Search

Summary Antibodies targeting uroplakin II (UPII) are highly specific for urothelial cells and are frequently used to determine if a primary bladder lesion or a metastatic lesion originates from the urothelium. However, to date, no studies have tested the expression of UPII in histological mimickers of bladder cancer that are nonurothelial in origin. Given the potential risk of misdiagnosis, immunohistochemical markers are often used to better characterize these lesions. In the present study, we analyzed the immunohistochemical expression of UPII in a set of urothelial carcinoma mimickers that included conventional nephrogenic adenoma (n = 8), papillary nephrogenic adenoma (n = 6), endometriosis/endosalpingiosis (n = 5), inflammatory myofibroblastic tumor (n = 4), ectopic prostate tissue (n = 2), and malakoplakia (n = 2). We also examined the expression of GATA-3, another commonly used immunohistochemical marker in bladder cancer diagnosis, in the same lesions. Weak immunoreactivity for UPII was identified in 6 of 27 mimickers (22%), and GATA-3 was expressed in 16 of 27 mimickers (59%). Strong immunoreactivity for UPII appeared to be a specific marker for urothelial cell of origin, although weak staining was seen in a significant proportion of mimickers. GATA-3 immunostaining was present in a greater number and broader spectrum of mimickers; however, only one case of papillary nephrogenic adenoma showed dual positivity for UPII and GATA-3. These findings support the immunohistochemical panel-based approach in the diagnosis of bladder lesions, especially if nonurothelial bladder cancer mimickers are in the differential diagnosis. Additional larger studies would be of value to expand on these findings.

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.

Nephrogenic metaplasia or nephrogenic adenoma of the urinary tract may present a diagnostic challenge in surgical pathology practice. Previous case reports suggest the possibility of nephrogenic metaplasia progressing to clear cell adenocarcinoma, but a malignant potential of nephrogenic metaplasia is generally not acknowledged. A case of a 70-year-old female patient with multiple recurrences of nephrogenic metaplasia of the urinary bladder and subsequent development of clear cell adenocarcinoma is described. Immunohistochemical studies help to differentiate the 2 entities. Results of molecular studies, particularly comparative genomic hybridization analysis, suggest clonal evolution of nephrogenic metaplasia to clear cell adenocarcinoma in this case.

Fascin-1 is an actin-bundling protein that plays an important role in cell motility and adhesion. The level of fascin-1 is low or undetectable in normal epithelial cells. However, overexpression is reported in transformed epithelial cells and in several common types of carcinomas [Bioessays. 2002;24:359-361]. Up-regulation of fascin-1 is associated with higher grades and with aggressive tumors with poorer prognoses. We found no report on the role or the protein expression of fascin-1 in urothelial carcinomas (UCs) of the urinary bladder. In this study, we examined by immunohistochemistry the expression of fascin-1 in the normal human transitional epithelium, benign vesical lesions, and different types of UCs. We found no detectable fascin-1 in the normal transitional epithelium. There was no increase of fascin-1 expression in cystitis cystica, cystitis glandularis, nephrogenic adenoma (n = 10), inverted papilloma (n = 5), and classic exophytic papilloma (n = 4) or in adjacent transitional epithelia associated with these conditions. Patchy or diffusely weak fascin-1 expression was observed in 42% (5/12) of superficial papillary UCs (Ta), and 95% (19/20) of invasive UCs (T2 or higher) demonstrated diffuse strong staining for fascin-1. The microinvasive foci in the lamina propria of UC (T1, n = 8) were also positive for fascin-1, although they were not as strongly stained as in the deeply invasive tumors. Interestingly, the neoplastic cells in the tips of microinvasive carcinomas were distinctly positive for fascin-1. There were significant numbers of fascin-1-positive cells (>50% of the neoplastic cells) in UCs in situ (n = 10). These findings suggest an association between increased fascin-1 expression and increased invasiveness of carcinomas in the urinary bladder.

