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Prognostic significance of atypical papillary urothelial hyperplasia
Prognostic Significance of Atypical Papillary Urothelial Hyperplasia SHARON L. SWIERCZYNSKI, MD, PHD, AND JONATHAN I. EPSTEIN, MD Typical papillary hyperplasia, a recently recognized precursor lesion to low-grade papillary urothelial neoplasms, consists of undulating folds of cytologically benign urothelium. Well-developed, branching fibrovascular cores of a papillary neoplasm are not evident. We have noted lesions with the architectural pattern of papillary hyperplasia; however, the overlying urothelium demonstrated varying degrees of cytologic atypia. We identified 15 cases of atypical papillary hyperplasia (13 males, 2 females, age 55 to 92) with overlying urothelium showing cytologic atypia. Of these cases, 8 (53%) were received in consultation. Of the 15 cases, 8 exhibited overlying flat carcinoma in situ (CIS), 4 had overlying dysplasia, and 3 were transitional between papillary hyperplasia with atypia and the earliest lesions of papillary neoplasia. Of these cases, 5 patients had multiple specimens with atypical papillary hyperplasia (range, 2 to 8) over time. Concurrent to the diagnosis of atypical papillary hyperplasia, there were 25 different urothelial lesions: CIS (n ⴝ 11), papilloma (n ⴝ 1), papillary neoplasm of low malignant potential with CIS (n ⴝ 1), high-grade papillary urothelial carcinoma (n ⴝ 10; 3 with CIS), small-cell carcinoma (n ⴝ 1), and infiltrating urothelial carcinoma (n ⴝ 1). Of 11 patients with known prior history, 2 had 12 prior urothelial neoplasms (9 low-grade papillary neoplasms, 2 papillary urothelial neoplasms of low malignant potential, and 1 high-grade
papillary cancer). Of 10 patients with atypical papillary hyperplasia and a minimum of 1 year of follow-up, 9 had 19 recurrences: CIS (n ⴝ 4), papilloma (n ⴝ 1), papillary neoplasm of low malignant potential (n ⴝ 1), infiltrating urothelial carcinoma (n ⴝ 3; 1 with CIS), and high-grade papillary urothelial carcinoma (n ⴝ 10; 5 with invasion and 2 with CIS). Whether the papillary hyperplasia had overlying CIS or dysplasia did not affect the correlation with urothelial neoplasms. Immunohistochemical analysis of p53 and Ki-67 expression in 8 cases demonstrated overexpression of p53 (n ⴝ 2; 1 with overlying dysplasia and 1 with overlying CIS), and Ki-67 (n ⴝ 5; 2 with overlying dysplasia and 3 with overlying CIS). Taken together, these results suggest that atypical papillary hyperplasia is most frequently associated with CIS and high-grade papillary cancer. In some cases, CIS or dysplasia may evolve into atypical papillary hyperplasia, with further progression to high-grade papillary cancer. This process may be analogous to papillary hyperplasia without cytologic atypia progressing to low-grade papillary urothelial neoplasms. HUM PATHOL 33: 512-517. Copyright 2002, Elsevier Science (USA). All rights reserved. Key words: bladder, urothelium, papillary hyperplasia, urothelial carcinoma. Abbreviation: CIS, carcinoma in situ.
Papillary hyperplasia of the urinary bladder is a pathologic entity consisting of undulating folds of urothelium that lack both the cytologic atypia and the well-developed, branching fibrovascular cores of a papillary neoplasm.1-3 The World Health Organization/ International Society of Urological Pathology has recognized papillary hyperplasia in its most recent consensus classification of urothelial neoplasms of the bladder.4 Recently, this architectural pattern has been recognized as a precursor lesion to low-grade papillary urothelial neoplasms.3 We have noted lesions with the pattern of papillary hyperplasia; however, the overlying urothelium demonstrated varying degrees of cytologic atypia. As with typical papillary hyperplasia, these lesions did not meet the architectural criteria for a papillary neoplasm. It is uncertain whether these lesions have any relationship to prior, concurrent, or subsequent development of papillary neoplasia. In this study we investigated the prior and subsequent courses of patients with atypical papillary hyperplasia to determine its prognostic significance.
MATERIALS AND METHODS
From the Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD. Accepted for publication January 10, 2002. Address correspondence and reprint requests to Jonathan I. Epstein, MD, The Johns Hopkins Hospital, Weinberg Pavilion, Rm 2242, 401 N. Broadway St., Baltimore, MD 21231. Copyright 2002, Elsevier Science (USA). All rights reserved. 0046-8177/02/3305-0009$35.00/0 doi:10.1053/hupa.2002.124031
We identified 15 cases of atypical papillary hyperplasia of the bladder in which the overlying urothelium demonstrated cytologic atypia ranging from dysplasia to flat carcinoma in situ (CIS). Eight cases (53%) were received in consultation, and the remaining 7 cases were retrieved from the surgical pathology files of The Johns Hopkins Hospital. Urologic history, including prior and subsequent bladder pathology, was obtained from either the patient’s urologist or clinical documents. Recurrences were considered in patients with a minimum of 1 year of follow-up. For 8 cases, tissue blocks fixed in formalin and embedded in paraffin were available. These blocks were immunostained for p53 and Ki-67 according to standard protocols. In brief, 5- sections were transferred to sialinated slides. Slides were incubated with antibodies to p53 (Dako Carpinteria, CA) or Ki-67 (Immunotech, Miami, FL) at 1:500 and 1:1000 dilutions, respectively. The slides were then treated with a secondary antibody using the horseradish peroxidase detection system (ChemMate; Ventana Medical Systems, Tucson, AZ). For each case, 400 consecutive urothelial cells in the region demonstrating papillary hyperplasia were counted. Nuclei with strong, homogenous brown staining were considered positive.
