An Approach to the Diagnosis of Bladder Lesions in Biopsy and Transurethral Resection Specimens
Section 2 -
Papillary Urothelial Neoplasms
Mahul B. Amin, MD
Jesse K. McKenney, MD
47 year-old man who presented with
hematuria. Cystoscopy revealed a 0.5 cm raised lesion in the trigone.
Papillary Urothelial Neoplasms
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.  The current WHO
2004 system is essentially identical to the WHO/ISUP (1998)
system,  which is a modified
version of the scheme proposed by Malmström et al. 
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
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
Inverted Urothelial Papilloma:
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,  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. 
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):
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
Papillary Urothelial Carcinoma, Low-Grade:
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:
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
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|
|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|
|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
| ||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 
Selected References for Papillary Urothelial Neoplasms
- Sauter G, Algaba F, Amin MB, Busch C et al: Non-invasive urothelial tumours. In: Epstein JI, Eble JN, Sesterhenn I, Sauter G (eds): World Health Organization Classification of Tumours Pathology and Genetics: Tumours of the Urinary System and Male Genital Organs. IARC Press, Lyon, 2004; pp 110.
- Epstein JI, Amin MB, Reuter VE, 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 22:1435-1448, 1998.
- Malmstrom P-U, Busch C, Norlen BJ. Recurrence, progression, and survival in bladder cancer: a retrospective analysis of 232 patients with 5-year follow-up. Scand J Urol Nephrol 1987;21:185-195.
- Eble JN, Young RH: Benign and low-grade papillary lesions of the urinary bladder: a review of the papilloma-papillary carcinoma controversy and a report of 5 typical papillomas. Sem Diagn Pathol 6:351-371, 1989.
- Amin MB, Murphy WM, Reuter VE, et al: Controversies in the pathology of transitional cell carcinoma of the urinary bladder. In: Rosen PP, Fechner RE (eds): Reviews in Pathology, Chicago IL, ASCP Press, 1996, pp.1-38.
- Kunze E, Schauer A, Schmitt M. Histology and histogenesis of two different types of inverted urothelial papillomas. Cancer 1983;51:348-358.
- Demeester LJ, Farrow GM, Utz DC. Inverted papilloma of the urinary bladder. Cancer 1975;36:505-513.
- Broussard JN, Tan PH, Epstein JI. Atypia in inverted urothelial papillomas: pathology and prognostic significance. Hum Pathol 2004;35:1499-1504.
- Amin MB, Gomez 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;21:1057-1068
- Cheng L, Darson M, Cheville JC, Neumann RM, Zincke H, Nehru A, Bostwick DG: Urothelial papilloma of the bladder. Clinical and biologic implications. Cancer 86:2098-2101, 1999.
- Magi-Galluzzi C, Epstein JI. Urothelial papilloma of the bladder. A review of 34 de novo cases. Am J Surg Pathol 2004;28:1615-1620.
- McKenney, Amin MB, Young RH. Urothelial (transitional cell) papilloma of the urinary bladder: a clinicopathologic study of 26 cases. Mod Pathol 2003;16:623-9.
- Holmang S, Hedelin H, Anderstrom C, Holmberg E, Busch C, Johansson S: Recurrence and progression in low-grade papillary urothelial tumors. J Urol 1999;162:702-707.
- Cheng L, Neumann RM, Bostwick DG: Papillary urothelial neoplasms of low malignant potential. Clinical and biologic implications. Cancer 1999;86:2102-2108.
- Pich A, Chiusa L, Formiconi A, Galliano D, Bortolin P, Navone R. Biologic differences between noninvasive papillary urothelial neoplasms of low malignat potential and low-grade (grade 1) papillary carcinoma of the bladder. Am J Surg Pathol 2001;25:1528-1533.
- Alsheikh A, Mohamedali Z, Jones E, Masterson J, Gilks CB. Comparison of the WHO/ISUP classification and cytokeratin 20 erxpression in predicting the behavior of low-grade papillary urothelial tumors. Mod Pathol 2001;14:267-272.
- Desai S, Lim SD, Jimenez RE, Chun T, Keane TE, McKenney JK, Zavala- Pompa A, Cohen C, Young RH, Amin MB: Relationship of cytokeratin 20 and CD44 protein expression with WHO/ISUP grade in pTa and pTI papillary urothelial neoplasia. Mod Pathol 2000;13:1315-1323.
- 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;165:1124-1128.
- Oosterhuis JW, Schapers RF, Janssen-Heijnen ML, Paulwels 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;55:900-905.
- Samaratunga H, Makarov DV, Epstein JI. Comparison of WHO/ISUP and WHO classification of noninvasive papillary urothelial neoplasms for risk of progression. Urology 2002;60:315-319.