Although clear cell adenocarcinoma have been described focally mimicking nephrogenic adenoma, we have identified a subset of clear cell adenocarcinoma that diffusely resembles nephrogenic adenoma (nephrogenic adenoma-like clear cell adenocarcinoma). Twelve classic clear cell adenocarcinomas of the bladder and urethra and 7 nephrogenic adenoma-like clear cell adenocarcinomas were compared to 10 nephrogenic adenomas. Classic clear cell adenocarcinomas and nephrogenic adenoma-like clear cell adenocarcinomas comprised 4 men and 15 women. The following features were seen in classic clear cell adenocarcinomas: nephrogenic adenoma-like clear cell adenocarcinomas: predominantly solid pattern (7/12:0/7), marked nuclear pleomorphism (7/12:1/7), prominent nucleoli (5/12:1/7), clear cytoplasm in 50% or greater of tumor (7/12:0/7), and necrosis (8/12:3/7), although the necrosis in nephrogenic adenoma-like clear cell adenocarcinomas was often focal and intraluminal. Both patterns of clear cell adenocarcinomas showed prominent hobnail features, although more pronounced in nephrogenic adenoma-like clear cell adenocarcinomas. Muscularis propria invasion was seen in 5 of 9 classic clear cell adenocarcinomas and 6 of 6 nephrogenic adenoma-like clear cell adenocarcinomas, where evaluable. Classic clear cell adenocarcinoma was associated with urothelial carcinoma (n = 2) and endometriosis (n = 1). The Ki-67 rate in clear cell adenocarcinomas ranged from 10% to 80% compared with 0% to 5% in nephrogenic adenoma. The following antibodies were not helpful in distinguishing nephrogenic adenoma-like clear cell adenocarcinoma from nephrogenic adenoma: CD10, estrogen receptor, p63, high-molecular-weight cytokeratin, and alpha-methylacyl coenzyme-A racemase. PAX2 expression was more frequent in nephrogenic adenoma (89%) compared to both patterns of clear cell adenocarcinoma (29%-32%). The key features discriminating between nephrogenic adenoma-like clear cell adenocarcinoma and nephrogenic adenoma include occasional clear cells, more prominent pleomorphism especially hyperchromatic enlarged nuclei, and extensive muscular invasion. Presence of mitoses and a high rate of Ki-67 expression in lesions resembling nephrogenic adenoma require clinical correlation, close follow-up, and repeat biopsy with more extensive sampling.

Nephrogenic adenoma (NA) of the prostatic urethra with involvement of the prostate gland can mimic other small-gland proliferations of the prostate, particularly adenocarcinoma of the prostate. To further characterize this lesion and refine diagnostic criteria we retrospectively reviewed the clinicopathologic features and immunohistochemical findings of eight cases of NA involving the prostate gland seen at The University of Texas M.D. Anderson Cancer Center from 1987 to 1992. The patients' ages ranged from 44 to 76 years (average age, 65 years). Six patients had lower genitourinary tract operations. Follow-up information was available for six patients (follow-up period, 5 to 38 months); only one patient had clinical evidence of recurrence (5 months after surgery). The remaining patients were alive and well with no evidence of disease. Histologically, NA was characterized by a proliferation of small tubules lined by a single layer of cuboidal or flattened cells with clear or eosinophilic cytoplasm. The nuclei were round with fine chromatin and there was no mitotic activity. Nucleoli were generally small, but occasionally prominent. All NA extended into the prostatic parenchyma, raising the possibility that these lesions may represent prostatic small-gland proliferations, particularly prostate adenocarcinoma. However, all cases tested were negative for prostate-specific antigen and prostatic acid phosphatase. Our findings indicate that the histologic features and the use of prostate-specific antigen and prostatic acid phosphatase immunostains will help to distinguish NA of the urethra involving the prostate from other small-gland proliferations (eg, small-acinar adenocarcinoma of the prostate, clear cell adenocarcinoma of the urethra, sclerosing adenosis, atypical adenomatous hyperplasia, florid hyperplasia of mesonephric remnants, simple lobular atrophy, and incomplete basal cell hyperplasia).

The histologic and ultrastructural features of nephrogenic adenomas of the urinary bladder and urethra were studied in multiple specimens obtained from eight patients. Three of these were studied by indirect immunofluorescence for Tamm-Horsfall uromucoprotein. The lesions are uncommon benign metaplastic proliferations of urothelium, occurring most frequently in males as small cystic, papillary, or nodular masses and most often presenting with hematuria. Typically the metaplastic tubules resemble nephronic tubules. A florid atypical and pseudoinfiltrative proliferation of these tubules may led to an erroneous diagnosis of adenocarcinoma. Ultrastructural features of proximal convoluted tubules were identified in some of the tubules, but resemblance to specific segments of distal tubules was less certain. The ultrastructural features combined with the absence of Tamm-Horsfall protein in tubular lumina or cells suggest a mesonephric rather than metanephric homology. The lesions are appropriately treated by transurethral resection or fulguration, but persistent lesions were present in three patients up to 18 yeas after initial treatment.