Vesical clear cell adenocarcinoma of Müllerian origin treated conservatively with partial cystectomy

A 71-year-old woman presented with an intravesical bladder mass found to be a clear cell adenocarcinoma of Müllerian origin with positive PAX-8 staining after transurethral resection. Partial cystectomy along with total hysterectomy were performed, and final pathology revealed no residual tumour and extensive endometriosis. She declined adjuvant therapy and was dispositioned to surveillance.

urological cancer, gynecological cancer, surgical oncology, urological surgery

Though bladder cancer is a common malignancy, clear cell carcinoma is a rare histological subtype that, in women, has been reported as Müllerian origin. Prior reports indicate that it may arise in a background of endometriosis.1 2 Radical treatment is commonly employed and here we report a case of clear cell adenocarcinoma of the bladder of Müllerian origin in an endometriotic implant that was treated surgically with partial cystectomy. Case presentation A 71-year-old woman presented to a urologist due to urinary frequency and haematuria. She reported urination in excess of 20 times daily along with haematuria for approximately 1 year and denied a history of smoking and alcohol use. Additionally, she reported no history of gynaecological problems, specifically no history of symptomatic endometriosis and denied postmenopausal bleeding. She had a history of hypercholesterolaemia, tinnitus and a remote history of Lyme disease without sequelae. An intravesical mass was detected on trans-abdominal ultrasonography. She underwent uncomplicated transurethral resection of bladder tumour (TURBT) of a single papillary tumour that arose from the posterior supratrigonal bladder wall, nearly filled the bladder, and had a base measuring 5 cm×3 cm. It was resected to gross completion and there was muscle in the specimen. Pathology resulted as clear cell carcinoma with Müllerian differentiation, supported by positive PAX8 immunostaining, with invasion limited to the lamina propria and without invasion into the underlying muscularis. The patient was referred to urological oncology where repeat cystoscopy demonstrated postsurgical changes from her TURBT; she declined repeat TURBT and random bladder biopsies. She was also referred to gynaecological oncology and presented at a multidisciplinary tumour board where staging total hysterectomy and bilateral salpingo-oophorectomy (TH-BSO) were recommended due to the Müllerian origin of her tumour. Preoperatively, both radical cystectomy and partial cystectomy were discussed with the patient who, after discussion, declined radical cystectomy and made an informed decision to consent to partial cystectomy, bilateral pelvic lymphadenectomy and TH-BSO. Investigations Prior to her TURBT, a CT urogram was performed (figures 1 and 2) which demonstrated a homogeneous intravesical mass outlined by a crescent of contrast, occupying the majority of the bladder in both sagittal and axial cross-sections. The remainder of the abdomen and pelvis were unremarkable, and specifically there were no adnexal masses. Prior to her surgical staging, she underwent both an upper endoscopy and colonoscopy with biopsies, which revealed Helobacter pylori gastritis, for which she received 10 days of oral bismuth, tetracycline and metronidazole. Serum workup revealed a cancer antigen-125 of 13 U/mL, carcinoembryonic antigen of <0.5 ng/mL, and a carbohydrate antigen-19–9 of 19 U/mL. She had a Papanicolaou smear that was negative for intraepithelial lesion or malignancy with negative human papillomavirus co-testing. Her cystoscopic resection revealed fragments of extensive and high-grade adenocarcinoma arranged in papillary and tubulocystic growth patterns with amphophilic to clear/pale and vacuolated cytoplasm, hobnail cells and involvement of the lamina propria. Muscularis propria was present and negative for carcinoma. PAX8, CK7, HNF1-beta, Napsin A, GATA3 and CA125 immunostains were positive in tumour cells. Case Urothelial carcinoma, squamous cell carcinoma of the bladder and small cell carcinoma of the bladder were all considered but, due to the immunohistochemical staining pattern, were considered to be unlikely and therefore lower on the differential diagnosis. Endometrial cancer and ovarian cancer were considered to be more likely due to the staining pattern in addition to the histological subtype of clear cell adenocarcinoma. Treatment The patient underwent robotic-assisted laparoscopic partial cystectomy with two-layer cystorrhaphy, diagnostic cystoscopy and bilateral pelvic lymphadenectomy by urological oncology along with concomitant robotic-assisted total laparoscopic hysterectomy and bilateral salpingo-oophorectomy by gynaecological oncology. Outcome and follow-up The patient had an uneventful postoperative hospital course and was discharged on postoperative day 1 with a 20 French silicone urinary catheter which was removed after in-office retrograde cystogram demonstrated no contrast extravasation on postoperative day 14. Surgical pathology demonstrated a postmenopausal 36 g uterus along with fallopian tubes and ovaries that were without significant diagnostic abnormality. The partial cystectomy specimen revealed extensive endometriosis involving the transmural bladder wall and no residual carcinoma. There was no evidence of endometriosis elsewhere, nor at the time of surgery. The final stage was considered to be a T0N0MX stage clear cell carcinoma of Müllerian origin (either endometrial or ovarian) with negative surgical margins. The recommendation was made for six cycles of adjuvant carboplatin and paclitaxel by gynaecological oncology and medical oncology. After an extensive discussion, the patient declined adjuvant therapy and was thus recommended to undergo surveillance, consisting of cystoscopy and CA-125 every 4 months. The patient has no evidence of disease after 4 months, which was confirmed on diagnostic surveillance cystoscopy.

