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This is a benign proliferation of glands that can occur at several sites within the urogenital tract. Although it is benign, the histopathological appearance may sometimes be mistaken for a malignancy, particularly in biopsies around the prostatic urethra.


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Derivation of nephrogenic adenomas from renal tubular cells in kidney-transplant recipients.

Mazal PR, Schaufler R, Altenhuber-Muller R, Haitel A, Watschinger B, Kratzik C, Krupitza G, Regele H, Meisl FT, Zechner O, Kerjaschki D, Susani M.

Department of Clinical Pathology and Center of Excellence in Clinical and Experimental Oncology, University of Vienna General Hospital, Austria.
N Engl J Med. 2002 Aug 29;347(9):653-9. Abstract quote

BACKGROUND: Nephrogenic adenomas are benign, tumor-like lesions within the urothelial mucosa of the urinary tract that are not uncommon in renal-transplant recipients. We investigated the origin of nephrogenic adenomas in renal-transplant recipients.

METHODS: Tissue sections were analyzed by fluorescence in situ hybridization with the use of probes for the X and Y chromosomes, by immunohistochemical methods with the use of antibodies to renal tubular antigens, and by lectin histochemical methods. Forty-six nephrogenic adenomas from 29 patients were analyzed.

RESULTS: All nephrogenic adenomas in 14 female recipients of transplants from male donors and 10 male recipients of transplants from female donors showed the same sex-chromosome status as the donor kidney, but not the same sex-chromosome status as the recipient's surrounding bladder tissue. The nephrogenic adenomas from all 6 female recipients of transplants from female donors showed female chromosomes, and those from the 16 male recipients of transplants from male donors showed male chromosomes. The presence of aquaporin 1, PAX2, and lectin-binding capacity for peanut agglutinin, Lotus tetragonolobus agglutinin, and Sophora japonica agglutinin in nephrogenic adenomas indicated an origin from renal tubular cells.

CONCLUSIONS: Nephrogenic adenomas in renal-transplant recipients are derived from tubular cells of the renal transplants and are not metaplastic proliferations of the recipient's bladder urothelium.
High incidence of nephrogenic adenoma of the bladder after renal transplantation.

Banyai-Falger S, Maier U, Susani M, Wiener H, Watschinger B, Horl WH, Banyai M.

Department of Internal Medicine III, University of Vienna, Austria.
Transplantation. 1998 Feb 27;65(4):511-4. Abstract quote  

BACKGROUND: Tumors of the bladder termed nephrogenic adenomas in kidney allograft recipients are believed to develop as urothelial metaplastic proliferations in response to mechanical trauma, chemical noxae, irradiation, and bacterial or viral pathogens. We report on the incidence of nephrogenic adenoma of the bladder in patients who received renal transplants during a period of 7 years and 3 months at the University Hospital of Vienna.

METHODS: Diagnosis was obtained by cystoscopy and histological analysis. Nephrogenic adenoma was treated by transurethral electroresection and administration of antibiotics in case of urinary tract infections. Follow-up consisted of cytological controls of urine and bladder irrigation fluid as well as of cystoscopy every 3 months.

RESULTS: In 7 of 1328 renal allograft recipients, nephrogenic adenoma could be detected after 7 to 60 months following renal transplantation. In five patients, recurrence was detected 9 to 23 months after diagnosis of the initial lesion. No evidence of malignant degeneration was observed in any patient. Nephrogenic adenoma was not related to immunosuppressive therapy, cytomegalovirus disease, or gancyclovir therapy.

CONCLUSIONS:We suggest that after successful transurethral electroresection of nephrogenic adenomas, cytological controls are adequate every 3 months. Only in renal transplant patients with recurrence of voiding disturbances, macrohematuria, or urinary tract infection are cystoscopy and biopsy indicated in the routine follow-up regimen.
Nephrogenic adenoma after urethral reconstruction using bladder mucosa: report of 6 cases and review of the literature.

Weingartner K, Kozakewich HP, Hendren WH.

Department of Surgery, Children's Hospital, Boston, Massachusetts 02115, USA.
J Urol. 1997 Sep;158(3 Pt 2):1175-7. Abstract quote  

PURPOSE: To our knowledge nephrogenic adenoma, an unusual benign metaplastic lesion of the urothelium, has not been reported previously following urethral reconstruction using bladder mucosa. Histopathological features, etiological factors and clinical features are discussed.

MATERIALS AND METHODS: We reviewed the records of 117 patients who underwent hypospadias repair with free grafts of bladder mucosa from 1982 to 1995.

