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Background. Nephrogenic adenoma of the urinary bladder (NAUB) is a rare lesion associated with nonspecific symptoms and could inadvertently be misdiagnosed. Aim. To review the literature. Methods. Various internet search engines were used. Results. NAUB is a benign tubular and papillary lesion of the bladder, is more common in men and adults, and has been associated with chronic inflammation/irritation, previous bladder surgery, diverticula, renal transplantation, and intravesical BCG; recurrences and malignant transformations have been reported. Differential diagnoses include clear cell adenocarcinoma, endocervicosis, papillary urothelial carcinoma, prostatic adenocarcinoma of bladder, and nested variant of urothelial carcinoma; most NAUBs have both surface papillary and submucosal tubular components; both the papillae and tubules tend to be lined by a single layer of mitotically inactive bland cells which have pale to clear cytoplasm. Diagnosis may be established by using immunohistochemistry (positive staining with racemase; PAX2; keratins stain positive with fibromyxoid variant), electron microscopy, DNA analysis, and cytological studies. Treatment. Endoscopic resection is the treatment but recurrences including sporadic malignant transformation have been reported. Conclusions. There is no consensus on best treatment. A multicentre study is required to identify the treatment that would reduce the recurrence rate, taking into consideration that intravesical BCG is associated with NAUB.
Nephrogenic adenoma of the urinary bladder is a rare lesion which could easily be confused with or could easily be misdiagnosed as a number of malignant lesions of the urinary bladder. Nephrognic adenoma of the urinary bladder may either be associated with or it may be induced/triggered by a variety of inflammatory insults to the urinary bladder; some of which include: recurrent urinary tract infections, recurrent urinary tract calculi, intravesical therapy, “diverticula of the urinary bladder”, kidney transplantation, foreign bodies, radiotherapy, chemical agents and a number of irritative factors . Mostofi in 1954 suggested that the urinary bladder epithelium had the ability to transform into several morphologic types under appropriate stimulation and also stated that squamous and glandular metaplasia of the urothelium is observed frequently associated with chronic infection .
Nephrogenic adenoma (nephrogenic metaplasia) is more common in the male in comparison with female with a male to female ratio of 2:1, and it has been reported to occur in a large range of age groups ranging from 4 years to 81 years . Nephrogenic adenoma is more common in adults but it has been reported that about 10% of nephrogenic adenomas affect children . There is some uncertainty about the origin of nephrogenic adenoma of the urinary bladder but a number of postulates exist regarding the pathogenesis of the disease and some of these include the following: it may be a metaplastic lesion; it may emanate embryonic tissue; it may be a metaplasia that occasionally coexists with multifocal urothelial carcinoma [3–5]; it may originate from embryonic mesonephroid tissue; a large number of reports had documented that cases of nephrogenic adenoma of the urinary bladder had emanated from urothelial injury pursuant to previous surgery or long-term inflammation; immunosuppressive therapy in kidney transplant patients and intravesical instillations of Bacillus Calmette-Guérin have also been linked with nephrogenic adenoma of the urinary bladder. The ensuing review paper on nephrogenic adenoma of the urinary bladder is divided into two parts: (A) overview and (B) miscellaneous narrations from some of the reported cases and case series of nephrogenic adenoma of the urinary bladder.
Various internet search engines including PUBMED were used to identify literature on nephrogenic adenoma of the urinary bladder which illustrate various aspects of nephrogenic adenoma of the urinary bladder. The key words used included nephrogenic adenoma of urinary bladder and nephrogenic metaplasia of urinary bladder. Seventy-four documents relating to nephrogenic adenoma of the urinary bladder were identified to be suitable for documenting the definition, presentation, investigation, and management as well as outcome following treatment for nephrogenic adenoma of the urinary bladder.