RESULTS Of the 15 identified cases of atypical papillary hyperplasia from consult cases and the surgical pathology files of The Johns Hopkins Hospital (Table 1), 13 of the patients were male and 2 were female. Age ranged from
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TABLE 1. Patient Demographics Case no.
Age (years) and sex
Degree of overlying atypia
No. of atypical papillary hyperplasia diagnoses
Prior history of urothelial neoplasm
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
76 M 74 M 63 M 65 M 69 M 69 M 55 F 64 M 72 M 92 M 75 M 77 M 80 M 81 F 57 M
CIS Dysplasia CIS CIS Dysplasia CIS Transition between atypia and papillary neoplasm Dysplasia Dysplasia CIS CIS CIS Transition between atypia and papillary neoplasm Transition between atypia and papillary neoplasm CIS
3 3 1 3 1 8 1 1 1 2 1 1 1 1 1
No No No No No No No Yes Yes No No No No No No
55 to 92 years (median, 72 years). Of these patients, 5 had multiple specimens with atypical papillary hyperplasia (range, 2 to 8) over time. Histology On bladder biopsy, all lesions exhibited the architectural pattern of papillary hyperplasia. In 8 patients,
the overlying urothelium exhibited cytologic atypia consistent with CIS (Figs 1 and 2). In 4 cases, the urothelium demonstrated dysplasia (Fig 3), and the urothelium in 3 cases represented a transition between papillary hyperplasia with atypia and the earliest lesions of papillary neoplasia (Fig 4). In all cases, the lesions did not fulfill the architectural criteria for a papillary cancer.
FIGURE 1. Papillary hyperplasia with overlying CIS. (A) Lowpower view demonstrates undulating folds of urothelium without papillary fronds. (B and C) High-power views demonstrate marked cytologic atypia and architectural disorganization at the level of CIS.
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FIGURE 2. Papillary hyperplasia with overlying CIS. Marked cytologic atypia with mitotic activity (arrow). FIGURE 4. Transition between papillary hyperplasia with atypia and early papillary urothelial carcinoma.
Prior History Of the 11 patients with known prior history, 2 patients had 12 prior urothelial neoplasms. These lesions consisted of 9 low-grade papillary carcinomas (1 with invasion into the lamina propria), 2 papillary neoplasms of low malignant potential, and 1 high-grade papillary carcinoma. Histology Concurrent With Atypical Papillary Hyperplasia Concurrent with the diagnosis of atypical papillary hyperplasia, 25 other urothelial lesions were present in these patients (Table 2). Eleven of the specimens also exhibited CIS. High-grade papillary carcinoma was present in 10 cases; CIS was also demonstrated in 3 of these specimens. The remaining 4 cases had the following histology: papilloma; CIS and a papillary lesion of low malignant potential; infiltrating urothelial carcinoma; and small-cell carcinoma. Subsequent History
FIGURE 3. Papillary hyperplasia with overlying dysplasia. (A) Low-power view demonstrates architecture of papillary hyperplasia. (B) High-power view demonstrates cytologic atypia falling short of CIS.
Of 10 patients with a minimum of 1 year of followup, 9 had 19 recurrences (Table 3). High-grade papillary carcinoma was identified in 10 specimens; these specimens also included invasion in 5 cases and CIS in 2 cases. CIS was identified in 4 specimens. Infiltrating urothelial carcinoma was present in 3 specimens, with 1 also including CIS. The remaining 2 cases demonstrated papillary neoplasia of low malignant potential and papilloma. We observed that the degree of cytologic atypia in the overlying urothelium of papillary hyperplastic lesions exhibited a range from dysplasia through CIS (Table 3). Of the 4 patients with dysplasia and at least 1 year of follow-up, all had at least 1 subsequent specimen with a high-grade carcinoma (flat or papillary). Of the 4 patients with CIS, 3 had at least 1 specimen with high-grade cancer; 1 of these patients demonstrated
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TABLE 2. Histology Concurrent to Atypical Papillary Hyperplasia Case no.
TABLE 4. Percentage of Cells Positive for p53 and Ki-67 in Atypical Papillary Hyperplasia
Concurrent histology
1
High-grade papillary carcinoma CIS CIS High-grade papillary carcinoma and CIS Papillary neoplasm of low malignant potential and CIS High-grade papillary carcinoma High-grade papillary carcinoma CIS CIS Infiltrating papillary carcinoma (pT1) CIS Infiltrating papillary carcinoma (pT1) CIS and infiltrating papillary carcinoma (pT2) High-grade papillary carcinoma CIS CIS Papilloma No other pathology No other pathology Infiltrating papillary carcinoma (pT1) CIS CIS CIS High-grade papillary carcinoma and CIS CIS Infiltrating urothelial carcinoma (pT1) Small-cell carcinoma
2 3 4 5 6
7 8 9 10 11 12 13 14 15
Case no.