RESULTS: Five children 6 to 11 years old and a 39-year-old man had nephrogenic adenoma of the urethra. Hematuria or dysuria was the usual reason for presentation. The lesions were located at the site of anastomosis between the graft and proximal urethra in 3 cases and the distal graft in 2, and they involved the whole graft in 1. Successful treatment consisted of endoscopic resection of the polyps in 4 patients, while open surgical correction was performed in 2, requiring complete excision of the previous graft in 1 and segmental resection in 1.

CONCLUSIONS: The gross appearance of the lesion may be confused with that of transitional cell carcinoma or clear cell adenocarcinoma of the urethra, necessitating biopsy to rule out malignancy. Endoscopic management is possible for small tumors, although severe nephrogenic adenoma involving most of the reconstructed urethra may require complete resection of the graft and creation of a new urethra.





Nephrogenic adenoma of the bladder: ultrasound demonstration. A case report.

Jequier S, Bugmann P, Brundler MA.

Clinique de Pediatrie, University Hospital of Geneva, Switzerland.

Pediatr Radiol. 1999 Mar;29(3):185-7. Abstract quote  

A 4-year-old girl developed a space-occupying lesion in the bladder. This was demonstrated by US after resection of a huge ureterocoele and bilateral re-implantation of ureters at 3 months of age and after three episodes of urinary tract infection. The mass developed outside the field of surgery and was removed endoscopically. Histology revealed a nephrogenic adenoma.

US findings have not been emphasised previously. US should be useful in the detection of such lesions and for surveillance of recurrence.


Nephrogenic adenoma of the urethra: an unusual cause of hematuria in the child.

de Buys Roessingh AS, Laurini RN, Meyrat BJ.

Department of Paediatric Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
J Pediatr Surg. 2003 Aug;38(8):E8-9. Abstract quote  

The authors describe a 9-year-old boy who had an accident with his bicycle. He presented with hematuria a few weeks later, and cystoscopy results showed a polypod lesion near the veru montanum.

The lesion was resected, and histologic examination showed a nephrogenic adenoma (NA), which recurred 6 years later with hematuria.

NA is a rare lesion in a child's urethra and can be a source of hematuria.
Nephrogenic adenoma in children. Case report and review of literature.

Schumacher K, Heimbach D, Bruhl P.

Department of Pediatric Urology, University of Bonn, Germany.
Eur J Pediatr Surg. 1997 Apr;7(2):115-7. Abstract quote  

Nephrogenic adenoma in children is an extremely rare kind of tumor (22 cases have been described to date).

We report and discuss here the case of a 7-year-old girl, taking into account the findings described in medical literature. In contrast to nephrogenic adenomas in adults, who present with this tumor in the entire ureteral tract, it has been observed exclusively in the bladder in children so far. The most frequent predisposing factors for the development of this tumor are extensive surgical injury such as ureter reimplantation or long-term stimuli on the urothelium caused by a foreign body. Diagnosis primarily includes sonography of the urinary tract and cystoscopy.

Transurethral resection is regarded as the treatment of choice. Owing to the frequency of persistence, control cystoscopies after primary therapy are necessary.
Nephrogenic adenoma of the prostatic urethra in a patient treated with ESWL for a lower ureteral stone.

Sakkas G, Simopoulou S, Zamparelou A, Moshos M.

Lithotripy-Endourology Dep., 7th IKA Hospital, Athens, Greece
Int Urol Nephrol. 2001;33(2):369-71. Abstract quote  

We present a case of prostatic urethral nephrogenic adenoma incidentally diagnosed in a patient treated with ESWL for ureteral stone disease, and we comment on this unusual urothelial lesion.
Nephrogenic adenoma of the bladder: two case reports and literature review.

Nakatani T, Kuratsukuri K, Uchida J, Sugimura K, Kuroki Y, Morikawa Y.

Department of Urology, Osaka City University Graduate School of Medicine.
Hinyokika Kiyo. 2002 Jul;48(7):463-6. Abstract quote  

In the two cases we report here, tumors were diagnosed as nephrogenic adenoma by pathohistological examination.

Case 1 was a 72-year-old female presenting with a bladder tumor 8 months after receiving ureteral tumor surgery. Transurethral resection of bladder tumor (TUR-Bt) was performed. Case 2 was a 57-year-old female who had received intravesical bacillus Calmette-Guerin (BCG) treatment 6 times after her fifth TUR-Bt. Two tumors were found by cystoscopy, and TUR-Bt was performed.

There have been 39 cases of nephrogenic adenoma of the bladder reported in Japan; 21 were male and 18 female with a mean age of 56.5 years. The main complaint was hematuria, which was seen in 16 cases followed by pollakisuria in 6 cases. Nephrogenic adenoma occurred after surgery of the urinary tract in 16 cases, followed by urinary tract infection in 9 cases and intravesical BCG treatment in 6 cases.

