Microscopic description:

Multiple small caliber tubules lined by cuboidal, low columnar and hobnail cells, exhibiting irregular smudged nuclei protruding into the lumen.

Intraluminal blue tinged mucin.

Tubules often surrounded by a thickened hyalinized basement membrane.

IHC: positive PAX8, CK7; negative CK20 (rare umbrella cells are highlighted). 

Discussion:

Nonneoplastic reactive metaplastic lesion with tubular, glandular, papillary or cystic architecture and surrounded (at least focally) by thick basement membrane.

Most cases confined to lamina propria.

May mimic urothelial carcinoma, clear cell or prostatic adenocarcinoma.

Most commonly seen in the bladder neck and trigone (80%) but may occur in the urethra (12%) and ureter (8%). 

Characterized by a single layer of cuboidal or hobnail epithelial cells with clear or eosinophilic cytoplasm and small, discrete nuclei without prominent nucleoli.

Commonly appears to be metaplastic and associated with secondary urothelial injury, such as past surgery (60%), calculi (14%) or trauma including chronic catheterization (9%) and urinary tract infection. 

Cystoscopy may have a friable and velvety appearance or a papillary / polypoid appearance mimicking a urothelial neoplasm.

Grossly, may be papillary (56%), polypoid (10%), fungating or sessile (10%) lesions.

Most (62%) are small lesions (1 cm), although rarely may be as large as 7 cm.

Exhibit spectrum of mixed histologic patterns: tubular, tubulocystic, papillary, polypoid and less frequently, solid growth.

Mostly limited to superficial lamina propria, lack a desmoplastic stromal response, necrosis, cytological atypia or brisk mitosis.

Background stroma may be variable depending upon the etiology and display edematous changes, mixed inflammatory infiltrates, reparative type fibrosis, granulomas or fibromyxoid changes.

IHC: Positive: AE1/AE3, CAM5.2, CK7, EMA, Napsin A, PAX8, PAX2, AMACR; Negative: Ki67 range 0 - 5%, p63, PSA, PSAP, NKX3.1, GATA3 (~40%), CK20 (rare umbrella cells are highlighted). 

Differential Diagnosis:

  • Clear Cell Adenocarcinoma: Commonly seen in women. Solid growth pattern with clear cells, marked atypia, complex hyalinized papillae. Muscularis propria invasion+, necrosis+. High mitotic rate. IHC: CAIX+, PAX8 variable, high Ki67.
  • Urothelial carcinoma, nested/microcystic variant: Small, crowded, tightly packed, multilayered, irregular nests with bland cytology and without any associated stromal changes. IHC: p63+, Uroplakin2+, GATA3+.
  • Prostatic adenocarcinoma of bladder: Diffuse nucleolar prominence, more atypia, infiltration in between normal prostatic glands. IHC: PSA+, NKX3.1+, CK7-, PAX8-.

References:

Kunju L. P. (2010). Nephrogenic adenoma: report of a case and review of morphologic mimics. Archives of pathology & laboratory medicine, 134(10), 1455–1459. https://doi.org/10.5858/2010-0226-CR.1

Bhagavan, B. S., Tiamson, E. M., Wenk, R. E., Berger, B. W., Hamamoto, G., & Eggleston, J. C. (1981). Nephrogenic adenoma of the urinary bladder and urethra. Human pathology, 12(10), 907–916. https://doi.org/10.1016/s0046-8177(81)80196-7

Kunju L. P. (2010). Nephrogenic adenoma: report of a case and review of morphologic mimics. Archives of pathology & laboratory medicine, 134(10), 1455–1459. https://doi.org/10.5858/2010-0226-CR.1

Piña-Oviedo, S., Shen, S. S., Truong, L. D., Ayala, A. G., & Ro, J. Y. (2013). Flat pattern of nephrogenic adenoma: previously unrecognized pattern unveiled using PAX2 and PAX8 immunohistochemistry. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 26(6), 792–798. https://doi.org/10.1038/modpathol.2012.239

CASE IMAGES