Degree of overlying atypia
1
CIS
2
Dysplasia
3 4 5 6
CIS CIS Dysplasia CIS
8
Dysplasia
9 14
Dysplasia Transition between atypia and papillary neoplasm
Degree of overlying atypia
p53 (% positive)
Ki-67 (% positive)
1 2 3 4 6 8 9 10
CIS Dysplasia CIS CIS CIS Dysplasia Dysplasia CIS
4 2.5 42 6 6 12 1.8 3
19 1.8 24 8 7 26 17 14
Expression of p53 and Ki-67
CIS as the high-grade lesion. The remaining patient demonstrated a papilloma. For the 1 patient with papillary hyperplasia in which the overlying urothelium demonstrated a transition between atypia and the earliest lesions of papillary neoplasia, infiltrating urothelial carcinoma was diagnosed on subsequent specimens. TABLE 3. Relationship of Atypical Papillary Hyperplasia to Urothelial Neoplasms
Case no.
Immunohistochemical analyses for p53 and Ki-67 were performed on 8 cases for which tissue blocks were available and the diagnostic lesion was present on deeper sectioning into the block (Table 4). Of these 8 cases, 3 represented papillary hyperplasia with overlying dysplasia, and 5 demonstrated papillary hyperplasia with overlying CIS. In the overlying CIS, 1 case demonstrated p53 overexpression (42%; mean, 12%; range, 3% to 42%; Fig 5). For the lesions with overlying dysplasia, 1 case showed marginal p53 overexpression (12%; mean, 5%; range, 1.8% to 12%). When the same cases were immunostained for Ki-67, 3 cases with CIS demonstrated overexpression (19, 24,17%; mean, 14%; range, 7% to 24%; Fig 6). Of the 3 cases with dysplastic urothelium, 2 cases exhibited an elevated proliferative index (26, 17%; mean, 15%; range, 1.8% to 26%). DISCUSSION A prior study examined 16 cases of typical papillary urothelial hyperplasia.3 Of these 16 patients, 11 had a history of prior or subsequent papillary urothelial neoplasms. These results implicated a relationship between typical papillary hyperplasia and the development of papillary urothelial neoplasms. In most cases, these
Subsequent urothelial neoplasms High-grade papillary carcinoma Infiltrating urothelial carcinoma (pT2) High-grade papillary carcinoma Papillary carcinoma (LMP) Papilloma CIS Infiltrating papillary carcinoma (pT1) CIS Infiltrating papillary carcinoma (pT1) CIS Infiltrating papillary carcinoma (pT2) High-grade papillary carcinoma Infiltrating urothelial carcinoma (pT2) High-grade papillary carcinoma High-grade papillary carcinoma CIS High-grade papillary carcinoma High-grade papillary carcinoma Infiltrating urothelial carcinoma (pT2) FIGURE 5. p53 expression in papillary urothelial hyperplasia with overlying CIS.
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FIGURE 6. Ki-67 expression in papillary urothelial hyperplasia with overlying CIS.
neoplasms were low-grade lesions, either papillomas or low-grade papillary carcinomas. However, 4 cases developed high-grade in situ papillary cancers. In 1 case of carcinoma in situ described in the previous study, the surrounding urothelium demonstrated papillary hyperplasia with a higher degree of cytologic atypia than was present in the other cases. This observation raised the possibility that papillary hyperplasia with increased cytologic atypia serves as a precursor lesion for higher-grade urothelial cancers. In the current study, we identified 15 cases of atypical papillary urothelial hyperplasia with varying degrees of overlying cytologic atypia to examine its relationship with prior and subsequent urothelial neoplasms. In contrast to the previous results for typical papillary hyperplasia,3 most subsequent neoplasms associ-
ated with atypical hyperplasia were of higher grade. Of 19 recurrences (Table 2), 17 demonstrated highergrade lesions, including high-grade papillary carcinoma, CIS, and infiltrating urothelial carcinoma. Concurrent to the atypical papillary hyperplasia, higher-grade lesions were present as well (Table 3). In the current study, we also wanted to investigate whether the degree of atypia had any correlation with the observed subsequent urothelial neoplasms and their severity in the patients who had at least 1 year of follow-up (Table 2). According to these data, the degree of cytologic atypia in the overlying urothelium does not correlate with the severity of subsequent neoplasia. High-grade lesions were found in patients with dysplasia as well as those with CIS in the urothelium overlying papillary hyperplasia. Taken together, the results of this and the previous study3 suggest that papillary hyperplasia is not simply a hyperplastic process without significance, but rather a precursor lesion to papillary neoplasms. In addition, other possible precursor lesions to papillary urothelial neoplasms have been described. For example, a recent study identified flat, thickened urothelial lesions adjacent to low-grade papillary urothelial carcinomas.5 These flat lesions demonstrated similar cytology to the papillary carcinomas. In addition, patients with dysplasia in the urothelium adjacent to papillary urothelial carcinoma demonstrated a significant increase in the rate of tumor recurrence.6-7 These data support models of progression from normal urothelium to papillary urothelial neoplasia with papillary hyperplasia and thickened, atypical urothelium serving as intermediate steps (Fig 7). Flat and papillary lesions with atypia may exist along a continuum in the development of papillary urothelial carcinoma. Similar models have been proposed for the
FIGURE 7. Models of progression of urothelial neoplasia (A) Papillary hyperplasia without atypia may represent a stage in the progression from normal urothelium to low-grade neoplasms such as papillomas. (B) In the formation of low-grade papillary urothelial neoplasms, papillary hyperplasia with atypia may represent a stage along a continuum that may or may not include flat, thickened urothelium with atypia. (C) In the formation of high-grade urothelial neoplasms, papillary hyperplasia with atypia may exist along a continuum that may or may not include flat dysplasia/CIS.