The ratio of cases occurring after intravesical BCG treatment has increased since BCG approval for bladder carcinoma treatment in December 1996 in Japan, and an increase in the number of cases is expected in the future.
Nephrogenic adenoma of the urinary bladder--a case report and review of the literature.

Chosia M, Switala J, Domagala W.

Department of Pathology, Pomeranian Academy of Medicine, Szczecin.

Pol J Pathol. 2002;53(2):91-5. Abstract quote  

Nephrogenic adenoma is a rare benign lesion of the urinary tract involving mainly the urinary bladder. The clinical manifestations, endoscopic signs and histopathological pattern of NA should be differentiated from a cancer, which may be a source of misinterpretation.

Here we report a case of a 70-year-old man previously treated for papillary urothelial carcinoma. Six months later he developed a tumour, giving rise to a suspicion of recurrence. Histopathologically the tumour was diagnosed as nephrogenic adenoma.

It is the first case of nephrogenic adenoma in Polish literature.
Nephrogenic adenoma of the urinary bladder: our experience and review of the literature.

Porcaro AB, D'Amico A, Ficarra V, Balzarro M, Righetti R, Martignoni G, Cavalleri S, Malossini G.

Department of Urology, Medical University of Verona, Italy.
Urol Int. 2001;66(3):152-5. Abstract quote  

OBJECTIVE: To assess our experience in the treatment and clinical outcome of bladder nephrogenic adenoma (NA) updating and reviewing the literature concerning this issue.

PATIENTS and METHODS: From September 1976 to June 1999, bladder NA was diagnosed in 8 patients: 6 men and 2 women with a 3:1 male ratio, aged 26-80 (mean 58.3) years. Follow-up ranged from 4 to 194 (mean 93.5) months.

RESULTS: NA was associated with transitional cell carcinoma in 3 cases. Predisposing factors were assessed in all patients. Previous surgery of the lower urinary tract was detected in 5 cases: ureterocystoneostomy in 2, partial cystectomy in 1, repair of vesicouterine fistula in 1, and multiple urethroplasties in 1. Previous endoscopic treatments were carried out in 2 patients, transurethral resection of the prostate in 1 and repeated transurethral resection of the vesicle in the other. A history of intravesical instillation of bacillus Calmette-Guerin was assessed in 1 case. Patients complained of irritative voiding symptoms in 6 cases and hematuria in 2. Endoscopically, the lesions appeared polypoid and multifocal in 5 patients, and flat and single in 3. The lesions were removed endoscopically, providing relief of symptoms in all cases. Histopathology assessed the diagnosis of nephrogenic adenoma, detecting focal atypic cells in 1 case only. Five patients (63%) relapsed 2-24 months after management. Recurrences were also treated endoscopically.

CONCLUSIONS: Clinical and endoscopic features of bladder NA are not specific, simulating urothelial carcinoma or chronic cystitis. Endoscopic management allows accurate histological diagnosis and provides long-lasting relief of symptoms. NA needs careful and long-term follow-up, because of the high risk of recurrences and the potential neoplastic degeneration of the metaplastic urothelium.
Nephrogenic adenoma of the bladder in renal transplant and non-renal transplant patients: a review of 22 cases.

Tse V, Khadra M, Eisinger D, Mitterdorfer A, Boulas J, Rogers J.

Department of Urology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
Urology. 1997 Nov;50(5):690-6. Abstract quote  

OBJECTIVES: To review diagnoses of nephrogenic adenoma and in particular to evaluate its association with transitional cell carcinoma (TCC) of the bladder and its relationship to renal transplantation.

METHODS: A retrospective review of 22 cases of nephrogenic adenoma (NA) diagnosed between 1989 and 1996 was conducted, 7 of which were in renal transplant patients. Data collected in each case included demographic details, predisposing factors, associated urologic pathology, mode of presentation, cystoscopic finding, management, and follow-up.

RESULTS: There was a 3:1 predominance of men. Mean follow-up was 21.4 months (range 3 to 50). Six patients (27%) had one or more recurrences. All 22 patients had some form of previous bladder insult or surgery, including recurrent urine infections, urinary tract instrumentation, placement of ureteric stents, cystodiathermy, and open bladder surgery. Six cases were associated with TCC of the bladder, of which 4 had NA lesions directly over or close to the site of previous fulguration. In 4 patients, there was a temporal relationship between the administration of intravesical doxorubicin hydrochloride or bacille Calmette-Guerin (BCG) and the onset of NA lesions. One case was associated with an inverted papilloma that had not been described before. In 7 renal transplant cases, 3 lesions were found contralateral to the side of the ureterovesical anastomosis. All 22 cases were benign histologically, but one NA was found within a low-grade baldder TCC. Nineteen cases were followed up regularly with no malignant transformation. Three patients were lost to follow-up.

