The nested variant of urothelial carcinoma is a recently described bladder tumor entity with a rare incidence. Two cases of this disease are presented in this report; the patients in both cases were elderly men, with a predominant involvement of the trigone region. Histologically, the tumor cells were arranged in ill-defined nests and had low-grade nuclear features. Both cases had a diffusely infiltrating growth pattern with widespread local disease at cystectomy. Strong immunohistochemical staining for p63 in the neoplastic cells supports the urothelial cell nature of this neoplasm. High p53 and Ki-67 indices of this tumor correlate with the aggressiveness of this subtype.

Urothelial carcinoma is the most common malignant urinary tumor; it accounts for more than 80% of all bladder cancers. The histologic appearances of urothelial carcinoma are very diverse; some represent distinctive patterns of invasive growth, and others represent variations of cellular morphology. The overwhelming majority of urothelial carcinomas are of the papillary type. There are nearly a dozen minor variants; among these is the recently described urothelial carcinoma-nested variant (UCNV). The incidence of the UCNV is considerably rare; it was initially described as a tumor with an irregularly nested/tubular infiltrating pattern involving the lamina propria.1 So far, in the literature, less than 10 groups have reported their experience with this variant.1–8 Knowledge about the UCNV is still developing. We report 2 additional such cases.

Case 1

A 69-year-old white man presented with 2 episodes of gross hematuria. Computed tomography imaging studies showed a moderate bilateral hydronephrosis and a diffuse thickening of the bladder wall. Lymphadenopathy or metastatic disease was not identified. Personal and family medical history was not significant, and his physical examination was noncontributory. Laboratory studies showed slightly increased serum creatinine levels (1.5 mg/dL [130 μmol/L]; normal, 0.5–1.4 mg/dL [44–120 μmol/L]) and mild anemia. Urinary cytology was never performed. A biopsy of the bladder showed muscle-invasive urothelial carcinoma involving the trigone. The carcinoma was immunoreactive for high-molecular-weight cytokeratin 903 and cytokeratins 7 and 20 and negative for prostate-specific antigen and prostatic acid phosphatase. Three weeks later, a radical cystoprostatectomy was performed. Grossly, the mucosa was edematous, with focal hemorrhage and necrosis around the trigone. The bladder wall was diffusely thickened and infiltrated by the tumor (Figure 1); the trigone region was most markedly involved, with obstruction of the ureteral orifices. Microscopically, except for the surface mucosa, the bladder wall was extensively infiltrated by neoplastic cells, which were arranged in a diffuse pattern of relatively ill-defined and variably sized nests (Figures 2 and 3). Focal urothelial carcinoma in situ and multiple foci of urothelial dysplasia were identified. The cytologic features of the underlying main neoplasm were markedly distinct from those of the surface urothelial mucosal lesions. The neoplastic cells were characterized by clear/pale or amophilic/eosinophilic cytoplasm with poorly defined borders and rounded nuclei with inconspicuous nucleoli. The chromatin was finely granular and evenly distributed. Occasionally, tumor cells displayed clear and signet ring features. There was generally no significant nuclear pleomorphism, and mitoses were rare (Figure 3). Occasionally, large atypical cells were present in the deeply infiltrated areas (muscularis propria and fat). A prominent desmoplastic reaction was easily appreciated in the infiltrating tumor. The main tumor extended through the bladder wall into the perivesicular soft tissue and involved the prostatic urethra and paraurethral tissues. Perivesicular lymph nodes contained metastatic carcinoma. Bilateral obturator and iliac lymph nodes were negative for the tumor; however, it was present in the adjacent obturator adipose tissue. On the basis of these histologic features and previous immunohistochemical studies, a high-grade UCNV was diagnosed. Adjuvant chemotherapy with taxol and carboplatin was subsequently initiated. Four months after the resection, the patient developed bone and soft tissue metastasis.

Figure 1.

