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Urethral strictures are a common cause of urinary obstruction which can be treated with surgical resection. Frozen sections are rare and pose a diagnostic challenge to pathologists due to the presence of benign lesions such as nephrogenic adenoma. We retrospectively examined all specimens of urethral stricture resections submitted to pathology at our institution from 2012 to 2022 (n = 258). Final pathology reports were searched to identify patients with dysplasia, carcinoma, or nephrogenic adenoma. When available, frozen section reports were also examined and compared to the final report, and additional clinical history and microscopic images were collected for patients with nephrogenic adenoma. Nephrogenic adenoma was identified in 3.8% (10/258) of urethral stricture resections. Dysplasia was identified in one patient who underwent two separate resections, and squamous cell carcinoma was found in one resection. Intraoperative frozen section was requested in 3.4% of resections (9/258). In two resections, an initial diagnosis of squamous cell carcinoma was initially favoured, however when reviewed with a genitourinary pathologist the diagnosis was changed to "reactive process" with a final diagnosis of nephrogenic adenoma. Nephrogenic adenoma can be challenging on frozen section due to variable architectural patterns, inflammation, and reactive changes. While urethral strictures are relatively common, their assessment by frozen section is rare and pathologists may lack familiarity with the variable morphology of benign entities that can be seen on frozen section resulting in their misinterpretation. We highlight this potential diagnostic pitfall and demonstrate the value of a second opinion prior to definitive frozen section diagnosis of malignancy., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Nephrogenic adenoma (NA) is a benign, reactive lesion seen predominantly in the urinary bladder and often associated with antecedent inflammation, instrumentation, or an operative history. Its histopathologic diversity can create diagnostic dilemmas and pathologists use morphologic evaluation along with available immunohistochemical (IHC) markers to navigate these challenges. IHC assays currently do not designate or specify NA's potential putative cell of origin. Leveraging single-cell RNA-sequencing technology, we nominated a principal (P) cell-collecting duct marker, L1 cell adhesion molecule (L1CAM), as a potential biomarker for NA. IHC characterization revealed L1CAM to be positive in all 35 (100%) patient samples of NA; negative expression was seen in the benign urothelium, benign prostatic glands, urothelial carcinoma (UCA) in situ, prostatic adenocarcinoma, majority of high-grade UCA, and metastatic UCA. In the study, we also used single-cell RNA sequencing to nominate a novel compendium of biomarkers specific for the proximal tubule, loop of Henle, and distal tubule (DT) (including P and intercalated cells), which can be used to perform nephronal mapping using RNA in situ hybridization and IHC technology. Employing this technique on NA we found enrichment of both the P-cell marker L1CAM and, the proximal tubule type-A and -B cell markers, PDZKI1P1 and PIGR, respectively. The cell-type markers for the intercalated cell of DTs (LINC01187 and FOXI1), and the loop of Henle (UMOD and IRX5), were found to be uniformly absent in NA. Overall, our findings show that based on cell type-specific implications of L1CAM expression, the shared expression pattern of L1CAM between DT P cells and NA. L1CAM expression will be of potential value in assisting surgical pathologists toward a diagnosis of NA in challenging patient samples., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Nephrogenic adenomas are benign lesions that develop within the urinary tract. Most often developing within the urinary bladder, these lesions have a debatable etiopathogenesis, with hamartoma, rest hyperplasia, and transplantation of renal tubular cells being the most widely accepted ones. Nephrogenic adenomas develop more often in adult males, and predisposing factors for their development are prior urinary system injury, infection, or malignancy, with a subset of cases developing in renal transplant patients. Herein, we present a case of a male patient in his seventies who initially presented to our institution with urinary disturbances and was subsequently diagnosed with low-grade, non-invasive urothelial carcinoma. After treatment, the patient remained disease-free for a period of seven calendar years. The current presentation was due to dysuria, and bladder endoscopy revealed a ureteral stricture and two small exophytic lesions neighboring the location of the previously treated urothelial carcinoma. Histology revealed complex papillary architecture and cystic spaces lined by a monolayer of monomorphous epithelial cells with foci of hobnail appearance. The papillary stroma consisted of edematous fibrous tissue with hyperemic blood vessels and focal infiltration by inflammatory cells. Based on the histological findings, the diagnosis of nephrogenic adenoma was established., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: The authors would like to disclose that one of the authors (George Stoyanov, MD, Ph.D.) was a member of the editorial approval board of the journal (Cureus Journal of Medical Science) at the time of the manuscript submission. The authors affirm that this in no way, shape, or form manipulated the reviewer selection process, reviews, or the initial or final editorial decision. ., (Copyright © 2024, Popov et al.)