Nephrogenic adenoma of the urinary bladder is defined as a metaplastic change in the urinary bladder with papillary or cryptic structures which are composed of small hollow tubules similar to mesonephric tubules, which are usually lined by a single layer of bland cuboidal or hobnail cells, surrounding eosinophilic or basophilic secretions .
Nephrogenic adenoma has also been referred to as mesonephric adenoma/metaplasia, adenomatoid tumour, and adenomatoid metaplasia .
A number of microscopic examination findings from specimens of nephrogenic adenoma of the urinary bladder have been illustrated in Figures 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), and 2(a). Some of these figures also illustrate the immunohistochemistry feature as well as cystoscopy finding (Figure 1(h)) in a case of nephrogenic adenoma of bladder : On the whole microscopic examination of specimens of nephrogenic adenoma of the urinary bladder tends to reveal.
The cytological characteristics of nephrogenic adenoma of the urinary bladder include the following.
Nephrogenic adenoma of the urinary bladder stains positively with the ensuing
Some of the differential diagnoses of nephrogenic adenoma of the urinary bladder include the following.
Vemulakonda et al.  reported a case of recurrent nephrogenic adenoma of the bladder in a 10-year-old boy with a history of prune belly syndrome. They stated in their opinion that their reported case was the first reported case of recurrent nephrogenic adenoma. Whilst most cases of nephrogenic adenoma of the urinary bladder have a benign and nonrecurrent biological behaviour the lesson learnt from this report would indicate that in order not to miss a recurrent nephrogenic adenoma of the bladder follow-up cystoscopies would be required.
Hungerhuber et al.  reported a 25-year-old man who had had a traumatic urinary bladder which was caused in a car accident. After he had recovered from the accident he developed nephrogenic adenoma and recurrent urinary tract infections. He presented with nephrogenic adenoma of the urinary bladder 18 months pursuant to the accident. The adenoma was treated repeatedly by means of transurethral resections. The initial pathological findings were benign; nevertheless, the last resection revealed that the previous benign adenoma had transformed into a moderately differentiated adenocarcinoma of the bladder (the tumour was present but there was no invasion; the tumour was multifocal; there was no evidence of lymph node invasion; there was no evidence of metastasis; the tumour was moderately differentiated and thus it was classified/reported as grade 2 tumour). He subsequently underwent radical cystectomy and had remained tumour-free for 4 years at the time of publication of the report. This case report would confirm that nephrogenic adenoma of the urinary bladder can recur many times in a benign form and furthermore nephrogenic adenoma of the urinary bladder may subsequently undergo malignant transformation in view of this long-term cystoscopy surveillance which would be necessary in order to detect early all recurrences. It is therefore important for clinicians to be aware of this rare benign tumour's potential to undergo malignant transformation.
Scelzi et al.  stated that nephrogenic adenoma is an infrequent benign lesion in the urinary system which occurs in patients who have a history of genitourinary surgery, stone disease, trauma, chronic urinary tract infection, and renal transplantation. They reported the first case of nephrogenic adenoma of the urinary bladder in a 53-year-old man who had a 5-year history of ibuprofen abuse for chronic arthritis. Scelzi et al.  stressed the importance of investigating the ibuprofen analgesic abuse for nephrogenic adenoma if nonvisible haematuria and/or irritating lower urinary tract symptoms are present. This report should remind clinicians of the possibility of patients who continuously take ibuprofen subsequently developing nephrogenic adenoma of the urinary bladder.
Campobasso et al.  reported the case of a 12-year-old boy with diffuse calculus-producing nephrogenic adenoma in the urinary bladder which was successfully treated with sodium hyaluronate. They stated that
Even though the main form of treatment for nephrogenic adenoma of the urinary bladder is by means of resection of the lesions, this anecdotal report would suggest that sodium hyaluronate may be an alternative form of treatment and perhaps this treatment option could be used as another option for the management of patients who are not fit to undergo surgical resection of the lesion. Furthermore in view of the fact that only one case has so far been reported it would be a good idea if a multicentre trial is done globally to confirm whether or not hyaluronate is an effective option for the management of nephrogenic adenoma of the urinary bladder.
