Pseudocarcinomatous Urothelial Hyperplasia of the Bladder: Clinical Findings and Followup of 70 Patients

Oleksandr N. Kryvenko and Jonathan I. Epstein*

From the Departments of Pathology (ONK), Urology and Oncology, The Johns Hopkins Medical Institutions (JIE), Baltimore, Maryland Accepted for publication December 4, 2012. Study received The Johns Hopkins Hospital institutional review board approval. * Correspondence: Department of Pathology, The Johns Hopkins Hospital, Weinberg 2242, 401 North Broadway, Baltimore, Maryland 21231 (e-mail: jepstein@jhmi.edu).

Purpose: Pseudocarcinomatous urothelial hyperplasia is rare and almost exclusively described in the pathology literature. Materials and Methods: We reviewed 70 cases during a 9.5-year period. Results: Two specimens were taken from biopsies done at our institution and 68 were from cases referred for consultation. Samples were obtained from a total of 60 men and 10 women with a mean age of 67 years (range 33 to 85). Of 68 patients with information available 52 (76.5%) underwent prior pelvic irradiation, 2 received systemic chemotherapy only, 3 had an indwelling bladder catheter, 2 received intravesical chemotherapy, 1 had been treated with radical prostatectomy, 4 had severe peripheral vascular disease, 1 had an arteriovenous malformation, 1 had sickle cell disease and only 2 (2.9%) had no identiable contributing factors. Pseudocarcinomatous urothelial hyperplasia developed an average of 54.6 months (range 9 months to 13 years) after prior irradiation. Hematuria was the most common clinical presentation, noted in 45 of 51 patients with data available. Of 48 patients with data endoscopy revealed erythema in 20, a papillary/polypoid lesion in 12, broad-based elevated erythematous lesions in 6, erythematous bullous edema in 5, shallow bleeding ulcers in 4 and prominent trabeculation in 1. Additional ndings in the bladder were carcinoma in situ in 3 cases, and dysplasia, low grade papillary urothelial carcinoma and papillary urothelial hyperplasia in 1 each. Three of the 40 patients with an average followup of 27 months (range 1 to 94) subsequently had urothelial carcinoma, including 1 who had prior positive cytology and uorescence in situ hybridization, 1 with prior high grade papillary urothelial carcinoma and 1 with an unknown history. Conclusions: Although pseudocarcinomatous urothelial hyperplasia mimics invasive urothelial carcinoma clinically and histologically, it is not related to urothelial neoplasms. Almost all patients have causes of bladder ischemia, most commonly a history of remote prior pelvic irradiation. Key Words: urinary bladder, urothelium, hyperplasia, radiotherapy, ischemia PSEUDOCARCINOMATOUS urothelial hyperplasia was rst described more than a decade ago by Baker and Young.1 Chan and Epstein subsequently expanded its morphological diagnostic criteria.2 While the original studies described radiation therapy with or without chemotherapy as the cause of
0022-5347/13/1896-2083/0 THE JOURNAL OF UROLOGY 2013 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION

pseudocarcinomatous urothelial hyperplasia, Lane and Epstein more recently expanded its association with other conditions that could result in bladder ischemia.3 We analyzed a large cohort of patients with pseudocarcinomatous urothelial hyperplasia of the bladder with emphasis
http://dx.doi.org/10.1016/j.juro.2012.12.005 Vol. 189, 2083-2086, June 2013 RESEARCH, INC. Printed in U.S.A.

AND

www.jurology.com

2083

2084

PSEUDOCARCINOMATOUS UROTHELIAL HYPERPLASIA OF BLADDER

on its etiology, clinical and endoscopic presentation, and prognosis.

Possible pseudocarcinomatous urothelial hyperplasia risk factors in 68 patients with available information No. Pts (%)

MATERIALS AND METHODS

The study cohort comprised patients whose bladder biopsies were referred in consultation to one of us (JIE) or were obtained at our institution from January 2003 to July 2012. We dened pseudocarcinomatous urothelial hyperplasia as nests of urothelium with mild to moderate atypia and variable mitotic activity extending into the lamina propria in a background of extensive hemorrhage and brin irrespective of the presence or absence of prior radiation therapy.13 A form was faxed to all referring urologists, inquiring about 1) a history of irradiation, chemotherapy and instrumentation, and reasons for such therapy, 2) clinical presentation at biopsy, 3) systemic atherosclerotic disease, 4) cystoscopic ndings, 5) urine cytology results, 6) radiological ndings and 7) followup. The current study included 28 cases that were previously described morphologically1,3 and for which additional clinical features and followup data were obtained. The study was approved by The Johns Hopkins Hospital institutional review board.