Bladder cancer is a common malignancy of the urinary tract, of which urothelial carcinoma is the most common subtype.3 Less common histologies include squamous cell carcinoma, small cell carcinoma and other rare variants, including clear cell adenocarcinoma.4 Clear cell adenocarcinoma is documented in men and women, though the latter predominates; <100 cases of bladder-confined clear cell adenocarcinoma have been reported in the English literature, of which 44 were in women.5 PAX-8 was reported as positive in only four patients. As demonstrated in figure 3, PAX-8 stains strongly in most epithelial ovarian cancers.6 Clear cell carcinoma is characterised by cells with hob-nailed cytoplasm and is pathologically indistinguishable from Müllerian clear cell carcinoma.7 Additionally, it has been reported to arise within extra-gynaecological deposits of endometriosis.5 There are no differences in the presenting symptoms, which are most commonly painless haematuria and urinary urgency.4 Reports of both surgical and adjuvant therapy are heterogenous, as evidenced in a recent systematic review of 70 patients with clear cell adenocarcinoma of the bladder that included 44 female patients. Sixty-seven of the total patients underwent some form of treatment, the majority of which (95.5%, n=64) included a surgical intervention. The most common procedure was radical cystectomy (43.3%, n=29) and only two patients (3%) underwent partial cystectomy. Additionally, 26.9% of patients underwent TURBT only. Lastly, adjuvant therapy was uncommon; only four patients had either adjuvant chemotherapy or chemoradiotherapy. Lastly, outcomes were overall poor with only 59.3% of patients alive at a mean follow-up of 19.9 months.5 We recommended adjuvant therapy based on the histological origin of her cancer. Several prior reports of clear cell adenocarcinoma of the bladder arising from endometriosis have been described, most recently in 2016; the patient was treated with a radical cystectomy and urinary diversion.1 Though it is not known if endometriosis is the inciting event in this rare cancer, it has long been understood that endometriosis increases the risk of endometrioid and clear cell carcinoma of the ovary.8 Endometriosis, which is defined by the histological presence of extra-uterine endometrial glands, is a common condition that affects up to 11% of reproductive-aged women.9 The most commonly affected anatomical locations are the pelvic peritoneum, ovaries and uterosacral ligaments, though distant involvement, including the bladder, is not uncommon.10 A recent population-based retrospective study suggests that the long-held association between endometriosis and malignancy is not only true but possibly of increased magnitude than once thought. The risk of uterine cancer and ovarian cancer were significantly increased with hazard ratios of 4.59 and 2.51, respectively. Interestingly, there was not an association between endometriosis and bladder cancer.9 In conclusion, clear cell carcinoma is a rare histological variant of bladder cancer and Müllerian origin should be considered in female patients. PAX-8 has utility in the differential diagnosis, as it is a sensitive immunohistochemistry marker for Müllerian origin.11 The current surgical and adjuvant treatment landscape is heterogeneous and based on the histological origin of the disease. Until more data are available, individualised approaches are necessary. Learning points. PAX-8 is useful in the pathological workup of vesical clear cell carcinoma. Evidence-based treatment is lacking, thus approaches to surgical and adjuvant therapy should be individualised. Partial cystectomy may be considered on a case-by-case basis. Footnotes Contributors: JAH, MCL, PAK and ESR each had substantial contributions to the conception or design of the work, drafting the work and revising it critically, and grant final approval of the version to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of anypart of the work are appropriately investigated and resolved. 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. Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy. Competing interests: None declared. Provenance and peer review: Not commissioned; externally peer reviewed. Ethics statements Patient consent for publication Consent obtained directly from patient(s).

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