Inverted urothelial papilloma is an uncommon urothelial neoplasm. Although it is traditionally regarded as a benign tumor, conflicting data on multiplicity, recurrence rate, and association with urothelial carcinoma have left uncertainties concerning its biologic behavior.
The authors analyzed the clinicopathological characteristics of 75 cases of inverted papilloma in the urinary tract without prior or concurrent urothelial carcinoma to determine its biologic behavior and prognosis, and to correlate these findings with surveillance strategies.
These patients ranged in age from 26 to 85 years (mean, 60 years). Of the 46 patients for whom tobacco use history was available, 28 gave a history of smoking. Inverted papillomas were located in the urinary bladder (67 cases), prostatic urethra (4 cases), and ureter (4 cases). The majority of vesical tumors arose from the trigone or near the bladder neck. Common presenting complaints included hematuria, dysuria, and irritative voiding symptoms. In 1 case of vesical inverted papilloma, there was a recurrence. All other patients were free of tumor recurrence or progression during a mean follow-up of 68 months (range, 2–240 months).
Inverted papilloma of the urinary tract is an uncommon urothelial neoplasm, which accounts for less than 1% of all urothelial neoplasms.1 Since Potts and Hirst first described this entity in 1963,2 over 300 cases have been reported in the English literature.3 Although it is generally regarded as a benign lesion, conflicting data on multiplicity, recurrence rate, and association with urothelial carcinoma have left uncertainties concerning the biologic behavior of inverted papilloma.3–19
We conducted the current study with the intention of clarifying the biologic behavior and prognosis of this somewhat controversial entity, and correlating these findings with the need for appropriate surveillance. We analyzed the clinicopathological characteristics of the largest series of inverted papilloma of the urinary tract reported to date.
MATERIALS AND METHODS
Cases of inverted papilloma of the urinary tract encountered between 1986 and 2005 were retrieved from the surgical pathology archives of the Indiana University Medical Center (Indianapolis, IN), Chang Gung Memorial Hospital (Kaohsiung, Taiwan), Cordoba University (Corboda, Spain), United Hospitals (Ancona, Italy), and University Hospitals of Cleveland (Cleveland, Ohio). The clinical features, including age, sex, presenting symptoms, cystoscopic findings (including tumor location, size, and multiplicity), smoking history, associated urine cytology, associated urothelial neoplasm, and follow-up status, were obtained from the medical records. All slides were retrospectively reviewed and diagnosed according to the current WHO criteria (Fig. 1)1 and those with complete clinical follow-up but no prior or concurrent urothelial carcinoma or carcinoma in situ were included in the current study.
Seventy-five patients, including 66 men and 9 women, whose resected tumors fulfilled the WHO diagnostic criteria for inverted papilloma, were included in this study. None had prior history or concurrent urothelial carcinoma or carcinoma in situ. The clinicopathological characteristics of these 75 patients are summarized in Table 1. The male-to-female ratio was 7.3:1. Patients ranged in age from 26 to 85 years (mean, 60 years). Of the 46 patients for whom tobacco use history was available, 28 gave a history of smoking.
Table 1. Patient and Tumor Characteristics in 75 Patients of Inverted Papilloma in the Urinary Tract
NA indicates not available.
Values in parentheses are percentages, unless otherwise stated.
One patient had multiple inverted papillomas in both trigone and neck of the urinary bladder
Inverted papillomas were located in the urinary bladder (67 cases), prostatic urethra (4 cases), and ureter (4 cases, 2 on the right and 2 on the left). The majority of inverted papillomas arising in the bladder were on or near the trigone (24 cases), or at the bladder neck (16 cases), and the remaining tumors were found on the dome (2 cases), posterior wall (8 cases), and lateral wall (9 cases, 5 on the right and 4 on the left) (Fig. 2). In 9 cases, the location was not recorded. Cystoscopically, most tumors were described as pedunculated masses or papillary tumors with smooth surfaces. All tumors but 1 were solitary, ranging in size from 1 to 29 mm (mean, 12 mm). In 1 case, multiple tumors were noted on the trigone and bladder neck.
Presenting complaints included hematuria (38 cases), dysuria (26 cases), and irritative voiding symptoms (12 cases). Other presenting symptoms included suprapubic pain (4 cases), pyuria (1 case), and acute urinary retention (1 case). Eighteen patients had more than 1 of these presenting symptoms. The presenting symptoms of 16 patients were unavailable for this study. Urine cytology examinations were performed in 9 inverted papilloma patients before tumor resection. In 2 cases, mild cellular atypia was noted, and in the remaining 7 cases no abnormal cells were found; urine cytology was essentially noncontributory in these cases. All but 4 patients underwent transurethral resection of their tumors; partial ureterectomy was performed in those 4 patients to resect the tumors in the ureter.