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development of papillary and nonpapillary urothelial carcinoma.8 However, these models do not specifically include papillary hyperplasia as an intermediate step. In addition to the search for morphologic precursors to papillary urothelial carcinomas, studies have been undertaken to identify molecular precursors of urothelial cancers. It is well established that carcinomas of the urinary bladder contain deletions on chromosomes 9 and 17.9-12 In addition, molecular studies have demonstrated loss of heterozygosity, particularly on chromosomal arm 9q, in papillary13 and simple14 hyperplasias. However, immunohistochemical analysis of 4 papillary hyperplastic lesions without cytologic atypia did not demonstrate overexpression of the tumor suppressor p53 or significant staining with the proliferative marker Ki-67.15 We wanted to determine whether these gene products (p53 and Ki-67) are significantly elevated in papillary hyperplastic lesions with overlying dysplasia or CIS using immunohistochemical techniques. In contrast to the previous study,15 several of the cases demonstrated overexpression of these markers (Table 4). However, the specimen with the highest p53 expression belonged to a patient who developed a subsequent papilloma (case 3). Due to the limited number of cases and apparent lack of correlation between staining and severity of eventual neoplasia, any prognostic significance cannot be attributed to these results at this time. Given that papillary urothelial hyperplasia with atypia has not been described previously, its diagnostic significance is not clear. The cases in the present study received in consultation were typically described as CIS or dysplasia, with no mention of the papillary architecture. These interpretations did not result in serious misdiagnosis. The significance of finding papillary hyperplasia with atypia is likely analogous to finding CIS from a prognostic standpoint. A potential difficulty in diagnosing atypical papillary hyperplasia is the recognition of difficulties in distinguishing between dysplasia and CIS. Although the latest World Health Organization/International Society of Urological Pathology consensus classification4 and a recent review16 have addressed this issue, the distinction between these 2 entities remains very subjective. According to our results, this distinction is not critical within a lesion of atypical papillary hyperplasia. Papillary hyperplasia with overlying dysplasia or CIS puts patients at risk for high-grade lesions. From a clinical perspective, patients with both CIS and dysplasia in the urothelium overlying the papillary hyperplasia were treated with bacillus Calmette-Gue´rin or some other form of intravesical chemotherapy. Because subsequent high-grade papillary cancers were demonstrated with both of these entities, the effective-
ness of chemotherapy does not appear to be different in the 2 groups. The current study has described papillary urothelial hyperplasia with overlying cytologic atypia. In addition, it has established the relationship between this entity and high-grade papillary urothelial cancers. Future studies aimed at comparing gene expression in atypical papillary hyperplasia to high-grade papillary carcinomas may further elucidate the relationship between the 2 entities. Comparison between atypical papillary hyperplasia and flat CIS may also determine whether these lesions demonstrate molecular similarities. REFERENCES 1. Koss LG: Tumors of the urinary bladder. in Atlas of Tumor Pathology, 2nd series, Fascicle 11. Washington, DC, Armed Forces Institute of Pathology, 1975 2. Sarma KP: Genesis of papillary tumours: Histological and microangiographic study. Br J Urol 53:228-236, 1981 3. Taylor DC, Bhagavan BS, Larsen MP, et al: Papillary urothelial hyperplasia: A precursor to papillary neoplasms. Am J Surg Pathol 20:1481-1488, 1996 4. Epstein JI, Amin MB, Reuter VR, et al: 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 5. Yang XJ, Kuznetsov D, Pytel P, et al: Presence of flat intraurothelial lesion adjacent to low-grade papillary urothelial carcinoma: A hitherto unrecognized lesion. Mod Pathol 14:129A, 2001 6. Heney NM, Ahmed S, Flanagan MJ, et al: Superficial bladder cancer: Progression and recurrence. J Urol 130:1083-1086, 1983 7. Smith G, Elton RA, Beynon LL, et al: Prognostic significance of biopsy results of normal-looking mucosa in cases of superficial bladder cancer. Br J Urol 55:665-669, 1983 8. Koss LG: Diagnostic Cytology of the Urinary Tract With Histopathologic and Clinical Correlations. New York, NY, Raven Press, 1996, pp 78-85 9. Ruppert M, Tokino K, Sidransky D: Evidence for two bladder cancer suppressor loci on chromosome 9. Cancer Res 53:5093-5095, 1993 10. Sauter G, Deng G, Moch H, et al: Physical deletion of the p53 gene in bladder cancer: Detection by fluorescence in situ hybridization. Am J Pathol 144:756-766, 1994 11. Sauter G, Moch H, Carroll P, et al: Chromosome-9 loss detected by fluorescence in situ hybridization in bladder cancer. Int J Cancer 64:99-103, 1995 12. Spruck CH, Ohneseit PF, Gonzalez-Zulueta M, et al: Two molecular pathways to transitional cell carcinoma of the bladder. Cancer Res 54:784-788, 1994 13. Chow NH, Cairns P, Eisenberger CF, et al: Papillary urothelial hyperplasia is a clonal precursor to papillary transitional cell bladder cancer. Int J Cancer 89:514-518, 2000 14. Hartmann A, Moser K, Kriegmair M, et al: Frequent genetic alterations in simple urothelial hyperplasias of the bladder in patients with papillary urothelial carcinoma. Am J Pathol 154:721-727, 1999 15. Cina SJ, Lancaster-Weiss KJ, Lecksell K, et al: Correlation of Ki-67 and p53 with the new World Health Organization/International Society of Urological Pathology classification system for urothelial neoplasia. Arch Pathol Lab Med 125:646-651, 2001 16. Bostwick DG, Ramnani D, Cheng L: Diagnosis and grading of bladder cancer and associated lesions. Urol Clin North Am 26:493507, 1999
