• bladder;
  • nephrogenic metaplasia;
  • urinary tract;
  • atypia;
  • precursor;
  • urothelial carcinoma;
  • adenocarcinoma


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  2. Abstract


Nephrogenic metaplasia with cytologic atypia (atypical nephrogenic metaplasia) is occasionally encountered and its biologic potential is uncertain.


The authors describe 18 cases of atypical nephrogenic metaplasia characterized by the presence of prominent cytologic atypia, including nuclear enlargement, nuclear hyperchromasia, and enlarged nucleoli. DNA ploidy analysis by digital image analysis and immunostaining for high-molecular-weight cytokeratin (34βE12), cytokeratin 7, cytokeratin 20, carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), p53, and MIB-1 were performed in 9 cases.


The mean patient age was 62 years (median, 65 years; range, 39–84 years). The male-to-female ratio was 2.6:1. Two patients had a history of noninvasive papillary urothelial carcinoma. The typical clinical presentation was hematuria (8 patients) and voiding symptoms (5 patients). Cystoscopic findings were suspicious for neoplasm in 7 of 13 cases. The neoplastic cells were positive for high-molecular-weight cytokeratin, cytokeratin 7, and EMA, and were usually negative for cytokeratin 20 and CEA. p53 nuclear accumulation and increased MIB-1 labeling index were seen in 4 cases. DNA ploidy analysis showed aneuploid pattern in 2 of 9 cases. The mean patient follow-up was 3.5 years (range, 0.5–10.6 years); 2 patients had recurrent nephrogenic metaplasia, and the remainder were alive without recurrence or urothelial carcinoma.


Atypical nephrogenic metaplasia is benign; it occasionally displays substantial cytologic abnormalities of no apparent clinical significance. Awareness of the spectrum of cytologic changes within this entity is critical to prevent overdiagnosis of cancer and avoid unnecessary treatment. There is no direct evidence that links atypical nephrogenic metaplasia to cancer. Cancer 2000;88:853–61. © 2000 American Cancer Society.

Nephrogenic metaplasia of the bladder is a common mimic of adenocarcinoma which presents a diagnostic challenge in the interpretation of bladder biopsies.1–7 Cases with cytologic atypia, which we refer to as atypical nephrogenic metaplasia (ANM), are occasionally encountered, but have not been previously described with follow-up data. We report the clinical, pathologic, DNA ploidy, proliferation index, and immunohistochemical characteristics of 18 cases of ANM.


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We reviewed all cases of nephrogenic metaplasia of the urinary tract in the Mayo Clinic surgical pathology files from the years 1981–1998. Eighteen cases of atypical nephrogenic metaplasia (ANM) were retrieved, including nine from the consultation files of one of the authors (D.G.B.). ANM was defined as the presence of cytologic atypia, including nuclear enlargement, nuclear hyperchromasia, and prominent nucleoli. Patient follow-up was obtained in all cases from the medical records and direct contact with referring clinicians and pathologists.

All immunohistochemical stains were performed on a Ventana ES autostainer (Tucson, AZ) using the routine avidin-biotin-complex method. Antibodies applied for immunostaining included high-molecular-weight, basal cell specific anticytokeratin (34βE12, 1:10 dilution, monoclonal (Dako, Carpinteria, CA), anticytokeratin 7 (1:100 dilution, monoclonal), anticytokeratin 20 (1:100 dilution, monoclonal, Dako), anti–carcinoembryonic antigen (1:25 dilution, monoclonal, Dako), anti–epithelial membrane antigen (1:20 dilution, monoclonal, Dako), anti-p53 (D0-7, 1:100 dilution, monoclonal, Dako), and anti-MIB-1 (1:20 dilution, monoclonal, Dako). Positive and negative controls were run in parallel and gave appropriate results.

The specimens were examined for deoxyribonucleic acid (DNA) ploidy by digital image analysis,8 and DNA histograms were classified as diploid, tetraploid, or aneuploid. Quantification of MIB-1 (Ki-67) labeling was performed using the CAS 200 digital image analyzer and proliferation index software programs (Beckton Dickinson, Cellular Image System, San Jose, CA).9


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The clinical findings in 18 cases of ANM are summarized in Table 1. The mean patient age was 62 years (median, 65 years; range, 39–84 years); the male-to-female ratio was 2.6:1. Two had histories of noninvasive papillary urothelial carcinoma. The typical clinical presentation was hematuria (8 patients) and voiding symptoms (5 patients). Cystoscopic findings were suspicious for neoplasm in 7 of 13 cases. There was no apparent predilection of bladder location.

Table 1. Atypical Nephrogenic Metaplasia of the Urinary Tract
Case no.Age (yrs)/genderClinical presentationEndoscopic findingsLocationSize (mm)MultifocalityTreatmentFollow-up (yrs)Outcome
  • ANED: alive with no evidence of disease; H/O: history of; TCC: transitional cell (urothelial) carcinoma; -: unknown.