Pelvic irradiation: Prostate Ca Prostate bladder Ca Uterine cervical Ca Colorectal Ca Endometrial Ca Urothelial Ca Systemic chemotherapy only: Colorectal Ca Unknown Indwelling Foley catheter Intravesical mitomycin Previous radical prostatectomy Severe peripheral vascular disease Arteriovenous malformation Sickle cell disease No known risk factors * Intravesical mitomycin in 1. Chemotherapy in 1.

52 (76.5) 42 2* 4 1 1 2 2 (2.9) 1 1 3 (4.4) 2 (2.9) 1 (1.5) 4 (5.9) 1 (1.5) 1 (1.5) 2 (2.9)

RESULTS
Specimens from 70 patients with pseudocarcinomatous urothelial hyperplasia of the bladder were seen at our institution during a 9-year period. A total of 68 specimens were referred for consultation and in 2 patients biopsy was performed at our institution. When interpretations were provided, the submitting pathologists considered certain diagnoses, including urothelial atypia possibly representing a neoplastic process in 15, high grade invasive urothelial carcinoma in 10, nested variant of invasive urothelial carcinoma in 4, reactive in 4, carcinoma in situ in 2, pseudocarcinomatous urothelial hyperplasia in 2, and cystitis glandularis, hemangioma, inammatory pseudotumor, inverted urothelial papilloma and low grade papillary urothelial carcinoma in 1 each. Of the patients 60 were male and 10 were female with an average age of 67.6 years (median 69, range 33 to 85). The table lists possible risk factors in our study associated with pseudocarcinomatous urothelial hyperplasia. The 2 patients without known risk factors were a 34-year-old female with lower abdominal pain and a 57-year-old male who had irritative symptoms with dysuria and microhematuria. In 39 of 52 patients treated with prior irradiation the date of therapy was known. Pseudocarcinomatous urothelial hyperplasia developed an average of 54.6 months (median 36, range 9 months to 13 years) after prior pelvic irradiation. The clinical presentation was known in 51 patients. Hematuria was the most common presenting

symptom, seen in 45 patients, including 2 who also had dysuria. In 2 patients dysuria was the only clinical manifestation. In 2 patients the lesion was discovered on surveillance cystoscopy for noninvasive, low grade papillary urothelial carcinoma and invasive, high grade urothelial carcinoma, respectively. Two patients sought medical attention due to lower abdominal pain. We obtained cystoscopic ndings in 48 patients, which showed erythema in 20, a papillary/polypoid lesion in 12, broad-based elevated erythematous lesions in 6, erythematous bullous edema in 5, shallow bleeding ulcers in 4 and prominent trabeculation in 1 (g. 1). Hyperemia and telangiectasia were often observed on cystoscopy. Additional pathological ndings in the bladder were urothelial carcinoma in situ in 3 cases, urothelial dysplasia in 1, low grade papillary urothelial carcinoma in 1, papillary urothelial hyperplasia in 1 and polypoid cystitis in 2. Urine cytology results were available in 26 patients. In 1 patient urine cytology was described as positive and UroVysion uorescence in situ hybridization revealed chromosomal abnormalities consistent with urothelial carcinoma. In another patient urine cytology was interpreted as atypical. The remaining 24 specimens were interpreted as negative for urothelial abnormalities. Average followup was 27 months (median 16.5, range 1 to 94) in 40 patients. Three patients were subsequently diagnosed with urothelial carcinoma. A 73-year-old man who received irradiation for prostate cancer 1 year before the diagnosis of pseudocarcinomatous urothelial hyperplasia had invasive, high grade urothelial carcinoma 2.5 years later and

PSEUDOCARCINOMATOUS UROTHELIAL HYPERPLASIA OF BLADDER

2085

Figure 1. Flat erythematous appearance of pseudocarcinomatous urothelial hyperplasia mimicking carcinoma in situ on cystoscopy. Note prominent congested vessels in surrounding mucosa. Reprinted with permission from Dr. Victor J. Ferlise, Urological Health Center of New Jersey, Toms River, New Jersey.

