CASE 16

1. CASE 16 L. Priya Kunju, M.D. Assistant Professor Department of Pathology The University of Michigan

2. Case History 71Y Male with previous history of urinary bladder cancer Underwent transurethral resections twice within last 12 months

4. Diagnosis Nephrogenic Adenoma (Nephrogenic Metaplasia)

5. Nephrogenic Adenoma • Composed of small tubules that resemble renal tubules • Generally thought to be a benign metaplastic response of urothelium to injury/insult. • Study (Mazal et al, 2002) on renal transplant patients have suggested NA is derived from shed renal tubular cells.

6. Nephrogenic Adenoma Predominant in males ( 2:1) 4-81 Y (one-third cases <30Y, 10% in children) Arise in setting of Past GU surgery 60% Calculi 14% Trauma 9% Renal transplantation 8%

7. Nephrogenic Adenoma Sites Urinary Bladder 80% Urethra 12% Ureter 8% Gross Papillary Polypoid (dome shaped) Sessile (friable, velvety) Size Majority <1.0 cm (62%) Rarely large 4-7 cm ( 10%) Multifocal 18%

8. Nephrogenic AdenomaMicroscopic Features Glandular lesion Predominantly lamina propria based with/without surface (mucosal) involvement Papillary, polypoid, tubular, cystic (vascular-like), or rarely solid Cuboidal, columnar, hobnail or signet ring cells with eosinophilic or clear cytoplasm Eosinophilic colloid-like secretions and/or blue mucin No significant cytologic atypia; degenerative nuclear atypia may be present

9. Nephrogenic Adenoma: typical papillary architecture

10. Nephrogenic Adenoma : tubules & cysts with hob-nail cells

11. Nephrogenic adenoma Useful Diagnostic Features Distinctive architectural patterns of NA: papillary, tubular, vascular-like dilated tubules Edematous stroma Associated inflammation Thickened basement membrane around tubules No significant cytologic atypia or mitosis Eosinophilic colloid-like secretions

12. Predominant papillary architecture & underlying edematous stroma with associated inflammation

13. NA with tubules surrounded by hyaline collars

14. NA with cysts and tubules filled with colloid like material

15. Nephrogenic adenomaFeatures that can cause concern Degenerative nuclear atypia especially within hobnail cells Haphazhard distribution of tubules containing blue mucin Tubules lined by a single cell with compressed nucleus simulating signet ring cells

16. NA with vascular-like structures & hob nail degenerative atypia

17. NA: Typical tubules with blue mucin

18. NA with tubules containing mucin , signet ring cells & degenerative cytologic atypia

19. Nephrogenic adenomaFeatures that can cause concern Degenerative nuclear atypia especially within hobnail cells Haphazhard distribution of tubules containing blue mucin Tubules lined by a single cell with compressed nucleus simulating signet ring cells Extension into muscularis mucosae and/or superficial muscularis propria Prominent fibromyxoid change in stroma with compressed spindle cells and distorted tubules

20. NA with pseudo-infilterative pattern into muscle

21. Nephrogenic AdenomaImmunohistochemistry AMACR Positive CK 7 Positive

22. Nephrogenic adenomaImmunohistochemistry P63 Negative Pax 2 Positive

23. Nephrogenic AdenomaClinical Significance Benign Can recur Diagnostic Pitfall

24. Nephrogenic adenomaDifferential Diagnosis Surface Lesions (papillary): Urothelial papilloma PUNLMP or Low-grade papillary UC Involving deep lamina propria &/or superficial muscle Prostatic adenocarcinoma Urothelial carcinoma with bland histology Hob-nail cells, solid growth of clear cells Clear cell adenocarcinoma of urinary bladder (rare)

25. Morphologic & Immunohistochemical Mimic of Prostate Cancer Nephrogenic Adenoma of Prostatic Urethra Morphology Tubules including signet ring-like tubules Cytologic atypia: prominent nucleoli and/or blue mucin Imunohistochemistry HMWCK: Variable Negative (40-50%) P63 : Negative PSA: Predominantly Negative Focal + (30%) AMACR: Positive Morphologic & Immunohistochemical Mimic of Prostate Cancer

27. Nephrogenic Adenoma of Prostatic UrethraUseful Diagnostic Features Distinctive architectural patterns of NA Adjacent urothelium Associated inflammation Degenerative type nuclear atypia Hyaline sheath around tubules Eosinophilic colloid-like secretions Positive CK 7, AMACR & Pax 2

28. AMACR positive PAX 2 positive

29. Urothelial carcinoma (UC) with bland histology Benign Mimics Nested variant of UCFlorid von Brunn nests Nephrogenic adenoma UC with small tubules Cystitis glandularis Nephrogenic Adenoma Microcystic UC Cystitis Cystica Cystitis glandularis Nephrogenic Adenoma Significance: Diagnostic pitfall in small biopsies Aggressive clinical course (Nested variant)

30. Urothelial Carcinoma: Nested Variant Irregularly sized, small, closely packed nests Lumina formation within nests and/or tubules Variable stroma: Scant, focally desmoplastic or loose myxoid; rarely edematous Infiltrative base: muscularis propria invasion common Low grade nuclei (bland cytology); greater “random” cytologic atypia /pleomorphism focally & in regions of deep invasion IHC:CK7, CK 903 and p63 positive

31. Small crowded nests of nested UC

32. Nested UC invading muscle

33. Nested UC with cytogic atypia and tubules

34. Urothelial carcinoma with small tubules Frequently admixed with nested variant Almost exclusive component of small to medium size tubules Tubules lined by attenuated urothelial cells Biologic Significance : unclear

35. Microcystic Urothelial Carcinoma Rare Widespread cystic change with nests of UC or UC with glandular differentiation Cytologically bland Marked variation in size and shape of epithelial formations and haphazard infiltrative growth pattern Biologic Significance: unclear

36. Clear Cell Adenocarcinoma Rare Female predilection Urethra more common Tubular, cystic, papillary and/or solid architecture Prominent nuclear atypia Hob-nail cells and solid growth of cells with clear cells Frequent mitosis and necrosis

38. Clear cell adenocarcinoma with solid growth & prominent nuclear atypia

39. “Take Away ” • NA is a benign metaplastic response of urothelium to injury • NA has a broad histologic spectrum • IHC: CK 7, AMACR and Pax 2 : Positive p63: negative. PSA, 34βE 12: Variable • Awareness of NA as a diagnostic pitfall in diagnosis of Prostate adenocarcinoma and Urothelial carcinoma with bland histology (esp. nested variant)

40. “Take Away” • Nested variant of UC shows aggressive clinical course: high frequency of progression with metastasis and death • Significant diagnostic pitfall in small biopsies • Composed of tightly packed ,often confluent nests, with/wout tubules, predominantly bland cytology with random cytologic atypia, infiltrative base • IHC: CK7, p63 and HMWCK : Positive

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