{"paper_id":"a2304d97-9440-4287-800f-b2712abb7f08","body_text":"Bladder cancer is one of the most common types of cancer in the United States, representing 4.2 % of all new cancer cases, and predominantly manifests as urothelial carcinoma in over 90 % of cases. 1 , 2 . Notably, about 25 % of these urothelial carcinoma cases exhibit variant histological features, which have been thoroughly documented in existing literature. 3 . However, clear cell adenocarcinoma (CCA) of the urinary bladder remains a notably rare histological subtype of bladder cancer, often affecting females. 4 , 5 . The pathogenesis of CCA is thought to involve Mullerian elements within the bladder, rendering it histo-genetically similar to cancers of the female genital tract, or as a unique expression of urothelial carcinoma with gland differentiation. 5 , 6 . CCA has emerged as the malignant transformation of endometriosis with the bladder being involved in less than 1 % of extragonadal endometriosis. 7 . Literature on CCA stemming specifically from bladder endometriosis is scant, with only a handful of published cases. Here, we present a case of a 50-year-old female patient with irregular bleeding found to have a bladder mass concerning for primary CCA of the urinary bladder, possibly secondary to malignant transformation of endometriosis.\n\nThis patient is a 50-year-old female with no pertinent medical history who presented for her annual gynecologic examination in July 2023 with complaints of irregular bleeding. Her last menstrual period had been in September 2020, and she had normal, routine Papanicolou test results to date. A transvaginal ultrasound (TVUS) ( Fig. 1 A) revealed a fibroid uterus with a suspicious, lobulated bladder mass with color flow, which required a referral to a urologist. A computed tomography of the abdomen/pelvis (CT A/P) ( Fig. 1 B) showed a large enhancing pedunculated mass along the posterior wall of the bladder measuring up to 4.6 x 7.8 cm. Radiologist assessment suggested a fat plane between the bladder and uterus but no discernible fat plane between the bladder and vagina, indicating possible extension of the mass directly into the vagina. Bilateral pelvic sidewall lymph nodes measuring up to 1.2 cm were also noted. Fig. 1 (A.) TVUS showing a lobulated bladder mass measuring 5.4 x 2.7 × 6.1 cm. (B.) Axial view on CT abdomen and pelvis showing large, enhancing pedunculated mass along posterior bladder wall, measuring 4.6 x 7.8 cm. Fig. 1\n(A.) TVUS showing a lobulated bladder mass measuring 5.4 x 2.7 × 6.1 cm. (B.) Axial view on CT abdomen and pelvis showing large, enhancing pedunculated mass along posterior bladder wall, measuring 4.6 x 7.8 cm.\nDue to clinical symptoms of gross hematuria and imaging findings, the patient underwent cystoscopy and transurethral resection of the bladder tumor (TURBT) with fulguration in November 2023. The surgery revealed an extremely vascular, pedunculated tumor with multiple lobulations involving half of the bladder. Pathological examination confirmed CCA with extensive infiltration of the subepithelial connective tissue but no muscularis propria invasion. Genetic analysis of the tumor identified mutations in several oncogenes including KRAS, PIK3CA, ARID1A, SDHA, KMT2C, DDX11, BRCA1, and CHEK2. After her procedure, the patient was discharged and followed up in the outpatient clinic.\nAt the discretion of the urologic oncologist, multiple imaging studies were completed to determine the extent of potential vaginal invasion and lymphadenopathy. A positron emission tomography (PET)/CT scan showed F-18-fluorodeoxyglucose (FDG)-avid retroperitoneal and right pelvic lymph nodes highly suspicious for metastatic disease ( Fig. 2 A). A magnetic resonance imaging (MRI) of the pelvis with and without contrast showed pelvic lymphadenopathy and a fibroid uterus, with an indeterminate complex pelvic mass measuring 4.1× 2.5 cm anterior to the uterus and to the right of the midline ( Fig. 2 B). This lesion was noted to be stable compared to prior CT scans dating back to August 2015, suggesting a benign finding. Given the rarity and aggressive nature of CCA of the bladder, it determined a neoadjuvant chemotherapy regimen would not be appropriate for the patient's disease. Fig. 2 (A.) Presence of right pericaval lymph node, measuring approximately 1.4 × 1.1 cm with a standardized uptake value (SUV) mac of 6.6 seen on PET/CT. (B.) Axial view on MRI pelvis with and without contrast showing a complex mass measuring 4.1 × 2.5 cm, stable compared to prior scans. Fig. 2\n(A.) Presence of right pericaval lymph node, measuring approximately 1.4 × 1.1 cm with a standardized uptake value (SUV) mac of 6.6 seen on PET/CT. (B.) Axial view on MRI pelvis with and without contrast showing a complex mass measuring 4.1 × 2.5 cm, stable compared to prior scans.\nIn February 2024, the patient underwent robotic-assisted laparoscopic radical cystectomy with ileal conduit creation, anterior vaginectomy, bilateral extended lymphadenectomy, total urethrectomy, transureteroureterostomy, total hysterectomy, and bilateral salpingo-oophorectomy. Powder burn lesions in the pelvis, specifically on the posterior bladder wall, consistent with endometriosis were noted. 