Gross photograph of case 1 shows an edematous urinary bladder mucosa and a markedly and diffusely thickened bladder wall. Figure 2. The neoplastic cells form ill-defined nests with a diffuse growth pattern. Some tumor cells have clear cytoplasm. The surface mucosa is not involved by the underlying tumor (case 1) (hematoxylin-eosin, original magnification ×200). Figure 3. The nuclei of the tumor cells are relatively uniform with finely granular chromatin, inconspicuous nucleoli, and rare mitosis (case 1) (hematoxylin-eosin, original magnification ×400). Figure 4. The neoplastic cells are strongly immunoreactive for p63 (case 1) (p63, original magnification ×200). Figure 5. The cytologically bland neoplastic cells are arranged in a diffuse pattern of relatively ill-defined and variably sized nests (case 2) (hematoxylin-eosin, original magnification ×600). Figure 6. The neoplastic cells are strongly immunoreactive for p63 (case 2) (p63, original magnification ×400).

Figure 1.

Gross photograph of case 1 shows an edematous urinary bladder mucosa and a markedly and diffusely thickened bladder wall. Figure 2. The neoplastic cells form ill-defined nests with a diffuse growth pattern. Some tumor cells have clear cytoplasm. The surface mucosa is not involved by the underlying tumor (case 1) (hematoxylin-eosin, original magnification ×200). Figure 3. The nuclei of the tumor cells are relatively uniform with finely granular chromatin, inconspicuous nucleoli, and rare mitosis (case 1) (hematoxylin-eosin, original magnification ×400). Figure 4. The neoplastic cells are strongly immunoreactive for p63 (case 1) (p63, original magnification ×200). Figure 5. The cytologically bland neoplastic cells are arranged in a diffuse pattern of relatively ill-defined and variably sized nests (case 2) (hematoxylin-eosin, original magnification ×600). Figure 6. The neoplastic cells are strongly immunoreactive for p63 (case 2) (p63, original magnification ×400).

Close modal

Case 2

Three years prior to his present procedure, the 70-year-old man of case 2 initially presented with urinary frequency, episodes of excretion of small blood clots, and occasional intermittent straining. At that time, urinalysis showed trace red blood cells. An intravenous pyelogram was normal, without hydronephrosis or obstruction. Cytoscopy showed a focal area of localized inflammation on the bladder floor lateral to the right ureteral orifice. Repeated cytology showed no malignant cells. His medical and family history was insignificant. The patient failed to return for follow-up until 3 years later, when he developed recurrent hematuria. Abdominal and pelvic computed tomography imaging studies showed a mild-to-moderate dilation of the right distal ureter and a thickening of the bladder wall (0.8 cm) around the right ureteral orifice. No other mass or significant lymphadenopathy was identified within the pelvis. A transurethral biopsy of the thickened region showed lamina propria infiltrated by ill-defined nested neoplastic cells with bland cytologic features (Figure 5). A focal perineural invasion by the tumor was present. Immunohistochemistry showed the tumor cells to be immunoreactive for high-molecular-weight cytokeratin 903 and cytokeratin 7 and negative for prostate-specific antigen, prostatic acid phosphatase, S100, and chromogranin. The diagnosis of a UCNV was made. The patient subsequently underwent a radical cystoprostatectomy at another institution. The pathology report from the other institution described a tumor that extended through the lateral wall of the right trigone with a vascular invasion and a focus of urothelial carcinoma in situ. Focal prostatic adenocarcinoma (Gleason pattern 3+3, total score 6) was identified and confined to the left lobe of the prostate. Perivesicular lymph nodes were negative for a metastatic tumor. The slides were unavailable for review. Two months after the surgery, the patient was lost to follow-up.

Additional immunohistochemical studies demonstrated the nested neoplastic cells in both cases to be strongly immunoreactive for p63 (a homolog of p53 protein) (Figures 4 and 6); 40% to 50% and 30% to 40% of the tumor cells in case 1 displayed strong positivity for p53 and Ki-67, respectively, and no staining difference for either p53 or Ki-67 was present between superficial and deep infiltrating tumor cells. Focally positive stains for both p53 and Ki-67 were demonstrated in the biopsy specimen of case 2.