Tissue-invasive cytomegalovirus (CMV) disease represents a well-recognized complication after kidney transplantation. However, direct involvement of the urogenital tract and CMV-ureteritis occur less frequently. Nephrogenic adenomas are benign lesions of the urinary tract preferentially reported in kidney transplant recipients. We herein report a second case of a 33-year-old male kidney transplant recipient with acute post-renal allograft dysfunction due to CMV-positive ureteral nephrogenic adenoma. A causal connection might be suspected but remains to be proven., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hosek, Montani and Mani.)

Nephrogenic adenoma (NA) is an epithelial lesion that usually occurs in the mucosa of the urinary tract. Rare cases of deep infiltrative or perinephric lesions have also been reported. Recently, NA with characteristic fibromyxoid stroma (fibromyxoid NA) has been proposed as a distinct variant. Although shedding of distal renal tubular cells due to urinary tract rupture has been postulated as the cause of NA in general, the mechanism underlying extraurinary presentation of NA and fibromyxoid stromal change in fibromyxoid NA remains unknown. In this study, we performed mass spectrometry (MS) analysis in a case of perinephric fibromyxoid NA of an 82-year-old man who underwent right nephroureterectomy for distal ureteral cancer. The patient had no prior history of urinary tract injury or radiation. Periodic acid-Schiff staining-positive eosinophilic structureless deposits in the stroma of fibromyxoid NA were microdissected and subjected to liquid chromatography/MS. The analysis revealed the presence of a substantial amount of uromodulin (Tamm-Horsfall protein). The presence of urinary content in the stroma of perinephric fibromyxoid NA suggests that urinary tract rupture and engraftment of renal tubular epithelial cells directly cause the lesion., (© 2024 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Nephrogenic adenoma (NA) is a rare metaplastic entity commonly associated with a prior urothelial injury. Most are seen in the urinary bladder and a minority involve the urethra. In this study, we evaluated the expression of p16 as a surrogate marker of this entity and correlated it with clinical pathological parameters. A total of 17 cases of NA were retrospectively studied to assess the immunohistochemical expression of p16 and its value for the diagnosis of this entity., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Alvarez Moreno et al.)

Nephrogenic adenomas are uncommon benign lesions that are typically cytologically bland, but degenerative and reactive changes may make it difficult to distinguish these lesions from malignant entities, such as urothelial carcinoma and prostatic adenocarcinoma. In this study, we explored whether napsin A, a sensitive marker for lung adenocarcinoma, may also have a role in distinguishing nephrogenic adenoma from other genitourinary lesions. Immunohistochemically, napsin A was expressed in all 43 nephrogenic adenomas (bladder: 38, prostatic urethra: 4, and ureter: 1; mean positive tumor cells: 72%, median: 80%, range: 15-100%) and showed regional variability in its expression pattern with a bias toward surface architectures (flat, papillary) compared with stromal architectures (tubular/glandular, microcystic). We also compared napsin A with other markers including PAX8, GATA3, p63, and 34BE12. Although napsin A matched PAX8 in terms of its sensitivity for nephrogenic adenoma (100%), napsin A stained a lower percentage of tumor cells than PAX8 (72% vs 99%, respectively, P = 1.0 × 10 -5 ). P63 was negative in all nephrogenic adenomas, whereas GATA3 showed variable staining in 25 cases (58%). All 43 nephrogenic adenomas showed variable 34BE12 staining. Finally, we profiled napsin A expression among 401 genitourinary tumors on tissue microarrays (n = 308) and full tissue blocks (N = 93) and observed napsin A positivity in 37 tumors (9%), which included urothelial carcinomas with the glandular/microcystic component differentiation (in the glandular/microcystic component in 4/6), bladder adenocarcinomas (primary: 4/4 and metastatic: 3/3), urinary tract clear-cell carcinomas (primary: 8/9, metastatic uterine primary: 1/1), and some renal tumors (17/174). All 81 pure urothelial carcinomas and 53 prostatic acinar adenocarcinomas were negative for napsin A. Our study indicates that napsin A is a highly sensitive marker for nephrogenic adenoma and can serve as a useful addition in immunohistochemical panels seeking to distinguish it from pure urothelial carcinoma and prostatic acinar adenocarcinoma but not clear-cell carcinoma or urothelial carcinoma with glandular differentiation., Competing Interests: Conflict of Interest Statement No conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Nested variant of urothelial carcinoma is a rare variant of urothelial carcinoma morphologically characterized by infiltrative nests of cytologically bland urothelial cells. It is widely recognized