6 × 80 mm bilateral ureteral stents and a pelvic drain were placed. Postoperative recovery followed the enhanced recovery after surgery (ERAS) protocol with the patient maintaining stable vital signs and demonstrating good recovery indicators, such as bowel function resumption and adequate urine output through her ureterostomy. JP creatinine on postoperative day three was consistent with serum and removed. The final pathology ( Fig. 3 ) confirmed CCA predominantly involving the bladder trigone, with complete excision and negative margins (pT1). Seven of the 22 lymph nodes were positive for metastatic carcinoma (pN2). Endometriosis in the posterior urinary bladder wall was also noted, where it was fibrously adhered to the uterus. The patient began adjuvant chemotherapy with carboplatin, paclitaxel, and pembrolizumab, completing six cycles without evidence of recurrence or metastasis at six months post-surgery. Fig. 3 Presence of clear cell adenocarcinoma, 0.7 × 0.3 cm at the largest dimension, involving mostly bladder trigone and extending into the lamina propria. No malignancy is identified in the uterus and adjacent bilateral ovaries and fallopian tubes. Fig. 3\nPresence of clear cell adenocarcinoma, 0.7 × 0.3 cm at the largest dimension, involving mostly bladder trigone and extending into the lamina propria. No malignancy is identified in the uterus and adjacent bilateral ovaries and fallopian tubes.\n\nThis case highlights the complex pathophysiology of malignant transformation of ectopic endometrial tissue in the urinary bladder into endometrioid adenocarcinoma or CCA. This type of transformation is a recognized pathology but an uncommon event, affecting only 0.7 %–2.5 % of cases with 75 % occurring in ovarian sites and 25 % in extra-ovarian sites, such as the rectovaginal septum, colon, and vagina. 8 , 9  The mechanisms underlying this etiology remain unclear but may involve genetic alterations, hormonal influences, oxidative stress, and inflammation. 10  Although much is unknown about primary CCA of the urinary bladder, our case describes how this uncommon cancer may present with symptoms of gross hematuria and secondary to endometriosis, as well as how we approached the management of this patient.\nFirst described by Dow and Young in 1968, primary CCA of the urinary bladder is an exceedingly rare and aggressive form of bladder cancer. 11  Existing literature reports a wide range of ages at presentation from 22 to 83 years old with most diagnoses occurring in women. 5  The histogenesis of bladder CCA has been a subject of significant debate. An original theory proposed a mesonephric origin, given the affinity of CCA for the trigone and urethra. 12  This notion has evolved with studies suggesting a urothelial or transitional origin, due to the significant overlap in the immunoprofiles of CCA and urothelial carcinoma. 13  However, alternative theories have posited a Mullerian origin, reflecting histogenetic similarity to the female genital tract and the female predominance of CCA. 14 , 15  These neoplasms have been associated with Mullerian duct cysts and, pertinent to our case, bladder endometriosis. 16 , 17\nThe extensive medical and surgical treatment necessitated in our patient case highlights the aggressive nature of CCA and the challenges in management, including procedures like radical cystectomy, total hysterectomy, and bilateral salpingo-opherectomy. An extended bilateral lymph node dissection was also required, due to severe lymph node involvement. Unfortunately, due to the paucity of data surrounding endometrioid-associated CCA of the bladder, there are no standardized treatment algorithms, especially regarding neoadjuvant and adjuvant chemotherapy. This patient was placed on six cycles of carboplatin and paclitaxel, with the addition of pembrolizumab. GOG0209 established the position of carboplatin and paclitaxel as standard first-line therapy for advanced endometrial cancer and prior case reports have demonstrated its success in endometriosis-associated uterine and abdominal wall CCA. 18 , 19  Based on recent data from a phase 3 trial by Eskander et al., the addition of pembrolizumab to this regimen for treatment of endometrial cancer demonstrated enhanced progression-free survival rates with pembrolizumab (74 % for pembrolizumab group vs. 38 % for placebo group) and a 70 % lower risk in the mismatch repair-deficient cohort and 46 % lower risk in the mismatch repair-proficient cohort. 18  These data suggest that immunotherapy can be incorporated into the first-line treatment of endometrial cancer, and might even be translated into improved oncologic outcomes for patients with endometriosis-associated CCA of the bladder.\n\nThis case report enriches the scant literature on CCA and underscores the unique phenomenon of malignant transformation of bladder endometriosis. Given the rarity of endometriosis-associated CCA of the urinary bladder, gaps exist in the literature regarding appropriate treatment, making this aggressive form of cancer difficult to manage and associated with a poor prognosis. Typically, primary CCA presents at an advanced stage posing additional significant clinical challenges due to its propensity for rapid progression, metastasis, and recurrence. In our patient case, the presence of bladder endometriosis added further diagnostic and management complexity leading to the decision to opt for a multimodal treatment approach consisting of surgical resection followed by adjuvant chemotherapy. Future research should aim to delineate the pathologic mechanisms of CCA and its development from endometriosis, elucidate risk factors associated with this uncommon pathology, and optimize therapeutic and surgical approaches.\n\nMeghana Singh:  Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.  Michael Raver:  Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.  Bianca DeAgresta:  Resources, Visualization, Writing – original draft, Writing – review & editing.  Alexandra Della Pia:  Resources, Visualization, Writing – original draft, Writing – review & editing.  Sonam Saxena:  Writing – original draft, Writing – review & editing.  Merieme Klobocista:  Supervision, Validation.  Nitin Yerram:  Conceptualization, Project administration, Supervision, Validation, Visualization, Writing – review & editing.\n\nWritten informed consent was obtained from the patient for publication of this manuscript.\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.","source_license":"CC0","license_restricted":false}