Non-muscle-invasive clear cell carcinoma of the urinary bladder: Is cystectomy necessary?

We report the clinical presentation, histological findings and management of a 49-year-old female patient with non-muscle-invasive clear cell carcinoma of the urinary bladder. In the literature, there are only seven such case reports. We feel that transurethral resection of the bladder tumour followed by close cystoscopy surveillance is a suitable management for non-muscle-invasive clear cell carcinoma of the urinary bladder.

urological cancer, pathology, urological surgery

Clear cell carcinoma (CCC) of the bladder is a very rare variant of bladder tumours. There are very few cases reported in the literature. The majority of the reported cases are muscle-invasive CCC of the bladder treated mainly with cystectomy. Although no consensus is currently agreed regarding treatment of CCC of the bladder, we feel that transurethral resection of the tumour (TURBT) followed by close cystoscopy surveillance and upper tract imaging is a suitable management option for non-muscle-invasive CCC of the urinary bladder. Case presentation A 49-year-old fit-and-well female patient presented to urology rapid access service with painless haematuria in October 2014. She reported no other urinary tract symptoms. She had no significant comorbidities and was not on any medications. There was no family history of any urological malignancy. Investigations Flexible endoscopic examination revealed a solid lesion approximately 1 cm in size at the dome of the bladder (figure 1). An urgent TURBT was performed. Multiple tumour fragments measuring approximately 45×55×5 mm in aggregate were sent for histology. Microscopy showed fragments of moderately differentiated CCC of the bladder, with tubulocystic spaces lined by cells with abundant clear cytoplasm. No urothelial differentiation was seen and no in situ component was identified. The tumour was invading the lamina propria, but not the deep muscle present in the sample. No vascular invasion was seen (figure 2). Immunohistochemistry showed strong cytokeratin 7 (CK7) staining and high proliferation index. Wilms tumour 1 (WT1), vimentin, CK20 and caudal type homeobox 2 (CDX2) were negative. There was some weak patchy cluster of differentiation 10 (CD10) staining and the tumour was paired box gene 8 (PAX-8) positive and GATA binding protein 3 (GATA-3) negative. The profile favoured a bladder origin for this tumour (figures 3–5). The final tumour staging was G3pT1N0M0 as further imaging showed no evidence of distant metastasis or lymphadenopathy. Differential diagnosis The most common malignancy of the bladder epithelium is urothelial carcinoma followed by squamous cell carcinoma and adenocarcinoma. CCC mainly affects the kidneys. Treatment After discussion of the management options, which included total cystectomy, partial cystectomy and cystoscopic surveillance, at the multidisciplinary meeting, the consensus was to offer surveillance cystoscopy and upper tract imaging. Outcome and follow-up A follow-up cystoscopy done 3 months after the initial TURBT showed a recurrence similar in size to the initial tumour in the right anterior wall adjacent to the bladder neck. The suspicious area was resected and microscopic examination showed sheets of cells with occasional gland formation showing abundant clear cytoplasm infiltrating into the lamina propria confirming a recurrence of the clear cell adenocarcinoma. There was no lymphovascular or muscle invasion seen. The immunohistochemistry results obtained were similar to the initial tumour and additionally stained negative for P504S too. The options of cystectomy and periodic cystoscopic surveillance were once again discussed and cystoscopic surveillance was agreed on as the path of management for the future. Since then the patient has been disease-free for 45 months at the time of submission of this article.

Primary CCC is a rare bladder tumour. Dow and Young1 first reported a case in 1968 since then there have been a total of 49 cases reported including the case presented in this paper. In the literature, the following suggestions have been made regarding the origin of clear cell bladder carcinoma2: (A) originates from the mullerian system in the urinary bladder, (B) is an adenocarcinoma of non-mullerian origin that has features of CCC and (C) is a variant of urothelial carcinoma that has undergone glandular differentiation. Some authors have referred to CCC as mesonephroid carcinoma and adenocarcinoma of the bladder despite lack of clear evidence of the definite origin of the tumour. The tumour was referred to as CCC as it appeared similar to the clear cell adenocarcinoma originating from the female genital tract and a few cases have been reported to be associated with endometriosis or remnants of the mullerian duct. A review done by Olivia et al, in 2002, showed that 9 out of 13 patients did not have a tumour associated with endometriosis or any mullerian remnants and four of the tumours showed foci of transitional cell carcinoma.3 The majority of the cases of CCCs discussed in the literature show a tumour unassociated with endometriosis. This in combination with the findings of the case review done by Olivia et al, and the tumour occasionally occurring in males favours the CCC to be a gland differentiation of urothelial carcinoma.3 The prognosis of CCC of the bladder is not well understood as it is a rare tumour and the follow-up post-treatment has mostly been less than 5 years.2 Surgery, which involves cystectomy, has been the primary method of treatment of clear cell bladder carcinoma as it is mostly diagnosed when the tumour is in its advanced stages. The current case was diagnosed at an early stage, with invasion only into the lamina propria but no invasion into the muscle wall. Sun et al, in 2008, reported three cases that were positive for the marker P504S and have shown the presence of this protein in tumours that are of high grade and stage. The tumour we resected was negative for P504S further confirming its superficial nature.4 Stage one tumours represent non-invasive tumours limited to the lining of the bladder wall with no muscle invasion. The details of these along with the present case have been summarised in table 1 5–9). Table 1. | Case reference | Age | Sex | Site | Treatment | Outcome | | Doddamani et al 5 | 80 | Female | Not available | TURBT followed by repeat TURBT and chemotherapy with carboplatin and methotrexate | No evidence of disease at 3 months post repeat TURBT+chemotherapy | | Young and Scully6 | 78 | Female | Trigone | TURBT | No evidence of disease at 4 years | | Drew et al 7 | 78 | Female | Not available | Radical cystectomy | No evidence of disease at 12 months | | Drew et al 7 | 50 | Male | Not available | TURBT and radical cystectomy | Alive with the progression of disease at 63 months | | Drew et al 7 | 43 | Male | Not available | TURBT | No evidence of disease at 30 months | | Lum8 | 68 | Male | Not available | TURBT | No evidence of disease at 8 months of follow-up | | Chor et al 9 | 35 | Female | Posterior wall | Radical cystectomy | Not available | | Current case | 49 | Female | Dome of bladder | TURBT followed by TURBT after 3 months | No evidence of disease at 33 months | CCC, clear cell carcinoma; TURBT, transurethral resection of bladder tumour. There have been seven cases of non-muscle-invasive CCC reported in the literature. Of these, 43% of patients (3/7) have been treated by TURBT alone, 43% of patients (3/7) were treated with radical cystectomy and 14% of patients (1/7) have been initially treated with TURBT followed by chemotherapy.2 Learning points. Clear cell carcinoma (CCC) of the bladder is a very rare form of bladder tumour commonly affecting females. There is no current consensus for the treatment of non-muscle-invasive CCC of bladder tumour. Primary transurethral resection of bladder tumour followed by surveillance flexible cystoscopy and staging imaging can be offered in patients with non-muscle-invasive CCC of the bladder. Footnotes Contributors: SM conceived the idea. TJ and HA wrote the first draft. AG reviewed histology. All authors reviewed and edited the manuscript. Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests: None declared. Provenance and peer review: Not commissioned; externally peer reviewed. Patient consent for publication: Obtained.

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