that nested variant of urothelial carcinoma can closely mimic von Brunn nests. However, nested variant of urothelial carcinoma with tubule formation can also resemble nephrogenic adenoma, where immunohistochemical positivity for PAX8 has been used to establish the diagnosis of nephrogenic adenoma. Following anecdotal examples of PAX8 positive nested variant of urothelial carcinoma, we formally evaluated 23 cases of nested variant of urothelial carcinoma from 2011 to 2018. Cases were collected from our institution and evaluated for their architectural pattern and PAX8 expression. Except for 1 case from the renal pelvis, cases were located in the bladder. The majority (14/23 [61%]) showed solid nests with at least focal tubular differentiation. PAX8 immunoreactivity was strong (3+) in 7 (30%), moderate (2+) in 6 (26%), and negative in 10 (44%) cases. Four (57%) of the cases with strong expression and 3 (50%) of those with moderate staining showed diffuse immunoreactivity. Moderate-strong immunoreactivity was seen in 4/6 (66.7%) cases with solid nests, 8/14 (57.1%) with solid nests and tubules, and 1/3 (33.3%) with large nests. In conclusion, PAX8 can be positive in a significant proportion of nested variant of urothelial carcinoma cases, and recognition of this finding is important to avoid misdiagnosis of nested variant of urothelial carcinoma as nephrogenic adenoma based on PAX8 expression, particularly in cases with tubular differentiation and limited sampling., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Nephrogenic adenoma is a common diagnosis in urological pathology that may be challenging for general pathologists. Due to its polymorphic appearance under the microscope, some cases can be misdiagnosed as malignancy and then unnecessarily overtreated. Aside from the typical tubules, cysts and papillae, nephrogenic adenoma may display a broad spectrum of histologic appearances and locations, some of them atypical or unexpected. These unusual and concerning features will have special consideration in this description. The goal of the review is to increase awareness of general pathologists of the varied histology of nephrogenic adenoma., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Background: Nephrogenic adenoma is an uncommon benign lesion that occurs at several sites in urinary tract, from the renal pelvis to urethra, with the highest frequency in urinary bladder. Nephrogenic adenoma displays a broad spectrum of architectural and cytological features. Hence, recognition of its characteristic histopathological features is needed to distinguish this lesion from its mimickers., Materials and Methods: A retrospective series of 21 cases of nephrogenic adenoma in 18 patients, which were diagnosed in our department between 2010 and 2016, were analyzed. All histological slides were reviewed by two pathologists and the diagnosis of each case was confirmed. Immunohistochemistry was performed for PAX-8 in all cases. CK7, PAX-2, PSA, p53, p63, GATA-3 and α-methylacyl-CoA racemase (AMACR) were applied in problematic cases., Results: The most common location of the lesion was urinary bladder (14 patients) followed by renal pelvis (2 patients), ureter (1 patient) and urethra (1 patient). A history of urothelial carcinoma and repeated TUR procedures were observed in 12 patients. There were 2 pediatric patients aged 3 years. Both of them had undergone previous urosurgery because of megaureter in one and bladder exstrophy in the other. Other clinical antecedents included bladder diverticulum (1 patient), cystitis (1 patient) and nephrolithiasis (1 patient). Recurrence of lesion was seen in two patients (once in one case and twice in the other one). The median time to disease recurrence in these patients was 11 months (range, 2-20 months). Histologically, the lesions exhibited various morphological findings, with mixed (15 cases, 71.4%), pure tubular (3 cases, 14.3%), pure papillary (2 cases, 9.5%) and pure flat (1 case, 4.8%) growth patterns. Of the 15 cases with mixed patterns, 8 cases were tubulocystic and flat, 3 cases were tubular and flat, 2 cases were tubular, papillary and flat, 1 case was tubulocystic, papillary and flat, and 1 case was tubular and papillary. Flat pattern was observed in 15 cases (71.4%). It was seen in association with other patterns in 14 cases (mixed morphology) and purely in 1 case. Our findings suggested that the flat pattern is a frequent finding in nephrogenic adenomas. Notably one case in this series showed superficial extension into bladder muscularis propria., Conclusions: Histologically nephrogenic adenoma may simulate a variety of malignancies. Awareness of characteristic morphologic features of nephrogenic adenoma is needed to diagnose this lesion correctly., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Nephrogenic adenoma (NA), referred to as nephrogenic metaplasia, is a rare benign lesion of the urinary tract. NA is histologically characterized by tubular and papillary formations lined by low cuboidal to columnar