Hansel et al.  stated that nephrogenic adenomas demonstrate various morphological patterns which may rarely be confused with malignant processes, including urothelial and prostatic carcinoma. Hansel et al.  described a series of 8 cases of nephrogenic adenoma which contained 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. They reported the following.
The treatment of choice in small nephrogenic adenomas of the urinary bladder is transurethral resection; nevertheless, a high recurrence rate of 37% to 88% had been documented . Rarely, these rare tumours have been reported to be associated with urothelial neoplasms, adenocarcinoma, or squamous cell carcinoma of the urinary bladder [32–34].
It has been stated that the majority of patients with nephrogenic adenoma of the urinary bladder are adults with an increasing incidence in patients who had undergone renal transplantation [35, 36]. Mazal et al.  detected the origin of the nephrogenic adenoma in these patients by means of genetic analysis.
It has been stated that approximately 55% of nephrogenic adenomas of the bladder occur in a papillary growth pattern, whilst 35% are sessile and 10% are polypoid .
Even though some authors [30, 31] have considered nephrogenic adenomas to be benign lesions, Schultz et al.  reported malignant transformation in nephrogenic adenoma which would suggest that nephrogenic adenoma is a premalignant disease, especially in patients who are immunocompromised. Bannowsky et al.  were of the opinion that the malignant entity of nephrogenic adenoma is the so-called mesonephroid adenocarcinoma of the urinary bladder; nevertheless, Tse et al.  reported an association with transitional cell carcinoma.
Tse et al.  undertook a retrospective review of 22 cases of nephrogenic adenoma (NA) which were diagnosed between 1989 and 1996 (7 of which were in renal transplant patients). Tse et al.  included in their data collection demographic details, predisposing factors, associated urologic pathology, mode of presentation, cystoscopic finding, management, and follow-up. With regard to the results, Tse et al.  reported the following.
Tse et al.  concluded the following.
Dow and Young Jr.  in 1968 reported the first mesonephroid adenocarcinoma and to emphasize the rarity of mesonephroid adenocarcinoma Vemulakonda et al.  stated that up to 2008 only 15 cases with mesonephroid adenocarcinoma had been reported in the literature. Young and Scully  stated that histologically a tubular growth pattern is pathognomonic for mesonephroid adenocarcinoma. Hartmann et al.  evaluated molecular genetic hybridization in a case of mesonephric adenocarcinoma and they postulated clonal evolution of nephrogenic adenoma to clear cell adenocarcinoma. Hartmann et al.  stated that
Hartmann et al.  reported a case of a 70-year-old woman who had multiple recurrences of nephrogenic metaplasia of the urinary bladder with the subsequent development of clear cell adenocarcinoma. Hartmann et al.  stated that
Chen and Cheng  in 2006 reported their clinical experience with nephrogenic adenoma of the urinary bladder. They stated that, between April 1994 and July 2004, eight patients in their institution were diagnosed with nephrogenic adenoma of the urinary bladder of which 3 were men and 5 were women. The mean age of the 8 patients was 49.6 years and the ages ranged between 23 years and 77 years. The mean follow-up of the patients was 56 months. Chen and Cheng  analysed multiple predisposing factors and summarized their findings as follows.
Chen and Cheng  concluded the following.
Zougkas et al.  reported four patients with nephrogenic adenoma of the urinary bladder. They stated the following:
They concluded the following.
Porcaro et al.  stated that, between September 1976 and June 1999, nephrogenic adenoma of the urinary bladder was diagnosed in 8 patients in their institution, 6 men and 2 women with a 3:1 male to female ratio. The ages of the patients ranged from 26 to 80 years and the mean age of the patients was 58.3 years. The follow-up of the patients ranged from 4 months to 194 months and the mean follow-up was 93.5 months. Zougkas et al.  summarized their results as follows.
