853 Atypical Nephrogenic Metaplasia of the Urinary Tract A Precursor Lesion? Liang Cheng, M.D.1 John C. Cheville, M.D.2 Thomas J. Sebo, M.D., Ph.D.2 John N. Eble, M.D.1 David G. Bostwick, M.D.2 1 Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana. 2 Department of Pathology, Mayo Clinic, Rochester, Minnesota. BACKGROUND. Nephrogenic metaplasia with cytologic atypia (atypical nephrogenic metaplasia) is occasionally encountered and its biologic potential is uncertain. METHODS. 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 (34␤E12), cytokeratin 7, cytokeratin 20, carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), p53, and MIB-1 were performed in 9 cases. RESULTS. 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. CONCLUSIONS. 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. KEYWORDS: bladder, nephrogenic metaplasia, urinary tract, atypia, precursor, urothelial carcinoma, adenocarcinoma. N Current address for Dr. Bostwick: Bostwick Laboratories, 6722 Patterson Ave., Richmond, VA 23226. Address for reprints: Liang Cheng, M.D., Department of Pathology, UH 3465, Indiana University School of Medicine, 550 North University Blvd., Indianapolis, IN 46202. Email: firstname.lastname@example.org Received June 9, 1999; revision received September 7, 1999; accepted September 30, 1999. © 2000 American Cancer Society ephrogenic 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. MATERIALS AND METHODS 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 854 CANCER February 15, 2000 / Volume 88 / Number 4 TABLE 1 Atypical Nephrogenic Metaplasia of the Urinary Tract Case no. Age (yrs)/ gender 1 2 84/M 72/M 3 4 Endoscopic findings Location Size (mm) Multifocality Treatment Follow-up (yrs) Outcome Erythematous Erythematous Vesical neck Bladder diverticulum 5 1 No No None None 1.0 0.5 ANED ANED 53/F 20/M Obstructive symptoms Hematuria and recurrent urinary tract infection Hematuria Reflex uropathy Erythematous Neoplasm Posterior wall Base and posterior wall and trigone 5 3 No Yes None None 3.3 10.6 5 62/M Hematuria Neoplasm 3 Yes None 2.0 6 63/F Hematuriaa Erythematous Lateral and posterior wall, and dome Right and left lateral wall Dead of other causes Recurrent nephrogenic metaplasia 2 yrs later, subsequent biopsies negative. No evidence of disease at the last follow-up ANED 4 Yes None 4.4 7 63/F Papillary lesion Lateral wall 4 No None 5.9 8 70/M Neoplasm Base 2 No None 3.2 Dead of other causes 9 10 11 12 13 48/M 39/M 70/F 72/M 68/M Irritative symptom and H/O interstitial cystitis Hematuriaa H/O noninvasive urothelial carcinoma Hematuria H/O hydronephrosis Hematuria Obstruction — Recurrent nephrogenic metaplasia half a yr later. No evidence of disease at the last follow-up ANED Erythematous — Neoplasm Neoplasm — 1 7 6 5 1 No No No No No None — — None — 3.0 — — 1.0 — ANED — — Dead of other causes — 14 15 48/M 79/M 6 1 No No — — — — — — 16 63/M 17 74/M Residual nephrogenic metaplasia at cystectomy — 18 75/F — Clinical presentation Hematuria Urinary calculi and recurrent urinary tract infection — — Erythematous Lateral wall Bladder Lateral wall Bladder Diverticulum of urethra Prostatic urethra Posterior wall — Lateral wall — No H/O noninvasive urothelial carcinoma — Papillary tumor Prostatic urethra 2 No Radical cystectomyb — — Bladder 1 No — 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. 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-molecularweight, basal cell specific anticytokeratin (34␤E12, 1:10 dilution, monoclonal (Dako, Carpinteria, CA), an- ticytokeratin 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, 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 (34␤E12) is shown. (F) Immunostaining for cytokeratin 7 is shown. FIGURE 1. (continued) Atypical Nephrogenic Metaplasia/Cheng et al. 857 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. 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 RESULTS 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. 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, 858 CANCER February 15, 2000 / Volume 88 / Number 4 TABLE 2 Atypical Nephrogenic Metaplasia of the Urinary Tract: Histopathologic Findings Findings No. of cases (%) Superficial location Lobular growth Stromal edema Chronic inflammation Luminal mucin Acute inflammation Hobnail cells Solid pattern Clear cell change Cystitis glandularis Squamous metaplasia Multifocality Stromal calcification Mitotic figures Necrosis 18/18 (100) 18/18 (100) 16/18 (89) 15/18 (83) 12/17 (71) 10/18 (56) 9/17 (53) 8/17 (44) 6/17 (35) 7/17 (24) 4/18 (22) 3/18 (17) 2/17 (12) 0/17 (0) 0/17 (0) and the patient subsequently underwent cystectomy; no cancer was found in the final specimen. 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 (34␤E12), 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). 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. DISCUSSION 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 car- Atypical Nephrogenic Metaplasia/Cheng et al. 859 TABLE 3 Immunohistochemical Findings and DNA Ploidy Analysis of Atypical Nephrogenic Metaplasia Case no. 34␤E12 CK7 CK20 CEA EMA p53 (%) MIB-1 (%) DNA ploidy 1 2 3 5 6 7 8 9 12 ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ Focal positivity ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫺ ⫺ Focal positivity ⫺ ⫺ ⫺ Focal positivity ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ 5 0 10 10 20 10 0 0 20 1.4 0 0 0 1.5 0.4 0 0 5 Diploidy Aneuploid Diploid Diploid Diploid Diploid Diploid Diploid Aneuploid 34␤E12: high-molecular-weight cytokeratin; CK: cytokeratin; CEA: carcinoembryonic antigen; EMA: epithelial membrane antigen; ⫹: positive; ⫺: negative. TABLE 4 Differential Diagnosis of Atypical Nephrogenic Metaplasia and Clear Cell Adenocarcinoma Characteristics ANM Clear cell adenocarcinoma Gender Male predominance (male-to-female ratio, 2.6:1) 62 Hematuria and voiding symptoms Benign No apparent predilection Small (mean, 3.9 mm) Female predominance (male-to-female ratio, 1:18) 58 Hematuria and voiding symptoms Aggressive (21% died within 4 yrs) Urethrab Large Absent Absent or inconspicuous Common Common May be seen Common Usually absent Absent Invariably present Often present (53%) Easily identifiable Uncommon Common Common Common Present May be seen May present Present Present Present Minimal Present Present Present Present Negative Positive Positive Negative Positive ⬍5% Occasional positive Aneuploid pattern may be seen Negative Positive (occasionally negative) Unknown Unknown Positive Often ⬎15% Positive Unknown Mean age (yrs) Clinical presentation Biologic behavior Location Size Microscopic findings Necrosis Mitotic figures Stromal edema Luminal mucin Clear cell change Hobnail cells Infiltrative growth Psammoma bodies Inflammation Cytologic atypia Nuclear enlargement Nuclear hyperchromasia Prominent nucleoli Nuclear pleomorphisma Immunostaining PSA 34␤E12 Cytokeratin 7 Cytokeratin 20 EMA MIB labeling index p53 DNA ploidy PSA: prostate specific antigen; 34␤E12: 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. 860 CANCER February 15, 2000 / Volume 88 / Number 4 cinoma;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 adja- cent 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 (34␤E12) staining and negative prostate specific antigen staining. 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