CONCLUSIONS: This study has demonstrated an association between NA and bladder cancer. Patients with NA, especially those treated with intravesical chemotherapy or BCG, should have regular cystoscopies. Fulguration or transurethral resection appear to be sufficient treatment. No renal transplant patients had vesical TCC and NA simultaneously. Neither immunosuppression nor ureterovesical anastomosis appeared to be a significant predisposing factor in the transplant patients.


Nephrogenic adenoma of the prostatic urethra: a mimicker of prostate adenocarcinoma.

Allan CH, Epstein JI.

Department of Pathology, Johns Hopkins Hospital Baltimore, Maryland, USA
Am J Surg Pathol. 2001 Jun;25(6):802-8. Abstract quote  

Nephrogenic adenoma, thought to be a benign metaplastic response of the urothelium to injury, can rarely affect the prostatic urethra. Extension of small tubules of nephrogenic adenoma into the underlying prostatic fibromuscular stroma can lead to the misdiagnosis of prostatic adenocarcinoma in transurethral resection specimens and prostate biopsies.

We reviewed 26 cases of nephrogenic adenoma involving the prostatic urethra, seen at The Johns Hopkins Hospital from 1990 to 1998, to evaluate the histologic features, which may better define this lesion. Immunohistochemical results were evaluated for cases where the lesion was present on deeper sections.

Histologic patterns included the following: tubules in 96% (25 of 26), structures resembling vessels in 73% (19 of 26), cords and individual cells in 46% (12 of 26), papillary configurations in 19% (5 of 26), and signet ring cell-like tubules in 12% (3 of 26). Other features of nephrogenic adenoma, such as thyroidization, were identified in 38% (10 of 26), and peritubular sheaths were seen in 65% (17 of 26) of cases. Nucleoli were prominent in 54% (14 of 26), and no case had mitoses. In the region of nephrogenic adenoma, urothelium was noted in 69% (18 of 26); in 61% (11 of 18) it showed cuboidal metaplasia and 28% (5 of 18) showed squamous metaplasia. Extension of nephrogenic adenoma into muscle was observed in 77% (20 of 26) of cases, 75% (15 of 20) of which had identifiable urothelium overlying the lesion. Blue-tinged mucinous secretions were observed in 32% (8 of 25) of cases. Inflammation was found in all but one case.

Nephrogenic adenomas were diffusely positive for 34betaE12 in 11% (1 of 9) of cases, focally positive in 44% (4 of 9), and negative in 44% (4 of 9). In 100% (9 of 9), cytokeratin 7 stains were positive. Focal prostate specific antigen and PSAP positivity were seen in 36% (4 of 11) and 50% (5 of 10) of nephrogenic adenoma cases, respectively.

In conclusion, nephrogenic adenoma of the prostatic urethra can mimic prostate cancer because of: 1) the presence of tubules, cords, and signet ring-like tubules; 2) prominent nucleoli; 3) muscle involvement; 4) blue-tinged mucinous secretions; 5) focal prostate specific antigen and PSAP positivity; and 6) negative staining in some cases for 34betaE12.

Features useful in the diagnosis of nephrogenic adenoma include the following: 1) distinctive nephrogenic patterns, such as papillary and "vascular," 2) adjacent urothelium, 3) thyroidization, 4) peritubular sheaths, 5) associated inflammation, and 6) positivity for cytokeratin 7 and, in some cases, 34betaE12.
Nephrogenic adenoma of the urinary tract: a review of the microscopic appearance of 80 cases with emphasis on unusual features.

Oliva E, Young RH.

Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
Mod Pathol. 1995 Sep;8(7):722-30. Abstract quote

A detailed review of the microscopic features of 80 nephrogenic adenomas of the urinary tract was undertaken.

The lesions occurred in patients who ranged in age from 15 to 94 (average, 52) years. There was a 2:1 male/female ratio. Fifty-five percent of the lesions occurred in the urinary bladder, 41% in the urethra, and 4% in the ureter.

The most common microscopic pattern, present in 96% of the cases, was tubular. The tubules were usually small, hollow, and round, but some were solid and occasionally elongated. Their arrangement varied from orderly, sometimes laminar, to pseudoinfiltrative. A basement membrane was appreciable around the tubules in 25% of the cases but was rarely prominent. In two prostatic urethral cases tubules involved the fibromuscular prostatic stroma. A cystic pattern was seen in 72% of the cases. The tubules and cysts most commonly contained eosinophilic secretion but in 25% of the cases the secretion was basophilic. In 12% of the cases some of the tubules were tiny and when they contained basophilic secretion occasionally mimicked signet-ring cells.

The third most frequent pattern, seen in 65% of the cases, was papillary to polypoid. Edematous polyps were commonest but thin, delicate filiform papillae were present in 10% of the cases.