The nested variant of urothelial carcinoma is rare; the estimated incidence is less than 0.3% of all invasive bladder tumors.2 The reported age at the time of diagnosis for the UCNV ranges from 45 to 97 years. Most of the patients are men. The symptoms associated with UCNV are similar to those of classic urothelial carcinoma. The most common symptom is hematuria, usually macroscopic; other signs are related to the irritation of the bladder including dysuria, frequency, and nocturia. Approximately half of the cases occur in the periureteral orifice. Grossly, a clearly defined tumor lesion may not be apparent, leading to a possible delay in diagnosis. Microscopically, the lamina propria and muscularis propria are infiltrated by uniform neoplastic cells, whereas the surface epithelium is always exempted from involvement by these tumor cells. The neoplastic cells, in general, exhibit low-grade histologic features, including a low nuclear-cytoplasm ratio and rare mitotic activity. The nuclei are rounded or slightly irregular, with finely granular chromatin and occasional prominent nucleoli. The cytoplasm of the neoplastic cells is abundant and clear or pale-to-faintly eosinophilic. A tendency for increasing cellular anaplasia with increasing depth of invasion is frequently noted.1,7 

The tumor usually grows in a diffuse manner. Focally, the patterns for the neoplastic cells include (1) diffuse or confluent small nests of variable sizes, which is the most commonly reported pattern, the nested pattern tending to be preserved even when the tumor invades the muscularis propria; (2) a microcystic pattern7; and (3) a tubular pattern, the least common, in which nests contain glandlike lumens.1,7 

The urothelial cell nature of the UCNVs of the 2 cases presented was supported by their positive staining for p63, a homolog of p53, whose expression has been shown to be extensive in squamous epithelium, urothelium, and some basal cells.9 The exact urothelial origin of the UCNV is unclear. The neoplastic cells are frequently arranged in nested structures resembling florid proliferations of Brunn nests or inverted papilloma.1,3,6,10,11 Some authors thereby have suggested that proliferations of Brunn nests or inverted papilloma are the precursors of the UCNV. A distinct transition from these benign structures to neoplastic nested lesions has never been documented, and there seems to be little evidence that the UCNV represents a malignant transformation of these benign lesions. A history of prior, coexistent, or subsequent severe dysplasia of urothelial mucosa, carcinoma in situ, and even papillary urothelial cell carcinoma has been observed in patients with UCNVs.2,3,7 However, there is no direct connection between these surface mucosa-associated lesions and the underlying UCNV; moreover, considering the marked difference of cytologic features between these superficial lesions and the underlying UCNV, there is no support for a derivation of the UCNV from these lesions. The structural resemblance to proliferative Brunn nests and the coexistence of dysplastic/malignant lesions are probably coincidental.

Despite the low-grade histologic appearance of this tumor, the biologic behavior of the UCNV is aggressive. The high p53 and Ki-67 indices, 2 of the most frequently used prognostic markers for papillary urothelial carcinomas,12 demonstrated in the UCNV of our study indicate the high intrinsic malignancy of this tumor. This intrinsic aggressiveness, along with the frequent delay in diagnosis, may attribute to its more advanced local stage compared to conventional high-grade urothelial carcinoma. The optimal treatment of the UCNV has yet to be determined because of the rarity of the tumor and the lack of randomized studies. At present, radical surgical resection is performed on these patients. Adjuvant chemotherapy and radiation therapy have not been shown to be significantly beneficial in our case or in other reported cases.2,8 Differentiating UCNVs from benign urothelial lesions (eg, nephrogenic adenoma) can be achieved by the presence of invasion and the nested growth pattern. Nephrogenic adenoma typically has a papillary component and a prominent tubular or cystic structure lined predominantly by a single layer of cuboidal cells. In addition, deep invasion is absent in nephrogenic adenoma.

In conclusion, although the UCNV is a rare neoplasm, given its aggressive features and the possibility of confusion with other benign lesions, an awareness of its existence is of extreme importance. The data regarding early diagnosis and optimum management for this disease are still accumulating.

We thank Joseph Samet for his expertise in photographs and Gan Li for assistance in immunohistochemistry.

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Author notes

Corresponding author: Pamela D. Unger, MD, Department of Pathology, Box 1194, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6574 ([email protected])