A rare yet benign neoplasm, the inverted papilloma is an endophytic urothelial tumor of moderate significance due to its variable similarity to inverted urothelial carcinoma, which holds a much more aggressive prognosis. The term inverted papilloma was first introduced by Potts & Hirst in 1963,  although originally Paschkis described the entity in the bladder in 1927,  calling it a polypoid adenoma. The term Brunnian adenoma has also been used, as the lesion bears a modest resemblance to normal Brunn's nests.
The key histologic criteria that separate this benign lesion from its malignant counterpart center on cytologic atypia, which is absent to minimal in inverted papillomas but invariably present in urothelial carcinoma. Although morphologic overlap does exist between the 2 entities, the inverted papilloma has a favorable prognosis, with little if any malignant potential.
Inverted papillomas are infrequent and account for less than 1% of urothelial neoplasms. [3, 4] They occur predominantly in men, with a male-to-female ratio of 4-7:1, typically in the 5th to 6th decade of life, although the incidence can range from early adolescence to the mid-90s. [3, 5] Most inverted papillomas are discovered incidentally during routine urologic investigations for bladder outlet obstruction, hematuria, or flank pain. Occasionally inverted papillomas are discovered on follow-up examinations for urothelial malignancies, which in part lends to the discussion regarding their malignant association. 
Although the prevalence of urothelial tumors is higher among smokers, this correlation is predominately seen with p53 gene mutations, and consequently, they are associated with higher-grade malignancies. [7, 8] Inverted papillomas have not been shown to harbor p53 gene mutations, though they have been shown to occasionally possess over accumulation of p53 gene products, with one study finding such accumulations in 18.9% of inverted papillomas examined. [4, 9, 10] It should be stressed, thus, that p53 mutations are inherently associated with malignancy but are not intrinsically related to inverted papillomas.
Inverted papillomas arise in the setting of molecular changes that are not fully understood but are genetically distinct from the alterations seen in urothelial carcinoma.  Rare cases have been documented regarding malignant transformation of inverted papillomas, but it is unclear whether such cases represent a true transformation, a misclassification of urothelial carcinoma, or inverted papilloma arising in the setting of urothelial carcinoma (and vice versa). [12, 13]
The fibroblast growth factor receptor (FGFR3) gene has been implicated in low-grade urothelial malignancies, and consequently some evidence points toward the involvement of FGFR3 mutations in inverted papillomas, although the evidence is variable and ranges from 9.8% in one study of 62 inverted papillomas  to 45% in a study of 20 inverted papillomas. 
Alexander et al investigate the suggestion that human papillomavirus (HPV) plays an etiologic role in the development of inverted papilloma of the urinary bladder by evaluating 27 inverted papillomas of the urinary bladder for the presence of HPV. Both immunohistochemical and in situ hybridization (ISH) studies for HPV and immunohistochemical analysis for p16, a surrogate marker for HPV infection, were used to assess HPV infection status. The authors’ findings indicate the absence of HPV in urothelial inverted papillomas and as a result concluded that HPV testing should not be used as a diagnostic adjunct for inverted papilloma cases. 
The majority (70%) of inverted papillomas occur in the bladder, most often in the trigone, followed by the bladder neck, bladder dome, posterior wall, and lateral wall. The remaining 30% of inverted papillomas occur in the ureter, renal pelvis, and urethra in decreasing frequency. 
Clinical Features and Imaging
The most common symptoms of inverted papillomas, leading to their discovery, are bladder outlet obstruction, hematuria, dysuria, and irritative voiding, with approximately 25% of cases presenting with more than one symptom. Less common symptoms are suprapubic pain and pyuria.
Grossly, inverted papillomas are a pedunculated polypoid lesion or a sessile lesion with a smooth surface, covered with grossly normal-appearing urothelial epithelium, and they are usually located in the trigone. Inverted papillomas range in size from a few millimeters to 3 to 4 centimeters in greatest dimension.