A complex branching pattern with prominent budding of small papillae was seen in three cases. The papillary-polypoid pattern was usually associated with a tubular component but in three cases it was pure. The final pattern, present in 14% of the cases, was diffuse, but it was prominent in only one case.
Fibromyxoid Nephrogenic Adenoma: A Newly Recognized Variant Mimicking Mucinous Adenocarcinoma.

*Department of Pathology, The Cleveland Clinic, Cleveland †Department of Pathology, Ohio State University Medical Center, Columbus, OH Departments of ‡Pathology §Urology ∥Oncology, The Johns Hopkins Hospital, Baltimore, MD.


Am J Surg Pathol. 2007 Aug;31(8):1231-1237. Abstract quote

Nephrogenic adenomas demonstrate a variety of morphologic patterns that may occasionally be confused with malignant processes, including urothelial and prostatic carcinoma.

In this series, we describe 8 cases of nephrogenic adenoma that contain an admixture of the classic tubular form of nephrogenic adenoma and an unusual spindled and fibromyxoid form of nephrogenic adenoma that closely mimics infiltrating carcinoma. In all cases, the classic tubular form of nephrogenic adenoma composed only a small proportion of the lesion, whereas the remainder consisted of compressed spindled cells within a fibromyxoid background, with only rare tubular and cordlike structures.

On close examination, minimal nuclear atypia was identified in 2 cases, which included small, pinpoint nucleoli, and nuclear pseudoinclusions. All 8 patients were elderly men who had a prior or concurrent history of acinar prostate cancer (n=4), combined acinar prostate and urothelial carcinoma (n=1), urothelial-type adenocarcinoma of the prostate (n=1), bladder urothelial carcinoma (n=1), or no prior reported prostatic or urothelial abnormalities (n=1).

Five patients received prior treatment with radiotherapy, 1 patient received intravesical mitomycin-C, and 1 also received bacillus Calmette-Guerin. The epithelial component of the lesions was positive in all cases for pancytokeratin (AE1/3) and racemase and demonstrated a variable cuff of type IV collagen surrounding the tubules. PAX-2 was positive with variable extent of labeling.

Immunostains for prostate-specific antigen were negative. Histochemical stains identified some of the background matrix as mucin, with intense staining for periodic acid-Schiff and focal staining for mucicarmine. Stains for reticulin and amyloid (Congo red stain) and immunohistochemistry for Tamm-Horsfall protein were negative.

This case series is the first report of a fibromyxoid subtype of nephrogenic adenoma. Awareness of this entity and the use of ancillary techniques can aid in the diagnosis of this unusual form of nephrogenic adenoma.


Expression of Alpha-Methylacyl-Coenzyme A Racemase in Nephrogenic Adenoma.

Gupta A, Wang HL, Policarpio-Nicolas ML, Tretiakova MS, Papavero V, Pins MR, Jiang Z, Humphrey PA, Cheng L, Yang XJ.

*Department of Pathology, Northwestern Memorial Hospital Northwestern University, Feinberg School of Medicine, Chicago, IL; daggerDepartment of Pathology & Immunology, Washington University, St. Louis, MO; double daggerDepartment of Pathology, University of Chicago, Chicago, IL; section signDepartment of Pathology, University of Massachusetts Medical School, Worcester, MA; and paragraph signDepartment of Pathology and Laboratory Medicine, Indiana University Medical Center, Indianapolis, IN.

Am J Surg Pathol. 2004 Sep;28(9):1224-1229. Abstract quote  

Nephrogenic adenoma is a benign lesion composed of small glandular structures that develops along the urothelium with uncertain pathogenesis. Some investigators believe that nephrogenic adenoma develops by a metaplastic process in response to injury to the urothelium, while others believe that it arises from detached renal tubules. Nephrogenic adenoma may be present in the prostatic urethra and morphologically mimic prostatic adenocarcinoma. Alpha-methylacyl-coenzyme A racemase (AMACR), a recently identified prostate cancer marker, is typically negative in normal urothelium and prostatic glands, and positive in distal convoluted renal tubules in addition to prostatic adenocarcinomas.

Therefore, evaluation of AMACR expression in nephrogenic adenoma will have significance in the pathologic diagnosis and in understanding pathogenesis of this lesion. We studied 38 nephrogenic adenomas by clinical, histologic, and immunohistochemical analyses for AMACR (P504S) and high molecular weight cytokeratin (34betaE12). Twenty-two of 38 nephrogenic adenomas (58%) demonstrated strong cytoplasmic positivity for AMACR, ranging from patchy, focal to diffuse staining. In addition, 16 of 26 (62%) nephrogenic adenomas were negative for 34betaE12. To our knowledge, this is one of the first report of a completely benign lesion, which can be found in the prostate, showing strong AMACR immunoreactivity.