died of the disease within 1 year. In this patient urine cytology and uorescence in situ hybridization results were positive at the time when pseudocarcinomatous urothelial hyperplasia was diagnosed. In a 77-year-old man with a history of irradiation for high grade urothelial carcinoma the record obtained from elsewhere indicated that urothelial carcinoma developed 19 months later. In a 72-year-old man with a Foley catheter and an unknown history invasive, high grade urothelial carcinoma was reported 8 months after biopsy revealed pseudocarcinomatous urothelial hyperplasia. The remaining 37 patients with available followup had no evidence of malignancy at the latest followup visit. Five patients continued to have intermittent or persistent hematuria, which was clinically attributable to repeat episodes of lower urinary tract infection in 2.

atypia (g. 2, B). Mitosis is absent in most cases but it can be frequent in rare cases. The process is limited to the lamina propria and never involves the muscularis propria.2,3 If pathologists are not aware of this entity, it may be misinterpreted as invasive urothelial carcinoma. In 20% of the cases in the current study pathologists from elsewhere strongly considered invasive urothelial carcinoma in the differential diagnosis. While the pathological features of pseudocarcinomatous urothelial hyperplasia are well described, its clinical aspects and prognosis are not as well characterized. Originally described by Baker and Young as irradiation induced pseudocarcinomatous proliferation, pseudocarcinomatous urothelial hyperplasia was considered a reactive proliferation of urothelium resulting from irradiation induced ischemic injury to the bladder.1 In our study this relation between pseudocarcinomatous urothelial hyperplasia and irradiation was maintained. Almost three-quarters of our patients presented with a history of pelvic irradiation. The increased frequency with which we see this lesion in our practice along with the strong male predominance reects the increasing use of radiation therapy for prostate cancer. Since pseudocarcinomatous urothelial hyperplasia typically manifests years after radiation therapy, in our experience pathologists are not routinely provided with this pertinent history. Consequently, it is critical for pathologists to recognize the histological ndings of this condition in the absence of a knowledge of prior therapy. In most cases contacting the clinician can lead to a reassuring history of prior treatment that is consistent with the diagnosis of pseudocarcinomatous urothelial hyperplasia. However, a higher incidence of secondary bladder carcinoma was also reported after irradiation for prostate cancer.46 Moon et al postulated that an increased risk of secondary cancer primarily occurs due to external beam radiation but not to radioactive seeds implanted in the prostate.7 However, in a literature review Mller et al concluded that the

DISCUSSION
Pseudocarcinomatous urothelial hyperplasia is a recently described, uncommon entity with a total of only 32 cases reported in 3 series to date.13 The condition is identied by small, inltrating nests of urothelium in the lamina propria that mimic invasive urothelial carcinoma. In contrast to urothelial carcinoma, the surrounding stroma is edematous with recent hemorrhage and hemosiderin deposition. A characteristic nding is nests of urothelium encircling abundant stromal brin (g. 2, A). Higher magnication reveals cells with eosinophilic to amphophilic cytoplasm and a mild to moderate degree of cytological

Figure 2. Microscopic appearance of pseudocarcinomatous urothelial hyperplasia. A, low power magnication shows inltrating appearance of epithelial nests in lamina propria with abundant hemorrhage and brin. Reduced from 100. B, high power magnication of same case reveals urothelial atypia mimicking malignancy. Reduced from 400.