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papillary cancer). Of 10 patients with atypical papillary hyperplasia and a minimum of 1 year of follow-up, 9 had 19 recurrences: CIS (n ⴝ 4), papilloma (n ⴝ 1), papillary neoplasm of low malignant potential (n ⴝ 1), infiltrating urothelial carcinoma (n ⴝ 3; 1 with CIS), and high-grade papillary urothelial carcinoma (n ⴝ 10; 5 with invasion and 2 with CIS). Whether the papillary hyperplasia had overlying CIS or dysplasia did not affect the correlation with urothelial neoplasms. Immunohistochemical analysis of p53 and Ki-67 expression in 8 cases demonstrated overexpression of p53 (n ⴝ 2; 1 with overlying dysplasia and 1 with overlying CIS), and Ki-67 (n ⴝ 5; 2 with overlying dysplasia and 3 with overlying CIS). Taken together, these results suggest that atypical papillary hyperplasia is most frequently associated with CIS and high-grade papillary cancer. In some cases, CIS or dysplasia may evolve into atypical papillary hyperplasia, with further progression to high-grade papillary cancer. This process may be analogous to papillary hyperplasia without cytologic atypia progressing to low-grade papillary urothelial neoplasms. HUM PATHOL 33: 512-517. Copyright 2002, Elsevier Science (USA). All rights reserved. Key words: bladder, urothelium, papillary hyperplasia, urothelial carcinoma. Abbreviation: CIS, carcinoma in situ.
Papillary hyperplasia of the urinary bladder is a pathologic entity consisting of undulating folds of urothelium that lack both the cytologic atypia and the well-developed, branching fibrovascular cores of a papillary neoplasm.1-3 The World Health Organization/ International Society of Urological Pathology has recognized papillary hyperplasia in its most recent consensus classification of urothelial neoplasms of the bladder.4 Recently, this architectural pattern has been recognized as a precursor lesion to low-grade papillary urothelial neoplasms.3 We have noted lesions with the pattern of papillary hyperplasia; however, the overlying urothelium demonstrated varying degrees of cytologic atypia. As with typical papillary hyperplasia, these lesions did not meet the architectural criteria for a papillary neoplasm. It is uncertain whether these lesions have any relationship to prior, concurrent, or subsequent development of papillary neoplasia. In this study we investigated the prior and subsequent courses of patients with atypical papillary hyperplasia to determine its prognostic significance.
MATERIALS AND METHODS
From the Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD. Accepted for publication January 10, 2002. Address correspondence and reprint requests to Jonathan I. Epstein, MD, The Johns Hopkins Hospital, Weinberg Pavilion, Rm 2242, 401 N. Broadway St., Baltimore, MD 21231. Copyright 2002, Elsevier Science (USA). All rights reserved. 0046-8177/02/3305-0009$35.00/0 doi:10.1053/hupa.2002.124031
We identified 15 cases of atypical papillary hyperplasia of the bladder in which the overlying urothelium demonstrated cytologic atypia ranging from dysplasia to flat carcinoma in situ (CIS). Eight cases (53%) were received in consultation, and the remaining 7 cases were retrieved from the surgical pathology files of The Johns Hopkins Hospital. Urologic history, including prior and subsequent bladder pathology, was obtained from either the patient’s urologist or clinical documents. Recurrences were considered in patients with a minimum of 1 year of follow-up. For 8 cases, tissue blocks fixed in formalin and embedded in paraffin were available. These blocks were immunostained for p53 and Ki-67 according to standard protocols. In brief, 5- sections were transferred to sialinated slides. Slides were incubated with antibodies to p53 (Dako Carpinteria, CA) or Ki-67 (Immunotech, Miami, FL) at 1:500 and 1:1000 dilutions, respectively. The slides were then treated with a secondary antibody using the horseradish peroxidase detection system (ChemMate; Ventana Medical Systems, Tucson, AZ). For each case, 400 consecutive urothelial cells in the region demonstrating papillary hyperplasia were counted. Nuclei with strong, homogenous brown staining were considered positive.
RESULTS Of the 15 identified cases of atypical papillary hyperplasia from consult cases and the surgical pathology files of The Johns Hopkins Hospital (Table 1), 13 of the patients were male and 2 were female. Age ranged from
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TABLE 1. Patient Demographics Case no.
