Table of Contents  

Kodzo-Grey Venyo and Lindsay Maloney: Inverted papilloma of the urinary tract – a review of the literature

Introduction

Because of the rarity of inverted papilloma of the genitourinary tract, some practitioners may not come across the lesion in their lifetime. In this paper we review the literature regarding various aspects of inverted papilloma of the urinary tract.

Materials and methods

Internet databases including PubMed, Google Scholar, Google and Educus were searched to identify papers reporting on inverted papilloma of the urinary tract. These papers formed the foundation of a review of the literature on inverted papilloma of the urinary bladder, ureter, renal pelvis and urethra.

Literature review

Definitions

Inverted papilloma (urothelial adenoma, Brunnian adenoma)

Inverted papilloma is an endophytic urothelial tumour which is generally considered a benign tumour although some urothelial carcinomas exhibit a prominent inverted growth pattern that may pose a diagnostic dilemma. The term ‘inverted papilloma’ was first coined by Potts and Hirst1 in 1963; however, Paschkis2 in 1927, was the first to describe the entity in the urinary bladder, naming it polypoid adenoma.

The terminology Brunnian adenoma has also been used for inverted papilloma, as the lesion bears a modest resemblance to normal Brunn's nests.3

The differentiation between inverted papilloma and malignant inverted urothelial carcinoma is based on cytological atypia, which is either absent or minimal in inverted papillomas but almost invariably present in urothelial carcinoma. Although there is some morphological overlap between the two entities, inverted papilloma, on the whole, is said to have a favourable outcome, with very little, if any, malignant potential.3

Epidemiology

According to Sung et al.,4,5 inverted papillomas account for less than 1% of urothelial neoplasms. Some authors3,4,6 have reported that inverted papillomas occur predominantly in men, with a male to female ratio of 4:1 to 7:1, and they typically occur in the fifth to sixth decade of life, but they can occur at any time from adolescence to the ninth decade. Roychowdhury7 found that inverted papilloma is more common in men than women, with a ratio of 7.3:1. Eaton and Cheng3 stated that majority of inverted papillomas are found incidentally during urological investigations for bladder outlet obstruction, haematuria or flank pain, and occasionally inverted papillomas are found on follow-up examinations for urothelial malignancies, which lends some weight to the discussion regarding their malignant association.

Van Rhijn et al. 8,9 stated that, although the prevalence of urothelial tumours is higher among smokers, the correlation is predominantly observed in association with p53 gene mutations and, consequently, such mutations are associated with higher-grade malignancies.

A number of authors3,10,11 have reported that inverted papillomas do not harbour p53 gene mutations, although they have occasionally been shown to display overaccumulation of p53 gene products. It has also been stated that p53 mutations are associated with malignancy; however, p53 mutations are not intrinsically related to inverted papillomas.3

Aetiology

There is no universally accepted cause of inverted papilloma. Although occasional cases of malignant transformation of inverted papillomas have been documented,3 it is not possible to determine whether such cases represent a true transformation, a misclassification of urothelial carcinoma or inverted papilloma arising in the setting of urothelial carcinoma or vice versa.12,13

According to Eaton and Cheng,3 the fibroblast growth factor receptor 3 (FGFR3) gene has been implicated in low-grade urothelial malignancies. There is also some evidence for the involvement of FGF receptor mutations in inverted papillomas; however, the evidence is variable, with the proportion of inverted papillomas affected ranging from 9.8% in one study of 62 inverted papillomas14 to 45% in another study of 20 inverted papillomas.10

Sung et al. 5 have reported that most cases of inverted papilloma are found in the urinary bladder (70%), most often in the trigone, followed by the bladder neck, dome, the posterior wall and the lateral wall. The remaining inverted papillomas (30%) are found, in decreasing frequency, in the ureter, renal pelvis and urethra.

Presenting features

The presenting symptoms of inverted papilloma include symptoms of bladder outlet obstruction, haematuria, dysuria and irritating voiding symptoms; about one-quarter of patients present with more than one symptom.3 Other presenting symptoms may include suprapubic pain, pyuria and loin pain.

Macroscopic features

On the whole, macroscopically inverted papillomas tend to be pedunculated lesions or sessile lesions with a smooth surface and covered with urothelial epithelia of a normal appearance. Inverted papillomas may vary in size, ranging from a few millimetres to 4 cm in diameter. The prevalence of multiple lesions ranges from 1.3% to 4.4%.7

Microscopic features

The overall pattern of inverted papillomas is that of cords and trabeculae of urothelial cells that grow into the underlying lamina propria but not the muscular propria, producing a localized, non-invasive endophytic mass that is covered by histologically and cytologically normal urothelium. Microscopic examination of inverted papilloma reveals a smooth surface with a minimal to absent exophytic component, lesional circumscription with a smooth base, no obvious infiltration and no, or minimal, cytological atypia. Figures 1 to 7 show pictures of two cases of inverted papilloma of the urinary bladder taken at various magnifications.

FIGURE 1

Case 1 – classic inverted papilloma of urinary bladder. Haematoxylin and eosin stain, ×40 magnification. Bladder mucosa with underlying muscle showing separate fragments from inverted papilloma. The papilloma is composed of cords and nests of benign transitional epithelium within the lamina propria.

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FIGURE 2

Case 1 – classic inverted papilloma of urinary bladder. Haematoxylin and eosin staining, ×100 magnification. This demonstrates classic inverted papilloma that comprises cords and nests of benign transitional epithelium in the lamina propria.

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FIGURE 3

Case 1 – classic inverted papilloma of urinary bladder. Haematoxylin and eosin staining, ×400 magnification. Benign epithelial cells are present, there is no cytological atypia and mitotic figures are absent.

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FIGURE 4

Case 1 – classic inverted papilloma of urinary bladder. Haematoxylin and eosin staining, ×500 magnification. A uniform population of epithelial cells.

