Inverted urothelial papilloma is a rare tumor that presents as a non-invasive endophytic urothelial neoplasm of the renal pelvis, ureter, or urinary bladder accounting for less than 1% of all urothelial neoplasms. Since its initial description by Paschkis in 1927, there have been more than 1,000 cases reported in the literature. It is usually detected incidentally during the cystoscopic evaluation of other conditions e.g. benign prostatic hyperplasia, hematuria or prostate cancer. It may present as gross or microscopic painless hematuria. However, the clinical and endoscopic features of inverted urothelial papilloma of the bladder are not specific, and the definitive diagnosis is based on the histopathological examination.
The etiology of inverted urothelial papilloma of the bladder remains unknown. However, several studies emphasize the importance of chronic inflammatory conditions and irritation. Some authors suggested that inverted urothelial papilloma of the bladder arises from reaction to inflammation, chronic infection, smoking, obstruction, or exposure to carcinogens. 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. 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.
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.
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. Inverted urothelial papilloma does not have p53 mutations, although they may have overexpression of p53.
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. 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%). 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. 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.
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.
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.
There are two main subtypes of inverted urothelial papilloma:
1. Trabecular subtype–Classic type
2. Glandular subtype showing morphological overlap with cystitis glandularis
The clinical features of inverted urothelial papilloma of the bladder are not specific . 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 : 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.
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:
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. 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.[
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. 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.
Since inverted urothelial papillomas of the bladder show no tendency to infiltration, their treatment involves complete transurethral resection. 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.
The differential diagnoses of inverted urothelial papilloma of the urinary bladder include :
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. 
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.
Inverted urothelial papilloma is associated with a low risk of recurrence (<5%) and is usually regarded as a benign neoplasm. Incomplete tumor resection contributes to its high recurrence rate. 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.
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. 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. 
When middle-aged males present with hematuria, dysuria or urinary retention, they should receive a urologist referral. While the differential diagnosis of such symptoms is vast, the primary caregiver and nurse practitioner should be aware that inverted urothelial papilloma of the bladder can also present in such a fashion. While these lesions are considered benign, there is evidence that they may be a risk factor for bladder cancer, hence a proper plan of monitoring and treatment must be made. A coordinated effort involving the nurse, patient and clinician will result in the best outcome. [Level V]
|||Ho L,Jones E,Kavanagh A, Benign inverted papilloma at bladder neck causing acute urinary retention. Journal of surgical case reports. 2018 Jun [PubMed PMID: 29942474]|
|||Sweeney MK,Rais-Bahrami S,Gordetsky J, Inverted urothelial papilloma: A review of diagnostic pitfalls and clinical management. Canadian Urological Association journal = Journal de l'Association des urologues du Canada. 2017 Jan-Feb [PubMed PMID: 28443149]|
|||Picozzi S,Casellato S,Bozzini G,Ratti D,Macchi A,Rubino B,Pace G,Carmignani L, Inverted papilloma of the bladder: a review and an analysis of the recent literature of 365 patients. Urologic oncology. 2013 Nov [PubMed PMID: 22520573]|
