ORIGINAL ARTICLE

Nephrogenic adenoma of the urinary tract: clinical,histological, and immunohistochemical characteristics

José I. López & Marco Schiavo-Lena & Alexandra Corominas-Cishek &

Adriana Yagüe & Kevin Bauleth & Rosa Guarch & Ondrej Hes &

Regina Tardanico

Received: 19 August 2013 /Revised: 24 September 2013 /Accepted: 7 October 2013 /Published online: 19 October 2013# Springer-Verlag Berlin Heidelberg 2013

Abstract Nephrogenic adenoma is a benign condition of theurinary tract resulting from the displacement and seeding ofrenal tubular cells from the renal pelvis to the urethra. Aretrospective series of 134 cases collected from four hospitalsin three different countries was analyzed in this study. Recordedclinical data included age and sex, topography, urologicalantecedents, coexistent lesions, and follow-up. Cytonuclearand architectural features were reviewed, and PAX-8, p63,PSMA, S100A1, CEA, EMA, CD117, cannabinoid receptorCB1, AMACR, E-cadherin, and CD10 antibodies wereincluded in an immunohistochemical panel.Males predominated(105 M/29 F) with an average age of 66 years (range, 14–96).Urothelial carcinoma was the most frequent clinical antecedent(43.2 %) and also the most common coexisting lesion (14 %).Tubular architecture was the most frequent pattern detected(40 %) although most cases showed a mixed pattern (45.5 %).Deep infiltrative growth into the muscularis propria occurred intwo cases. EMA and PAX-8 were expressed in 100 % ofnephrogenic adenomas, while E-cadherin reactivity wasobserved in 66.6 % of cases, cannabinoid receptor CB1 in25 %, CD10 in 13.6 %, CD117 in 4.1 %, and AMACR in

2.7 %. For the rest of the antigens, no reactivity was found.The average time lapse between the pathological antecedentand the discovery of a nephrogenic adenoma was 32 months.We conclude that nephrogenic adenoma displays a broadspectrum of histological features that may mimic malignancy.In our experience, CB1 immunostaining adds a further argu-ment in favor of a renal origin of this lesion. The combinationof PAX-8+, p63−, and EMA+distinguishes nephrogenic ade-noma from urothelial and prostate carcinoma, its most fre-quent malignant look-alikes.

Keywords Nephrogenic adenoma . Urinary tract . Renaltubule cell . Immunohistochemistry . Differential diagnosis

Introduction

Nephrogenic adenoma (NA) is a well-recognized mimicker ofmalignancy along the urinary tract [1–6]. It was initiallyconsidered as a special response to injury as it was found inpatients with chronic inflammation or lithiasis or those whohad undergone urinary tract surgery, or with other irritatingconditions in the ureter, urinary bladder, prostate and urethrain adults [7–9]. However, NA has also been described atpediatric age [10, 11]. Friedman and Kuhlenbeck [12] namedthis lesion “nephrogenic adenoma” in one of the first descrip-tions of this condition, owing to its resemblance to renaltubules. This idea was subsequently supported by ultrastruc-tural studies [13]. Finally, Mazal et al. [14] used in situhybridization with X and Y chromosome-specific probes inmale to female renal transplant recipients to prove the renalorigin of NA. Since then, several series have been publishedcontributing to the immunohistochemical profile of this entity[4, 11, 15–21], but the results are far from uniform.

In this report, we describe the clinical context, histology,and immunohistochemical markers of 134 cases of NA

J. I. López (*) :A. Corominas-CishekDepartment of Anatomic Pathology, Hospital Universitario Cruces,University of the Basque Country (UPV/EHU),Plaza de Cruces s/n, 48903 Barakaldo, Bizkaia, Spaine-mail: joseignacio.lopez@osakidetza.net

M. Schiavo-Lena : R. TardanicoDepartment of Pathology, Spedali Civili, University of Brescia,Brescia, Italy

A. Yagüe : R. GuarchDepartment of Pathology, Hospital Virgen del Camino,Pamplona, Spain

K. Bauleth :O. HesDepartment of Pathology, Charles University Hospital,Plzen, Czech Republic

Virchows Arch (2013) 463:819–825DOI 10.1007/s00428-013-1497-y

collected from four hospitals from three different Europeancountries. To the best of our knowledge, this is the largestseries of NA published to date.