  • a

    History of radiation therapy for cervical carcinoma one year prior to the diagnosis.

  • b

    This case was initially diagnosed as adenocarcinoma at another institution, and the patient was subsequently treated by radical cystectomy 3 mos after the diagnosis.

184/MObstructive symptomsErythematousVesical neck5NoNone1.0ANED
272/MHematuria and recurrent urinary tract infectionErythematousBladder diverticulum1NoNone0.5ANED
353/FHematuriaErythematousPosterior wall5NoNone3.3Dead of other causes
420/MReflex uropathyNeoplasmBase and posterior wall and trigone3YesNone10.6Recurrent nephrogenic metaplasia 2 yrs later, subsequent biopsies negative. No evidence of disease at the last follow-up
562/MHematuriaNeoplasmLateral and posterior wall, and dome3YesNone2.0ANED
663/FHematuriaaErythematousRight and left lateral wall4YesNone4.4Recurrent nephrogenic metaplasia half a yr later. No evidence of disease at the last follow-up
763/FIrritative symptom and H/O interstitial cystitisPapillary lesionLateral wall4NoNone5.9ANED
870/MHematuriaa H/O noninvasive urothelial carcinomaNeoplasmBase2NoNone3.2Dead of other causes
948/MHematuriaErythematousLateral wall1NoNone3.0ANED
1039/MH/O hydronephrosisBladder7No
1170/FHematuriaNeoplasmLateral wall6No
1272/MObstructionNeoplasmBladder5NoNone1.0Dead of other causes
1368/MDiverticulum of urethra1No
1448/MHematuriaProstatic urethra6No
1579/MUrinary calculi and recurrent urinary tract infectionErythematousPosterior wall1No
1663/MLateral wallNoRadical cystectomybResidual nephrogenic metaplasia at cystectomy
1774/MH/O noninvasive urothelial carcinomaPapillary tumorProstatic urethra2No

ANM was usually unifocal, small (mean, 4 mm in greatest dimension; range, 1–6 mm), and well circumscribed. Various growth patterns, including tubular, papillary, and solid growth, were seen. Most of the cells lining tubules, cysts, and papillae were cuboidal or low columnar with scant cytoplasm (Fig. 1). Prominent nucleoli were readily visible (Figs. 1–2). Luminal mucin production (71%) (Fig. 2), hobnail cells (53%), and clear cell change (35%) were common (Table 2). Mitotic figures were absent, and there was no necrosis. ANM usually occurred in a background of acute and chronic inflammation and stromal edema, and often coexisted with squamous metaplasia (22%) or cystitis glandularis (24%). Stromal calcifications were present in two cases. One case (Case 16) was misinterpreted as adenocarcinoma at another institution, and the patient subsequently underwent cystectomy; no cancer was found in the final specimen.

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Figure 1. Atypical nephrogenic metaplasia (Case 12) is shown. (A) Papillae and tubules are common patterns. (B) Multiple nucleoli are present in some cells. (C) Large nucleoli are present. (D) Inflammatory cells are invariably present, and a few multinucleated epithelial cells are also present. (E) Immunostaining for high-molecular-weight cytokeratin (34βE12) is shown. (F) Immunostaining for cytokeratin 7 is shown.

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Figure 2. Atypical nephrogenic metaplasia is shown. (A) Prominent nucleoli and intraluminal mucin secretion are readily seen (Case 13). (B) Case 15 shows intraluminal mucin secretion and clear cell changes, mimicking signet ring cell adenocarcinoma.

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Table 2. Atypical Nephrogenic Metaplasia of the Urinary Tract: Histopathologic Findings
FindingsNo. of cases (%)
Superficial location18/18 (100)
Lobular growth18/18 (100)
Stromal edema16/18 (89)
Chronic inflammation15/18 (83)
Luminal mucin12/17 (71)
Acute inflammation10/18 (56)
Hobnail cells9/17 (53)
Solid pattern8/17 (44)
Clear cell change6/17 (35)
Cystitis glandularis7/17 (24)
Squamous metaplasia4/18 (22)
Multifocality3/18 (17)
Stromal calcification2/17 (12)
Mitotic figures0/17 (0)
Necrosis0/17 (0)

Table 3 summarizes the results of DNA ploidy analysis, MIB-1 labeling index, p53 protein nuclear accumulation, and other immunohistochemical stains. An aneuploid DNA pattern was detected in two of nine cases (case 2 and 12). All cases displayed positive immunoreactivity for high-molecular-weight cytokeratin (34βE12), cytokeratin 7, and EMA. Focal positivity for cytokeratin 20 was detected in 1 case. Positive immunostaining for CEA was evident in 3 cases. p53 nuclear accumulation (range, 0–20%) and increased MIB-1 labeling index (range, 0–5%) occurred in 4 cases (Table 3).