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FIGURE 5

Case 2 – inverted papilloma of urinary bladder. Haematoxylin and eosin staining, ×100 magnification. A more solidly cellular inverted papilloma (also a classic type) showing some cords but predominantly nests of benign transitional epithelial cells in the lamina propria.

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FIGURE 6

Case 2 – inverted papilloma of the urinary bladder (also a classic type). Haematoxylin and eosin staining, ×400 magnification. Benign transitional epithelial cells are shown here.

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FIGURE 7

Case 2 – inverted papilloma of urinary bladder (also a classic type). Haematoxylin and eosin staining, ×500 magnification. Benign transitional epithelial cells are shown here.

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Inverted papillomas may be divided into two main types: the trabecular subtype and the glandular subtype.7

The trabecular subtype, the classical type, has the following features:

  • Irregular, downward-growing, ramifying thin and orderly cords and sheets arise from the overlying urothelium.7

  • The cords have peripheral palisading of basaloid cells.

  • The neoplastic cells within the cords and nests of urothelium often have a spindled appearance.

  • The intervening stroma is variable in amount and can be fibrotic.

  • Urothelial buds are frequent at various points under surface of the urothelium.

  • The overlying surface urothelium can be normal, attenuated or hyperplastic.

  • Trabecular papillomas are occasionally punctuated by cystic spaces lined by flattened urothelial cells and containing eosinophilic material.

  • Foci of non-keratinizing squamous metaplasia or neuroendocrine differentiation are rarely present.

  • Marked cytological atypia and mitotic activity are absent.

  • There may be mild cytological atypia due to prominent nucleoli, atypical squamous features, degenerative-appearing multinucleated cells or large atypical squamous cells with pagetoid appearance (designated as inverted papilloma with atypia).

  • Cases displaying atypia have not been associated with urothelial carcinoma (it has been recommended that be classified as ‘inverted papilloma with atypia’ rather than as not low-grade urothelial carcinoma).15

The glandular subtype is associated with morphological overlap with cystitis glandularis and has the following features:

  • Nests of mature urothelium contain either pseudoglandular spaces lined by urothelium or true glandular spaces containing mucus-secreting goblet cells.7

  • The luminal secretions stain with mucicarmine.7

Immunohistochemistry

Eaton and Cheng3 reported that classic inverted papillomas rarely express the immunohistological markers of urothelial carcinoma including p53, Ki-67 and cytokeratin 20. On the other hand, inverted papillomas with atypia have, on rare occasions, been found to harbour positivity for p53 and Ki-67, but typical inverted papillomas exhibit no immunohistochemical positivity. Eaton and Cheng3 also recommended that scant positivity to immunohistochemical markers should be interpreted in conjunction with cellular features, overall architecture and fluorescence in situ hybridization (FISH) analysis.

Molecular genetics

High-grade urothelial malignancies often exhibit mutations of the p53 gene whereas inverted papillomas have not been shown to exhibit such consistent mutations.3 There is variable evidence to suggest that inverted papillomas do occasionally possess mutations in the FGFR3 gene, which normally produces FGF receptor that is involved in signalling.8,16

Eaton and Cheng3 also reported that few tumours harbouring both p53 and FGFR3 mutations have been identified and it remains to be resolved whether these findings represent alternative tumorigenesis pathways or reflect a role of inverted papilloma as a precursor lesion. However, they state that recent developments in molecular testing using FISH assays to detect abnormalities in chromosomes 3, 7, 17 and 21 support the theory of a distinct tumorigenesis pathway. They point out that such anomalies have been detected in urothelial carcinomas but not in inverted papillomas, which would support this theory. In addition, similar mutations have been identified in studies reporting on loss of heterozygosity (LOH), which results in consistent changes in urothelial carcinoma but not in inverted papilloma.3

Treatment

Transurethral resection is the usual treatment of inverted papilloma of the lower urinary tract. In the case of inverted papilloma of the upper urinary tract, various types of surgical resection have been used based on the level of certainty of the behaviour of the tumour and whether or not there is concurrent urothelial carcinoma.

Outcome and predictive factors

The recurrence rate of inverted papilloma following treatment is less than 5% and the probability of synchronous or subsequent development of urothelial carcinoma is 6% and 3%, respectively.3

Differential diagnosis

With regard to the differential diagnosis of inverted papilloma, additional considerations include aggregates of von Brunn's nests (distinct nests of solid urothelium within the lamina propria) and inverted papillary urothelial neoplasm of low malignant potential, similar to von Brunn's nests but with prominent branching. Another condition to bear in mind, especially in younger patients, is fibroepithelial polyps. Fibroepithelial polyps can present in a clinically similar manner to inverted papillomas and they may exhibit similar histological appearances; nevertheless, architecturally, fibroepithelial polyps are characteristically exophytic or pedunculated and they exhibit a denser stroma with a fibrovascular core.3

Distinction between inverted papilloma and urothelial carcinoma may sometimes be difficult; however, the characteristics of the two lesions can be summarized as follows: urothelial carcinoma inverted growths are usually exophytic papillary lesions but inverted papillomas are usually smooth and dome shaped with an intact surface and are cytogenetically unremarkable.17

With regard to growth pattern, urothelial carcinoma inverted growths are endophytic with variable lesional circumscription. Inverted papillomas are endophytic, expansive, sharply delineated and they contain anastomosing cords and trabeculae. Cytologically, urothelial carcinoma inverted growths exhibit maturation and spindling whereas palisading is minimal or absent; inverted papillomas, in contrast, exhibit orderly polarized cells, some spindling and palisading at periphery, an absence of diffuse severe atypia and no or rare mitoses.17

Urothelial carcinoma inverted growths have the potential to recur and, although inverted papillomas are benign, rare recurrences related to incomplete surgical excision can occur.17

With regard to immunohistochemistry, urothelial carcinoma with inverted growth may have variable expressions; both p53 accumulation and Ki-67-MIB1 count vary according to the grade of differentiation but are usually high. Inverted papillomas exhibit low p53 accumulation and Ki-67-MIB1 count.17