2086

PSEUDOCARCINOMATOUS UROTHELIAL HYPERPLASIA OF BLADDER

cause and effect relationship between irradiation for prostate cancer and an increased risk of subsequent urothelial carcinoma is controversial.8 The reported average latency period between radiation and carcinoma is 5 years, similar to the interval between pseudocarcinomatous urothelial hyperplasia and prior irradiation. Consequently, classic histological ndings of pseudocarcinomatous urothelial hyperplasia are needed to establish a denitive benign diagnosis. As in our earlier studies, we noted that pseudocarcinomatous urothelial hyperplasia can also develop in patients treated with systemic chemotherapy without radiotherapy.2 In our most recent prior study of the condition we described 7 patients who did not receive prior chemotherapy or radiation therapy.3 Three patients had severe peripheral vascular disease, 2 had an indwelling Foley catheter, 1 had an arteriovenous malformation and 1 had a history of radical prostatectomy. This expands the etiology of pseudocarcinomatous urothelial hyperplasia to include potential causes of bladder ischemia unrelated to radiation therapy or chemotherapy. In addition to the 7 patients from the study by Lane and Epstein,3 we identied another 3 with similar nontreatment related reasons for pseudocarcinomatous urothelial hyperplasia. One of these patients had severe peripheral vascular disease and another had a history of an indwelling Foley catheter. The remaining patient had the novel nding of sickle cell disease as a risk factor. In rare cases with classic histological ndings of pseudocarcinomatous urothelial hyperplasia there are no identiable risk factors, which were seen in only 2.9% of our cases. Clinically, no specic symptoms can distinguish this entity from urothelial carcinoma. Nonspecic hematuria was the leading clinical symptom in patients with pseudocarcinomatous urothelial hyperplasia. Cystoscopy may suggest a benign reactive process in more than 50% of cases with ndings of

broad-based elevated erythematous lesions, erythematous bullous edema, shallow bleeding ulcers or prominent trabeculation. Negative urine cytology can further help rule out high grade carcinoma. Urine cytology was also helpful since it identied 1 of the 3 patients in whom urothelial carcinoma developed after pseudocarcinomatous urothelial hyperplasia was diagnosed. Consequently, positive urine cytology in the setting of pseudocarcinomatous urothelial hyperplasia should prompt reevaluation of the histological diagnosis to verify the diagnosis. If it is accurate, close patient followup is warranted since positive cytology cannot be explained by pseudocarcinomatous urothelial hyperplasia.

CONCLUSIONS
Pseudocarcinomatous urothelial hyperplasia is a rare reactive process resulting from an ischemic insult to the urothelium. Most affected individuals are male with a history of irradiation for prostate cancer. Less often, the condition may develop in patients treated with chemotherapy and in those with peripheral vascular disease or an indwelling catheter and other bladder insults. Cystoscopic ndings and negative urine cytology may provide some clue to the benign nature of the process. In patients with benign urine cytology without neoplastic changes elsewhere in the bladder the diagnosis of pseudocarcinomatous urothelial hyperplasia is not associated with an increased risk of subsequent urothelial carcinoma. However, as in 1 of our patients, there still exists the risk of unsampled urothelial carcinoma, such that additional biopsies may be indicated depending on clinical ndings. Recognition of this clinicopathological entity by urologists can prompt them to provide pathologists with a pertinent history of prior therapies, helping pathologists to arrive at the correct diagnosis and avoid a misdiagnosis of invasive urothelial carcinoma.

REFERENCES
1. Baker PM and Young RH: Radiation-induced pseudocarcinomatous proliferations of the urinary bladder: a report of 4 cases. Hum Pathol 2000; 31: 678. 2. Chan TY and Epstein JI: Radiation or chemotherapy cystitis with pseudocarcinomatous features. Am J Surg Pathol 2004; 28: 909. 3. Lane Z and Epstein JI: Pseudocarcinomatous epithelial hyperplasia in the bladder unassociated with prior irradiation or chemotherapy. Am J Surg Pathol 2008; 32: 92. 4. Bostrom PJ, Soloway MS, Manoharan M et al: Bladder cancer after radiotherapy for prostate cancer: detailed analysis of pathological features and outcome after radical cystectomy. J Urol 2008; 179: 91. 5. Liauw SL, Sylvester JE, Morris CG et al: Second malignancies after prostate brachytherapy: incidence of bladder and colorectal cancers in patients with 15 years of potential follow-up. Int J Radiat Oncol Biol Phys 2006; 66: 669. 6. Shah SK, Lui PD, Baldwin DD et al: Urothelial carcinoma after external beam radiation therapy for prostate cancer. J Urol 2006; 175: 2063. 7. Moon K, Stukenborg GJ, Keim J et al: Cancer incidence after localized therapy for prostate cancer. Cancer 2006; 107: 991. 8. Mller AC, Ganswindt U, Bamberg M et al: Risk of second malignancies after prostate irradiation? Strahlenther Onkol 2007; 183: 605.