Table 3. Immunohistochemical Findings and DNA Ploidy Analysis of Atypical Nephrogenic Metaplasia
Case no.34βE12CK7CK20CEAEMAp53 (%)MIB-1 (%)DNA ploidy
  1. 34βE12: high-molecular-weight cytokeratin; CK: cytokeratin; CEA: carcinoembryonic antigen; EMA: epithelial membrane antigen; +: positive; −: negative.

1++Focal positivity++51.4Diploidy
6++Focal positivity+201.5Diploid
12++Focal positivity+205Aneuploid

The mean follow-up was 3.5 years (range, 0.5–10.6 years). Two patients had recurrent nephrogenic metaplasia (none had cytologic atypia), and none had carcinoma in situ or urothelial carcinoma at last follow-up.


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  2. Abstract

Atypical nephrogenic metaplasia is characterized by a circumscribed proliferation of tubules, cysts, and papillae lined or covered by cells with enlarged hyperchromatic nuclei and prominent nucleoli. In this study, we examined the clinical, pathologic, DNA ploidy, proliferation index, and immunohistochemical features of 18 cases of ANM. We found that patients with ANM usually presented with hematuria and/or voiding symptoms. Cystoscopic findings were often suspicious for neoplasm. Aneuploid DNA pattern, p53 nuclear accumulation, and increased MIB-1 labeling index occurred in some lesions. However, ANM was benign, and none of the patients developed urothelial carcinoma, adenocarcinoma, or carcinoma in situ during a mean follow-up period of 3.5 years.

Nephrogenic metaplasia is a metaplastic process of the urinary tract, including the bladder (55%), urethra (41%), and ureter (4%).4 It probably represents a host response to local traumatic irritation, such as a surgical or cystoscopic procedure, chronic infection, calculi, prolonged catheterization, intravesical therapy, or renal transplantation. Typically, nephrogenic metaplasia occurs in adults (mean age, 52 years) with male predilection (male-to-female ratio = 2:1).4 Clinical presentations include hematuria, frequency, and dysuria. It may be cystoscopically indistinguishable from a small papillary urothelial neoplasm; therefore, biopsies are recommended.10, 11 Nephrogenic metaplasia is usually small (<1 cm) and solitary.1 Microscopically, tubules are the most common histologic finding, but the proliferation may also be cystic, polypoid, papillary, and, on rare occasions, diffuse and solid. The tubules are circumscribed and surrounded by prominent basement membranes, and often contain eosinophilic or basophilic secretions that are weakly mucicarminophilic.

Cytologically abnormal cells may occur in nephrogenic metaplasia.2–4, 12–17 ANM is characterized by the presence of enlarged hyperchromatic nuclei and prominent nucleoli. This cytologic atypia raises the diagnostic consideration of adenocarcinoma. In men, the presence of enlarged nucleoli is suggestive of prostatic adenocarcinoma, especially if the lesion occurs in the bladder neck or the prostatic urethra. Nine of our 18 cases of ANM were referred to one of authors (D.G.B.) because of the unusual cytologic appearance, underscoring the diagnostic concern. Published reports on ANM are limited. Malpica et al.12 found that “the nucleoli were occasionally prominent” in their eight cases of nephrogenic metaplasia of the prostatic urethra. Mild to moderate nuclear atypia was seen in 8 of 15 reported cases.2 Oliva and Young found prominent nucleoli at least focally in 20% of their 80 reported cases,4 and mild to moderate nuclear atypia was frequent.2 Due to the paucity of reports of these unusual findings, it is not surprising that misinterpretation of ANM has occurred.18 One case was initially reported by a pathologist as signet ring cell adenocarcinoma.18

There is no convincing evidence linking nephrogenic metaplasia to cancer. A recent cytogenetic study indicated that some examples of nephrogic metaplasia harbor the same genetic alterations as urothelial carcinoma.19 The authors of that study postulated that these lesions may exhibit an aggressive phenotype.19 Nephrogenic metaplasia may show monosomy 9 and trisomy 7 and may coexist with vesical urothelial carcinoma;11, 20, 21 however, malignant transformation has not been reported. Tse et al.20 studied 22 patients with nephrogenic metaplasia and observed that 6 had coexisting bladder carcinoma, including 1 with nephrogenic metaplasia arising within urothelial carcinoma. With less than 2 years of follow-up, none underwent malignant transformation.20 In another study of vesical nephrogenic metaplasia in renal transplant recipients, all cases were diploid and recurrent lesions remained diploid.22 The authors concluded that nephrogenic metaplasia lacked malignant potential.22 Similarly, a diploid DNA pattern was found by Gaylis et al.23 In our study, none of the patients, including 2 patients with aneuploid ANM, developed malignancy during a mean follow-up period of 3.5 years. It appears that ANM is not biologically different from typical nephrogenic metaplasia and may be merely an unusual type of metaplastic transformation of urothelial cells without malignant potential. The importance of recognizing this lesion is to avoid misinterpretation or overdiagnosis of cancer. However, the findings of DNA aneuploid in two cases and the limited length of our follow-up warrant caution in the interpretation of our data.