Following molecular analysis, urothelial carcinoma inverted growths exhibit frequent FGFR3 mutations and chromosome 9 and 17 deletions; however, inverted papillomas rarely do so.17

Discussion

Table 1 contains a summary of some of the reported cases of inverted papilloma of the urinary tract. Tiwari et al. 18 reviewed all cases of inverted papilloma of the urinary bladder in their institution in order to determine the biological behaviour of the tumour and the need for strict follow-up. They included patients examined from August 2004 to August 2008 with inverted papilloma of the urinary bladder who did not have prior, or concurrent, urothelial carcinoma in their study. A single pathologist performed the histological review examination of all the specimens. All the patients had adhered to strict follow-up schedule of every 6 months. Tiwari et al. 18 reported the results of their study of 24 patients and found that the mean age at presentation was 53.5 years (range 22–81 years). The mean follow-up period was 25.8 months (range 6–58 months). Of the 24 patients, three were women and 21 were men. No patient had a synchronous or previously diagnosed bladder tumour. The most common presenting symptoms were macroscopic haematuria and dysuria. All the tumours, with the exception of one, were solitary tumours and they were most commonly found at the bladder neck and trigone. The average reported follow-up period without any evidence of recurrence was 2.5 years. Tiwari et al. 18 concluded that when diagnosed by strictly defined criteria, the incidence of recurrence of inverted papilloma is extremely low and prognosis is good. Inverted papilloma of the urinary bladder does not seem to be a risk factor for transitional cell carcinoma, especially if located in the bladder. Therefore, a good transurethral resection of the tumour is adequate therapy and a rigorous follow-up protocol, as for transitional cell carcinoma, may not be necessary.

Cheng et al. 19 presented a case series of inverted papilloma of urinary bladder and urethra together with a review of the literature with regard to multiplicity, recurrence rate and association with transitional cell carcinoma and discussion on surveillance of the lesion. Cheng et al. 19 reviewed cases of inverted papilloma of the lower urinary tract in a single centre. They reported on patient and tumour characteristics, tumour recurrence and associated transitional cell carcinoma. Cheng et al. 19 included 20 patients (18 male and two female) in their study. They also reported that the mean age of the patients was 60.8 years (range 35–78 years). All patients had solitary tumours ranging from 3 to 30 mm in size. The median cystoscopic follow-up time was 30 months (range 2–140 months). They also reported that there was no recurrent inverted papilloma; however, one patient subsequently developed transitional cell carcinomas 44 and 76 months later. Cheng et al. 19 then reviewed a total of 322 cases of inverted papilloma of the lower urinary tract reported in the English literature, including their own 20 cases mentioned above, and they found that the recurrence rate of inverted papilloma was 3.85%. They also found that 1.55%, 5.90% and 1.54% of cases were associated with previous, synchronous and subsequent transitional cell carcinoma, respectively. They concluded that recurrence of inverted papilloma of the lower urinary tract is not common but the risk of subsequent transitional cell carcinoma is not rare, such that non-invasive surveillance with flexible cystoscopy is recommended.

Cheon et al. 20 investigated the histological characteristics of inverted papilloma of the urinary bladder, including the likelihood of malignant transformation. They studied the indicators of cellular proliferation activity in seven inverted papillomas of the urinary bladder, including two cases of malignant inverted papilloma of the urinary bladder. They used the labelled streptavidin–biotin (LSAB) immunoperoxidase method of staining of proliferating cell nuclear antigen (PCNA) in routinely formalin-fixed and paraffin-embedded tissue sections36 by using a 1:10 monoclonal mouse antibody, DAKO-PCNA, PC-10 (DAKO UK Ltd, Cambridgeshire, UK). All the slides were reviewed independently by two investigators (Cheon and Kim). For a positive control, they used three samples of adenocarcinoma taken from the prostate tissues and replaced the primary antibody with irrelevant negative reagent as a negative control. The pattern of PCNA expression was classified into four scores by estimating the percentage of stained tumour cell nuclei. A score of 0 (negative) was defined as ‘the tumour contained less than 5% positive nuclei’, a score of 1 was defined as ‘the tumour showed patchy positive nuclei ranging from 5% to 19%’, a score of 2 was defined as ‘heterogeneously positive nuclei ranging from 20% to 75%’ and a score of 3 was defined as ‘homogeneously positive for PCNA in more than 75%’.

Cheon et al. 20 also stained all the samples with colloidal silver nitrate solution to identify argyrophilic nucleolar organizer regions (AgNORs), and counted the dots in the nuclei.37 They reported that careful focusing allowed visualization of AgNORs as black dots arranged in both clusters and clumps and as individual ‘satellites’ within the cell nucleus. In order to assess the reproducibility of the counting procedure, all counts were repeated and the repeated counts for each area varied by less than 10% from the initial value. To detect c-erbB–2 oncoprotein, Cheon et al. 20 used an indirect immunoperoxidase technique previously described by Wright et al. 38 involving polyclonal rabbit antihuman immunoglobulin (Dakapatis, Copenhagen, Denmark). Staining was classified as absent, weak, moderate or strong and a positive reaction was defined as the observation of distinct cell membrane staining; however, only faint (weak) cytoplasm staining could be noted.

Cheon et al. 20 reported that, cytoscopically, inverted papillomas were polypoid (pedunculated or sessile) and quite often appeared as nodular with grey to white surface elevations. They were observed to be usually 1–2 cm in diameter and six of the inverted papillomas were situated in the trigone and bladder neck region. None of the tumours had been recognized as inverted papillomas prior to the transurethral resection of the vesicle lesions. The average age of patients at the time of diagnosis was 52 years with a range of 37–63 years. The two patients with malignant inverted papillomas were aged 47 and 54 years. The male to female ratio was 5  :  2 and the patients with malignant inverted papillomas were both male.

