Inverted Urothelial Papilloma

Etiology

The etiology of inverted urothelial papilloma of the bladder remains unknown. However, several studies emphasize the importance of chronic inflammatory conditions and irritation.[3] Some authors suggested that inverted urothelial papilloma of the bladder arises from reaction to inflammation, chronic infection, smoking, obstruction, or exposure to carcinogens.[4]  Other authors argue that inverted urothelial papilloma growth occurs from hyperplasia of von Brunn’s nests and represents either a regenerative or a reactive process.[5] A few authors have reported p16 positivity and therefore suggest a pathogenesis correlated with HPV infection, athough more specific tests like in-situ hybridization have not detected HPV DNA in the papilloma tissue. Thus HPV as an etiologic agent for inverted urothelial papilloma is not yet substantiated.[6]

Epidemiology

Inverted papillomas account for <1% of all bladder urothelial neoplasms. Most patients are in their fifth or sixth decade of life, with a reported patient age range of 9-88 years. It affects males more commonly than females, with a male-to-female ratio of 5.8 to 1.[1]

There is a higher prevalence of urothelial neoplasms among smokers. However, in smokers, the lesions are usually positive for p53 gene mutations, and the papillomas tend to coexist with higher-grade malignancies.[7] Inverted urothelial papilloma does not have p53 mutations, although they may have overexpression of p53.[8]

Pathophysiology

A number of molecular chromosomal and other molecular changes may be seen in inverted urothelial papillomas. The finding of nonrandom inactivation of X chromosomes is well documented which suggests that inverted papilloma is a clonal neoplasm that arises from a single progenitor cell.[9] The incidence of loss of heterozygosity (LOH) in inverted papilloma is low (8-10%) and contrasts to the high frequency of LOH (29% to 80%) in urothelial carcinoma and papillary urothelial neoplasm of low malignant potential. Some studies reported FGFR3 mutations in 9.8-45% of inverted papillomas, but others have found no such mutations. Similarly, some tumors have been reported to harbor 9p deletions (in 3.9% of cases), 9q deletions (in 13.2%), and 17p deletions (in 51%).[10] One study reported recurrent HRAS mutations (061R) in 60% of cases. The markedly reduced frequency of loss of heterozygosity, the absence of TP53 mutations, the absence of telomere shortening, and the pattern of FGFR3 mutations in inverted papilloma, in contrast to that of urothelial carcinoma, all are suggestive that inverted papilloma does not harbor the key genetic abnormalities that predispose to the development of urothelial carcinoma. This suggests that these entities arise through separate and distinct pathogenetic mechanisms.[11][12] However, there are some reports of coexisting urothelial cancer or development of urothelial cancer within 1-8 years of diagnosis of inverted urothelial papilloma. This is believed to be due to underdiagnosis of urothelial cancer due to sampling or other issues rather than a true progression. It is generally believed that inverted urothelial papilloma does not have malignant or metastatic potential.

Histopathology

Macroscopic Findings: The tumor is a raised, pedunculated, or polypoidal lesion with a smooth overlying surface. Tumor size varies from small lesions up to 8.0 cm, and most lesions are solitary. The most common site is the bladder neck followed by the trigone, lateral walls, and posterior wall.[13]

Microscopic Findings: Inverted urothelial papillomas have a trabecular growth pattern, sometimes with associated cystic changes and vacuolization of the luminal cells simulating florid cystitis cystica and cystitis glandularis. The anastomosing cords and trabeculae are of relatively uniform width, arise from the surface urothelium, and invaginate into the lamina propria. The overlying urothelium can be normal, attenuated, or hyperplastic. By definition, an exophytic papillary structure is absent or minimal. The base of the lesion has a smooth interface with the adjacent stroma. The periphery of the cords and trabeculae is lined by darker cells, which are often palisading (basal cells). These vary from 5 to 10 cell layers thick to more nodular or solid areas. The lack of cytological atypia denotes an inverted papillary urothelial neoplasm which needs to be differentiated from urothelial tumors of low malignant potential or urothelial carcinoma with an inverted growth pattern. The tumor cells may have foamy cytoplasm which may be a focal or diffuse feature. 

The central portion of the tumor is composed of bland spindle-shaped cells parallel to the cords (streaming).  Squamous metaplasia, microcyst formation, and true glandular differentiation may also be present. The intervening stroma is minimal and commonly fibrotic, with minimal inflammation. The neoplastic cells in inverted papilloma show no or minimal cytological atypia, but degenerative atypia may occasionally be in evidence. Rare mitotic figures may be present in the periphery of the trabeculae or cords. The presence of nuclear atypia, such as irregular chromatin distribution, enlarged irregular nucleoli, expansile growth and increased mitoses, denotes inverted urothelial carcinoma. 

