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Inverted Papilloma

Definition

  • Benign urothelial neoplasm with an inverted, pseudoinvasive pattern

Diagnostic Criteria

  • Distinguishing inverted from everted/exophytic can be tricky in fragmented specimens
    • If inverted, the stroma is around the outside of the epithelial nest and there is no central fibrovascular core (as seen in exophytic papillary processes)
  • Regular anastomosing trabeculae of urothelium within submucosa
    • Periphery including deep aspect circumscribed, but may not be assessible in fragmented specimens
      • No muscularis propria invasion
    • Trabeculae are randomly oriented with respect to surface
    • Peripheral cells in trabeculae are palisaded
      • Central cells appear abruptly to spindle and flow perpendicularly to palisaded cells
      • Nonkeratinizing squamous differentiation may be present
    • Cystic spaces lacking secretory differentiation may be present
  • Covered by a surface of flat normal urothelium
    • At most, a minimal exophytic component
    • May require careful examination in a fragmented specimen
    • Process usually shows multiple contacts/take-offs from the surface
  • Predominantly cytologically bland
    • Occasional cases show foci of mild to moderate cytologic atypia with nucleoli, hypercellularity, squamous metaplasia and multinucleated cells
      • Has been termed "inverted papilloma with atypia"
      • Mitotic figures rare
      • No adverse behavior has been reported for such cases
    • High grade cytologic features are not permitted
  • Stroma generally loose and not reactive
  • A glandular variant has been described (Kunze)
  • Rare variant with foamy or clear cytoplasm has been described (Broussard)

Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting/updates: 10/20/12, 8/22/13

Supplemental studies

Immunohistology

  • CK20, p53 and Ki67 negative
  • p16 positive in 40% but in situ hybridization negative for HPV (Alexandr)

Differential Diagnosis

  • Florid von Brunn nests and cystitis cystica/glandularis
  • Nested variant urothelial carcinoma
  • Inverted urothelial carcinoma

Inverted Papilloma Florid von Brunn Nests, Cystitis Cystica/Glandularis
Regular pattern of anastomosing cords and trabeculae Round nests, may show fusion
Peripheral palisading and central streaming Lacks biphasic palisading/streaming pattern
Criteria above apply to both solid and cystic processes
An older description of inverted papilloma composed of cystic nests (Kunze) may not be separable from florid von Brunn nests

Nested Variant Urothelial Carcinoma Inverted Papilloma
Overall invasive pattern, not circumscribed Circumscribed (if sample permits assessment)
May involve muscularis propria Does not involve muscularis propria
Varying sizes and shapes of nests Uniform trabeculae and cords
Disorder of cells in nests Orderly peripheral palisading and central streaming

Urothelial Carcinoma with Inverted Growth Pattern Inverted Papilloma
Usually has a surface papillary component Surface everted papillary component absent or minimal
Cytologic features and disorder of carcinoma, appropriate to grade Bland, uniform, orderly cells
Mitotic figures present, appropriate to grade No mitotic figures
These may represent a spectrum, with an intermediate PUNLUMP with inverted pattern

Grading / Staging

Grading

  • Not applicable

Staging

  • Not applicable

Clinical

  • Frequent concurrent or prior urothelial carcinoma
    • Considered by some to be a risk factor for development of carcinoma
    • If no prior history of urothelial neoplasia, recurrence is very rare and progression is not reported
  • Most cases in men (7:1 M:F)
  • May appear sessile or pedunculated on cystoscopy with smooth surface
  • Most common in bladder but may occur anywhere in urinary tract

Classification / Lists

Flat Lesions of the Urinary Bladder

Papillary Lesions of the Urinary Bladder

Subtypes of High Grade Urothelial Carcinoma

Inverted Lesions of the Urinary Bladder

Glandular Lesions of the Urinary Bladder

Bibliography

  • Murphy WM, Grignon DJ, Perlman EJ. Tumors of the Kidney, Bladder and Related Urinary Structures, Atlas of Tumor Pathology, AFIP Fourth Series, Fascicle 1, 2004
  • Eble JN, Sauter G, Epstein JI, Sesterhenn IA eds. World Health Organization Classification of Tumors. Pathology and genetics of tumors of the Urinary System and Male Genital Organs. IARC Press: Lyon 2004.
  • Albores-Saavedra J, Chable-Montero F, Hernández-Rodríguez OX, Montante-Montes de Oca D, Angeles-Angeles A. Inverted urothelial papilloma of the urinary bladder with focal papillary pattern: a previously undescribed feature. Ann Diagn Pathol. 2009 Jun;13(3):158-61.
  • Dhall D, Al-Ahmadie H, Olgac S. Nested variant of urothelial carcinoma. Arch Pathol Lab Med. 2007 Nov;131(11):1725-7.
  • 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 Int. 2011 Feb;107(4):532-7.
  • Jones TD, Zhang S, Lopez-Beltran A, Eble JN, Sung MT, MacLennan GT, Montironi R, Tan PH, Zheng S, Baldridge LA, Cheng L. Urothelial carcinoma with an inverted growth pattern can be distinguished from inverted papilloma by fluorescence in situ hybridization, immunohistochemistry, and morphologic analysis. Am J Surg Pathol. 2007 Dec;31(12):1861-7.
  • Lin O, Cardillo M, Dalbagni G, Linkov I, Hutchinson B, Reuter VE. Nested variant of urothelial carcinoma: a clinicopathologic and immunohistochemical study of 12 cases. Mod Pathol. 2003 Dec;16(12):1289-98
  • Volmar KE, Chan TY, De Marzo AM, Epstein JI. Florid von Brunn nests mimicking urothelial carcinoma: a morphologic and immunohistochemical comparison to the nested variant of urothelial carcinoma. Am J Surg Pathol. 2003 Sep;27(9):1243-52.
  • Wasco MJ, Daignault S, Bradley D, Shah RB. Nested variant of urothelial carcinoma: a clinicopathologic and immunohistochemical study of 30 pure and mixed cases. Hum Pathol. 2010 Feb;41(2):163-71.
  • Williamson SR, Lopez-Beltran A, Montironi R, Cheng L. Glandular lesions of the urinary bladder:clinical significance and differential diagnosis. Histopathology. 2011 May;58(6):811-34.
  • Kunze E, Schauer A, Schmitt M. Histology and histogenesis of two different types of inverted urothelial papillomas. Cancer. 1983 Jan 15;51(2):348-58.
  • 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. Urol Oncol. 2012 Apr 18.
  • Broussard JN, Tan PH, Epstein JI. Atypia in inverted urothelial papillomas: pathology and prognostic significance. Hum Pathol. 2004 Dec;35(12):1499-504.
  • Fine SW, Epstein JI. Inverted urothelial papillomas with foamy or vacuolated cytoplasm. Hum Pathol. 2006 Dec;37(12):1577-82.
  • 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. J Urol. 2003 Oct;170(4 Pt 1):1209-12.
  • Alexander RE, Davidson DD, Lopez-Beltran A, Montironi R, Maclennan GT, CompĂ©rat E, Idrees MT, Emerson RE, Cheng L. Human Papillomavirus is Not an Etiologic Agent of Urothelial Inverted Papillomas. Am J Surg Pathol. 2013 Aug;37(8):1223-8.
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