Cheon et al. 20 made the following observations in relation to the characteristics of benign inverted papillomas. In five patients with inverted papillomas, there were peculiar microscopic configurations in that the epithelial cord pattern was invaginated deeply into the body of the lumen, while the external epithelial surface was smooth and without folds. The benign inverted papilloma was usually covered, or partly covered, by a thin epithelial layer and the epithelial cells were identical with normal transitional epithelium. They had little or no mitotic activity and cellular atypia was minimal. Of the five benign inverted papillomas, one occurred separately with transitional cell carcinoma of the urinary bladder. The five patients with benign inverted papillomas of the urinary bladder regularly underwent check cystoscopies and urine cytology examinations and there was no evidence of tumour recurrence or development of a de novo lesion of the bladder.

Cheon et al. 20 also reported that, in two other patients, the second patterns of inverted papillomas(the glandular types) exhibited increased cellularity, nuclear crowding and some dispolarities; additionally, the tumour was approximately 11–13 cells thick, which was a marked increase on the 6.8 cell thickness of normal urothelium. These appearances were interpreted as malignant transformation of the surface urothelial component of a benign inverted papilloma and malignant inverted papilloma. The tumour was regarded as malignant transformation of the urothelial component of a benign inverted papilloma and malignant inverted papilloma or transitional cell carcinoma with a feature of inverted papilloma. A benign inverted papilloma was also found concomitantly in the tumour that was adjudged to have undergone malignant transformation.

The 54-year-old man reported by Cheon et al. 20 in whom benign inverted papilloma transformed into malignant inverted papilloma had been treated with left nephroureterectomy and resection of bladder cuff 33 months previously. Radiological and pathological examinations found no metastatic lesions. However, subsequent follow-up check cystoscopy revealed multiple papillary masses on the posterior wall and neck of the urinary bladder. In addition, chest radiography revealed multiple metastatic lesions on the posteroanterior film. The patient underwent complete transurethral resection of the bladder tumours and four cycles of methotrexate, vinblastine, doxorubicin and cisplatin combination systemic chemotherapy, following which, the metastatic lesions in both lungs reduced appreciably in size. He was followed up for 6 months without any further treatment and appeared to be well.

The 47-year-old man reported by Cheon et al.,20 who had a grade 2 malignant inverted papilloma, was given a single 6-week course of intravesical instillations of bacillus Calmette–Guérin (BCG) immunotherapy following transurethral resection of the bladder tumour. Over a period of 52 months' follow-up, there was no evidence of tumour recurrence or progression.

Cheon et al. 20 reported that all of five patients with benign inverted papilloma of the bladder scored either no expression of PCNA (a score of 0 in one case) or patchy immunoreactivity (a score of 1 in four cases). In contrast, two malignant inverted papillomas showed inhomogeneous (a score of 2) and homogeneous (a score of 3) nuclear immunoreactivities. The nuclei of the two malignant inverted papillomas exhibited higher PCNA expression than benign inverted papillomas of the urinary bladder.

The mean numbers of AgNORs per nucleus in the five benign inverted papillomas reported by Cheon et al. 20 were 1.5, 2.2, 2.2, 2.5 and 2.7, which gave an average score of 2.2. Multiple AgNORs were seen in the malignant inverted papillomas. Furthermore, the nuclei of the malignant inverted papillomas displayed larger nucleoli and AgNORs of variable size. Mean AgNOR counts were higher in two malignant inverted papillomas depicted than in the benign inverted papillomas.

Cheon et al. 20 reported that c-erbB-2 immunohistochemical membrane staining was not seen in the five benign inverted papillomas. One inverted papilloma depicted a diffuse, faint intracytoplasmic staining pattern, but no outlining of cell membranes. In view of this, staining characteristics were deemed inappropriate for classification of c-erbB-2 immunoreactivity. However, both malignant inverted papillomas depicted high degrees of immunoreactivity (moderate and strong staining); thus, c-erbB-2 immunoreactivity was found in malignant, but not benign, inverted papillomas of the urinary bladder.

Brown and Cohen21 studied the clinical and pathological details of inverted papilloma of the urinary tract in Western Australia in order to determine the need for post-treatment cystoscopic follow-up. They summarized the clinical and pathological details of 41 cases of inverted papilloma of the urinary tract that were diagnosed in Western Australia between 1988 and 2010. They also reviewed and summarized publications on inverted papillomas of the urinary tract. In their series of 41 cases, all 38 subjects with lower urinary tract inverted papilloma underwent transurethral resection of the lesion. Of the three patients with upper urinary tract inverted papilloma, two were treated by nephroureterectomy because of high-grade ureteric obstruction, while percutaneous endoscopic resection was performed in the third patient, who subsequently underwent a partial ureterectomy 2 weeks later because residual inverted papilloma was identified postoperatively. The authors also reported that multiple lesions occurred in two cases (4.9%), and two patients (4.9%) had a history of transitional cell carcinoma, one of whom (2.4%) was also diagnosed with synchronous transitional cell carcinoma. Among the 25 patients with no previous coexisting transitional cell carcinoma and for whom cystoscopic follow-up was available, none developed recurrent inverted papilloma but two were diagnosed with transitional cell carcinoma within 9–28 months; both patients developed inverted papilloma of the ureter whereas the transitional cell carcinoma arose in the bladder.

Brown and Cohen21 concluded that inverted papilloma of the urinary tract is a rare benign tumour that is most commonly diagnosed in older men who present with haematuria or symptoms of lower urinary tract obstruction. Inverted papilloma is most frequently identified in the bladder neck or trigone as a polypoid growth with a smooth surface and the major differential diagnosis is transitional cell carcinoma with an inverted growth pattern, with the differentiation based mainly upon morphological criteria. Treatment of inverted papilloma of the lower urinary tract involves transurethral resection in the case but upper urinary tract inverted papillomas may be removed by (1) resection at ureteroscopy or percutaneous endoscopy, (2) partial ureterectomy or (3) nephroureterectomy. Inverted papillomas are weakly associated with a history of transitional cell carcinoma and with increased risk of concomitant or subsequent transitional cell carcinoma. Brown and Cohen21 concluded that, based upon the association with transitional cell carcinoma, post-treatment follow-up for inverted papilloma of the urinary tract should include cystoscopic follow-up.