Materials and methods

A total of 134 NA cases were retrospectively collected fromfour hospitals from Spain, Italy, and the Czech Republic,encompassing a 7-year period (2006–2012). Age, sex, topog-raphy of the lesion, and type of specimen (biopsy, transure-thral resection, cystectomy, nephrectomy…) were retrievedfrom the clinical records. When available, clinical antecedents,coexisting lesions, and follow-up data were also obtained.

Formalin-fixed and paraffin-embedded material wasselected for H & E and periodic acid–Schiff (PAS) routinestains and for immunohistochemical analysis. A panel ofcommercially available antibodies (Table 1) was tested inthree different laboratories under the same conditions on arandomly chosen number of cases following standard proce-dures. Selected slides were immunostained in an automatedimmunostainer (Envision FLEX, Dako Autostainer Plus),using Tris-EDTA for antigen retrieval. Tissue present in theparaffin blocks adjacent to NAwas used as an internal nega-tive control. Immunohistochemical results were assessed byvisual impression.

Results

Clinical data

Males predominated in the series (105 M/29 F), the averageage being 66 years (range, 14–96). The urinary bladder wasthe most common location of NA (92 cases, 68.6 %) followedby the urethra (18 cases, 13.5 %) (Table 2). Tissue for

histological diagnosis was obtained mainly by transurethralresection (94 cases, 70 %) and biopsy (24 cases, 18 %).Cystectomy or nephroureterectomy had been performed in16 cases (12 %).

A specific urological disease had been recorded in theclinical histories of 76 of the cases (56.7 %) with an averagetime lapse between antecedent and NA of 32 months. Asprevious antecedents, urothelial carcinoma (58 cases, 43.2 %),prostatic adenomyomatous hyperplasia (5 cases, 3.7 %), oradenocarcinoma (4 cases, 3 %) was found. Other clinical ante-cedents included urethral stenosis (two cases), and interstitialcystitis, urothelial dysplasia, neurogenic bladder, bladder diver-ticulum, and renal cyst, one case each. A history of long-termbladder catheterization had also been recorded in one case.

Morphologic findings

NA showed varied morphology (Fig. 1), with papillary(15 cases, 11.2 %), tubular cystic (54 cases, 40.3 %), and flat(4 cases, 3 %) growth patterns. Cases composed of mixedgrowth patterns were predominant (61 cases, 45.5 %). NAtended to be located at the surface and in the underlyinglamina propria and was well circumscribed, sometimes mul-tifocal, when the surgical specimens were of sufficient extent.Tubules sometimes fused to form solid cords of cells, givingthe appearance of malignancy. In addition, a pseudoinfiltrative

