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Nephrogenic metaplasia

Reviewer: Rugvedita Parakh, M.D. (see Reviewers page)
Revised: 9 February 2013, last major update July 2010
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.


● Metaplastic change with papillary or cystic structures composed of small hollow tubules similar to mesonephric tubules, usually lined by a single layer of bland cuboidal or hobnail cells, surrounding eosinophilic or basophilic secretions


● Also called mesonephric adenoma / metaplasia, nephrogenic adenoma; also adenomatoid tumor (but a different entity), adenomatoid metaplasia


● Usually adults; rarely children (J Pediatr Urol 2006;2:323)
● 2/3 male


● Affects bladder, urethra, ureter and renal pelvis in decreasing frequency
● More common at bladder neck and adjacent urethra


● Increased incidence after organ transplantation and immunosuppression
● In renal transplant recipients, derived from exfoliated and implanted renal tubular cells in the urinary tract (N Engl J Med 2002;347:653)
● In other patients, appears to be metaplastic and not a neoplasm
● Associated with inflammation (Urology 1976;8:283), bcg, calculi, chronic catheterization, exstrophy, interstitial cystitis, intravesical thiotepa, malakoplakia, Mullerian lesions, surgery (adults: prostatic lesions, children: congenital lesions); note that these conditions also cause cystitis glandularis and cystitis cystica

Clinical features

● Irritative bladder symptoms, occasionally hematuria
● Velvety appearance on cystoscopy; often mistaken for papillary urothelial carcinoma
● Benign behavior; no malignant transformation even if significant cytologic atypia (Cancer 2000;88:853, but see Hum Pathol 2006;37:117)

Case reports

● 10 year old boy with prune belly syndrome and recurrent nephrogenic adenoma (Pediatr Surg Int 2008;24:605)
● 25 year old man with adenocarcinoma after nephrogenic adenoma (J Med Case Rep 2008;2:164)
● 53 year old man with tumor after ibuprofen abuse for chronic arthritis (Urology 2004;64:1030)


● Resection, but often recurs; requires long term follow-up
● Case report of 12 year old boy treated with sodium hyaluronate (J Pediatr Urol 2007;3:156)
● May regress if underlying cause is removed

Gross description

● Polypoid, sessile or papillary, 20% are multiple

Micro description

● Small hollow tubules similar to mesonephric tubules, usually lined by single layer of bland cuboidal or hobnail cells, surrounding eosinophilic or basophilic secretions (Mod Pathol 1995;8:722)
● Cells have clear or eosinophilic cytoplasm, small nuclei, no prominent nucleoli
● May have thickened basement membrane
● Usually inflammatory infiltrate (plasma cells and lymphocytes) and stromal edema
● Involves lamina propria but spares muscularis propria
● Most cases also have a cystic pattern; occasionally are pseudoinfiltrative, may contain <10% clear cells, may have small slender papillary structures on mucosal surface
● Occasionally luminal blue mucin compresses the nuclei giving a signet ring-like appearance
● Minimal atypia, minimal mitotic figures
● No necrosis, no desmoplasia

Fibromyxoid subtype: compressed spindled cells within a fibromyxoid background with only rare tubular and cordlike structures, mimics mucinous carcinoma (Am J Surg Pathol 2007;31:1231)
Prostatic urethra: lesions closely resemble prostatic adenocarcinoma and are AMACR+

Micro images

Papillary and cystic structures lined by cuboidal epithelium

Some cells have hobnail appearance Papillary mucosal surface epithelium

Tiny tubules and apparent compressed single nucleus mimic appearance of signet-ring cells

Cuboidal (straight arrow) or teardrop-shaped (curved arrow) cells; note the papillations (arrowheads) on the luminal surface

(a) Typical tubules with a single lining of cells, (b) A mixed pattern of small tubules and cysts

Tubules containing colloid-like material

Tubules surrounded by conspicuous hyaline material

Pseudoinfiltrative pattern

Focal development of an invasive adenocarcinoma

Tubulopapillary lesion lined by a low columnar epithelium

Small grouped ducts lined by a low columnar epithelium

Papillary lesion lined by a bland low columnar epithelium

Atypical nephrogenic metaplasia

Various stains

Virtual slides

Several transurethral resection fragments of 59 year old man with nodular hyperplasia of the prostate

Cytology description

● Benign features and PAX2+ (Diagn Cytopathol 2008;36:47)
● Small clusters and single scattered cells with central nuclei and vacuolated cytoplasm
● Nuclei show evenly distributed chromatin with small nucleoli and regular nuclear membranes
● Occasional small pseudopapillary clusters of cells with slightly irregular nuclear membranes and prominent nucleoli
● Background of reactive urothelial cells and squamous cells (Diagn Cytopathol 2009;37:468)

Positive stains

● AE1/ AE3 (pancytokeratin), CAM5.2, CK7, CK20, EMA
● CA-125, PAX8 and PAX2 (89-100%, Am J Surg Pathol 2008;32:1380)
● PSA or PAP (weak, 33%), variable P504S (Am J Surg Pathol 2004;28:701)
● Luminal mucin is PAS+, mucicarmine+

Negative stains

● CK903, p63, CD10 (may be focally positive, Arch Pathol Lab Med 2008;132:1417, Mod Pathol 2006;19:356)

Electron microscopy description

● Resembles proximal convoluted tubules (Hum Pathol 1981;12:907)

Molecular / cytogenetics description

● Monosomy 9, trisomy 7 (Urology 1998;52:756)

Differential diagnosis

Clear cell adenocarcinoma: usually women, lacks clinical features of nephrogenic adenoma; very large tumors, mostly clear cells, marked atypia, muscularis propria invasion; also high mitotic rate, necrosis, high Ki-67 percentage, usually PAX2 negative (although distinction is usually made on morphologic grounds), strong p53 staining (Hum Pathol 1998;29:1451, Am J Surg Pathol 1986;10:268, Hum Pathol 2010;41:594)
Endocervicosis: may resemble mucinous variant of nephrogenic adenoma
Papillary urothelial carcinoma: > 1 layer of urothelial type cells with atypia
Prostatic adenocarcinoma of bladder: more atypia, strongly PSA+
Urothelial carcinoma-nested variant: cystic degeneration of nests, not a single layer; also marked atypia

End of Bladder > Metaplasia > Nephrogenic metaplasia

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