Follow-up was conducted in all 75 patients. Mean follow-up was 68 months (range, 2–240 months). Twenty patients had more than 8 years of follow-up. All but 5 cases remained alive during the follow-up period. Five patients died of unrelated diseases (1 of pneumonia, 1 of chronic obstructive pulmonary disease, 1 of lung cancer, 1 of pancreatic carcinoma, and 1 of brain hemorrhage at 20, 189, 88, 2, and 240 months after the initial diagnosis, respectively). Of the 75 patients, 1 patient developed recurrent inverted papilloma 10 months after resection of the initial tumor, and the remaining 74 patients remained free of urothelial neoplasms during follow-up.
Urinary tract inverted papilloma is an uncommon urothelial neoplasm that demonstrates an inverted growth pattern, usually composed of anastomosing islands and trabeculae of histologically and cytologically normal urothelial cells invaginating from the surface urothelium into the subjacent lamina propria but not into the muscularis propria. Although the term inverted papilloma was initially introduced in 1963 by Potts and Hirst to describe this architecturally distinctive urothelial neoplasm,2 the Viennese urologist Paschkis had previously reported 4 morphologically identical urothelial tumors in 1927 under the name of adenomatoid polyp.20 In 1983, Kunze et al. proposed the subdivision of inverted papillomas into 2 morphologically distinct variants.21 The trabecular variant is composed of anastomosing cords and trabeculae of urothelial cells invaginating the lamina propria at various angles. These invaginating structures demonstrate mature urothelium centrally, with darker and palisading basal cells peripherally, usually surrounded by fibrotic stroma without marked inflammation. The glandular variant was described as being composed of nests of urothelium with either pseudoglandular spaces lined by mature urothelium, or even true glandular elements, containing mucicarminophilic secretions and mucous-secreting cells. The glandular variant failed to gain widespread acceptance because of its morphologic overlap with florid cystitis glandularis.22
Urothelial inverted papilloma is usually found in men in their sixth or seventh decade of life,3, 19, 21 a demographic trend noted in our current series. Male predominance (male-to-female ratio, 7.3:1) and mean age of 60 years were observed in our patients, though a wide age range (from 26 to 85 years) was noted. In the current series, the majority of inverted papillomas developed in the urinary bladder (89%, 67 of 75 cases), especially on the trigone (32%, 24 cases) and bladder neck (21%, 16 cases), which is consistent with prior reports.3, 5, 10, 19 Our patients often complained of hematuria (51%), dysuria (35%), or irritable symptoms (16%) and 24% had more than 1 symptom, in keeping with previous studies.3, 19
The incidence of multiplicity in our study is 1.3% (1 of 75), which is significantly lower than in previous studies. In a literature review of 322 inverted papillomas of the urinary tract, Cheng noted an incidence of multiplicity of 4.4%.3 In addition, a significant number of patients in the current study (61%, 28 of 46 cases with available data) had a smoking history, suggesting a possible link between tobacco smoking and inverted papilloma. The relationship between inverted papilloma and smoking is inconclusive, but perhaps worthy of further investigation.
Inverted papilloma is a neoplasm with an endophytic growth pattern, covered by an intact layer of histologically and cytologically normal urothelium. Since the urothelium overlying the tumor is normal, it is not surprising that urine cytology is inefficient in detecting these neoplasms. In the current study, urine cytology was entirely negative for abnormal cells in 7 of 9 cases, and mildly atypical but nondiagnostic cells were noted in 2 other cases. Similar findings were noted in a literature review by Witjes et al., who reported that urine cytology had disclosed only mild aytpia of urothelial cells in 14% of cases (3 of 22).19
Transurethral resection is regarded as the standard treatment for inverted papilloma in the lower urinary tract,5, 7, 10, 19 and all tumors arising from the urinary bladder and prostatic urethra in our series were treated by this modality. As for tumors in the upper urinary tract, a variety of surgical options exist, including endoscopical resection, partial ureterectomy, and nephroureterectomy. Resection of ureteral inverted papilloma endoscopically or by partial resection of the ureter is considered adequate treatment by some experts23; however, difficulty in differentiating ureteral inverted papilloma from urothelial carcinoma and occasional coexistence of inverted papilloma and urothelial carcinoma make nephroureterectomy unavoidable in some cases. In our series, 4 patients who had inverted papillomas in the ureter underwent partial ureterectomy to resect the tumors.