The most important differential diagnostic consideration with ANM is clear cell adenocarcinoma (Table 4).1–5, 24–26 The greatest difficulty in separating ANM from cancer is encountered in the interpretation of small, poorly oriented biopsies. Oliver and Young reviewed a large series of clear cell adenocarcinoma arising in the urethra, and found that clear cell adenocarcinoma occurred predominantly in elderly women (male-to-female ratio = 1:17).24 Mitotic figures were easily found in all cases, and necrosis was present in 53%.24 Alsanjari et al. found that the presence of solid islands, increased number of mitotic figures (>1 of 10 high-power fields), and increased MIB-1 labeling index (>14%) were helpful in distinguishing clear cell adenocarcinoma from nephrogenic metaplasia.26 Gilcrease et al. believed that the findings of severe cytologic atypia, a predominance of clear cell change, high MIB-1 labeling index, and strong p53 (>15%) immunoreactivity were suggestive of clear cell carcinoma rather than nephrogenic metaplasia.7 ANM is often composed of mucin-containing tubules lined by single hobnail cells with clear cytoplasm and prominent nucleoli, closely mimicking clear cell adenocarcinoma. In some cases, it may be composed of diffuse solid growth of clear cells with cytologic atypia. The features that we consider helpful to distinguish ANM from cancer are circumscribed growth, confinement within the lamina propria, small size of the lesion, absence of necrosis, absence of mitotic figures, absence of nuclear pleomorphism, the presence of adjacent acute and chronic inflammation, and stromal edema. Unlike clear cell adenocarcinoma, ANM had no predilection for women or for urethral location. Cystitis glandularis and squamous metaplasia may coexist with ANM. The findings of clear cells, mucin production, diffuse solid growth, hobnail cells, and p53 immunostaining are not specific and may be seen in both ANM and clear cell adenocarcinoma. ANM is distinguished from prostatic adenocarcinoma by positive high-molecular-weight cytokeratin (34βE12) staining and negative prostate specific antigen staining. DNA ploidy and p53 immunostaining were not helpful in distinguishing ANM from cancer.

Table 4. Differential Diagnosis of Atypical Nephrogenic Metaplasia and Clear Cell Adenocarcinoma
CharacteristicsANMClear cell adenocarcinoma
  • PSA: prostate specific antigen; 34βE12: high-molecular-weight cytokeratin; EMA: epithelial membrane antigen.

  • a

    Nuclear pleomorphism is more pronounced in clear cell adenocarcinoma.

  • b

    Clear cell adenocarcinoma of the urinary bladder is rare, and the diagnosis should be made with extreme caution.

GenderMale predominanceFemale predominance
(male-to-female ratio, 2.6:1)(male-to-female ratio, 1:18)
Mean age (yrs)6258
Clinical presentationHematuria and voiding symptomsHematuria and voiding symptoms
Biologic behaviorBenignAggressive
(21% died within 4 yrs)
LocationNo apparent predilectionUrethrab
SizeSmall (mean, 3.9 mm)Large
Microscopic findings
 NecrosisAbsentOften present (53%)
 Mitotic figuresAbsent or inconspicuousEasily identifiable
 Stromal edemaCommonUncommon
 Luminal mucinCommonCommon
 Clear cell changeMay be seenCommon
 Hobnail cellsCommonCommon
 Infiltrative growthUsually absentPresent
 Psammoma bodiesAbsentMay be seen
 InflammationInvariably presentMay present
 Cytologic atypia
  Nuclear enlargementPresentPresent
  Nuclear hyperchromasiaPresentPresent
  Prominent nucleoliPresentPresent
  Nuclear pleomorphismaMinimalPresent
 34βE12PositivePositive (occasionally negative)
 Cytokeratin 7PositiveUnknown
 Cytokeratin 20NegativeUnknown
MIB labeling index<5%Often >15%
p53Occasional positivePositive
DNA ploidyAneuploid pattern may be seenUnknown

In summary, we describe here a series of cases of ANM with clinical follow-up. Our observations indicate that ANM is a benign lesion without apparent malignant potential. Although ANM is unlikely a precursor of bladder carcinoma, it should be considered in the differential diagnosis of adenocarcinoma, and awareness of this entity may avoid misinterpretation or overdiagnosis of cancer.


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  2. Abstract