Age (years) and sex
Degree of overlying atypia
No. of atypical papillary hyperplasia diagnoses
Prior history of urothelial neoplasm
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
76 M 74 M 63 M 65 M 69 M 69 M 55 F 64 M 72 M 92 M 75 M 77 M 80 M 81 F 57 M
CIS Dysplasia CIS CIS Dysplasia CIS Transition between atypia and papillary neoplasm Dysplasia Dysplasia CIS CIS CIS Transition between atypia and papillary neoplasm Transition between atypia and papillary neoplasm CIS
3 3 1 3 1 8 1 1 1 2 1 1 1 1 1
No No No No No No No Yes Yes No No No No No No
55 to 92 years (median, 72 years). Of these patients, 5 had multiple specimens with atypical papillary hyperplasia (range, 2 to 8) over time. Histology On bladder biopsy, all lesions exhibited the architectural pattern of papillary hyperplasia. In 8 patients,
the overlying urothelium exhibited cytologic atypia consistent with CIS (Figs 1 and 2). In 4 cases, the urothelium demonstrated dysplasia (Fig 3), and the urothelium in 3 cases represented a transition between papillary hyperplasia with atypia and the earliest lesions of papillary neoplasia (Fig 4). In all cases, the lesions did not fulfill the architectural criteria for a papillary cancer.
FIGURE 1. Papillary hyperplasia with overlying CIS. (A) Lowpower view demonstrates undulating folds of urothelium without papillary fronds. (B and C) High-power views demonstrate marked cytologic atypia and architectural disorganization at the level of CIS.
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FIGURE 2. Papillary hyperplasia with overlying CIS. Marked cytologic atypia with mitotic activity (arrow). FIGURE 4. Transition between papillary hyperplasia with atypia and early papillary urothelial carcinoma.
Prior History Of the 11 patients with known prior history, 2 patients had 12 prior urothelial neoplasms. These lesions consisted of 9 low-grade papillary carcinomas (1 with invasion into the lamina propria), 2 papillary neoplasms of low malignant potential, and 1 high-grade papillary carcinoma. Histology Concurrent With Atypical Papillary Hyperplasia Concurrent with the diagnosis of atypical papillary hyperplasia, 25 other urothelial lesions were present in these patients (Table 2). Eleven of the specimens also exhibited CIS. High-grade papillary carcinoma was present in 10 cases; CIS was also demonstrated in 3 of these specimens. The remaining 4 cases had the following histology: papilloma; CIS and a papillary lesion of low malignant potential; infiltrating urothelial carcinoma; and small-cell carcinoma. Subsequent History
FIGURE 3. Papillary hyperplasia with overlying dysplasia. (A) Low-power view demonstrates architecture of papillary hyperplasia. (B) High-power view demonstrates cytologic atypia falling short of CIS.
Of 10 patients with a minimum of 1 year of followup, 9 had 19 recurrences (Table 3). High-grade papillary carcinoma was identified in 10 specimens; these specimens also included invasion in 5 cases and CIS in 2 cases. CIS was identified in 4 specimens. Infiltrating urothelial carcinoma was present in 3 specimens, with 1 also including CIS. The remaining 2 cases demonstrated papillary neoplasia of low malignant potential and papilloma. We observed that the degree of cytologic atypia in the overlying urothelium of papillary hyperplastic lesions exhibited a range from dysplasia through CIS (Table 3). Of the 4 patients with dysplasia and at least 1 year of follow-up, all had at least 1 subsequent specimen with a high-grade carcinoma (flat or papillary). Of the 4 patients with CIS, 3 had at least 1 specimen with high-grade cancer; 1 of these patients demonstrated
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TABLE 2. Histology Concurrent to Atypical Papillary Hyperplasia Case no.
TABLE 4. Percentage of Cells Positive for p53 and Ki-67 in Atypical Papillary Hyperplasia
Concurrent histology
1
High-grade papillary carcinoma CIS CIS High-grade papillary carcinoma and CIS Papillary neoplasm of low malignant potential and CIS High-grade papillary carcinoma High-grade papillary carcinoma CIS CIS Infiltrating papillary carcinoma (pT1) CIS Infiltrating papillary carcinoma (pT1) CIS and infiltrating papillary carcinoma (pT2) High-grade papillary carcinoma CIS CIS Papilloma No other pathology No other pathology Infiltrating papillary carcinoma (pT1) CIS CIS CIS High-grade papillary carcinoma and CIS CIS Infiltrating urothelial carcinoma (pT1) Small-cell carcinoma
2 3 4 5 6
7 8 9 10 11 12 13 14 15
Case no.
Degree of overlying atypia
1
CIS
2
Dysplasia
3 4 5 6
CIS CIS Dysplasia CIS
8
Dysplasia
9 14
Dysplasia Transition between atypia and papillary neoplasm
Degree of overlying atypia
p53 (% positive)
Ki-67 (% positive)
1 2 3 4 6 8 9 10
CIS Dysplasia CIS CIS CIS Dysplasia Dysplasia CIS
4 2.5 42 6 6 12 1.8 3
19 1.8 24 8 7 26 17 14
Expression of p53 and Ki-67
CIS as the high-grade lesion. The remaining patient demonstrated a papilloma. For the 1 patient with papillary hyperplasia in which the overlying urothelium demonstrated a transition between atypia and the earliest lesions of papillary neoplasia, infiltrating urothelial carcinoma was diagnosed on subsequent specimens. TABLE 3. Relationship of Atypical Papillary Hyperplasia to Urothelial Neoplasms
Case no.