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 muscularis propria, producing a localized, noninvasive endophytic mass covered by histologically and cytologically normal urothelium. The cords and trabeculae generally contain normal urothelial cells centrally, with darkened, palisading basal cells at the periphery. Rare atypical cells can be found, but these are more of the exception than the rule. Conversely, the more aggressive urothelial carcinoma generally has a thicker, irregularly shaped pattern of cords with transitioning into solid areas, cytologic atypia, nuclear pleomorphism with irregular chromatin distribution, and prominent nucleoli. The general order and peripheral palisading are usually absent in urothelial carcinoma. See the images below.
Debate arises in the literature pertaining to different subclasses of inverted papillomas, specifically, trabecular and glandular variants; however evidence suggests the glandular subtype is histologically indistinguishable from another urothelial entity, cystitis cystica or glandular cystitis. Other variations, however, are occasionally recognized, including basaloid, hyperplastic, and spindle cell / medullary, in addition to nonkeratinizing or neuroendocrine differentiation.
Classic inverted papillomas rarely express the immunohistologic markers of the more worrisome urothelial carcinoma, which include p53, Ki-67, and cytokeratin 20. Whereas inverted papillomas with atypia have been found to occasionally harbor some positivity for p53 and Ki-67, typical inverted papillomas show no immunohistochemical positivity. Scant positivity to immunohistochemical markers should be interpreted in conjunction with cellular features, overall architecture and, if necessary, fluorescence in situ hybridization (FISH) analysis.
High-grade urothelial malignancies often harbor mutations of the p53 gene, a tumor suppressor gene known to be influenced by smoking, whereas inverted papillomas have not been shown to consistently exhibit such mutations. Evidence does exist, albeit of variable nature, that inverted papillomas do occasionally possess mutations in the FGFR3 gene, which normally produces a receptor known as the fibroblast growth factor receptor and which is involved in cell signaling. [7, 16]
Very few tumors have been identified that harbor both p53 and FGFR3 mutations, and it has not been definitively answered whether this equates to alternate tumorigenesis pathways or inverted papillomas as a precursor lesion. Supporting separate tumorigenesis are recent developments in molecular testing using FISH assays to detect abnormalities in chromosomes 3, 7, 17, and 21. Such anomalies have been detected in urothelial carcinoma but not in inverted papillomas, supporting the alternate pathogenesis hypothesis. Similar mutations have been identified in loss of heterozygosity (LOH) studies, which consistently exhibit changes found in urothelial carcinoma but not in inverted papilloma.
Tumor Spread and Staging
The standard treatment for inverted papilloma of the lower urinary tract is transurethral resection (TUR), whereas cases involving the upper urinary tract require various degrees of surgical resection depending on the level of certainty of the behavior of the tumor and whether there is concurrent urothelial carcinoma. The benignity of the lesion precludes any staging.
Prognosis and Predictive Factors
The prognosis for inverted papilloma is quite good, with a recurrence rate of less than 5%, and the likelihood of synchronous or subsequent development of urothelial carcinoma 6% and 3%, respectively.
The main consideration in the differential diagnosis is urothelial carcinoma with inverted pattern. Distinction between the two entities can sometimes be difficult histologically due to specimen size, crush and thermal artifact, and general histologic features which overlap, although the amount of cytologic atypia, morphologic and architectural patterns, and mitotic count should be helpful in pointing to a benign or malignant diagnosis.
In cases of difficult histologic discernment, immunohistochemistry can be of assistance, as urothelial carcinoma has positivity for Ki-67, p53, and cytokeratin 20, whereas inverted papillomas generally do not express these markers. Additionally, FISH analysis is capable of detecting chromosomal anomalies that are often present in urothelial carcinoma but absent in inverted papilloma.
Additional considerations include aggregates of von Brunn's nests (distinct nests of solid urothelium within the lamina propria) and inverted papillary urothelial neoplasms of low malignant potential (PUNLMP; similar to von Brunn's nests but with prominent branching). Another entity to keep in mind, particularly in younger patients, is fibroepithelial polyps. Fibroepithelial polyps can present in a manner clinically similar to inverted papillomas and may have a histologically similar appearance, although architecturally fibroepithelial polyps are -- by nature -- exophytic or pedunculated, and display a more dense stroma with fibrovascular cores.