Nested Variant of Urothelial Carcinoma Open Access

The histology of urothelial carcinoma is variable, with most noninvasive or superficially invasive carcinomas being papillary and showing different degrees of differentiation, whereas most muscle-invasive carcinomas are nonpapillary and are of high-grade cytomorphology. These tumors are readily identified histologically and do not usually pose a diagnostic problem. Nested variant of urothelial carcinoma (NVUC) is one of the morphologic variants of urothelial carcinoma that is characterized by an unusual, bland morphology and a clinical behavior similar to that of high-grade conventional urothelial carcinomas. Although rare, with a reported prevalence of 0.3%,1 it is more often underrecognized. Since it was first reported by Stern in 1979,2 approximately 50 cases have been reported in the literature. The first reported case was interpreted as benign, but the lesion recurred. Later, Talbert and Young3 reported 3 cases of this entity in 1989 and described them as the carcinomas of the urinary bladder with deceptively benign-appearing foci. Murphy and Deana in 19924 named this neoplasm as the nested variant of transitional cell carcinoma, as it resembles proliferation of von Brunn nests.

Nested variant of urothelial carcinoma presents at a mean age of 68 years (range, 45–97 years) with an age and sex distribution similar to that of conventional urothelial carcinoma.5,6 Hematuria is the most common clinical presentation, and other symptoms are increased urinary frequency, dysuria, and nocturia.4 There is a marked male predominance.5,7 

Grossly, these tumors may be papillary or solid, or they may manifest as a focus of a hemorrhagic area or slight mucosal irregularity.1,4,5,8–10 The tumors range in size from 1 to 8 cm.9 These tumors are mostly located in the bladder, commonly involving the ureteral orifice and trigone, although one case solely involving the ureter has been reported.5 Multifocality is well described in the literature.4 

These tumors are characterized histologically by large numbers of small, closely packed, poorly defined, confluent, and irregular nests of uniform urothelial cells infiltrating the lamina propria, reminiscent of von Brunn nests, and also infiltrating the muscularis propria with retained nested pattern (Figures 1 and 2). The nests show an infiltrative base.7 Small tubules and microcysts may be seen.3,11 The overlying urothelium may be normal in appearance. The cells comprising this neoplasm show no significant cytologic atypia; they are mildly pleomorphic, show slightly increased nuclear-cytoplasmic ratio and occasional prominent nucleoli (Figure 3). Although the tumor cells appear histologically bland, some authors have observed significant pleomorphism, particularly within regions of muscle invasion.1,4,5 Mitotic figures are not readily seen. Mucin also is not identified. The surrounding stroma varies from dense and collagenous to loose and myxoid, or even edematous. Lymphatic invasion may be seen.1 

Due to their deceptively bland appearance, the tumors are sometimes misdiagnosed as benign lesions, especially in the biopsy material, leading in some cases to a significant delay in establishing the correct diagnosis.11 In fact, in some cases it is very difficult to establish an unequivocal diagnosis of NVUC in the biopsy material until multiple biopsies are performed.

Previous, synchronous, and subsequent conventional urothelial carcinoma has been reported.5 Nested variant of urothelial carcinoma has also been seen in coexistence with adenocarcinoma and squamous cell carcinoma.1 In situ urothelial carcinomas have been described in cases of NVUC; however, no direct connection could be established.6,12 

Nested variant of urothelial carcinoma must be differentiated from the benign proliferative lesions of the urothelium, such as von Brunn nests, cystitis cystica, cystitis glandularis, nephrogenic adenoma, paraganglioma, and inverted papilloma. These lesions comprise the major differential diagnosis of NVUC and closely mimic this neoplasm.1,3–5,7,11 Urothelial nests or epithelial aggregates of von Brunn nests, cystitis cystica, and cystitis glandularis are larger, well circumscribed with a lobular or plaquelike configuration, regularly distributed, and have a flat base (Figure 4), whereas nests in NVUC are numerous, closely packed, haphazardly arranged, and infiltrative in nature. Mild nuclear atypia can be seen in florid von Brunn nests, but any amount of significant atypia raises the possibility of NVUC. In addition, muscularis propria involvement is not seen with von Brunn nests. Nephrogenic adenoma can be papillary or tubular. Tubules in nephrogenic adenoma are lined by a single layer of cuboidal or columnar cells, with occasional nuclear atypia that appears to be degenerative. The atypical nuclei reside in cells with an endothelial or hobnail appearance. In contrast to the cuboidal and columnar cells of nephrogenic adenoma, the tubules and nests in NVUC are formed by urothelial cells. Inverted papillomas consist of anastomozing urothelial trabeculae and nests with peripheral palisading and central streaming. On superficial biopsies, NVUC and inverted papillomas can be confused because of the tightly packed nests of urothelial cells that are cytologically bland. However, the haphazard arrangement of the nests and the lack of peripheral palisading in NVUC may be helpful in differentiating between these two lesions. Nested variant of urothelial carcinoma may mimic paraganglioma, but the prominent vascular network that surrounds the individual nests is not usually present in NVUC, and immunohistochemistry with NVUC-expressing keratins and paraganglioma-expressing neuroendocrine markers may be helpful. The benign entities can be excluded easily if invasion of the muscularis propria is present.