Our findings suggest using caution when interpreting positive AMACR immunostaining in prostatic specimens. These findings could be explained by possible renal tubular origin or renal differentiation, at least in a subset, of nephrogenic adenomas.
Expression of alpha-methylacyl-CoA racemase (P504S) in nephrogenic adenoma: a significant immunohistochemical pitfall compounding the differential diagnosis with prostatic adenocarcinoma.

Skinnider BF, Oliva E, Young RH, Amin MB.

Department of Pathology, Vancouver Hospital and Health Sciences Center and University of British Columbia, Vancouver, BC, Canada.
Am J Surg Pathol. 2004 Jun;28(6):701-5. Abstract quote  

Alpha-Methylacyl-CoA racemase (AMACR, P504S) has recently been shown to be a useful marker for the diagnosis of prostatic adenocarcinoma and a potential aid in its distinction from its many mimics, one of which is the benign lesion, nephrogenic adenoma (NA).

The goal of this study was to assess the expression of AMACR in NA by immunohistochemistry, as well as other potentially useful markers, high-molecular-weight cytokeratin clone 34betaE12, p63, and prostate-specific antigen (PSA). AMACR was expressed in 4/4 NAs involving the prostatic urethra and underlying stroma, and in 3/16 NAs involving the bladder. The prostatic cases showed circumferential granular cytoplasmic AMACR expression of at least moderate intensity, in >75% of tubules in 3 cases and in <10% of tubules in the remaining case. The AMACR-positive cases in the bladder typically showed focal weak noncircumferential staining of the tubules and stronger staining of the cells lining the papillae. 34betaE12 staining was observed in 1/4 prostatic NAs and 4/16 bladder NAs, typically in a cytoplasmic pattern in a minority of cells. p63 and PSA were negative in all cases.

Our data indicate that NA of the prostatic urethra commonly expresses AMACR and lacks basal cell-specific markers, making it not only a potential morphologic mimic of prostatic adenocarcinoma but also a significant immunohistochemical mimic as well.

Awareness of NA as a significant pitfall in the diagnosis of prostatic adenocarcinoma and careful examination of hematoxylin and eosin-stained sections remains the key to the correct diagnosis, which can be supported by a negative PSA stain.
Nephrogenic adenoma of the prostatic urethra involving the prostate gland: a clinicopathologic and immunohistochemical study of eight cases.

Malpica A, Ro JY, Troncoso P, Ordonez NG, Amin MB, Ayala AG.

Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Hum Pathol. 1994 Apr;25(4):390-5. Abstract quote  

Nephrogenic adenoma (NA) of the prostatic urethra with involvement of the prostate gland can mimic other small-gland proliferations of the prostate, particularly adenocarcinoma of the prostate.

To further characterize this lesion and refine diagnostic criteria we retrospectively reviewed the clinicopathologic features and immunohistochemical findings of eight cases of NA involving the prostate gland seen at The University of Texas M.D. Anderson Cancer Center from 1987 to 1992. The patients' ages ranged from 44 to 76 years (average age, 65 years). Six patients had lower genitourinary tract operations. Follow-up information was available for six patients (follow-up period, 5 to 38 months); only one patient had clinical evidence of recurrence (5 months after surgery). The remaining patients were alive and well with no evidence of disease. Histologically, NA was characterized by a proliferation of small tubules lined by a single layer of cuboidal or flattened cells with clear or eosinophilic cytoplasm. The nuclei were round with fine chromatin and there was no mitotic activity. Nucleoli were generally small, but occasionally prominent. All NA extended into the prostatic parenchyma, raising the possibility that these lesions may represent prostatic small-gland proliferations, particularly prostate adenocarcinoma. However, all cases tested were negative for prostate-specific antigen and prostatic acid phosphatase.

Our findings indicate that the histologic features and the use of prostate-specific antigen and prostatic acid phosphatase immunostains will help to distinguish NA of the urethra involving the prostate from other small-gland proliferations (eg, small-acinar adenocarcinoma of the prostate, clear cell adenocarcinoma of the urethra, sclerosing adenosis, atypical adenomatous hyperplasia, florid hyperplasia of mesonephric remnants, simple lobular atrophy, and incomplete basal cell hyperplasia).
PAX2: a reliable marker for nephrogenic adenoma.

Tong GX, Melamed J, Mansukhani M, Memeo L, Hernandez O, Deng FM, Chiriboga L, Waisman J.

1Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.

Mod Pathol. 2006 Mar;19(3):356-63. Abstract quote  

Nephrogenic adenoma is a rare lesion of the urinary tract. The diagnosis usually is straightforward when characteristic microscopic and clinical findings are present, and the entity is familiar. However, misdiagnosis, in particular of adenocarcinoma of the prostate gland, may occur. Immunohistochemical stains often are needed to make such a distinction, but currently available markers offered only partial help. It recently was demonstrated that nephrogenic adenoma in renal transplant patients originated from the renal tubular epithelium. This newly proved, but long sought information may be helpful in the differential diagnosis of neophrogenic adenoma.

