CASE NUMBER 6

Dr. Marc Pusztaszeri

Service de Pathologie Clinique

Hôpitaux Universitaires de Genève

Case 6

• 53-year-old male with a prior history of right kidney transplant for

end-stage diabetic and hypertensive nephropathy.

• During the investigations for a glomerular microhematuria 5 months after the transplant, a cystoscopy revealed a small polypoid lesion of the right posterior wall of the bladder next to the ureteral orifice.

• A biopsy of the lesion was performed....

Cytokeratin 7

PAX-8

P504-S (racemase)

CMV

Nephrogenic adenoma with superimposed CMV infection.

DIAGNOSIS

SUBMITTED DIAGNOSIS (N=107)

Nephrogenic or mesonephroid adenoma/hyperplasia: 64 NA with CMV (or suggestive of CMV): 7 NA with BK (or suggestive of BK): 5 NA with viral inclusions NOS: 1 NA with reactive atypia: 2

Others: Adenocarcinoma: 6 CMV cystitis: 5 Cystitis glandularis +/- CMV or reactive atypia: 4 Nested/microcystic variant of urothelial carcinoma: 4 Benign/inflammatory polyp: 2 Hemangioma: 2 Viral infection?: 2 Paraganglioma: 1 Urothelial carcinoma with gland-like lumen: 1

• A rare benign lesion arising mostly in the bladder (70-80% of cases). • First reported case in 1949 by Davis as “Hamartoma of Bladder”. • In 1950, Friedman and Kuhlenbeck first named this lesion as “Nephrogenic adenoma” owing to its histological resemblance to renal tubules. • Various other terminology including metanephric adenoma and nephrogenic metaplasia (reflecting unclear origin and pathogenesis).

NEPHROGENIC ADENOMA (NA)

PATHOGENESIS

• Still not fully understood. • Numerous risk factors for NA including: renal calculi, genito-urinary trauma, infection, prior surgery, repeated instrumentation, BCG therapy, pelvic radiation, immunosuppression, drugs (NSAIDs), and renal transplantation (10% of cases). Role of CMV? • Various theories have been proposed including the: “embryologic theory”: NA arises from the embryogenic mesonephric tissue remnants in the bladder. “metaplastic theory”: chronic inflammation and irritation to the urothelium result in metaplasia presenting as NA. “implantation theory” of exfoliated renal tubular cells.

Mazal et al. used in situ hybridization with X and Y chromosome specific probes in male to female renal transplant recipients

(and vice versa) to prove the renal origin of NA.

“implantation theory” of exfoliated renal tubular cells

• more common in males than in females (M/F: 3-4/1). • usually an incidental microscopic finding. • in about 33% of cases, NA is visible on cystoscopy as single or multiple (20%) flat or papillary lesions (often mistaken for papillary UC). • most cases <1 cm but may form masses up to 7cm. • hematuria or irritative voiding symptoms. • treatment is resection, but NA often recurs (up to 90% of cases), requiring long term follow-up.

CLINICAL FEATURES OF NA

• growth pattern can be either tubular or tubulo-cystic, papillary or solid. • most cases show a mixed pattern. • tubules, cysts, and papillae are lined by a single layer of columnar to cuboidal cells, typically with eosinophilic cytoplasm and dark, small, and round nuclei. • hobnail/signet-ring/clear/oncocytic cells may be seen. • luminal eosinophilic (“colloid-like”) or basophilic secretions may be present. • usually restricted to LP but deep infiltrative growth into the muscularis propria or even the perinephric fat can be seen.

SALIENT HISTOLOGICAL FEATURES OF NA

• Positive for EMA, cytokeratins CK-7, CAM5.2 and AE1/AE3, PAX-2, PAX-8 and acquaporin-1. • May be positive for AMACR (common), CD 10 (33%), and PSA (weakly in 33%) • Negative for uroplakin, thrombomodulin, p63, CA-125, CEA, cytokeratin 20.

IMMUNOCHEMISTRY

IMMUNOHISTOCHEMISTRY

IMMUNOCYTOCHEMISTRY

• Cell clusters appearing in the urine of patients with NA are also positive for PAX-2. • Distinction from repair renal tubular cells may not be possible. • Urine cytology with PAX-2 immunocytochemistry may be useful in the follow-up of patients with an established diagnosis of NA.

● Papillary urothelial carcinoma (UC) or nested, microcystic and tubular variants of UC: Several layers of cells with atypia, at least focally. Usually p63 positive. CAVEAT Patients with NA often have a previous history of UC (73%). NA may coexist with UC (14%). ● Prostatic adenocarcinoma: More atypia, typically high Gleason grade (solid and cribriform architecture). PSA usually strongly positive. ERG may be useful. Clinical history (elevated serum PSA)! ● Clear cell adenocarcinoma: Lacks clinical features of NA. Usually women; very large tumors; mostly clear cells with marked atypia and high mitotic rate, necrosis, muscularis propria invasion. Usually PAX2 negative, high Ki-67 percentage and strong p53 staining.

MAIN DIFFERENTIAL DIAGNOSIS

TAKE HOME MESSAGES ON NA

Potential diagnostic pitfall mostly with urothelial and prostate carcinomas. Knowledge of the broad spectrum of morphological patterns and immunoprofile is essential in order to recognize NA and to avoid a diagnostic pitfall. A small panel of immunohistochemical markers, including PAX-8, p63, and EMA, will solve problematic cases. In immunosupressed patients, typically in those with a transplanted kidney, look for superimposed CMV inclusions.

TAKE HOME MESSAGES ON NA

Questions?