The cytologic features of NVUC in urine specimens have been described by Cardillo et al.13 The authors observed morphologically similar–appearing neoplastic cells in the urine specimens of patients who were diagnosed with NVUC from their resection specimens. The neoplastic cells were characterized as medium sized, round to polygonal in shape, and having abundant dense and slightly granular basophilic cytoplasm, well-defined cell borders, and increased nucleocytoplasmic ratio with irregular nuclear membrane, coarse chromatin, and occasional prominent nucleoli. Although the authors did not recommend the primary diagnosis of NVUC in urine specimens as the findings were subtle, it was recommended that the presence of these cytologic features warrant a cystoscopic examination.13 

Few studies have described the immunohistochemical findings of these tumors and shown that NVUC shares some immunohistochemical characteristics with conventional urothelial carcinoma, such as immunoreactivity with high-molecular-weight keratin 903 and cytokeratins 7 and 20.7,14 In addition, NVUC showed similar staining patterns with markers associated with poor prognosis in conventional urothelial carcinoma, such as loss of p27 expression in the deeper component of the tumor and high proliferation index.6,7 Lin et al6 observed a distinct pattern of staining with p21 and p27 in which expression of p21 was observed in the deepest tumor regions and p27 expression was limited to the most superficil area. Nested variant of urothelial carcinoma consistently showed higher MIB-1 labeling compared with benign proliferating lesions, such as von Brunn nests, cystitis cystica, and inverted papilloma. In one study comparing NVUC to florid von Brunn nests, the authors reported that MIB-1 labeling was significantly higher in NVUC than in von Brunn nests (8.8% vs 2.8%, P = .01).7 Additionally, in two other reports of 14 total cases of NVUC, the authors found MIB-1 labeling to be greater than 15% in all but one case.6,14 Therefore, MIB-1 can be considered as a helpful marker in distinguishing NVUC from benign proliferative lesions.6,7 However, it should be kept in mind that some cases of NVUC show very low MIB-1 values. Volmar et al7 reported a higher expression of p53 in NVUC in comparison with florid von Brunn nests (4.2% vs 1.4%), but the difference was not statistically significant. Although some immunohistochemical differences have been noted in NVUC, the staining pattern appears to be very variable and is of limited value in the diagnosis and differentiation of these tumors from benign entities.

Nested variant of urothelial carcinoma usually presents at an advanced stage and tends to have a persistent and progressive clinical course.1,5,12,14 Reports of outcome are variable and are confounded by the small number of cases in them and the lack of comparative analyses with conventional urothelial carcinoma. Drew et al5 reported that only 3 of the 12 patients with available follow-up were alive after an average follow-up of 16.6 months. However, in their review of the literature, the same authors reported a death rate of up to 25% of cases and persistent or progressive disease in up to 60% of cases, leading them to conclude that NVUC has a clinical course similar to that of high-grade urothelial carcinoma.5 In the study by Holmang and Johansson,1 7 of 10 patients died of disease 4 to 10 months after diagnosis. In the study by Lin et al,6 all 12 patients were alive after a mean of 17.6 months, but 3 of 12 patients developed metastases. Survival difference in the study by Lin et al could be due to the fact that most patients in that series were treated by cystectomy rather than by transurethral resection.

The optimal treatment of NVUC is yet to be determined because of the rarity of the tumor and the lack of randomized studies. It is suggested that NVUC should be approached clinically as a high-risk disease, with early cystectomy as an option for pT1 and pT2 tumors.6 Adjuvant chemotherapy and radiation therapy have not been shown to be significantly beneficial in the reported series.1,10,14 

Nested variant of urothelial carcinoma should be kept in mind as a histologically unique variant that should not be confused with florid von Brunn nest. Any bladder biopsy with tightly packed nests with any degree of architectural or cytologic atypia should be evaluated with caution, and the possibility of NVUC should be raised in such circumstances.