Immunohistochemical analyses for p53 and Ki-67 were performed on 8 cases for which tissue blocks were available and the diagnostic lesion was present on deeper sectioning into the block (Table 4). Of these 8 cases, 3 represented papillary hyperplasia with overlying dysplasia, and 5 demonstrated papillary hyperplasia with overlying CIS. In the overlying CIS, 1 case demonstrated p53 overexpression (42%; mean, 12%; range, 3% to 42%; Fig 5). For the lesions with overlying dysplasia, 1 case showed marginal p53 overexpression (12%; mean, 5%; range, 1.8% to 12%). When the same cases were immunostained for Ki-67, 3 cases with CIS demonstrated overexpression (19, 24,17%; mean, 14%; range, 7% to 24%; Fig 6). Of the 3 cases with dysplastic urothelium, 2 cases exhibited an elevated proliferative index (26, 17%; mean, 15%; range, 1.8% to 26%). DISCUSSION A prior study examined 16 cases of typical papillary urothelial hyperplasia.3 Of these 16 patients, 11 had a history of prior or subsequent papillary urothelial neoplasms. These results implicated a relationship between typical papillary hyperplasia and the development of papillary urothelial neoplasms. In most cases, these
Subsequent urothelial neoplasms High-grade papillary carcinoma Infiltrating urothelial carcinoma (pT2) High-grade papillary carcinoma Papillary carcinoma (LMP) Papilloma CIS Infiltrating papillary carcinoma (pT1) CIS Infiltrating papillary carcinoma (pT1) CIS Infiltrating papillary carcinoma (pT2) High-grade papillary carcinoma Infiltrating urothelial carcinoma (pT2) High-grade papillary carcinoma High-grade papillary carcinoma CIS High-grade papillary carcinoma High-grade papillary carcinoma Infiltrating urothelial carcinoma (pT2) FIGURE 5. p53 expression in papillary urothelial hyperplasia with overlying CIS.
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FIGURE 6. Ki-67 expression in papillary urothelial hyperplasia with overlying CIS.
neoplasms were low-grade lesions, either papillomas or low-grade papillary carcinomas. However, 4 cases developed high-grade in situ papillary cancers. In 1 case of carcinoma in situ described in the previous study, the surrounding urothelium demonstrated papillary hyperplasia with a higher degree of cytologic atypia than was present in the other cases. This observation raised the possibility that papillary hyperplasia with increased cytologic atypia serves as a precursor lesion for higher-grade urothelial cancers. In the current study, we identified 15 cases of atypical papillary urothelial hyperplasia with varying degrees of overlying cytologic atypia to examine its relationship with prior and subsequent urothelial neoplasms. In contrast to the previous results for typical papillary hyperplasia,3 most subsequent neoplasms associ-
ated with atypical hyperplasia were of higher grade. Of 19 recurrences (Table 2), 17 demonstrated highergrade lesions, including high-grade papillary carcinoma, CIS, and infiltrating urothelial carcinoma. Concurrent to the atypical papillary hyperplasia, higher-grade lesions were present as well (Table 3). In the current study, we also wanted to investigate whether the degree of atypia had any correlation with the observed subsequent urothelial neoplasms and their severity in the patients who had at least 1 year of follow-up (Table 2). According to these data, the degree of cytologic atypia in the overlying urothelium does not correlate with the severity of subsequent neoplasia. High-grade lesions were found in patients with dysplasia as well as those with CIS in the urothelium overlying papillary hyperplasia. Taken together, the results of this and the previous study3 suggest that papillary hyperplasia is not simply a hyperplastic process without significance, but rather a precursor lesion to papillary neoplasms. In addition, other possible precursor lesions to papillary urothelial neoplasms have been described. For example, a recent study identified flat, thickened urothelial lesions adjacent to low-grade papillary urothelial carcinomas.5 These flat lesions demonstrated similar cytology to the papillary carcinomas. In addition, patients with dysplasia in the urothelium adjacent to papillary urothelial carcinoma demonstrated a significant increase in the rate of tumor recurrence.6-7 These data support models of progression from normal urothelium to papillary urothelial neoplasia with papillary hyperplasia and thickened, atypical urothelium serving as intermediate steps (Fig 7). Flat and papillary lesions with atypia may exist along a continuum in the development of papillary urothelial carcinoma. Similar models have been proposed for the
FIGURE 7. Models of progression of urothelial neoplasia (A) Papillary hyperplasia without atypia may represent a stage in the progression from normal urothelium to low-grade neoplasms such as papillomas. (B) In the formation of low-grade papillary urothelial neoplasms, papillary hyperplasia with atypia may represent a stage along a continuum that may or may not include flat, thickened urothelium with atypia. (C) In the formation of high-grade urothelial neoplasms, papillary hyperplasia with atypia may exist along a continuum that may or may not include flat dysplasia/CIS.