Table 1 Immunohistochemistry panel in nephrogenic adenomas

Antibodies Source/clone Dilution

PAX-8 Cell-Marque/polyclonal Ready to use

AMACR Biocare/P504S Ready to use

p63 Biocare/BC4A4 1:150

EMA Dako/E29 Ready to use

CEA Dako/II-7 Ready to use

PSMA Dako/3E6 1:100

S100A1 Dako/polyclonal Ready to use

CD117 Dako/polyclonal 1:700

Cannabinoid receptor CB1 ABR/polyclonal 1:1,000

E-cadherin Dako/NCH-38 Ready to use

CD10 Dako/56C6 Ready to use

Table 2 Clinicopathological data in 134 nephrogenic adenomas of theurinary tract

Number Percent

Location Renal pelvis 11 8.2

Ureter 11 8.2

Urinary bladder 92 68.6

Prostate 2 1.5

Urethra 18 13.5

Histology Papillary 15 11.2

Tubular cystic 54 40.3

Flat 4 3

Mixed 61 45.5

Coexisting lesion Urothelial carcinoma 19 14

Relevant inflammation 14 10

Lithiasis 5 4

Stenosis 3 2

Others 8 6

None 45 33.5

Not recorded 41 30.5

Antecedent Urothelial carcinoma 58 43.2

Prostate hyperplasia 5 3.7

Prostate adenocarcinoma 4 3

Others 9 6.7

Not recorded 58 43.2

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pattern resembling malignancy was regularly seen. Two casesin this series presented invasion of the urinary bladdermuscularis propria. Cells in NA also had a varied appearance(Fig. 2). As a general rule, papillae and/or tubules with vari-able cystic transformation were covered by a single layer ofcuboidal cells with eosinophilic cytoplasm and dark, small,and round nuclei. Atypical nuclear features were not observed.However, flat elements resembling endothelial cells, columnarcells, signet ring-like cells, and clear cells were also occasion-ally seen. Edema and inflammation were seen in the stroma,but fibromyxoid features were not observed. EosinophilicPAS-positive material resembling Tamm–Horsfall proteinwas frequently present in the cystic lumina. Microtubulessometimes contained a basophilic secretion product. One casein the series presented foci of oncocytic change in sometubules, resembling renal oncocytoma.

NAwas seen in association with other lesions in 46 cases(34.3 %), including urothelial carcinoma (19 cases, 41.3 %) orprominent chronic inflammation (14 cases, 30.4 %). Lithiasis(five cases), urethral stenosis (three cases), bladder diverticu-lum (two cases), squamous metaplasia (one case), postradiationcystitis (one case), and urothelial papilloma (one case) wereother NA-associated findings.

Immunohistochemical findings

EMA (73/73) and PAX-8 (48/48) were positive in 100 % ofthe tested NA (Fig. 3). EMA had a predominantly

membranous staining pattern, and PAX-8 displayed nuclearstaining (Fig. 3). PAX-8 was never expressed in urotheliumand prostate epithelium. E-cadherin immunostained NA in66.6 % of cases (32/48) but was positive in urothelium andprostate epithelium (Fig. 3). CB1 (12/48, 25 %; Fig. 4), CD10(10/73, 13.6 %), AMACR (2/73, 2.7 %), and CD117 (2/48,4.1 %; Fig. 4) were expressed in different subsets of NA. p63,CEA, S100A1, and PSMA were consistently negative. p63was consistently expressed in urothelium (Fig. 3). Interesting-ly, in NA and in urothelium, the staining pattern of PAX-8 andp63 was exactly inverse (Fig. 3).

Discussion

NA is the result of the seeding of renal tubular cells along theurinary tract. Although it is most frequently found in the urinarybladder, the entire urinary tract from the renal pelvis to theurethra may be involved. Solid evidence for a renal origin ofNA was first provided by Mazal et al. [14] when they provedthat these lesions in renal transplant recipients were donorkidney-derived. This finding ended the widespread belief of a“special inflammatory local response to injury” as the cause ofthis condition [7–9]. Interestingly, years before Mazal's paper[14], some authors reported ultrastructural similarities betweenNA cells and renal tubular cells [13], but in the absence ofirrefutable evidence, the connection between normal renaltubular cells and NA was difficult to imagine and accept.