Huang et al. 22 reported a case of a large inverted papilloma over the right lateral wall of the urinary bladder. The solid pedunculated mass had a slender stalk, which resulted in a check-value (check-valve) mechanism that contributed to relapsing acute obstructive symptoms that completely disappeared following transurethral resection of the bladder tumour. They also reported that the pathological picture showed the characteristics of an inverted papilloma and focal areas of cytological atypical. They did not detect any evidence of recurrence 3 months postoperatively.

According to Sung et al.,39 the relationship of inverted papilloma of the urinary bladder to urothelial carcinoma is controversial and little is known of the genetic abnormalities of inverted papilloma. In order to understand the genetics of inverted papilloma of the urinary bladder, Sung et al. 39 analysed 39 inverted papillomas, 36 in men and three in women, for LOH. They examined four polymorphic microsatellite markers, one located on chromosome 9q32–33 (D9S177), one on chromosome 9p22 (IFNA), one on chromosome 3p14.2 (D3S1300) and one on chromosome 17p13.1 (TP53), where genetic alterations occur frequently in urothelial carcinomas. In addition, they examined the status of inactivation of the X chromosome in the three female patients. They reported that the frequency of LOH in informative cases was 8% (3 of 37 cases) for D9S177, 11% (4 of 38 cases) for TP53, 8% (3 of 37 cases) for IFNA and 8% (3 of 36 cases) for D3S1300. In the analysis of X chromosome inactivation, they found that all three cases yielded informative results and one had non-random inactivation of X chromosomes. Sung et al. 39 stated that the monoclonal origin that was demonstrated in the study of X chromosome inactivation marks the clonal process of inverted papilloma; nevertheless, the low incidence of LOH supports the view that inverted papilloma in the urinary bladder is a benign neoplasm with molecular genetic abnormalities different from those of urothelial carcinoma.

Inverted papilloma of the urinary tract is a rare tumour, and inverted papilloma of the renal pelvis is extremely rare. A PubMed search retrieved only 37 records of the latter. Darras et al. 23 reported a case in 2005 of synchronous inverted papilloma of bladder and renal pelvis.

Mercant et al. 24 reported a case of inverted papilloma of the renal pelvis in 1992 and asserted that it invariably has a benign character and is cured by conservative surgery. They also stated that this biological behaviour of inverted papilloma of the renal pelvis should be borne in mind when encountering pelvic repletion defects (where there is a mass occupying the renal pelvis, ureter or urinary bladder, as seen by radiology after contrast medium), which can be mistaken, even after exfoliative cytologies, for low-level transitional cell carcinoma. In view of this, it is necessary to exhaust all procedures within one's grasp in order to establish a diagnosis prior to definitive surgery.

Ueda et al.,25 in 1992, reported the case of a 71-year-old man who was admitted to hospital for assessment of a right renal mass detected by excretory urography, computed tomography (CT) and magnetic resonance imaging. He underwent right nephrectomy and histological examination confirmed presence of a renal cell carcinoma that was staged as a pT2N0M0 tumour. In addition, histological examination of the specimen revealed an inverted papilloma in the renal pelvis. According to the authors, at that time, in 1992, 21 cases of inverted papilloma of the renal pelvis had been described and the reported case inverted papilloma of renal pelvis was the first associated with renal cell carcinoma.

In 1988, Yamaguchi et al. 26 reported a case of inverted papilloma of renal pelvis associated with transitional cell carcinoma of the urinary bladder. Uyama and Moriwaki,27 in 1981, reported a case of a renal pelvis tumour, the morphological structure of which resembled inverted papilloma of the urinary bladder but the tumour cells constituting the lesion underwent malignant transformation.

In 2012, Murtaza et al. 28 reported the case of a 35-year-old man who presented with pain in the left lumbar region. He had a history of left ureterolithotomy. On admittance to hospital, he underwent ultrasonography scan and intravenous urography, which revealed left hydroureteronephrosis. CT subsequently showed left hydroureteronephrosis with narrowing at the lower end of the left ureter. Left ureterorenoscopy confirmed multiple small and large polypoidal growths in the left lower ureter that were completely obliterating the lumen and involving the whole circumferential wall of the lower ureter. A biopsy of the lesion was taken and the histology of the specimen revealed an inflammatory polyp. Open surgical intervention comprising excision of the lower third of the left ureter followed by ureteric reimplantation with a Boari flap was undertaken. A later histology report of the lower third of the left ureter confirmed there had been inverted papilloma of ureter; however, following the excision and reimplantation with a Boari flap, the patient made a smooth postoperative recovery.

Inverted papilloma of the urethra is rare. A PubMed search for inverted papilloma of urethra revealed only 31 records. Fine et al. 29 found scant data on inverted papilloma of urethra prior to their 1996 publication, and no comprehensive study of inverted papilloma originating in the prostatic urethra. They identified 21 cases of inverted papilloma of urethra and evaluated the demographic, clinical and histopathological features. They reported that the patients had a mean age of 65.1 years (range 30–89 years). Ten out of 21 (47.6%) patients presented with gross haematuria (n = 8) or irrigative symptoms (n = 2) related to the inverted papilloma. Eleven out of the 21 cases (52.4%) were detected incidentally during treatment of prostate cancer (n = 6) or benign prostatic hypertrophy (n = 5). Fourteen lesions that were evaluated by cystoscopy measured 0.1–2.0 cm and were described as polypoid (n = 9), papillary (n = 4) or an enlarged median lobe (n = 1). The inverted papilloma lesions were diagnosed after transurethral resection (n = 8), biopsy/polypeptomy targeted to the lesion (n = 6), radical prostatectomy for prostate cancer (n = 4) or biopsy unrelated to the lesion (n = 3).

