| Abstract|| |
Nephrogenic adenoma is a rare, benign, metaplastic lesion predominantly seen in urinary bladder, which occurs even more rarely in the ureters. We report two such cases, arising in the ureter. Both patients were young adult males. Histology of both cases was similar, showing tubules lined by columnar cells with hobnailing of nuclei. Immunohistochemically, both cases resembled their counterparts in urinary bladder. These lesions are important to recognize, since they can easily be confused with several malignancies.
Keywords: AMACR, cytokeratin AE1-AE3, metaplastic, nephrogenic adenoma, ureter
|How to cite this article:|
Hussain M, Din NU, Khan HA, Tehseen M. Ureteric nephrogenic adenoma: A report of two cases. Indian J Pathol Microbiol 2012;55:250-2
| Introduction|| |
Nephrogenic adenoma (NA) (synonymous with "Nephronic Metaplasia") is a rare benign tumor of urinary system that has gathered interest in recent years. Approximately 80% of nephrogenic adenomas have been identified in the bladder, with the remainder present in the urethra (15%), ureter (5%) or rarely, in the renal pelvis.  On account of the rarity of the lesion, information about ureteric nephrogenic adenoma is limited. It is a metaplastic lesion which arises after the mucosal irritation and insult by injuries, infections, stones, and instrumentation.  Nephrogenic adenoma has been described after the administration of intravesical Bacille Calmette-Guerin for urothelial carcinoma.  Rare cases have also been reported in the mucosa of bowel wall after cystectomy for urothelial carcinoma. 
Morphologically it is proliferation of small tubules involving lamina propria, lined by cuboidal cells with hobnailling of small nuclei without nucleoli. No cellular atypia or mitosis is noted. Associated chronic inflammation is also seen. ,,, The cells of nephrogenic adenoma are immunoreactive for Amacar and Cytokeratin AE1-AE3. Basement membrane around the tubules is highlighted by PAS and PASD. The MIB-1 proliferative index is <1%. In small biopsies this lesion has been confused with clear cell carcinoma (CCC) and prostatic adenocarcinoma. ,,, We are describing two cases of nephrogenic adenoma, in which one case was suspected as malignancy on account of clinical symptoms and size of the lesion.
| Case Report|| |
A 16-year-old boy presented with urinary tract obstruction, left-sided hydronephrosis, microscopic hematuria, and a ureteric mass in the mid of ureter. After excluding renal causes radiologically segmental resection of ureter was performed. Grossly segment of ureter showed polypoidal and nodular fragments completely obstructing the lumen. On sectioning, the lesion was fleshy and soft.
A 17-year-old male patient had a history of right flank pain and microscopic hematuria. An intravenous pyelogram showed partial obstruction of distal portion of ureter. The mass was excised and sent for histopathological evaluation, which showed nodular shape with soft and fleshy consistency on gross examination.
Sections from both the specimens were taken, fixed in 10% formalin and embedded in paraffin. Hematoxylin and eosin sections were viewed. Additional sections were taken for special and immunohistochemical stains. The antibodies used were cytokeratin AE1-AE3 dilution 1:100, Amacar dilution 1:100, and Ki67 dilution 1:100. Positive and negative controls were included on the slides.
Similar morphological features were found in both cases. The lesion was present in lamina propria and no infiltration into smooth muscle was seen. Both lesions were composed of tubules lined by cuboidal cells with hobnailing of nuclei [Figure 1] and [Figure 2]. Thick basement membrane was present around the tubules, which was highlighted by periodic acid Schiff (PAS) and periodic acid Schiff with diastase (PASD) histochemical stains. Long solid and cystically dilated tubules were also seen, which were lined by flattened cells and showing hobnailing of nuclei. There were no mitoses, papillary structures or clear cells in any of the cases. The tumor was infiltrated by chronic inflammatory infiltrate, predominantly lymphocytes. In both cases, tumor tubules were reactive for CK AE1-AE3 and AMACAR [Figure 2]. Ki67 labeling index was <5% [Figure 3].
|Figure 1: Nephrogenic adenoma with benign urothelium (H and E stain 100×). Inset shows tubules of nephrogenic adenoma with hobnailing of nuclei (Hematoxylin and eosin, ×400)|
Click here to view
|Figure 2: Positive staining of cytokeratin AE1/AE3 in benign urothelium and nephrogenic adenoma (IHC, ×100) on right side. Positive staining of AMACR in benign urothelium and nephrogenic adenoma (IHC, ×100) on left side of the image|
Click here to view
| Discussion|| |
Nephrogenic adenoma of urinary bladder is extensively studied and reported but limited information is available for its ureteric origin on account of the rarity of this lesion. It is estimated that 80% nephrogenic adenoma originate from urinary bladder, 15% located in urethra, and only 5% arises from ureter.  We have reported two cases of nephrogenic adenoma of ureter that led to unilateral ureteral obstruction and one larger lesion was simulating malignancy radiologically. One of the patients had a history of cystitis and other patient had history of injury and pyelonephrirtis. These clinical features are supporting evidence that occurrence of nephrogenic adenoma is the aftermath of chronic infection and injury in the urinary tract. In contrast to urinary bladder the lesion in the ureter commonly arise in males, similar to both of our cases. 