In this study, we investigated the expression of a renal transcription factor, PAX2, in 39 nonrenal transplant-related nephrogenic adenomas, 100 adenocarcinomas of the prostate gland, and 47 urothelial carcinomas of the urinary tract. A strong and distinct nuclear staining of PAX2 was found in all 39 cases of nephrogenic adenoma (100%), but not in normal prostate tissue, normal urothelium, adenocarcinomas of the prostate gland, and invasive urothelial carcinomas. Focal CD10 was detected in six of 13 nephrogenic adenomas in the superficial papillary component and in normal prostate epithelium, normal urothelium, lymphocytes, adenocarcinoma of the prostate gland, and urothelial carcinoma. There was no uroplakins detected in nephrogenic adenoma. Therefore, these findings are suggesting that nephrogenic adenoma in nonrenal transplant patients may also arise from the renal epithelium, as did the comparable lesions after transplantation.

PAX2 is a specific and sensitive immunohistochemical marker in identification and differential diagnosis of nephrogenic adenoma.


Clear cell adenocarcinoma and nephrogenic adenoma of the urethra and urinary bladder: a histopathologic and immunohistochemical comparison.

Gilcrease MZ, Delgado R, Vuitch F, Albores-Saavedra J.

Department of Pathology, University of Texas Southwestern Medical Center, Dallas 75235-9073, USA.
Hum Pathol. 1998 Dec;29(12):1451-6. Abstract quote  

Because of histological similarities between nephrogenic adenomas and clear cell adenocarcinomas of the urinary tract, there is the potential for diagnostic confusion between these two entities.

The histopathologic features of 13 nephrogenic adenomas and five clear cell adenocarcinomas of the urethra and urinary bladder are compared in this report, and detailed immunohistochemical staining profiles are provided for these tumors. Only 2 of the 13 nephrogenic adenomas contained clear cells, and these constituted less than 10% of the lesions. In contrast, four of the five clear cell adenocarcinomas contained prominent areas with clear cells. Nephrogenic adenomas generally showed only mild cytologic atypia, whereas four of the five clear cell adenocarcinomas showed severe atypia. A single mitotic figure was identified in only two of the nephrogenic adenomas, whereas the mitotic rate in the clear cell adenocarcinomas ranged from 2 to 14 per 10 high-power fields.

None of the nephrogenic adenomas showed evidence of necrosis, but focal necrosis was noted in four of the five clear cell adenocarcinomas.

In general, the nephrogenic adenomas and clear cell adenocarcinomas showed negative to weak staining with CK903 but strong staining with AE1, AE3, and Cam 5.2. Variable staining was observed with Brst-3 and antibodies to S-100, CEA (monoclonal and polyclonal), LeuM-1, and CA19.9.

Nephrogenic adenomas and clear cell adenocarcinomas were all negative for prostate-specific acid phosphatase (PSAP), prostate-specific antigen (PSA), and estrogen and progesterone receptors (except for two nephrogenic adenomas, which showed only focal weak staining for estrogen receptor). Neither bcl-2 nor c-erbB-2 staining was able to discriminate between the tumors. However, strong staining for p53 was noted in each clear cell adenocarcinoma and in none of the nephrogenic adenomas. MIB-1 positivity in nephrogenic adenomas ranged from 0 to 13 (average of 5.5) per 200 cells, whereas the positive range for clear cell adenocarcinomas was 33 to 70 (average of 47) per 200 cells.

In summary, histopathologic features that favor clear cell adenocarcinoma over nephrogenic adenoma include a predominance of clear cells, severe cytological atypia, high mitotic rate, necrosis, high MIB-1 positivity, and strong staining for p53.
Vesical clear cell adenocarcinoma. V. Nephrogenic adenoma: a diagnostic problem.

Alsanjari N, Lynch MJ, Fisher C, Parkinson MC.

Department of Histopathology, Royal Marsden Hospital, London.
Histopathology. 1995 Jul;27(1):43-9. Abstract quote  

Following the diagnosis of nephrogenic adenoma in a bladder lesion, which was later interpreted as early clear cell adenocarcinoma, the morphological and immunocytochemical features of these two lesions were reviewed to see if differences could be established for future diagnostic application.

The architecture, extent, cell type, nuclear pleomorphism, presence of mitotic figures and glycogen content were recorded in 28 nephrogenic adenomas and the clear cell carcinoma. Similarly, the immunoreactivity for CAM 5.2, LP34, EMA and CEA of 10 nephrogenic adenomas and the clear cell carcinoma were compared. Proliferation rate in five nephrogenic adenomas and the carcinoma was assessed by antibody M1B1. Many of the features showed differences in degree or extent (clear cell change, nuclear pleomorphism, CAM 5.2 and CEA positivity).

