Nephrogenic Adenoma
Synonyms Nephrogenic metaplasia Mesonephric adenoma
Definition Benign epithelial lesion of urinary tract with tubular, glandular, papillary growth pattern Most frequently in the urinary bladder Other sides in the urinary tract
History Friedman and Kuhlenbeck 1950: nephrogenic adenoma 1985: Ultrastructural similarities between NA cells and renal tubular cells Mazal et al. 2002: NA in renal transplanted donor kidneyderived Studies to the immunohistochemical profile Results not uniform
Etiology/Pathogenesis Injury of Urothelium Displacement of renal tubular cells from the renal pelvis Renal Transplant Also described in pediatric age
Pathogenesis transurethral resection act as a triggering factor for exfoliated tubular cells to be attached to the local surgical bed Subsequent reparative process might explain why some rare cases of NA deep in the wall of the urinary tract display a pseudoinfiltrative pattern
Clinical Presentation M:F ratio 2:1 Usually incidental microscopic finding Rare non-specific symptoms of gross hematuria, dysuria, pollakisuria
Macroscopy Papillary polypoid mass Irregular flat, velvety lesion
Histology Well circumscribed, sometimes multifocal Tubular/glandular, cystic pattern Exophytic papillary cores with a single epithelial layer Rarely fibromyxoid pattern or diffuse sheet like growth
Histology papillary cystic tubular -solid mixed
Histology thick basement membrane eosinophilic PAS-positive material in cystic lumina
Cell morphology Cytoplasm from eosinophilic to clear Nucleoli Degenerative type atypia
Cell morpholgy cuboidal flat hobnail like clear cell type oncocytic signet ring-like
Appearance of malignancy Tubules sometimes fused to form solid cords Pseudoinfiltrative pattern
Immunhistochemistry Positive Cytokeratins (CK7, HMWK) Pax-2 Pax-8 May express: PSA PAP AMACR CK7 Pax-8
Differential diagnosis Clear cell adenocarcinoma of the bladder Urothelial carcinoma with glandular differentiation Nested or tubular variant of urothelial carcinoma Papillary urothelial carcinoma Prostatic adenocarcinoma
DD Clear Cell Adenocarcinoma Mixed papillary, cystic tubular, solid, diffuse Prominent nuclear pleomorphism Mitotically active High proliferation rate May express p53 and CA125
DD Urothelial Carcinoma with Glandular differentiation Admixed typical urothelial carcinoma May express Uroplakin and GATA3 Typically deeply invasive
DD Nested tubular variant of Urothelial Carcinoma Admixed typical urothelial carcinoma More irregular nests of urothelium Occasionally nuclear atypia Deep, irregular infiltration border Stromal clefting arround invasive foci P63+
DD Papillary Urothelial carcinoma Lined by stratified layer of urothelium Tubular/glandular pattern uncommon Urothelial markers frequently+ (Uroplakin, GATA3, p63, CK20)
DD Prostatic Adenocarcinoma More homogenous glands Cystic and atrophic patterns uncommon When involving urinary bladder high Gleason grade Solid ore cribriform architecture common Pax-2 or Pax-8 negative Elevated serum PSA
Treatment Treatment is not necessary Curettage for larger lesions
Prognosis Completely benign Spontaneous regression described Recurrence in 80% of children
Clinical context, histology, and immunohistochemical markers of 134 cases of NA from four hospitals from three different European countries Largest study of NA published to date
Results Males predominated Average age 66 years Most common location urinary bladder (69%) followed by the urethra (14%) Two cases presented invasion of the urinary bladder muscularis propria
Association Antecedent urothelial carcinoma (43%) Coexistence of a urothelial carcinoma (13 %) Prominent chronic inflammation (30%) Prostatic hyperplasia (4 %) Adenocarcinoma (3 %) Lithiasis, urethral stenosis, interstitial cystitis, urothelial dysplasia, neurogenic bladder, diverticulum, renal cyst, long-term catheterization, postradiation cystitis, squamous metaplasia, urothelial papilloma
Immunhistochemical findings p63 - in NA PAX-8 + in NA (100%) In NA and in urothelium, staining pattern of PAX-8 and p63 was exactly inverse p63 + in urothelium, - in NA PAX-8 + in NA, - in urothelium
Epithelial membrane antigen (EMA) Positive in urothelial umbrella cells, distal renal tubular cells 100% positive in NA Not expressed in prostatic adenocarcinoma
E-cadherin Positive in NA (67%) Positive in urothelium and prostate epithelium
Cannabinoid receptors CB1 and CB2 recently tested in adult and fetal human kidneys and in renal tumors Cells in the distal nephron and related neoplasms, chromophobe renal cell carcinoma and renal oncocytoma express CB1 but not CB2
Cannabinoid receptors CB1 staining in 25 % of NA CB1 in scattered cells of normal renal distal tubules CB1+ in NA
Others CD10 (14 %) CD117 (4%) AMACR (3 %) CEA, S100A1, and PSMA- CD117
(Am J Surg Pathol 2014;00:000 000)
63 NA specimens from various locations in the urinary tract from 2 institutions PIN-4 cocktail and GATA-3 antibodies
PIN-4 Cocktail Antibody cocktail (p63, CK903, and AMACR) utilized to evaluate foci of possible prostatic adenocarcinoma Staining characteristics of the individual components of the PIN-4 cocktail have been reported for NA Expression patterns for NA when the stains are applied as a cocktail?
Results A variety of staining patterns were present most common staining pattern: AMACR- /CK903+/p63- Number of samples with an immunoprofile consistent with PCa was small GATA-3+ (40%) (does not distinguish from urothelial carcinoma)
Conclusions Benign condition that may simulate malignancy Wide spectrum of morphologic patterns May express immunhistochemical markers of prostate cancer NA expresses PAX-8 but not p63 and urothelial carcinomas express the opposite PIN-4 cocktail is effective in the vast majority of cases for discriminating between NA and Prostatic cancer