Nephrogenic adenoma is positive for cytokeratin (low molecular weight) and negative for p63, a marker of benign and neoplastic urothelium that is only rarely expressed in renal cell carcinoma and distal convoluted renal tubular epithelial cells in focal areas. Nephrogenic adenoma and renal tubules both stain for α-methylacyl-coenzyme-A racemase (AMACR, P504S) and epithelial membrane antigen (EMA), findings that supports the relationship between nephrogenic adenoma and renal tubules.,, Both of our cases showed a similar immunohistochemical profile, as documented in previous literature. Cytokeratin (low molecular weight) and AMACR were positive.
Several histological features have been described in nephrogenic adenoma that can mimic nested variant of urothelial carcinoma, clear cell carcinoma, and metastatic prostatic adenocarcinoma. Despite their bland appearance at times, the clinical course of these diseases is typically aggressive, underscoring the importance of distinguishing it from a benign proliferation such as nephrogenic adenoma. ,,, Histologically, the presence of carcinoma in situ, indolent epithelial proliferation in muscularis propria, cytologic atypia, mitotic activity, and infiltrative glands should raise suspicion for malignancy. The use of immunohistochemical stains may be helpful in differentiating these lesions from urothelial carcinoma variants; however, differentiating prostatic adenocarcinoma or clear cell carcinoma on the basis of immunohistochemistry can be confusing and the use of a panel of stains is recommended. ,,, It has been postulated by some investigators that nephrogenic adenoma may be a precursor lesion of clear cell carcinoma; this theory has never been proven conclusively, even by the use of molecular analysis. ,
Some cases show a few foci of atypia with prominent nuclei, the term atypical nephrogenic adenoma has been used in the literature for such lesions but it has no clinical significance. Nephrogenic adenoma may coexist with urothelial carcinoma and adenocarcinoma, raising the possibility of malignant transformation.  However, there is no such transformation, despite the fact that both nephrogenic adenoma and clear cell carcinoma has the same cytogenetics. 
In conclusion, nephrogenic adenoma lesion commonly causes ureteral obstruction and simulates malignancy clinically and radiologically, It should be a diagnostic consideration in the clinical setting of prior trauma or longstanding inflammation, particularly when different architecture are identified in the lesion being assessed. As the immunoprofile of nephrogenic adenoma overlaps considerably with malignant entities in the differential diagnosis, clinicopathologic correlation, and careful histologic examination are paramount in avoiding a misdiagnosis of carcinoma.
| References|| |
|1.||Ford TF, Watson GM, Cameron KM. Adenomatous metaplasia (nephrogenic adenoma) of urothelium. An analysis of 70 cases. Br J Urol 1985;57:427-33. |
|2.||Kilciler M, Tan O, Ozgok Y, Tahmaz L, Deveci S, Erduran D. Nephrogenic adenoma of the bladder after intravesical bacillus Calmette-Guerin treatment. Urol Int 2000;64:229-32. |
|3.||Tse V, Khadra M, Eisinger D, Mitterdorfer A, Boulas J, Rogers J. Nephrogenic adenoma of the bladder in renal transplant and non-renal transplant patients: A review of 22 cases. Urology 1997;50:690-6. |
|4.||Gokaslan ST, Krueger JE, Albores-Saavedra J. Symptomatic nephrogenic metaplasia of ureter: A morphologic and immunohistochemical study of four cases. Mod Pathol 2002;15:765-70. |
|5.||Young RH, Scully RE. Nephrogenic adenoma. A report of 15 cases, review of the literature, and comparison with clear cell adenocarcinoma of the urinary tract. Am J Surg Pathol 1986;10:268-75. |
|6.||Kaufmann O, Fietze E, Mengs J, Dietel M. Value of p63 and cytokeratin 5/6 as immunohistochemical markers for the differential diagnosis of poorly differentiated and undifferentiated carcinomas. Am J Clin Pathol 2001;116:823-30. |
|7.||Skinnider BF, Oliva E, Young RH, Amin MB. Expression of alphamethlacyl- CoA racemase (P504S) in nephrogenic adenoma: a significant immunohistochemical pitfall compounding the differential diagnosis with prostatic adenocarcinoma. Am J Surg Pathol 2004;26:701-5. |
|8.||Lin O, Cardillo M, Dalbagni G, Linkov I, Hutchinson B, Reuter VE. Nested variant of urothelial carcinoma: A clinicopathologic and immunohistochemical study of 12 cases. Mod Pathol 2003;16:1289-98. |
|9.||Alsanjari N, Lynch MJ, Fisher C, Parkinson MC. Vesical clear cell adenocarcinoma. V. Nephrogenic adenoma: A diagnostic problem. Histopathology 1995;27:43-9. |
|10.||Hartmann A, Junker K, Dietmaier W, Schröder S, Lopez D, Hofstädter F, et al. Molecular evidence for progression of nephrogenic metaplasia of the urinary bladder to clear cell adenocarcinoma. Hum Pathol 2006;37:117-20. |
Department of Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Johar Town, Lahore
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]