Henderson et al. suggested the following histological features to establish the diagnosis of inverted urothelial papilloma of the urinary bladder:[13][14]

1. Inverted architecture similar to inverted papilloma of the upper urinary tract
2. Normal urothelial lining
3. Uniformity of urothelial cells
4. Absent or infrequent mitosis
5. Microcyst formation
6. Squamous metaplasia 

There are two main subtypes of inverted urothelial papilloma:1. Trabecular subtype–Classic type 2. Glandular subtype showing morphological overlap with cystitis glandularis

History and Physical

The clinical features of inverted urothelial papilloma of the bladder are not specific [2]. It may be asymptomatic or may have one or more presenting complaints. The most common presenting symptom is painless gross hematuria. Other uncommon clinical presentations may include the following signs and symptoms [3][15]: microscopic hematuria, dysuria, flank pain, low back pain, occasional pyuria, or vague abdominal discomfort. Flank pain or low back pain may be the presenting symptoms of lesions of the renal pelvis or ureteric papillomas, which may have associated features of urinary obstruction. 

Evaluation

Inverted urothelial papilloma is seen most frequently in the bladder. They are usually incidentally discovered on imaging studies or cystoscopy during the evaluation of other conditions like benign prostatic hyperplasia, hemturia or prostate cancer. Although ultrasonography of the bladder may detect a bladder mass, cystoscopy remains the diagnostic procedure of choice. 

Cystoscopy: On cystoscopy, inverted urothelial papilloma of the bladder appears as:[16]

• A pedunculated or sessile mass with a relatively obvious smooth surface, or as a polypoid/papillary tumor with a smooth surface
• The diameter of the mass is less than 3 cm in most cases but can sometimes be much larger, with a diameter of up to 8 cm.
• Generally, it is a single lesion, but can rarely be multiple.

Magnetic resonance imaging: Inverted urothelial papilloma of the bladder is iso-intense on T1-weighted images and either iso-intense or slightly higher in intensity than the wall of the bladder on T2-weighted images.[17] Radiologic diagnosis is similar to the cystoscopic appearance and is based on the shape and surface characteristics of the lesion. The shape could be polyploid or flat. The polyploid lesions may have a short stalk or may be sessile. The tumor surface may be smooth (non-papillary), papillary, or may show spinous projections. 

Urine cytology: Urine cytology is not useful in the diagnosis of inverted urothelial papilloma of the bladder since normal urothelium covers it.[[18] 

Immunohistochemistry, genetics, and molecular studies may be necessary to differentiate inverted urothelial papilloma from urothelial cancer in some cases.[19][20]

Photodynamic diagnosis of superficial bladder cancer using 5-aminolevulinic acid (5-ALA) is becoming increasingly useful in the detection and diagnosis of urothelial neoplasms. Recent reports indicate that inverted urothelial papillomas will fluoresce after 5-ALA administration. This indicates that photodynamic means cannot distinguish between a superficial bladder cancer and inverted urothelial papillomas.[21] This may also indicate that inverted urothelial papillomas have more malignant potential than previously thought or could be a risk factor for the development of future urothelial carcinoma. 

Treatment / Management

Since inverted urothelial papillomas of the bladder show no tendency to infiltration, their treatment involves complete transurethral resection.[5]  Inverted urothelial papillomas of the upper urinary tracts are even less common than bladder lesions. However, when the upper urinary tracts are involved, the lesions tend to be sizeable.  Treatment of smaller upper tract inverted urothelial papillomas can be with ureteroscopy, but larger lesions may require percutaneous access for direct resection, partial ureterectomy, or even nephrectomy.[5] 

Differential Diagnosis

The differential diagnoses of inverted urothelial papilloma of the urinary bladder include [3]:

• Florid proliferation of Von Brunn nests
• Invasion of Brunn's nest by urothelial carcinoma
• Exophytic papilloma
• Urothelial carcinoma with an inverted (endophytic) pattern of growth
• Papillary urothelial neoplasm of low malignant potential
• Cystitis glandularis
• Other rarer differential diagnoses include:  nephrogenic adenoma, paraganglioma, carcinoid tumor, cystitis cystica

Inverted urothelial papilloma may have overlapping gross and histopathologic features. However, urothelial cancer will show focal or diffuse invasive nests of cells with irregular borders and desmoplasia around the nests. Additionally, urothelial cancers may have lymphatic and vascular invasion along with cellular atypia along with nuclear pleomorphism, necrotic changes, and mitoses. [2]

Immunohistochemistry is a useful tool for distinguishing urothelial cancer from inverted urothelial papilloma. Inverted urothelial papillomas will have a low Ki-67 positivity due to the low cellular proliferation, and are CK20 negative, unlike urothelial cancers.[22] 

Prognosis

Inverted urothelial papilloma is associated with a low risk of recurrence (<5%) and is usually regarded as a benign neoplasm.[5] Incomplete tumor resection contributes to its high recurrence rate.[18] Some clinical reports have shed doubt on the innocuous nature of inverted urothelial papilloma of the bladder with significant clinical implications regarding long-term cystoscopic surveillance.[18]

Complications

Based on some recent studies, inverted urothelial papilloma of the urinary bladder could be a risk factor for transitional cell carcinoma of the urinary tract. It is clinically prudent to exclude urothelial cancer when inverted urothelial papilloma of the urinary bladder is diagnosed and plan a careful course for follow-up.[3] It is reported that from 2.5-10% of patients with inverted urothelial papillomas of the bladder will develop urothelial carcinoma over the following 9-96 months. [2]