Porcaro et al.  made the following conclusions.
Martínez-Sanchíz et al.  reported 2 cases of nephrogenic adenoma of the urinary bladder with a history of transurethral resection of the bladder and the prostate and a history of prolonged voiding symptoms. In both cases, the findings of encysted tubular structures lined with flattened cuboidal cells without atypia were consistent with the diagnosis of nephrogenic adenoma of the urinary bladder. The two cases were summarized as follows.
Case 1. A 60-year-old man who had a history of chronic renal failure presented with a history of severe voiding symptoms and haematuria. He had been having haemodialysis and had previously had transurethral resection of prostate and a bladder diverticulectomy after transurethral resection of bladder neck. He had an ultrasound scan which revealed a raised intravesical lesion. He underwent cystoscopy which revealed multiple trabeculae and diverticula of the urinary bladder and on the left side a superficial papillary lesion which measured about 3cm in diameter and which was resected. Histological examination of the specimen showed the presence of focal ducts which were lined with cuboidal epithelium without atypia, located in areas of urothelial denudation. The histopathological findings were reported as compatible with nephrogenic adenoma of the urinary bladder. At the time of the report of the paper, the patient was asymptomatic, had been undergoing regular checkups, and had been waiting for a kidney transplant due to end-stage renal disease.
Case 2. An 80-year-old man presented with haematuria. He had a history of two previous transurethral resections for a bladder tumour and benign prostatic hyperplasia. He had an ultrasound scan which revealed a small lesion on the right side of the urinary bladder. He had cystoscopy which showed a 1cm lesion in the perimeatic area (around the internal urethral meatus) which was resected. Histological examination of the specimen showed encysted tubular structure which was lined with flattened cuboidal cells and the features were reported to be consistent with nephrogenic adenoma of the urinary bladder. The patient at the time of publication of the paper had been undergoing monitoring and his condition remained well.
Kuzaka et al.  reported 3 cases of nephrogenic adenoma of the urinary bladder which were treated in their hospital between February 2011 and December 2012. They stated that all of the 3 patients had undergone previous open surgery. Two patients had had kidney transplantation. Visible haematuria and nonvisible haematuria were found in 2 patients. One patient had recurrent urinary tract infection. One patient had nephrogenic adenoma which was associated transitional cell carcinoma (TCC). The remaining two patients had nephrogenic adenoma of the bladder only. Kuzaka et al.  also reported that
Kuzaka et al.  concluded that
Filly and Baskin  reported a 16-year-old male patient who had visible haematuria and whose ultrasound scan showed multipapillary excrescences in the urinary bladder. When he was aged 4 years, he underwent bilateral reimplantation of ureters for recurrent urinary tract infections and vesicoureteric reflux. The kidneys showed calyceal dilatation of the infundibula or renal pelvis. There were no overlying cortical scars. He subsequently underwent cystoscopy which showed frond-like sessile lesions throughout the posterior and lateral walls of the urinary bladder. He had random biopsies of the bladder lesions and histological examination of the lesions confirmed nephrogenic adenoma as the underlying cause of the ultrasound scan findings. By the time of publication of the paper, he had had a 2-year follow-up during which there were 2 additional sporadic episodes of visible haematuria.
Pierre-Louis et al.  reported 2 cases of nephrogenic adenoma of the urinary bladder as follows.
Case 1. A 62-year-old, black man presented with haematuria. He underwent cystoscopy which revealed multiple papillary excrescences covering the right hemitrigone and the posterolateral wall of the urinary bladder. Histological examination of the excised tissue was diagnosed as nephrogenic adenoma. One year prior to his admission he had undergone suprapubic prostatectomy. Subsequently he had repeatedly complained of urinary frequency, urgency, nocturia, and intermittent haematuria. Small fungating masses were found on the lateral wall of the urinary bladder and were partially resected. A pathological diagnosis of cystitis cystica was made. A bladder biopsy which was performed two days prior to admission revealed cystitis glandularis.