Traditionally, inverted urothelial papilloma had been regarded as a benign neoplasm or a hyperplastic reactive lesion. However, cases associated with recurrence, or those with synchronous or metachronous urothelial carcinoma have generated uncertainty concerning its malignant potential.4, 8, 11, 12, 14–17 Cheng et al., in a cumulative literature review of 322 cases of inverted papilloma in the lower urinary tract, found that the recurrence rate was 4% and the incidences of associated synchronous urothelial carcinoma and development of subsequent urothelial carcinoma was 6% and 3%, respectively.3 Overaccumulation of p53 protein, overexpression of HER-2/neu, and increased proliferative index have been identified in inverted papillomas, suggesting that it might be susceptible to malignant transformation.8, 18 In our series, 74 of 75 patients were free of recurrent inverted papilloma during the follow-up period. Excluding those patients whose clinical status was complicated by synchronous or prior urothelial carcinoma, no patient diagnosed as having only inverted papilloma subsequently developed urothelial malignancy, a fact that strongly supports the benign nature of inverted papilloma.
Although several reports have raised concern about the malignant potential of inverted papilloma based on the development of subsequent urothelial carcinoma, the majority of these cases had a history of a prior or concurrent urothelial carcinoma.5, 7, 9, 13 Urothelial carcinoma, whether previously diagnosed or coexisting with inverted papilloma, clouds the clinical picture and introduces potential variability in the outcome after resection of inverted papilloma. In our series, all but 1 patients had an uneventful course without either tumor recurrence or progression to urothelial malignancy. The extremely favorable prognosis of inverted papilloma documented in the current series is similar to the findings in some recently reported large series (Table 2). In a clinical investigation of 20 patients of inverted papilloma in the lower urinary tract, Cheng et al. found that all patients were free of recurrence of inverted papilloma and only 1 man presented with a subsequent superficial urothelial carcinoma.3 Witjes et al. studied 37 cases of inverted papilloma in the urinary tract without a history of urothelial malignancy and found that only 1 patient developed a superficial urothelial carcinoma 49 months after resection of an inverted papilloma; they concluded that inverted papilloma does not seem to be a risk factor for urothelial carcinoma.19
Table 2. Follow-up of Inverted Urothelial Papilloma in Large Series Studies (Over 10 Cases)
In recent years, sporadic cases of inverted papilloma with concurrent urothelial carcinoma or with malignant features have been reported, raising concern that inverted papilloma may be a precursor lesion of urothelial malignancy.4, 8, 11, 12, 14, 16, 17 However, Amin et al. found that urothelial carcinoma with an inverted growth pattern may have features resembling inverted papilloma, and they considered many of the reported cases of inverted papilloma with urothelial carcinoma to be examples of urothelial carcinoma with inverted architecture.24 This viewpoint has also been supported by others.25 To differentiate between inverted papilloma and urothelial carcinoma with inverted growth pattern may be difficult, especially in limited specimens or when interpretation is confounded by crush artifact; such cases require close attention to the cytological and architectural characteristics of the tumor. Inverted papilloma usually exhibits orderly maturation of invaginated trabeculae and cords, composed of spindling and peripherally palisading cells. In contrast, urothelial carcinoma with inverted growth pattern often has thick and irregular tumor columns with transition to more solid nests. Additionally, the presence of an exophytic papillary component and unequivocal tumor invasion in the lamina propria or muscularis propria clearly justify a diagnosis of carcinoma. Marked cytological atypia, including nuclear pleomorphism, nucleolar prominence, and abundance of mitotic activity, favors a diagnosis of inverted urothelial carcinoma. However, focal mild cytological atypia is considered acceptable in inverted papilloma.25 In a study of 11 inverted urothelial papillomas with focal cytological atypia (less than 5%) by Broussard et al., cases harboring focal cytologic atypia did not demonstrate significantly cellular proliferation characteristics, and no tumor recurrence or progression to urothelial carcinoma was noted during the follow-up period.25
In conclusion, in this investigation of 75 inverted papillomas in the urinary tract, both the extremely low incidence of tumor recurrence and strikingly favorable prognosis during follow-up suggest that inverted urothelial papilloma is a benign urothelial neoplasm, lacking any close connection with urothelial carcinoma, provided that the diagnosis of inverted papilloma is based on strictly defined criteria. Consequently, transurethral resection of inverted papilloma is adequate treatment, and surveillance protocols as rigorous as those employed in the management of urothelial carcinoma seem unnecessary for this benign entity.