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Papillary Urothelial (Transitional Cell) Carcinoma

Definition

  • Papillary urothelial neoplasms

Alternate/Historical Names

  • The term Urothelial is preferred over Transitional as is is more specific and includes neoplasms with non-transitional differentiation arising in urothelium
  • (Flat) urothelial carcinoma in situ is covered separately

Diagnostic Criteria

  • Papillary urothelial lesions span a range from hyperplasia to high grade carcinoma
    • Papillary urothelial hyperplasia
      • An essentially sessile, undulating lesion without well formed papillae
      • Short stromal spikes but no thin fibrovascular cores
        • Spikes usually no longer than the thickness of the epithelium
      • Bland epithelium
        • Thickness may be normal or increased
    • Urothelial papilloma
      • Infrequent branching of fibrovascular cores
        • Infrequent fusing of papillae
      • Epithelial lining is identical to normal urothelium
        • Normal thickness (4-6 cells)
        • No atypia
          • No nucleoli
        • Orderly maturation
        • Intact umbrella cell layer
        • No mitotic figures
    • Papillary urothelial neoplasm of low malignant potential (PUNLUMP)
      • Occasional branching of fibrovascular cores
        • Occasional fusing of papillae
      • Epithelial lining is identical to normal urothelium but increased in thickness
        • Normal thickness is 4-6 cells
        • Atypia absent to minimal
          • Nuclei normal size to slightly enlarged but uniform
          • Nucleoli absent or inconspicuous
        • Orderly maturation
        • Intact umbrella cell layer
        • Rare to no mitotic figures
      • No invasion
    • Low grade papillary urothelial carcinoma
      • Frequent branching of fibrovascular cores
        • Frequent fusing of papillae
      • Lining epithelium is predominantly orderly with only mild abnormalities in maturation and polarity
      • Epithelial cells only mildly atypical
        • Uniform slight enlargement
        • Nucleoli generally inconspicuous
          • If present they should be small and uniform without other high grade features
        • Scattered hyperchromatic cells may be present
      • Umbrella cells usually present
      • Occasional mitotic figures may be present
        • No atypical figures
      • Foci with high grade features may be present but make up <5% of the tumor
    • High grade papillary urothelial carcinoma
      • Frequent branching of fibrovascular cores
        • Frequent fusing of papillae
      • Lining epithelium is disordered, lacking maturation and polarity
        • Umbrella cells usually absent
      • Frequent epithelial cells are markedly atypical
        • Moderate to marked nuclear hyperchromatism and pleomorphism
        • Nucleoli prominent and multiple
      • Frequent mitotic figures
        • May be atypical
      • May be poorly cohesive
      • High grade features make up ≥5% of the tumor
    • Variant patterns are described separately

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

Original posting/updates: 10/20/12, 12/29/12

Supplemental studies

Immunohistology

  • Most cases positive for p63, high molecular weight keratin and GATA3
    • May be useful for separation from high grade prostate carcinoma local spread
    • Of the three markers, only GATA3 is useful for separation from squamous carcinoma
      • Lung SCC negative
      • Anal and cervical SCC 20% positive but focal or weak
      • High grade urothelial carcinoma 70% moderate to strong diffuse positive
    • Thrombomodulin is variably positive in lung SCC
    • Uroplakin has low sensitivity for high grade invasive urothelial carcinoma (20-60%)

Differential Diagnosis

  • Summary of differences, see Criteria page for details
    Papillary Hyperplasia Papilloma PUNLUMP Low Grade Ca High Grade Ca
    Undulating, no true papillae, bland Papillae lining normal thickness, no atypia Lining thicker than normal, atypia absent to minimal, rare mitoses Orderly maturation, mild atypia, scattered mitoses and atypical nuclei Disorderly, marked atypia, pleomorphism, frequent mitoses

  • Nephrogenic adenoma
  • Polypoid/papillary cystitis
  • Fibroepithelial polyp
  • Florid von Brunn nests
  • Florid cystitis cystica/glandularis

Nephrogenic Adenoma Urothelial Papilloma
Papillae lined by single layer of cells, frequently hobnailed Papillae lined by normal multilayered transitional epithelium
No umbrella cells Normal umbrella cells present
Usually associated with tubular submucosal component No associated tubular component

Papillary Urothelial Neoplasms Papillary / Polypoid Cystitis
Delicate papillary stalks Broad, edematous base and stalks
Lining may be atypical Lined by normal urothelium
Frequent branching papillae Broad fronds, little branching