epithelial cells. NA is also immunohistochemically characterized by positivity for paired box (PAX) 2, PAX8 and cytokeratin 7, and negative for p63 and prostate-specific antigen. In this study, we present 3 cases of NA arising in the urinary bladder of elderly male patients with predisposing factors: patient 1 had undergone transurethral lithotripsy due to a ureteral stone; patient 2 had undergone transurethral resection of a urothelial carcinoma in the urinary bladder; and patient 3 had been treated with Bacillus-Calmettle-Guérin due to a urothelial carcinoma in the urinary bladder. The characteristics of the NAs of our 3 cases were histologically and immunohistologically consistent with previously reported cases, although 1 patient exhibited a pseudoinvasive pattern. Since NA is a tumor-like benign lesion, it should be clearly differentiated morphologically and immunohistologically from other tumors arising in the urinary tract and from invasion by prostate cancer.

Objectives: The aim of this study is to determine if the diagnosis of nephrogenic adenoma (NA) can be made on cytologic criteria alone and if pair box gene transcription factor 8 (PAX8) is useful in the diagnosis of NA in daily cytology practice., Methods: Cytologic features of NA previously described in a literature were used to identify NA cells in urinary specimens. Subsequently, all cytology and corresponding biopsy specimens were stained with the PAX8 immunohistochemistry stain. The stains were examined; the results were tabulated., Results: A total of 44 specimens were reviewed (35 with corresponding biopsy specimens diagnosed as NA and nine negative for NA diagnosis on corresponding biopsy specimens). Of them, 14 demonstrated features previously described as NA. None of atypical cells that were morphologically suspicious for NA showed positive staining, whereas all of the corresponding biopsy sections demonstrated nuclear PAX8 positivity. Only rare lymphocytes present in cytology specimens showed nuclear staining with PAX8., Conclusions: Assuming that the results of the PAX8 stain performed are accurate at least in most cases, as suggested by the presence of internal positive controls, our study shows that the previously described cytologic features of NA cannot be used as diagnostic criteria, since they are not characteristic for this entity., (© American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Nephrogenic adenoma (NA) is an unusual, benign lesion of the urinary tract, generally presenting in the bladder and with less frequency in the renal pelvis, urethra or ureter. It consists of tubules, microcysts and papillae lined by a single layer of low cuboidal epithelium without atypia. Recently, a fibromyxoid variant mimicking an infiltrating mucinous adenocarcinoma has been described. We report hereby the case of a 70-year-old female with a fibromixoid NA protruding in a renal cortical cyst. Only one case of NA in a renal cortical cyst has been found in the literature and it was of the classical type. The development of a NA in a renal cortical cyst lends support to the theory that the NA results from proliferation of secondarily implanted exfoliated renal epithelial cells., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Background: Patients following solid organ transplantation have an increased risk of developing de novo bladder tumors, but their biology is poorly characterized., Methods: We studied 1743 patients who underwent a transurethral resection of a newly diagnosed bladder tumor at a single institution. The histopathology, treatment, recurrence-free survival and overall survival were evaluated and compared between transplant and non-transplant patients., Results: We identified 74 transplant patients who developed a de novo bladder tumor after a median post-transplantation interval of 62 months. The tumor was malignant in 29 patients (39 %). The most common benign lesion was nephrogenic adenoma (84 %), which neither coexisted with nor developed into malignant tumors during follow-up. Compared with non-transplant patients (n = 1669), transplant patients were significantly younger (median 55 vs 69 years, P < 0.001) and had a 9.0-fold higher odds of benign tumors (P < 0.001), while there were no differences in pathology among patients with urothelial carcinoma of the bladder (UCB). In a multivariable analysis for non-muscle-invasive UCB that was adjusted for the risk group, patients with a transplant had a 1.8-fold increased risk of recurrence (P = 0.048). Four of five transplant patients did not respond to Bacillus Calmette-Guérin instillations. There were no differences in overall survival after radical cystectomy (P = 0.87)., Conclusions: The majority of bladder tumors in transplant patients are benign, and they neither coexist with nor develop into malignant tumors. Transplant patients with non-muscle-invasive UCB show an increased risk of disease recurrence, while those treated with radical cystectomy have similar outcomes to patients without a transplant.