With regard to histological appearances of the lesions, 14 out of 21 cases (67%) depicted classic inverted papilloma architecture and the remainder foci of squamous metaplasia with moderate atypical fronds (n = 4), rare true papillary fronds in a classic inverted papilloma background (n = 2) or a combination of both (n = 1). Histological examination of the 11 cases in which prostatic tissue was present in the specimen revealed adenocarcinoma of the prostate [n = 6; Gleason score 6 (n = 3) or 7 (n = 3)], high-grade prostatic intraepithelial neoplasia (n = 1), benign prostatic hypertrophy (n = 3) or adenosis (n = 1). Fine et al. 29 also reported that none of the patients had a previous history of either inverted papilloma or urothelial carcinoma; however, two patients were diagnosed with high-grade urothelial carcinoma of the urinary bladder concurrent with their inverted papilloma diagnosis. Of the 18 patients for whom follow-up data were available, only one had a recurrence of inverted papilloma in the prostatic urethra. Of the other patients, none had local recurrences or recurrences at other sites or locations in the urinary tract following a mean follow-up of 39.9 months (range 3–120 months). Fine et al. 29 concluded that inverted papillomas of the prostatic urethra are benign lesions that are commonly detected incidentally and are not associated with a history of urothelial malignancy. Although urothelial carcinoma elsewhere in the genitourinary tract may occur simultaneously, malignant transformation or recurrence as a malignant lesion has not been identified in inverted papilloma of the prostatic urethra.

Viguri Diaz et al.,30 in 1995, reported the case of a 53-year-old woman with transitional cell inverted papilloma of the urethra presenting as postmenopausal metrorrhagia. The lesion was removed surgically and found to be round, 1.5 cm in diameter and polypoid. The lesion was resected and standard pathological analyses revealed a trabecular type of inverted papilloma. According to these authors, transitional cell inverted papilloma of the female urethra is rare: at the time of publication of their paper, inverted papilloma of the urethra had been reported only in male patients. Their reported case was the first to be described in a female.

Occhipinti et al. 31 reported the case of a 40-year-old man with a 2-year history of perineal and urethral symptoms that had been attributed to chronic prostatitis. He experienced urethral pain during ejaculation and also dull perineal and rectal pain, as well as occasional interrupted flow during voiding that was associated with perineal pain. He had been treated with multiple antibiotics and anti-inflammatory agents without any improvement in his symptoms. Courses of prostatic massages and hot baths also failed to provide any benefit. Urine cultures and cultures of prostatic secretions were negative for bacteria. Digital rectal examination revealed a slightly tender prostate but no fluid could be expressed. Transrectal ultrasonography of the prostate gland revealed a normal prostate but also a small polypoid mass measuring 0.7 cm × 0.6 cm at the bladder neck with a stalk extending into a slightly dilated prostatic urethra. Cystoscopy revealed a polypoid structure arising from an extremely narrow, long stalk that originated just to the left of the verumontanum. During instillation of fluid, the structure stretched proximally and extended to the bladder neck. The polypoid lesion was removed endosmotically and histological examination of the specimen revealed inverted papilloma but there was no evidence of inflammation or malignant degeneration. Following removal of the polypoid lesion, the patient's symptoms dramatically improved. His urinary stream became strong and steady and he was able to ejaculate postoperatively without any discomfort. His remaining symptoms improved progressively.

The resemblance of inverted papilloma to urothelial carcinoma inverted growths came to light in 1976 when Cameron and Lupton32 described two cases of urothelial carcinoma that mimicked inverted papilloma in architecture but also possessed high-grade cytological abnormalities. A number of authors have reiterated the potential of misinterpretation of urothelial carcinoma inverted growth as inverted papilloma.11,40,41 Amin et al. 11 stated that in a number of cases, the tumour possesses an identical architecture to inverted papilloma, whereas others grow with more of a broad-pushing front analogous to carcinoma.

Eble et al. 42 stipulated that this variant of urothelial carcinoma shows significant nuclear pleomorphism, mitotic figures and architectural abnormalities that are consistent with low- or high-grade urothelial carcinoma, graded using the WHO 2004 calssification scale.42 It has been stated that, in the majority of cases, the overlying epithelium depicts similar abnormalities and quite often contains typical urothelial carcinoma.17 It has also been said inverted papilloma-type carcinomas with minimal cytological and architectural abnormalities possess high mitotic activity and high Ki-6 labelling index. According to Amin et al.,11 an invasive or exophytic component is quite often associated with the inverted element. Nevertheless, in situations when there is fragmentation of inverted papilloma during the process of transurethral resection, a ‘pseudoexophytic pattern’ may result. In such instances, the stromal ‘cores’ are noted to be more variable and wider than the fibrovascular cores of true papillary neoplasms.11 Amin et al. 11 further stipulated that, at times, inverted papillary-type carcinoma and inverted papilloma are intimately admixed and that large papillary tumours with prominent entophytic growth ‘invade’ the lamina propria with a pushing border. Amin et al. 11 and Cameron and Lupton32 suggested that, unless this pattern is accompanied by true destructive stromal invasion, the likelihood of metastasis is minimal because the basement membrane has not been truly breached. Eble et al. 42 stated that assessing the presence of invasion is a major problem associated with this type of growth. This is particularly the case when the tumour is seen to be intermingling with slender muscle bundles of lamina propria or in juxtaposition with well-defined fascicles of muscularis propria. Eble et al. 42 also suggested that a diagnosis of invasion must be made in the presence of irregularities of the contours of the neoplastic nests, if the edges are jagged and inflammatory or if thermoplastic stroma is identified surrounding these nests.