Papillary Urothelial Neoplasms Fibroepithelial Polyp
Delicate papillary stalks Broad, fibrous base and stalks
Lining may be atypical Lined by normal urothelium

Invasive Urothelial Carcinoma Florid von Brunn Nests, Cystitis Cystica/Glandularis
Single cell invasion Intact nests only
Jagged, irregular nests Round regular nests
Mitotic figures and atypia present, appropriate to grade No mitotic figures or atypia
Stroma may be desmoplastic No stromal response

Grading / Staging

Grading

  • See main criteria page for grading criteria
  • Invasive urothelial carcinoma is graded with the same criteria as papillary carcinomas
  • Invasion by low grade carcinomas is rare but can occur (Toll 2012)

Staging

  • Although technically in situ, non-invasive papillary urothelial neoplasms are staged as pTa and are not referred to as carcinoma in situ
  • If possible, the extent of lamina propria / submucosa invasion should be reported
  • Muscularis mucosae is variable and its involvement does not affect staging
    • Generally loose strands of muscle
  • Muscularis propria involvement is significant and should be evaluated carefully
    • Dense, well defiined bundles of muscle
    • Depth of muscularis propria involvement cannot be assessed in transurethral specimens
    • Presence or absence of propria should be reported even if not involved
  • Lymphatic invasion should be confirmed by immunohistochemistry
    • Pseudovascular tissue retraction is common

Clinical

  • Papillary hyperplasia may be seen with concurrent or prior papillary neoplasia
    • Primary/de novo hyperplasia is of unknown significance
  • Papilloma has a low rate of recurrence (0-30%)
    • Very low rate of progression to higher grade if presenting de novo
  • PUNLUMP frequently recurs (15-50%)
    • Progressiion to higher grade is infrequent (<5%)
  • Low grade carcinoma very frequently recurs (50-75%)
    • Progression to high grade is not infrequent (5-20%)

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.
  • Epstein JI. The new World Health Organization/International Society of Urological Pathology (WHO/ISUP) classification for TA, T1 bladder tumors: is it an improvement? Crit Rev Oncol Hematol. 2003 Aug;47(2):83-9.
  • Epstein JI. Diagnosis and classification of flat, papillary, and invasive urothelial carcinoma: the WHO/ISUP consensus. Int J Surg Pathol. 2010 Jun;18(3 Suppl):106S-111S.
  • Magi-Galluzzi C, Epstein JI. Urothelial papilloma of the bladder: a review of 34 de novo cases. Am J Surg Pathol. 2004 Dec;28(12):1615-20.
  • McKenney JK, Amin MB, Young RH. Urothelial (transitional cell) papilloma of the urinary bladder: a clinicopathologic study of 26 cases. Mod Pathol. 2003 Jul;16(7):623-9.
  • Miyamoto H, Brimo F, Schultz L, Ye H, Miller JS, Fajardo DA, Lee TK, Epstein JI, Netto GJ. Low-grade papillary urothelial carcinoma of the urinary bladder: a clinicopathologic analysis of a post-World Health Organization/International Society of Urological Pathology classification cohort from a single academic center. Arch Pathol Lab Med. 2010 Aug;134(8):1160-3.
  • Miyamoto H, Miller JS, Fajardo DA, Lee TK, Netto GJ, Epstein JI. Non-invasive papillary urothelial neoplasms: the 2004 WHO/ISUP classification system. Pathol Int. 2010 Jan;60(1):1-8.
  • Samaratunga H, Makarov DV, Epstein JI. Comparison of WHO/ISUP and WHO classification of noninvasive papillary urothelial neoplasms for risk of progression. Urology. 2002 Aug;60(2):315-9.
  • Tavora F, Epstein JI. Urothelial carcinoma with abundant myxoid stroma. Hum Pathol. 2009 Oct;40(10):1391-8.
  • Toll AD, Epstein JI. Invasive low-grade papillary urothelial carcinoma: a clinicopathologic analysis of 41 cases. Am J Surg Pathol. 2012 Jul;36(7):1081-6.
  • Chang A, Amin A, Gabrielson E, Illei P, Roden RB, Sharma R, Epstein JI. Utility of GATA3 immunohistochemistry in differentiating urothelial carcinoma from prostate adenocarcinoma and squamous cell carcinomas of the uterine cervix, anus, and lung. Am J Surg Pathol. 2012 Oct;36(10):1472-6
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