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development of papillary and nonpapillary urothelial carcinoma.8 However, these models do not specifically include papillary hyperplasia as an intermediate step. In addition to the search for morphologic precursors to papillary urothelial carcinomas, studies have been undertaken to identify molecular precursors of urothelial cancers. It is well established that carcinomas of the urinary bladder contain deletions on chromosomes 9 and 17.9-12 In addition, molecular studies have demonstrated loss of heterozygosity, particularly on chromosomal arm 9q, in papillary13 and simple14 hyperplasias. However, immunohistochemical analysis of 4 papillary hyperplastic lesions without cytologic atypia did not demonstrate overexpression of the tumor suppressor p53 or significant staining with the proliferative marker Ki-67.15 We wanted to determine whether these gene products (p53 and Ki-67) are significantly elevated in papillary hyperplastic lesions with overlying dysplasia or CIS using immunohistochemical techniques. In contrast to the previous study,15 several of the cases demonstrated overexpression of these markers (Table 4). However, the specimen with the highest p53 expression belonged to a patient who developed a subsequent papilloma (case 3). Due to the limited number of cases and apparent lack of correlation between staining and severity of eventual neoplasia, any prognostic significance cannot be attributed to these results at this time. Given that papillary urothelial hyperplasia with atypia has not been described previously, its diagnostic significance is not clear. The cases in the present study received in consultation were typically described as CIS or dysplasia, with no mention of the papillary architecture. These interpretations did not result in serious misdiagnosis. The significance of finding papillary hyperplasia with atypia is likely analogous to finding CIS from a prognostic standpoint. A potential difficulty in diagnosing atypical papillary hyperplasia is the recognition of difficulties in distinguishing between dysplasia and CIS. Although the latest World Health Organization/International Society of Urological Pathology consensus classification4 and a recent review16 have addressed this issue, the distinction between these 2 entities remains very subjective. According to our results, this distinction is not critical within a lesion of atypical papillary hyperplasia. Papillary hyperplasia with overlying dysplasia or CIS puts patients at risk for high-grade lesions. From a clinical perspective, patients with both CIS and dysplasia in the urothelium overlying the papillary hyperplasia were treated with bacillus Calmette-Gue´rin or some other form of intravesical chemotherapy. Because subsequent high-grade papillary cancers were demonstrated with both of these entities, the effective-
ness of chemotherapy does not appear to be different in the 2 groups. The current study has described papillary urothelial hyperplasia with overlying cytologic atypia. In addition, it has established the relationship between this entity and high-grade papillary urothelial cancers. Future studies aimed at comparing gene expression in atypical papillary hyperplasia to high-grade papillary carcinomas may further elucidate the relationship between the 2 entities. Comparison between atypical papillary hyperplasia and flat CIS may also determine whether these lesions demonstrate molecular similarities. REFERENCES 1. Koss LG: Tumors of the urinary bladder. in Atlas of Tumor Pathology, 2nd series, Fascicle 11. Washington, DC, Armed Forces Institute of Pathology, 1975 2. Sarma KP: Genesis of papillary tumours: Histological and microangiographic study. Br J Urol 53:228-236, 1981 3. Taylor DC, Bhagavan BS, Larsen MP, et al: Papillary urothelial hyperplasia: A precursor to papillary neoplasms. Am J Surg Pathol 20:1481-1488, 1996 4. Epstein JI, Amin MB, Reuter VR, et al: 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 5. Yang XJ, Kuznetsov D, Pytel P, et al: Presence of flat intraurothelial lesion adjacent to low-grade papillary urothelial carcinoma: A hitherto unrecognized lesion. Mod Pathol 14:129A, 2001 6. Heney NM, Ahmed S, Flanagan MJ, et al: Superficial bladder cancer: Progression and recurrence. J Urol 130:1083-1086, 1983 7. Smith G, Elton RA, Beynon LL, et al: Prognostic significance of biopsy results of normal-looking mucosa in cases of superficial bladder cancer. Br J Urol 55:665-669, 1983 8. Koss LG: Diagnostic Cytology of the Urinary Tract With Histopathologic and Clinical Correlations. New York, NY, Raven Press, 1996, pp 78-85 9. Ruppert M, Tokino K, Sidransky D: Evidence for two bladder cancer suppressor loci on chromosome 9. Cancer Res 53:5093-5095, 1993 10. Sauter G, Deng G, Moch H, et al: Physical deletion of the p53 gene in bladder cancer: Detection by fluorescence in situ hybridization. Am J Pathol 144:756-766, 1994 11. Sauter G, Moch H, Carroll P, et al: Chromosome-9 loss detected by fluorescence in situ hybridization in bladder cancer. Int J Cancer 64:99-103, 1995 12. Spruck CH, Ohneseit PF, Gonzalez-Zulueta M, et al: Two molecular pathways to transitional cell carcinoma of the bladder. Cancer Res 54:784-788, 1994 13. Chow NH, Cairns P, Eisenberger CF, et al: Papillary urothelial hyperplasia is a clonal precursor to papillary transitional cell bladder cancer. Int J Cancer 89:514-518, 2000 14. Hartmann A, Moser K, Kriegmair M, et al: Frequent genetic alterations in simple urothelial hyperplasias of the bladder in patients with papillary urothelial carcinoma. Am J Pathol 154:721-727, 1999 15. Cina SJ, Lancaster-Weiss KJ, Lecksell K, et al: Correlation of Ki-67 and p53 with the new World Health Organization/International Society of Urological Pathology classification system for urothelial neoplasia. Arch Pathol Lab Med 125:646-651, 2001 16. Bostwick DG, Ramnani D, Cheng L: Diagnosis and grading of bladder cancer and associated lesions. Urol Clin North Am 26:493507, 1999
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