Inverted Urothelial Papilloma


Article Author:
Faten Limaiem


Article Editor:
Stephen Leslie


Editors In Chief:
Stephen Leslie
Karim Hamawy


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
6/4/2019 7:04:49 PM

Introduction

Inverted urothelial papilloma is a rare non-invasive endophytic urothelial tumor of the urinary bladder accounting for less than 1% of urothelial neoplasms.[1] Since its initial description by Paschkis in 1927, there have been more than 1,000 cases reported in the literature.[2] The clinical and endoscopic features of inverted urothelial papilloma of the bladder are not specific, and the definitive diagnostis is based on the histopathological examination. 

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 carcinogens.[4]  Other authors argue that inverted urothelial papilloma growth occurs from hyperplasia of Von Brunn’s nests through a regenerative or reactive process.[5]

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]

Pathophysiology

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.[6]

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%).[7] 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.[8][9]

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 wall, and posterior wall.[10]

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 of low malignant potential or a urothelial carcinoma with an inverted growth pattern. 

The central portion is composed of bland spindle-shaped cells parallel to the cords (streaming).  Squamous 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[10][11]:

  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]. The presenting symptoms of inverted urothelial papilloma include[3][12]:

  • Painless gross hematuria 
  • Microscopic hematuria 
  • Dysuria 
  • Pyuria
  • Abdominal discomfort
  • Acute urinary retention

Evaluation

Inverted urothelial papilloma of the bladder is usually incidentally discovered on imaging studies or cystoscopy. 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[13]:

  • 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.[14]

Urine cytology:

Urine cytology is not useful in the diagnosis of inverted urothelial papilloma of the bladder since normal urothelium covers it.[[15]

Immunohistochemistry, genetics and molecular studies may be necessary to differentiate inverted urothelial papilloma from urothelial cancer in some cases.[16][17]

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
  • 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

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.[15] 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.[15]

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]

Enhancing Healthcare Team Outcomes

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 and clinician will result in the best outcome. [Level V]


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Inverted Urothelial Papilloma - Questions

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A hemiplegic male had a long history of an indwelling foley catheter. He underwent a cystoscopy for microscopic hematuria and was found to have exophytic mucosal projections on fibrous stalks. Histology revealed inflammatory cells covered by normal appearing epithelial cells. What is the most likely diagnosis?



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Which of the following statements regarding inverted urothelial papilloma of the bladder is false?



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Which of the following statements is a differential diagnosis of inverted urothelial papilloma of the bladder?



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A 65-year-old man presented with a one-month history of hematuria. Cystoscopy showed a polypoid mass, approximately 1.5 cm in diameter, with intact overlying epithelium. Both ureteral orifices and the rest of the bladder linings were normal. The lesion was removed by endoscopic resection. Histological examination showed anastomosing islands and cords of normal urothelium originating from the overlying mucosa and growing downward into the stroma. Cytologic atypia and mitotic figures were absent. What is the most likely diagnosis?



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Which of the following statements regarding inverted urothelial papilloma of the bladder is false?



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Which of the following statements regarding inverted urothelial papilloma of the bladder is false?



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A 12-year-old boy presented to the urology service with a history of asymptomatic gross hematuria. Cystoscopy showed a polypoid, papillary lesion approximately 2 cm above and lateral to the left ureteral orifice. The lesion was connected to the wall of the bladder by a thin stalk. The lesion was entirely removed by transurethral resection and sent for pathologic examination. The specimen received in the fresh state consisted of an exophytic, friable, pale yellow mass. The mass exhibited multiple papillary projections as well as a cauterized stalk. Microscopically, the lesion consisted of intramucosal and submucosal papillary and anastomosing islands and cords of urothelium. Associated glandular spaces lined by urothelium and sometimes containing eosinophilic secretion were focally present. In other areas, submucosal glands resembling Brunn nests and submucosal cyst formations were seen. Neither cytologic atypia nor mitosis was seen. A minimal amount of edematous stroma with associated mild and focal inflammation is seen. What is the most likely diagnosis?



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Inverted Urothelial Papilloma - References

References

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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]
Sung MT,Maclennan GT,Lopez-Beltran A,Montironi R,Cheng L, Natural history of urothelial inverted papilloma. Cancer. 2006 Dec 1     [PubMed]
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]
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]
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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]
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]
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]
Williamson SR,Zhang S,Lopez-Beltran A,Montironi R,Wang M,Cheng L, Telomere shortening distinguishes inverted urothelial neoplasms. Histopathology. 2013 Mar;     [PubMed]
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]
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]
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]

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