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PATHOLOGY

Are nephrogenic adenomas renal stem/progenitor cell-derived lesions? An immunohistochemical study
Devaraj KM, Castillo-Martin M, Tian HS, Hamele-Bena D, Tong G-X
Dep. of Pathology, Columbia University Medical Center, New York, USA
Mod Pathol. 2009; 22 (suppl. 1): 165A

  • Background: Nephrogenic adenoma (NA) is a benign tumor-like lesion of the urinary tract that histologically resembles the developing distal nephron. Recent evidence suggests that NA is truly a “nephrogenic” lesion, arising from downstream seeding of shed renal tubular cells with implantation and proliferation in areas of damaged urothelium. This proposed pathogenesis and the rarity of the lesion suggest the possibility that NAs arise from kidney stem/progenitor cells that retain the ability to proliferate and develop into renal tubule-like structures when implanted at a distant site. Renal stem/progenitor cells have recently been identified in adult kidney tubules with several markers, including CD133 and PAX2. In our study, we investigate the expression of stem cell surface markers CD133 and CD44 as well as renal-specific transcription factors PAX2 and PAX8 by immunohistochemistry.
  • Design: Twenty-nine cases of NA from 2000 to 2004 were retrieved from the tissue archives, 18 of which were from urinary bladder and 19 from prostatic urethra. CD133, CD44, PAX2, and PAX8 immunohistochemical staining was performed using the avidin-biotin peroxidase method following antigen retrieval. Complete circumferential membranous staining was considered positive for CD133 and CD44. Distinct nuclear staining was required for PAX2 and PAX8 positivity.
  • Results: All NAs were positive for renal-specific transcription factors PAX2 and PAX8, consistent with previous studies. CD133 staining was detected focally in eight of 29 (28%) cases. The CD133 positive cells were seen in papillary surfaces, small tubules, and occasionally in the stroma. CD44 staining was detected in seven of ten cases, including five CD133 positive lesions. In the CD44 positive/CD133 positive cases, CD44 was present in the corresponding CD133 areas. CD44 expression, however, was also seen in other areas and in two CD133 negative cases. No staining for these for markers was identified in the epithelium or stroma in prostatic glands, prostatic urethra, or urinary bladder.
  • Conclusions: Stem cell markers CD44 (70%) and CD133 (28%) were identified in a subpopulation of cells in nephrogenic adenomas, all of which were also positive for renal-specific transcription factors PAX2 and PAX8. Therefore, we suggest that nephrogenic adenomas may arise from transplantation and proliferation of primitive renal cells into an extrarenal stem cell niche. The expression of additional stem cell markers in this regard is currently under investigation.

  • Editorial Comment
    Nephrogenic adenomas usually arise in the setting of prior urothelial injury, such as past surgery, calculi, or trauma. An intriguing and elegant study was able to demonstrate a derivation from renal tubular cells occurring in renal transplant patients.
    Mazal et al. (1) reported that the sex-chromosome pattern in examples of bladder nephrogenic metaplastic lesions in the recipient reflected the pattern of the donor patient, and was different from the chromosome pattern of adjacent urothelium in the recipient patient. An additional support for nephrogenic adenomas arising from shed renal tubular cells is positivity for PAX2. Tong et al. (2) reported that 100% of a series of 39 examples of nephrogenic adenomas stained with PAX2, a renal transcription factor which is specific for tubular epithelium. Urothelium and prostate epithelium do not stain with this antibody. These studies support that nephrogenic adenoma is not of urothelial origin and most probably originates from implanted cells shed from renal tubules.
    Devaraj et al. considered the possibility that nephrogenic adenomas arise from kidney stem/progenitor cells that retain the ability to proliferate and develop into renal tubule-like structures when implanted at a distant site. They investigated the expression of stem cell surface markers CD133 and CD44 as well as renal-specific transcription factors PAX2 and PAX8 by immunohistochemistry. Renal stem/progenitor cells have recently been identified in adult kidney tubules with several markers, including CD133 and PAX2. Stem cell markers CD44 (70%) and CD133 (28%) were identified in a subpopulation of cells in nephrogenic adenomas, all of which were also positive for renal-specific transcription factors PAX2 and PAX8. These findings suggest that nephrogenic adenomas may arise from transplantation and proliferation of primitive renal cells into an extrarenal stem cell niche.

References
1. Mazal PR, Schaufler R, Altenhuber-Müller R, Haitel A, Watschinger B, Kratzik C, et al.: Derivation of nephrogenic adenomas from renal tubular cells in kidney-transplant recipients. N Engl J Med. 2002; 347: 653-9. Erratum in: N Engl J Med. 2002; 347: 1390.
2. Tong GX, Melamed J, Mansukhani M, Memeo L, Hernandez O, Deng FM, et al.: PAX2: a reliable marker for nephrogenic adenoma. Mod Pathol. 2006; 19: 356-63.

Dr. Athanase Billis
Full-Professor of Pathology
State University of Campinas, Unicamp
Campinas, São Paulo, Brazil
E-mail: athanase@fcm.unicamp.br