A

C

B

D

Fig. 1 Architectural patterns innephrogenic adenoma: apapillary, b cystic, c tubule solid,d mixed (original magnifications:×40, ×100, and×250)

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Several authors [8, 9, 11, 22] have shown that earliersurgery, inflammatory conditions, coexisting neoplasia, lithi-asis, and other injuries are frequently associated with NA. Forinstance, transurethral resection might eventually act as atriggering factor for exfoliated tubular cells to be attached tothe local surgical bed, which are then later engulfed by thesubsequent reparative process. This might explain why somerare cases of NA deep in the wall of the urinary tract display apseudoinfiltrative pattern [6]. Urothelial carcinoma, eitherprevious or synchronous, is most frequently associated withNA. We found a history of a resected urothelial carcinoma in73 % of our 134 patients and coexistence of a urothelialcarcinoma and NA in 13.5 %. Similarly, mucosal erosionsprovoked by lithiasis or a urinary catheter may predispose tothe success of the seeding process.

NA displays a wide variety of histological patterns, someof them simulating malignancy [3, 5, 9, 11, 23]. Tubular,

cystic, and papillary arrangements, often as a mixture, in astroma with variable inflammation are typical. Eosinophilic(Tamm–Horsfall protein) and basophilic intraluminal secre-tion products are frequently detected. Some authors [24] haverecently called attention to the underecognized flat pattern inNA and described pagetoid growth in the adjacent transitionalmucosa, which might be related to incomplete resection andearly recurrence because this mode of spreading can only bedetected by microscopy. Particularly difficult to distinguishfrom malignancy are the (rare) infiltrative pattern of growthinto the urinary tract wall [6, 23] and the presence of a spindlecell fibromyxoid stroma [25]. Cells usually have a columnar,cuboidal, flattened, signet ring, or hobnail-like appearance.However, some cases may show cells with clear cytoplasm,simulating clear cell adenocarcinoma, signet ring cell carcino-ma, or prostatic adenocarcinoma [2, 3, 5, 9], notably in NAarising in the urethra. Oncocytic morphology, not previously

A B C

D E F

Fig. 2 Cell morphology in nephrogenic adenoma: a cuboidal, b flat, c hobnail-like, d clear cell type, e oncocytic, f signet ring-like (originalmagnification, ×400)

A B

Fig. 3 Inverse immunoreactivitypattern of p63 and PAX-8 inurothelium and nephrogenicadenoma.While p63 is positive inurothelium and negative innephrogenic adenoma (a), PAX-8is positive in nephrogenicadenoma and negative inurothelium (b) (originalmagnification, ×250)

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described, was detected in some tubular structures of one ofour NA. Hyperchromatic large nuclei with prominent nucleoliwere an occasionally observed atypical cell feature [1].

In recent years, several publications set out to define theimmunohistochemical profile of NA [3, 4, 15–21, 24], but theresults are contradictory. The most discriminative, consistent,and widespread marker expressed in NA is PAX-2 proteinand, even better, PAX-8 protein [24]. PAX family genes areimplicated in the developmental control of the kidney andother organs in vertebrates, and their mutations have beenassociated with various congenital diseases [5, 17, 26]. Ozcanet al. [27] reported that PAX-8 is positive in 100 % of NA, butalso in malignant lymphomas and thyroid follicular-derivedneoplasms, and in 90 % of Müllerian-derived and renal carci-nomas. We also found PAX-8 to be positive in our NA cases.As we found PAX-8 not to be expressed in urothelium ofprostatic epithelium, we consider this marker to be helpful todistinguish between NA and its most common diagnosticalternatives. PAX-2 is also a reliable marker for NA [24,28], even in urinary cytology [29]. PAX-5 is negative [11].

p63, a well-known marker of normal and neoplasticurothelium [30], is constantly negative in NA [4, 21] whichmakes this antibody an ideal complement of PAX-8 to distin-guish between NA and other urothelial-derived lesions. EMA,a good marker of distal renal tubular cells, is not expressed inprostatic adenocarcinoma and only in urothelial umbrellacells, but constantly positive in NA [4]. CEA is not expressed[21] but CK7 [5] is consistently positive in NA and constitutesreliable markers but does not rule out other possible diagnostic

alternatives. Similarly, E-cadherin is expressed in most NA inour series but also in urothelium. S100A1 has been recentlyreferred to as a reliable marker of NA [18, 21], but this couldnot be confirmed in our cases, tested under conditions similarto those previously reported.

