Clear cell urothelial carcinoma of the urinary bladder: a case report and review of the literature

Urinary bladder carcinomas that differ on histology from typical urothelial carcinomas were reviewed by Young and Eble [1]. These tumors account for approximately 15% of all bladder carcinomas and fall into four major categories: variant forms of urothelial carcinoma, squamous cell carcinoma, adenocarcinoma, and undifferentiated carcinoma [1]. Variant forms of urothelial carcinoma include squamous and glandular differentiation, but these are only focal changes, with typical urothelial carcinoma seen elsewhere in the tumor [1].

The identification of clear cell tumors in the bladder is not uncommon [2]. Clear cell dysplasia is well-described and characterized by focal replacement of transitional mucosa by cells with abundant clear cytoplasm, nuclear enlargement, and a granular chromatin pattern [3]. Clear cells can also be seen in clear cell adenocarcinoma, which is rare, comprising 0.5% to 2.0% of the reported bladder carcinomas [1]. The name clear cell adenocarcinoma is used because of the histologic similarity to clear cell adenocarcinomas of the female genital tract [1]. Clear cell urothelial carcinoma is exceedingly rare, with only nine clinical cases described in the literature [2, 4‐7]. Other clear cell tumors found in the bladder to be considered in the differential diagnosis are metastatic lesions, such as renal cell carcinoma or melanoma.

We report the case of a male patient who underwent radical cystoprostatectomy for a urinary bladder tumor featuring rounded to polygonal cells with abundant clear cytoplasm, which deeply infiltrated the vesical wall. We discuss the morphologic features, immunohistochemical, and special staining pattern, and review the literature on clear cell urothelial carcinoma.

Our patient was a 75-year-old Caucasian man with a history of intermittent hematuria for a few days the month preceding a cystoscopy. He was otherwise asymptomatic and denied bone pain, jaundice, hemoptysis, or weight loss. Of clinical relevance, he was a former smoker who quit 21 years ago and had been using smokeless tobacco for the last 16 years. His referring institution performed a cystoscopy revealing a bladder tumor and a biopsy that showed a high-grade urothelial carcinoma with widespread clear cell differentiation (>80%), with severe necrosis, and extensive invasion into the muscularis propria. An ultrasound at the time showed a large urinary bladder mass with no evidence of extravesical disease, and mild right-sided hydronephrosis suggestive of obstruction of his distal right ureter. Because of an elevated serum creatinine of 1.6mg/dL, neoadjuvant chemotherapy was not attempted. A radical cystoprostatectomy was soon performed at our institution. On follow-up, his creatinine levels continued to be elevated and cisplatinum-based chemotherapy was further deferred. After one year of follow-up, our patient had no evidence of disease recurrence.

The cystoprostatectomy specimen was fixed in 10% buffered formalin, and the prostate was dissected out for independent processing. Macroscopic examination showed a fungated and hemorrhagic urinary bladder mass arising from the mucosal surface, measuring 5.5×5.0×2.3cm, involving the inferior right lateral wall, and with near obliteration of the right ureteral orifice (Figure 1). Representative sections of the bladder tumor were embedded in paraffin, sectioned at 5μm, and stained with hematoxylin-eosin. Microscopic examination revealed a tumor consisting of sheets and nodules of rounded to polygonal malignant cells with enlarged nuclei, prominent nucleoli, and abundant clear cytoplasm (>90% clear cell differentiation) (Figure 2A,B). No glandular differentiation or hobnail cells were observed. The tumor invaded through the full thickness of the muscularis propria (detrusor muscle) into the perivesical adipose tissue, approaching within 0.5mm of the perivesical serosal surface (pathology stage pT3b). Extensive necrosis accompanied by prominent acute inflammation was present. Lymphovascular invasion was identified. Focal carcinoma in situ was present in the adjacent surface urothelium. This tumor showed very similar histopathology to the prior bladder biopsy from the referring institution.