This report describes the morphological and immunohistochemical features of the first case of a nephrogenic adenoma (NA) of the urinary bladder infected with polyomavirus. The findings occurred in a female patient, 6 months post cadaveric renal transplant. Voided urine cytology was positive for decoy cells. Renal transplant biopsy showed no evidence of BKV allograft nephropathy. Cystoscopy demonstrated multiple erythematous patchy and nodular areas. These were found in the left and right posterior wall, and the right lateral wall toward the bladder neck, and were suspicious for either chronic inflammation or neoplasia. Hematoxylin-eosin stained sections showed a NA with scattered pleomorphic nuclei demonstrating smudged chromatin and amorphous basophilic ground glass inclusions. Strong expression of polyomavirus large T antigen (SV40) and VP1 was seen in atypical lesional cells, consistent with cytopathic lytic polyomavirus infection. Positive staining with PAX8 supports the renal cell derivation of NA. The findings in the present case suggest that polyomavirus infection, as an irritant of the bladder mucosa, contributed to the cytologic atypia of infected lesional cells but is not a pathogenic factor of NA., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Metanephric adenoma (MA) is a rare, benign renal tumor that can be found in individuals of any age. The histological features of this lesion are well known; however, cytological features of this entity have rarely been described. Herein, we present the case of a 37-year-old white woman with multiple endocrine dysfunctions and a renal mass. The diagnosis of metanephric adenoma was suggested as a differential diagnosis during imprint cytology; this diagnosis was later confirmed by core needle biopsy (CNB) and the results of immunostaining. To our knowledge, this is the first time in the literature that the diagnosis of metanephric adenoma was initially suggested on imprint cytologic testing of a CNB. We review the literature regarding the cytologic features and immunohistochemical reactivity of this tumor to raise awareness of this entity among pathologists and to distinguish it from other lesions, such as renal-cell carcinoma, so physicians can use this information to help them avoid calling for an unnecessary radical nephrectomy., (Copyright© by the American Society for Clinical Pathology (ASCP).)

Pediatric nephrogenic adenoma (NA) is an uncommon benign metaplastic lesion occurring in the urothelium. Herein we report a case of NA of the urinary bladder in a 14-year-old boy. The patient presented with macroscopic hematuria and had a history of ureteral surgery and long-term smoking. NA should be considered in the differential diagnosis of any urinary tract tumor in the pediatric population., (© 2014 Japan Pediatric Society.)

Prostate needle biopsy currently is the gold standard method for the diagnosis, management, and prognosis of prostate cancer. Obtaining an accurate diagnosis is crucial for pursuing proper patient management. This article discusses histologic mimickers of prostate carcinoma highlighting microscopic features that are helpful to reach a correct diagnosis and emphasizing potential diagnostic pitfalls., (Copyright © 2008 Elsevier Inc. All rights reserved.)

Benign diseases of the bladder often present diagnostic challenges to practicing pathologists due to their diverse nature and ability to mimic a variety of epithelial or mesenchymal neoplasms. Categories of benign bladder disease include infectious cystitis, noninfectious cystitis, reactive proliferative processes, and benign processes that secondarily involve the bladder. An understanding of the key clinical and morphologic features of these lesions and the useful ancillary techniques specific for these entities is critical to the correct diagnosis of these lesions. This article reviews the key features of these benign bladder diseases and highlights methods to distinguish these lesions from other benign and malignant processes involving the bladder., (Copyright © 2008 Elsevier Inc. All rights reserved.)