Results with AMACR are controversial in NA [4, 11, 15,16, 19–21]. Gupta et al. [15] obtained AMACR immunoreac-tivity in 58 % of 32 cases and stressed that NA is the firstbenign condition expressing this antigen. However, others[16, 21] have noticed that AMACR expression in NA maybe related to the specific topographic location of the lesionsince cases in the prostatic urethra were all positive whereascases in the bladder were not, which makes this antibodyunreliable for use in differential diagnosis. To make mattersworse, Fromont et al. [19] criticized these results stating thatAMACR expression in NA is an artefact, probably due tononspecific background staining when using the avidin–biotindetection procedure. These findings have been offset by Ortiz-Rey et al. [20] using biotin-free methods.

CD10, a marker of proximal convoluted tubule cells in thekidney, has also been occasionally tested in NA [4, 11, 20].CD10 expression has been recorded in roughly one third ofcases [4, 20]. We have found focal cell surface expression ofNA in 13.6 % of our cases. CD117 stains single cells incollecting ducts in the distal nephron [31]. This marker hasbeen focally positive in two cases of our series (4.1 %) and inone case of a previous report [20].

Expression of cannabinoid receptors CB1 and CB2 hasbeen recently tested in normal adult and fetal human kidneys

A B

C D

Fig. 4 CD117 expression inscattered cells of normal renaldistal tubules (a) and innephrogenic adenoma (b).Cannabinoid receptor CB1 isexpressed in scattered cells ofnormal renal distal tubules (c) andin nephrogenic adenoma (d)(original magnification, ×400)

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and in renal tumors. Results show that intercalated cells in thedistal nephron and in related neoplasms, chromophobe renalcell carcinoma and renal oncocytoma, express CB1 but notCB2 [32, 33]. Interestingly, we found CB1 staining in 25 % ofNA cases, adding further evidence to its renal tubule origin.

Differential diagnosis of NA includes clear cell adenocar-cinoma of the urinary bladder and urethra [34], urothelialcarcinoma with deceptively bland features [35], and prostaticcarcinoma [2]. Clear cell adenocarcinoma of the urinary tractis a rare tumor entity with a strong predilection for females andtypically lacking the clinical features associated with NA.Clear cell adenocarcinomas are usually large tumors detect-able on gross examination. Microscopically, they show adiffuse infiltrative growth pattern with clear cells with prom-inent pleomorphism, hyperchromatic enlarged nuclei, mito-ses, a high rate of Ki67 expression, and extensive invasion ofthe muscularis, features not seen in NA [34]. Urothelial car-cinomas with deceptively benign features include a nestedpattern, small tubular/glandular features, a microcystic pat-tern, and inverted growth. Immunohistochemistry may behelpful since NA expresses PAX-8 but not p63 and urothelialcarcinomas express just the opposite, as demonstrated in thisstudy. Prostatic adenocarcinoma may mimic NA when theprostatic urethra is involved. Distinctive nephrogenic patterns,adjacent urothelium, cystic spaces with proteinaceous eosin-ophilic material, associated inflammation, and expression ofCK7 are features useful in differential diagnosis.

Conclusions

NA is a benign condition that may simulate malignancy, bothcytologically and architecturally. The clinicopathologicalbackground in addition to a small panel of immunohisto-chemical markers, including PAX-8, p63, and EMA, willsolve problematic cases and notably rule out urothelialand/or prostate adenocarcinoma. CB1 is expressed in asubset of NA. As to the etiopathogenesis of NA, givenits renal tubular origin, we hypothesize that different cellsfrom different levels of the nephron may give rise to thislesion, in view of the marker pattern detected whichcorresponds to various cells along the nephron.

Conflict of interest The authors declare that they have no conflict ofinterest.

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