Broussard et al. 15 stated that atypical inverted papilloma is a major differential diagnosis of urothelial carcinoma with inverted growth. They also reported that data are available confirming that these cases rarely exhibit mitotic figures and have an extremely low proliferation index, as seen by the Ki-67 labelling index. Hartmann et al. 43 suggested that a cut-off point of < 5% Ki labelling index should favour a diagnosis of inverted papilloma. Furthermore, there has been no documented association with urothelial carcinoma in the follow-up of patients diagnosed as having atypical inverted papilloma to date. It has been suggested that these atypical nuclei characteristics should probably be considered as degenerative in nature.17

According to Kunze et al.,6 the trabecular pattern of inverted papilloma comprises anastomosing cords and sheets of urothelium arranged at various angles to the mucosal surface and, in some cases, within the epithelial islands cystic spaces that are lined by attenuated urothelium. Kunze et al. 6 also stated that these cystic spaces may contain eosinophilic secretions that stain with periodic acid–Schiff but not mucicarmine and that the glandular pattern comprises nests of urothelium, with pseudoglandular or true glandular differentiation with goblet cells. Pseudoglandular spaces are lined with urothelium, whereas glandular spaces are composed of mucus-secreting cells with mucicarminophilic secretions and, at times, show intestinal metaplasia of goblet cells.

Lopez-Beltran17 reported that, in both the trabecular and glandular patterns of inverted papilloma, the epithelial elements are surrounded by intact basement membrane and fibrovascular stroma. Unusual inverted papilloma growth patterns include basaloid, hyperplastic, spindle cell (also referred to as medullary) and neuroendocrine patterns, quite often occurring with mixed forms. Furthermore, Lopez-Beltran17 stated that mild cytological atypia is often encountered in inverted papilloma and the precise demarcation with carcinoma is unresolved. Fortunately, this is an uncommon problem but there are cases that are difficult to resolve. The authors also stated that in rare cases, nuclear atypia may be prominent but these atypical nuclear features are most probably best considered degenerative in nature. Lopez-Beltran17 claimed that inverted papilloma and papillary urothelial carcinomas may be related; however, controversial and recent molecular data from a number of studies argue against it.12,43 46

Stosiek et al. 47 found that there has been an increase in cases of coexistent carcinoma or in situ urothelial carcinoma. However, a number of authors have suggested that some cases of inverted papilloma may actually represent an inverted growth pattern.11,15,32,40 42,48

Urakami et al. 33 reported a case of inverted papilloma associated with leiomyoma. Flow cytometry studies had shown that inverted papillomas are usually diploid,33,49 but Khoury et al. 40 found that one of three cases of inverted papilloma with associated urothelial carcinoma was aneuploid. Sauter50 stated that recurrent lesions developing after initial treatment of inverted papilloma have been observed in less than 1% of cases and that an initial diagnosis of inverted papilloma should be challenged if progression is observed.

Before the 1970s, inverted urothelial papilloma of the urinary bladder was generally regarded as a benign neoplasm.34 However, in the 1980s, a number of reported cases suggested the malignant potential of papillomas, which included cases with features indicative of malignancy and recurrent cases and cases of inverted papilloma synchronous or metachronous with transitional cell carcinoma. Picozzi et al. 34 reviewed the literature on inverted papillomas from 1990 to 2012 in order to contribute to unresolved issues relating to the biological behaviour and prognosis of inverted papillomas and to establish some key points in the clinical and surgical management of these papillomas. Database searches yielded 109 references, of which 10 references were relevant and described studies that fulfilled the authors' predefined inclusion criteria. According to Picozzi et al.,34 one problem in characterizing inverted papillomas is the difficulty of obtaining a correct histological diagnosis. They reported that the main differential diagnosis is endophytic urothelial neoplasm, including papillary urothelial neoplasia of low malignant potential or urothelial carcinoma of low or high grade; other, much rarer, differential diagnoses include nephrogenic adenoma, paraganglioma, carcinoid tumour, cystitis cystica, cystitis glandularis and Brunn's cell nests. Picozzi et al. 34 summarized the main findings of their review of the literature as follows:

  • The size of the lesions ranged from 1 to 50 mm (mean 12.8 mm).

  • Most cases occurred in the fifth and sixth decades of life. The mean age of affected patients was 59.3 years (range 20–88 years).

  • Analysis of the literature revealed a strong male predominance with a male to female ratio of 5.8:1.

  • The most commonly reported sites of inverted papilloma of the urinary bladder were the bladder neck region and trigone.

  • Of 285 cases included in eight studies, 12 cases (4.2%) had multiple papillomas.

  • Out of the total of 348 patients, six patients (1.72%) had a previous history of transitional cell carcinoma of the urinary bladder, five patients (1.44%) had synchronous transitional cell carcinoma of the urinary bladder and four patients (1.15%) had subsequent transitional cell carcinoma of the urinary tract.

  • Recurrence occurred < 45 months post surgery (range 5–45 months, mean 27.7 months).

Picozzi et al. 34 drew the following conclusions:

  • Inverted papilloma can be considered a risk factor for transitional cell carcinoma and it is clinically prudent to exclude transitional cell cancer when it is diagnosed.

  • Follow-up is required if the histological diagnosis is definitive or doubtful.

  • Flexible cystoscopy should be carried out every 4 months for the first year and then every 6 months for the subsequent 3 years.

  • Routine surveillance of the upper urinary tract in cases of inverted papilloma of the lower part of the urinary tract is not deemed necessary.

Yagi et al. 35 reported the case of inverted papilloma of the urinary bladder in a 10-year-old girl. She was referred with intermittent asymptomatic visible haematuria. A polypoid pedunculated mass, which had a thin stalk, was observed at cystoscopy and measured approximately 6 × 20 mm in diameter and was located at the right paratrigone. This was resected endoscopically and the histological findings were compatible with trabecular type of inverted papilloma. The authors reported that there are only three cases reported of inverted papilloma in children and none in a girl. They also stated that, in view of the fact that the biological potential of paediatric inverted papilloma remains unclear, it was their belief that their patient should undergo periodic and detailed urological examination.