|||Witjes JA,van Balken MR,van de Kaa CA, The prognostic value of a primary inverted papilloma of the urinary tract. The Journal of urology. 1997 Oct [PubMed PMID: 9302151]|
|||Sung MT,Maclennan GT,Lopez-Beltran A,Montironi R,Cheng L, Natural history of urothelial inverted papilloma. Cancer. 2006 Dec 1 [PubMed PMID: 17078053]|
|||Alexander RE,Davidson DD,Lopez-Beltran A,Montironi R,MacLennan GT,Compérat E,Idrees MT,Emerson RE,Cheng L, Human papillomavirus is not an etiologic agent of urothelial inverted papillomas. The American journal of surgical pathology. 2013 Aug; [PubMed PMID: 23681080]|
|||van Rhijn BW,Montironi R,Zwarthoff EC,Jöbsis AC,van der Kwast TH, Frequent FGFR3 mutations in urothelial papilloma. The Journal of pathology. 2002 Oct [PubMed PMID: 12237885]|
|||van Rhijn BW,van der Kwast TH,Vis AN,Kirkels WJ,Boevé ER,Jöbsis AC,Zwarthoff EC, FGFR3 and P53 characterize alternative genetic pathways in the pathogenesis of urothelial cell carcinoma. Cancer research. 2004 Mar 15 [PubMed PMID: 15026322]|
|||Sung MT,Eble JN,Wang M,Tan PH,Lopez-Beltran A,Cheng L, Inverted papilloma of the urinary bladder: a molecular genetic appraisal. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2006 Oct; [PubMed PMID: 16862073]|
|||Eiber M,van Oers JM,Zwarthoff EC,van der Kwast TH,Ulrich O,Helpap B,Stoerkel S,Blaszyk H,Cheville J,Sauter G,Wild PJ,Stoehr R,Hofstaedter F,Hartmann A, Low frequency of molecular changes and tumor recurrence in inverted papillomas of the urinary tract. The American journal of surgical pathology. 2007 Jun; [PubMed PMID: 17527084]|
|||Hodges KB,Lopez-Beltran A,Maclennan GT,Montironi R,Cheng L, Urothelial lesions with inverted growth patterns: histogenesis, molecular genetic findings, differential diagnosis and clinical management. BJU international. 2011 Feb; [PubMed PMID: 21091975]|
|||Williamson SR,Zhang S,Lopez-Beltran A,Montironi R,Wang M,Cheng L, Telomere shortening distinguishes inverted urothelial neoplasms. Histopathology. 2013 Mar; [PubMed PMID: 23379729]|
|||El Bote H,Atik S,Fares R,Hage E, [Inverted papilloma of the bladder: a rare benign tumor: a case report]. The Pan African medical journal. 2017 [PubMed PMID: 28690719]|
|||Isaac J,Lowichik A,Cartwright P,Rohr R, Inverted papilloma of the urinary bladder in children: case report and review of prognostic significance and biological potential behavior. Journal of pediatric surgery. 2000 Oct; [PubMed PMID: 11051166]|
|||Asano K,Miki J,Maeda S,Naruoka T,Takahashi H,Oishi Y, Clinical studies on inverted papilloma of the urinary tract: report of 48 cases and review of the literature. The Journal of urology. 2003 Oct [PubMed PMID: 14501726]|
|||Fine SW,Epstein JI, Inverted urothelial papillomas with foamy or vacuolated cytoplasm. Human pathology. 2006 Dec [PubMed PMID: 16949916]|
|||Takeuchi M,Sasaguri K,Naiki T,Mitsumori A,Ito H,Takahama J,Yamada K,Marugami N,Tsuboyama T,Okumura Y,Ohgiya Y,Kawai N,Kohri K,Shibamoto Y, MRI Findings of Inverted Urothelial Papilloma of the Bladder. AJR. American journal of roentgenology. 2015 Aug [PubMed PMID: 26204280]|
|||Ho H,Chen YD,Tan PH,Wang M,Lau WK,Cheng C, Inverted papilloma of urinary bladder: is long-term cystoscopic surveillance needed? A single center's experience. Urology. 2006 Aug [PubMed PMID: 16904447]|
|||Isharwal S,Hu W,Sarungbam J,Chen YB,Gopalan A,Fine SW,Tickoo SK,Sirintrapun SJ,Jadallah S,Loo FL,Pietzak EJ,Cha EK,Bochner BH,Berger MF,Iyer G,Solit DB,Reuter VE,Al-Ahmadie H, Genomic landscape of inverted urothelial papilloma and urothelial papilloma of the bladder. The Journal of pathology. 2019 Mar 5 [PubMed PMID: 30838648]|
|||Wang CC,Huang CY,Jhuang YL,Chen CC,Jeng YM, Biological significance of TERT promoter mutation in papillary urothelial neoplasm of low malignant potential. Histopathology. 2018 Apr [PubMed PMID: 29193225]|
|||Oshina T,Kawai T,Sato Y,Miyakawa J,Miyama Y,Makino K,Akiyama Y,Yamada Y,Nakamura M,Yamada D,Suzuki M,Ushiku T,Kume H, Inverted papilloma of the urinary bladder shows fluorescence on photodynamic diagnosis using 5-aminolevulinic acid. Photodiagnosis and photodynamic therapy. 2020 Jun [PubMed PMID: 32311542]|
|||Sun JJ,Wu Y,Lu YM,Zhang HZ,Wang T,Yang XQ,Sun MH,Wang CF, Immunohistochemistry and Fluorescence In Situ Hybridization Can Inform the Differential Diagnosis of Low-Grade Noninvasive Urothelial Carcinoma with an Inverted Growth Pattern and Inverted Urothelial Papilloma. PloS one. 2015 [PubMed PMID: 26208279]|