The prostate gland revealed multifocal and bilateral prostatic adenocarcinoma, Gleason grade 3+3 (score=6), measuring 6mm in greatest dimension and involving <5% of the prostate. There was focal extension of prostatic adenocarcinoma into the left posterior surgical margin (2mm in length).To characterize the content of the clear, vacuolated cytoplasm of the malignant cells in the bladder tumor, special histochemical stains were performed. The tumor cells were positive for periodic acid-Schiff (PAS) staining, which disappeared with diastase (PAS-D) treatment (Figure 2C,D). The cells were negative for mucicarmine staining and for oil red O on frozen sections of the formalin-fixed tissue. This staining pattern confirmed the cells contained polysaccharides such as glycogen, as opposed to mucin or fat.

Immunohistochemical stains were done with the following markers: Cytokeratin (CK) 7, CK20, Cell adhesion molecule (CAM) 5.2, p63, Uroplakin III, Vimentin, E-cadherin, p53, Cluster of differentiation (CD) 10, Paired box protein (PAX) 8, Renal cell carcinoma (RCC), CD117, Placental alkaline phosphatase (PLAP), S-100 protein, Human melanoma black (HMB) 45, Prostate Specific Antigen (PSA), Cancer Antigen 125 (CA-125), and Ki-67. Appropriate positive and negative controls were used. The tumor cells were positive for CK7 (Figure 2E), p53 (approximately 30% nuclear, Figure 2F), p63 (>80% nuclear, Figure 2G), Vimentin, E-cadherin (focal), CD10 (patchy), and Ki-67 (>70% nuclear, Figure 2H). The tumor cells were negative for Cancer antigen 125, CAM 5.2, CD117, CK20, HMB-45, PAX 8, PLAP, Prostate specific antigen, S-100 protein, Uroplakin III, and RCC. Additionally, the cells were negative for Leukocyte common antigen, a test previously performed and reported by the referring institution. This tumor marker profile ruled out clear cell carcinoma of Müllerian origin and other tissue origins and was most diagnostic of a primary urothelial origin. The immunostain and histochemical stain results are detailed in Table 1.

Urothelial carcinoma is the most common tumor arising in the urinary tract [4], and the most common variants have glandular or squamous differentiation [1]. Little is known, however, about urothelial carcinoma with predominantly clear cells, other than the few clinical cases reported previously, as listed in Table 2[5].

Although the presence of clear cells in otherwise typical urothelial carcinoma is not uncommon [3, 4], the tumor in this case had clear cells far in excess of what is normally seen in urothelial carcinoma. To the best of our knowledge, no study to date has shown that clear cell dysplasia progresses to clear cell urothelial carcinoma [3, 4]. “In fact, the infrequent reporting of clear-cell transitional cell carcinoma, when compared with the relatively common observation of clear-cell dysplasia, makes this unlikely,” per Braslis et al.[4].

Regarding PAS staining, Braslis and colleagues similarly reported dense and spotty positivity for cytoplasmic glycogen in one of their cases of clear cell urothelial carcinoma (Table 2) [4]. Normal urothelium contains glycogen, and positive reactivity of urothelial carcinomas for glycogen was explored by Kotliar and colleagues [6]. They selected 24 random urothelial carcinomas ranging from low-grade superficial papillary tumors to high-grade invasive tumors [6]. Approximately two thirds of tumors, despite their non-clear cytoplasm, showed varying degrees of PAS positivity that disappeared with diastase digestion (PAS-D). The overall apparent pattern of PAS/PAS-D reactivity correlated with tumor grade; in general, low-grade superficial urothelial cell carcinomas tended to have stronger diffuse staining, whereas poorly differentiated tumors tended to have negative or focal positivity [6].

The glycogen-rich, clear cell variant of urothelial carcinoma is an exceedingly rare tumor which we report in a case where malignant clear cells were far in excess of that seen in usual urothelial carcinomas. Immunohistochemical and histochemical stains helped exclude more common malignant tumors primary to the bladder, as well as metastatic lesions. Given the small number of reported cases, prognosis is not known; the continued report of these cases may eventually shed light on the biology and prognosis of these very rare tumors. Our patient is alive at the time of writing and constantly followed in our hospital system.

Written informed consent was obtained from our patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.