Conclusions

Inverted papillomas are rare endophytic neoplasms of the genitourinary tract and are more common in males than females. They are usually benign and do not usually recur after complete resection or excision. Inverted papillomas can be differentiated from inverted urothelial carcinomas based upon the macroscopic appearances, microscopic appearances and by means of FISH and immunohistochemistry for Ki-67, p53 and cytokeratin. Inverted papilloma could be considered a risk factor for transitional cell carcinoma and it is clinically prudent to exclude transitional cell cancer when it is diagnosed. Follow-up is required regardless of whether the histological diagnosis is definitive or doubtful and flexible cystoscopy is recommended every 4 months for the first year and then every 6 months for the subsequent 3 years. Routine surveillance of the upper urinary tract in cases of inverted papilloma of the lower part of the urinary tract is not deemed necessary.

TABLE 1

Summary of some of the reported cases of inverted papilloma of urinary tract

Authors Site of origin Inverted papilloma Synchronous/metachronous tumours Size Sex Age Follow-up
Tiwari et al. 18 Mostly bladder neck and trigone Total 24
Solitary tumours 23
Multiple tumours 1
None Not reported 21 male patients and 3 female Mean: 53.5 years
Range: 22–81 years
25.8 months
Range: 6–58 months
Cheng et al.19 own series Bladder and urethra Total 20 patients, all solitary inverted papillomas 1 metachronous transitional cell carcinoma of bladder at 44 months and again at 76 months 3–30 mm 18 male patients and 2 female Mean: 60.8 years
Range: 35–78 years
Median: 30 months
Range: 2–140 months
Cheng et al.19 review inclusive of their 20 cases Lower urinary tract Total in review 322
Recurrence rate 3.85%
Previous transitional cell carcinoma of bladder 1.55%
Synchronous transitional cell carcinoma of bladder associated with 5.90% cases
Metachronous transitional cell carcinoma associated with 1.54% cases
Details not available in our source of information Details not available in our source of information Details not available in our source of information Details not available in our source of information
Cheon et al. 20 Bladder
6 out of 7 in the bladder neck and trigone
Total 7
5 benign inverted papilloma
2 malignant inverted papilloma
54-year-old man with synchronous malignant inverted papillomas
47-year-old man with metachronous malignant inverted papillomas
1–2 cm 5 male patients (3 benign, 2 malignant) and 2 female (both benign) Mean: 52 years
Range: 37–63 years
Variable up to 5 years
Brown and Cohen21 38 cases in bladder
3 cases in upper urinary tract (ureter)
Trigone and bladder neck, bladder wall, prostatic urethra and ureter
Total 41
[2 (4.9%) were multiple lesions]
2 of the 41 patients (4.9%) had previously had transitional cell carcinoma. One of these two patients (2.4%) also had synchronous transitional cell carcinoma Mean 15.2 mm
Range 8–28 mm
Male to female ratio 5:1 Mean: 62 years Available follow-up of 25 patients ranged from 9–28 months
Huang et al. 22 Bladder (lateral wall) Total 1 None Large, approximately 5 cm 1 male patient 71 years 3 months
Darras et al. 23 Bladder and renal pelvis Total 1 This was a synchronous inverted papilloma of bladder and renal pelvis Not stated 1 male patient 52 years 3 weeks after the second operation
Mercant et al. 24 Renal pelvis Total 1 Details in Spanish and not available Details in Spanish and not available Details in Spanish and not available Details in Spanish and not available Details in Spanish and not available
Ueda et al. 25 Renal pelvis Total 1 Synchronous inverted papilloma of renal pelvis associated with renal cell carcinoma found when a right nephrectomy was performed for a PT2N0M0 renal carcinoma 4.0 cm × 2.5 cm × 3.0 cm inverted papilloma (associated with a 4.0 cm × 5.0 cm × 3.0 cm as well as 3.5 cm × 4.0 cm × 3.0 cm renal cell carcinoma) 1 male patient 71 years 21 months
Yamaguchi et al. 26 Renal pelvis Total 1 Synchronous inverted papilloma and transitional cell carcinoma of urinary bladder found Details not available in our source of information Details not available in our source of information Details not available in our source of information Details not available in our source of information
Uyama and Moriwaki27 Renal pelvis Total 1 None Details not available in our source of information Details not available in our source of information Details not available in our source of information Details not available in our source of information
Murtaza et al. 28 Left lower ureter Total 1 None Size was not stated, CT scan report marked dilatation of ureter down to lower third at point of stricture 1 male patient 35 years 6 months
Fine et al. 29 Urethra Total 21
14 had classic inverted papilloma
2 patients had synchronous rare true papillary fronds in classic inverted papilloma
1 patient had synchronously both classic inverted papilloma and papillary fronds
6 patients had synchronous adenocarcinoma of prostate
3 patients had synchronously benign prostatic hyperplasia
14 patients with classic inverted papilloma, 0.1 – 2.0 cm Not available in abstract Mean: 65.1 years
Range: 30–81 years
Mean: 39.9 months
Range: 3–120 months
Mean: 39.9 months
Range: 3–120 months
Viguri Diaz et al. 30 Urethra Total 1 None 1.5 cm 1 female patient 53 years Details not available in our source
Occhipinti et al. 31 Verumontanum into bladder neck Total 1 None 0.7 cm 1 male patient Details not available in our source of information Details not available in our source of information
Cameron and Lupton32 Sites of 37 inverted papillomas:
bladder neck 17, trigone 8, around orifice 9, prostatic urethra 1, elsewhere 2
Total 2 None Details not available in our source of information Details not available in our source of information Details not available in our source of information Details not available in our source of information
Urakami et al. 33 Bladder Total 1 Synchronous leiomyoma
Picozzi et al. 34 Bladder
Out of 285 cases, 12 were multiples
Total 348 cases Out of 348 cases
5 (1.43%) had synchronous transitional cell carcinoma of bladder
4 (1.15%) had metachronous transitional cell carcinoma of bladder
Mean 12.8 mm
Range 1–50.0 mm
Male to female ratio 5.8:1 Mean: 59.3 years
Range: 20–88 years
Mean: 27.7 months
Range: 5–45 months
Yagi et al. 35 Right paratrigone Total 1 None 6 mm × 20 mm 1 female patient 10 years Not stated

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