The only features distinct to clear cell carcinoma were the presence of solid islands, mitoses greater than 1/10 HPF (HPF area = 0.4 mm2) and M1B1 counts in excess of 29/200 in clear cell carcinoma (range 30/200-83/200). Only the high M1B1 count was present in the first biopsy of the clear cell carcinoma.
Verumontanum mucosal gland hyperplasia.

Gagucas RJ, Brown RW, Wheeler TM.

Department of Pathology, Baylor College of Medicine, Houston, Texas.

Am J Surg Pathol. 1995 Jan;19(1):30-6. Abstract quote  

Prostatic adenocarcinoma of the small acinar type can be mimicked by benign proliferative lesions, such as atypical adenomatous hyperplasia (adenosis), sclerosing adenosis, nodular hyperplasia (cellular areas), lobular hyperplasia, basal cell hyperplasia, mesonephric hyperplasia, and nephrogenic adenoma.

In our study, we describe another microacinar proliferation, which we have termed verumontanum mucosal gland hyperplasia (VMGH) because it occurs exclusively in the verumontanum and adjacent posterior urethra where the ejaculatory ducts and utricle empty into the urethra.

We reviewed 341 radical prostatectomies and cystoprostatectomies done from 1988 through 1993 for prostate and bladder carcinoma, respectively. Forty-nine prostates (14%) from patients aged 47 to 87 contained foci of VMGH. Of a total of 88 foci, a single lesion was present in 19 cases and multiple lesion in 30 cases. Fifty-nine of the foci arose around the ejaculatory or prostatic ducts, 17 from around the utricle, and 13 from adjacent posterior urethral mucosa. Individual lesions were quantified as to the number of acini per focus as follows: 6 to 10 in 28 (1+), 11 to 25 in 29 (2+), 25 to 50 in 16 (3+), and more than 50 in 15 (4+). No crystalloids or intraluminal mucin were seen, but; intraluminal corpora amylacea, usually numerous, were present in 57 of the 88 voci. The microacini were frequently "back to back" architecturally. The lining epithelium consisted of bland cuboidal to columnar luminal cells with underlying basal cells.

VMGH, a previously undescribed benign microacinar proliferation, occurs in a very restricted and specific location and appears to be unrelated to other lesions with which it may be confused.


DNA profiles and numeric histogram classifiers in nephrogenic adenoma.

Wiener HG, Remkes GW, Birner P, Pycha A, Schatzl G, Susani M, Breitenecker G.

Department of Clinical Pathology, University of Vienna, Vienna, Austria.
Cancer. 2002 Apr 25;96(2):117-22. Abstract quote  

BACKGROUND: The malignant potential of nephrogenic adenoma is still a matter of controversy and therapeutic regimens of this morphologic entity range from partial, even total cystectomy to watchful waiting. The objective of the current study was to evaluate several robust image cytometry-DNA histogram classifiers and to search among those for factors that separate a biologically nonaggressive metaplastic lesion from lesions with increased malignant potential.

METHODS: The study included bladder irrigation specimens, 23 preceding transurethral resection of nephrogenic adenoma and 24 preceding resection of papillary bladder carcinoma. Feulgen-stained nuclei were imported to a static image analysis system, and densitometric data were interpreted by two different software programs. Histograms were described numerically by DNA index, 2c deviation index, and by 5c/9c-exceeding and euploid polyploidy rates. In addition, an interpretation algorithm based on a dual parameter analysis with an integrated automatic threshold was used.

RESULTS: The numeric classification of DNA histograms of patients suffering from nephrogenic adenoma resulted in DNA indices between 0.91 and 1.15. The 2c deviation indices ranged from 0.03 to 0.43, and the 5c exceeding rates ranged from 0.0 to 1.58. None of the measurements showed nuclei exceeding 9c. The p25-75 ranges of 2c deviation indices in nephrogenic adenoma and papillary urothelial carcinoma did not overlap. These findings might be explained by minor proliferative activity in nephrogenic adenoma. Euploid polyploidy rates less than 5% confirm this explanation. Risk analysis documented high risk only for those patients with nephrogenic adenomas who had proven transitional cell carcinoma in their history.

CONCLUSIONS: DNA estimation by image cytometry of urinary bladder irrigation specimens appears able to separate papillary bladder lesions. The method detects those lesions with higher malignant potential but is limited in separating entities with low malignant potential. Comparison of the discriminative power of robust numeric DNA classifiers reveals the 2c deviation index superior to the widely used DNA index and the 5c exceeding rate in this material.



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Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
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Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
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