuria. Cystoscopy revealed a 0.5 cm raised lesion in the trigone. Diagnosis : Inverted Papilloma Papillary Urothelial Neoplasms Background: Although many different classification systems have been proposed for papillary bladder neoplasms over the past 30 years, the International Society of Urologic Pathologists and the World Health Organization have developed a consensus derived system that has become the accepted standard by urologic pathologists and urologists worldwide. [1] The current WHO 2004 system is essentially identical to the WHO/ISUP (1998) system, [2] which is a modified version of the scheme proposed by Malmström et al. [3] Although the WHO 1973 system had been used widely, the diagnostic criteria were not well-defined, leading to many diagnoses that "bridged" different categories (e.g.- Transitional cell carcinoma, Grade II-III). In addition, the use of the term "urothelial papilloma" had been expanded by some authors to include a spectrum of low-grade lesions (including lesions termed "Grade I carcinomas" under the WHO 1973 system) in order to avoid a diagnosis of carcinoma for a lesion that seemed to pose little immediate threat to patients' health. The WHO and ISUP felt a new consensus classification was needed to resolve these major issues and insure that a unified terminology was in place to better study patient outcome and treatment modalities. [4, 5] The diagnostic categories provided for papillary urothelial neoplasms include inverted papilloma, urothelial papilloma, papillary urothelial neoplasm of low malignant potential, low-grade papillary urothelial carcinoma, and high-grade papillary urothelial carcinoma. The histologic criteria for each of these diagnoses are discussed individually below and summarized in Table 2, followed by outcome data in Table 3. Inverted Urothelial Papilloma: [1, 6, 7, 8] Although not strictly a papillary lesion, inverted papilloma is described here because it shares certain features with exophytic urothelial papilloma. The histology of inverted papillomas has been well described, but it typically consists of complex interanastomosing cords of urothelium within the lamina propria. The amount of intervening stroma is variable. There is usually a well-circumscribed border at the base, and a characteristic palisading of basaloid cells at the periphery of the nests/cords. Centrally within the nests/cords, the neoplastic cells often have a spindled appearance or rarely, show non-keratinizing squamous metaplasia. Mitotic figures are rare or absent. Rarely, cases are hybrid with different areas of the lesion resemble exophytic urothelial papillomas and inverted urothelial papillomas; these lesions are generally classified as papillomas with both exophytic and inverted features. By definition, inverted papillomas lack nuclear pleomorphism, nuclear hyperchromasia, or significant mitotic activity; however, scattered cells with multinucleation or degenerative type atypia have been described and do not seem to alter the benign clinical course. Central cystic change (cystitis cystica-like or colloid cyst pattern) has also been described. When prominent, this cystitis cystica-like pattern of inverted papilloma may have a glandular appearance at low-power; in some cases, the distinction from cystitia cystica may be somewhat arbitrary. The differential diagnosis is limited. Inverted papillomas usually show the anastomosing growth pattern with peripheral basaloid cells that is distinct from florid cystitis cystica which is characterized by well-delineated, round nests of normal appearing urothelium; however, this distinction may be somewhat arbitrary in occasional cases. Endophytic patterns of urothelial carcinoma may also closely resemble inverted papillomas, [9] but the invaginated cords are typically broader with greater variation in size including transition to solid areas. In addition, carcinomas typically have a greater degree of cytologic atypia, do not demonstrate the homogeneous basaloid appearance of inverted papillomas, and often have a prominent exophytic component that does not resemble a urothelial pailloma (as discussed below). Any true stromal invasion (discussed under patterns of invasion) would disqualify a lesion from being classified as inverted papilloma. When diagnosed by these strict criteria and completely excised, inverted papillomas have a very low risk of recurrence (less than 1%). The controversy in the literature (conflicting reports) regarding the prognosis of inverted papillomas and their association with carcinoma is likely due to endophytic patterns of urothelial carcinoma being classified as inverted paplloma in some insatnces. A recent study has questioned whether the degree of atypical features allowable for a diagnosis of inverted papilloma might be expanded, but we currently follow the strict criteria outlined by the WHO 2004. [1] Urothelial Papilloma: [1, 10, 11, 12] Under the WHO 2004 classification, very restrictive criteria are employed for the diagnosis of urothelial papilloma. "Urothelial papilloma" without qualifiers refers to the exophytic variant of papilloma, defined as a discrete papillary growth with a central fibrovascular core lined by urothelium of normal thickness and normal cytology. The low-power papillary architecture is a relatively simple branching pattern without fusion. The umbrella cell layer is often prominent and may show prominent vacuolization, nuclear enlargement, or cytoplasmic eosinophilia. Some unusual features that have been reported in papillomas include dilation of lymphatic spaces within the papillae, gland-in-gland patterns, and foamy histiocytes within the papillae. This is a rare, benign condition typically occurring as a small, isolated growth, commonly but not exclusively seen in younger patients. The outcome review in Table 2 refers to urothelial papillomas as defined above; we have selected the reported series that utilize the restrictive WHO 2004 criteria. Although the term "papilloma" has been used in the literature for a variety of papillary neoplasms with variable degrees of architectural and cytologic atypia (including lesions currently classified as papillary urothelial neoplasms of low malignant potential), the data from those studies was not included. Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP): [1, 13, 14, 15, 16, 17, 18, 19, 20] These tumors resemble urothelial papillomas, but generally have a markedly thickened (hyperplastic) urothelial lining. By definition, the nuclei may be slightly enlarged, but there is minimal to absent cytologic atypia. There is also normal polarity of the urothelial cells with an orderly, predominantly linear arrangement perpendicular to the basement membrane. Mitotic figures are infrequent in papillary urothelial neoplasms of low malignant potential, and usually limited to the basal layer. The umbrella cell layer is frequently maintained. Like papillomas, the papillae of PUNLMP generally have a simple branching pattern with discrete, slender papillae. These patients are at an increased risk of developing recurrent or new papillary lesionswhichoccasionally are of higher grade and may progress. The diagnosis of PUNLMP should be carefully reconsidered in the presence of stromal invasion because that finding would be highly unusual. Histologically bland patterns of invasion have been reported under various names, and are discussed under the section on variants of urothelial carcinoma. Papillary Urothelial Carcinoma, Low-Grade: [1, 13, 15, 16, 17, 18, 19, 20] Low-grade papillary urothelial carcinomas are characterized by an overall orderly appearance but with easily recognizable variation of architectural and or cytologic features seen at scanning magnification. Variation of polarity (loss of perpendicular arrangement to the basement membrane) and nuclear size, shape, and chromatin texture comprise the minimal criteria for the diagnosis of low grade carcinoma. Mitotic figures are infrequent and usually seen in the lower half; but may be seen at any level of the urothelium. Tangential sections near the base of the urothelium may be misleading and result in sheets of immature urothelium with frequent mitotic activity. A spectrum of cytologic and architectural abnormalities may exist within a single lesion, stressing the importance of examining the entire lesion and noting the highest grade of abnormality. Papillary Urothelial Carcinoma, High-Grade: [17, 18, 19, 20] High-grade carcinomas are characterized by a complex, disordered architecture and moderate to marked cytologic atypia. Although the low-power papillary architecture is frequently complex with obvious anastomosis of adjacent papillae creating fused, confluent formations, the definitional feature for a diagnosis of high-grade carcinoma is the cytology of the neoplastic cells. Cytologically, there is a spectrum of pleomorphism ranging from moderate to marked, but obvious nuclear membrane irregularity and irregular, clumped chromatin represent the minimal diagnostic criteria. The individual neoplastic cells are often more rounded than in lower grade lesions and have a loss of polarity in relation to the basement membrane (random, non-perpendicular arrangement within the urothelium). Mitotic figures, including atypical forms, are frequently seen. In tumors with variable histology, the tumor should be graded according to the highest grade. High-grade papillary urothelial carcinomas have a much higher risk of progression than low-grade lesions, with figures varying from 15% to 40%. These tumors also have a high risk of association with invasive disease at the time of diagnosis. Paralleling the high-grade cytologic atypia within these lesions, the surrounding flat urothelial mucosa may also demonstrate urothelial carcinoma in-situ. Comparison of WHO 2004/ISUP Classification to WHO 1973 Since many pathologists have practiced under the WHO 1973 system, it should be emphasized that the WHO 2004 diagnostic categories are not directly translatable into the WHO 1973 system. Although the criteria for papilloma are identical, as shown in the schematic below, the PUNLMP category is more restrictive than the 1973 Grade I carcinoma category and the diagnostic threshold for high-grade carcinoma has been lowered. Clinical Relevance of WHO /ISUP Classification Emerging clinical follow-up data suggest that the WHO 2004/ISUP diagnostic category of papillary urothelial neoplasm of low malignant potential (PUNLMP) identifies a clinically and biologically distinct lesion within the spectrum of papillary urothelial neoplasia. Table 3 compares the recurrence rates, grade progression, stage progression and survival rates between tumors in the different categories of non-invasive papillary urothelial neoplasms of the bladder by WHO/ISUP classification system. Table 2: Histologic Features of Urothelial Papillary Lesions Papilloma Papillary neoplasm of low malignant potential Low-grade papillary carcinoma High-grade papillary carcinoma Architecture Papillae Delicate Delicate. Occasional fused Fused, branching, and delicate Fused, branching and delicate Organization of cells Identical to normal Polarity identical to normal. Any thickness Cohesive Predominantly ordered, yet minimal crowding and minimal loss of polarity. Any thickness. Cohesive Predominantly disordered with frequent loss of polarity. Any thickness. Often discohesive Cytology Nuclear size Identical to normal May be uniformly enlarged Enlarged with variation in size Enlarged with variation in size Nuclear shape Identical to normal Elongated, round-oval, uniform Round-oval. Slight variation in shape and contour Moderate-marked pleomorphism Nuclear chromatin Fine Fine Mild variation within and between cells Moderate-marked variation both within and between cells with hyperchromasia Nucleoli Absent Absent to inconspicuous Usually inconspicuous* Multiple prominent nucleoli may be present Mitoses Absent Rare, basal Occasionally at any level Usually frequent, at any level Umbrella cells Uniformly present Present Usually present May be absent * If present, small and regular and not accompanied by other features of high-grade carcinoma TABLE 3 Papilloma Papillary neoplasm of low malignant potential Low-grade papillary carcinoma High-grade papillary carcinoma Recurrence 0-8.8% 25-35% 48-77% 55% Grade progression 0-8.8% 11% 7% Not applicable Stage progression 0%** 0-4% 2-12% 27% Survival 100% 93-100%* 82-96% 80-90% *4% of PUNLMPs in one series developed invasive disease (mean interval 13.3 years) and 3% died of bladder cancer, suggesting that long-term follow-up is clearly needed for patients with these tumors **One reported patient progressed to invasive carcinoma, but the case was complicated by immunosuppressive therapy for a renal transplant [12] Selected References for Papillary Urothelial Neoplasms Sauter G, Algaba F, Amin MB, Busch C et al: Non-invasive urothelial tumours. 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