Case 2. A 67-year-old, black man presented with respiratory distress. He had undergone right inguinal herniorrhaphy and a transurethral prostatectomy four years preceding his admission. His urinalysis revealed pyuria and haematuria. Several polypoid masses which measured 1/5cm × 1.2cm × 1cm were noted over the posterolateral wall of the urinary bladder. Nephrogenic adenoma of the urinary bladder was diagnosed.
Pierre-Louis et al.  reported the pathological findings of the two tumours as follows.
Pierre-Louis et al.  commented that:
Kunju  reported a 71-year-old man who had a previous history of carcinoma of the urinary bladder and who had undergone transurethral resection of bladder tumour twice in the preceding 12 months. His latest transurethral resection specimen had shown a proliferation of numerous small tubular structures which had attenuated hobnail cells, haphazard growth pattern, luminal blue mucin, and mild degenerative nuclear atypia, presence of signet ring-like tubules, infiltrating pattern into the deep lamina propria, including focal involvement of muscularis mucosae and superficial muscularis propria which were considered to be unusual, and hence immunohistochemical studies were undertaken to exclude malignancy. A diagnosis of nephrogenic adenoma of the urinary bladder with some unusual morphological characteristics was made. Kunju  stated the following:
Safaei et al.  reported a 55-year-old woman with urinary problem. She underwent cystoscopy which revealed a sessile mass which was resected. Histology of the specimen revealed circumscribed proliferation of tubules, cysts, and papillae which were lined by low cuboidal to columnar epithelial cells. Immunohistochemical staining of the tumour was strongly positive for CK7, P504S, CD10, and EMA but negative for CK20, PSA, and P63. A diagnosis of nephrogenic adenoma of urinary bladder was made. Her urinary symptoms improved after resection of the lesion. She was lost to follow-up after 5 months of follow-up.
Nephrogenic adenoma of the urinary bladder (NAUB) is a peculiar lesion of the urinary bladder which is characterized partly by villous structures and partly by gland-like lesions.
The clinical presentation and endoscopic characteristics of NAUB are nonspecific.
Diagnosis of NAUB can be established with the help of microscopic and immunohistochemical staining characteristics of the tumour and also with the help of cytology and electron microscopic features of the tumour.
Combinations of cytology, flow cytometry, DNA image analysis, and fluorescence in situ hybridization of bladder washings and voided urine are useful in the monitoring of NAUB.
NAUB is not considered malignant but it is associated with high recurrence rate. In view of this following the initial treatment for NAUB a long-term follow-up by cystoscopic examination should be undertaken in order to identify and treat recurrent tumours and to identify early the few recurrent tumours that may undergo malignant transformation.
There is no consensus opinion regarding the best treatment option that would avoid or reduce recurrence of NAUB following initial treatment and considering the fact that intravesical therapy has been documented to be associated with NAUB there is need for a global multicentre trial to identify the best treatment option that would help reduce and avoid subsequent recurrences.
The author would like to acknowledge the following: http://webpathology.com/ as well as Dr. Dharam Ramnani, President of http://webpathology.com/, who on behalf of http://webpathology.com/ granted the author permission to reproduce figures from their website which have been placed in http://pathologyoutlines.com/; Dr. Dharam Ramnani also kindly reported and commented on all the figures and allowed the author to be the first or one of the initial people to see and read the report and comments on the figures; Dr. Nat Pernick, President of http://pathologyoutlines.com/, and http://pathologyoutlines.com/ for directing the author to the source of the figures used which enabled the author to obtain copyright permission; Archives of Pathology and Laboratory Medicine and the College of American Pathologists that granted the author permission to reproduce figures from their journal Archives of Pathology and Laboratory Medicine.
The author does not have any conflict of interests to declare.