膀胱透明細胞腺癌合併類風濕性關節炎及乾燥症長期免疫抑制治療：
病例報告暨文獻回顧

陳韋辰^{1, 2}、林奕豪¹、裘坤元^{1, 3}、李建儀¹

¹臺中榮民總醫院泌尿部；²臺中榮民總醫院急診部外傷科；³臺中慈濟醫院外科部泌尿科

Bladder Clear Cell Adenocarcinoma in an Elderly Female with Rheumatoid Arthritis and Sjögren Syndrome under Long-term Immunosuppressive Therapy: Case Report and Literature Review

Wei-Cheng Chen^{1, 2}、Yi-Hao Lin¹、Kuan-Yuan Chiu ^{1, 3}、Jian-Ri Li¹

¹Department of Urology, Taichung Veteran General Hospital, Taichung, Taiwan (R.O.C.); ²Division of Traumatology, Department of Emergency, Taichung Veteran General Hospital, Taichung, Taiwan (R.O.C.); ³Division of Urology, Department of Surgery, Taichung Tzu Chi Hospital, Taichung, Taiwan (R.O.C.)

Introduction: Clear cell adenocarcinoma (CCA) of the urinary bladder is a rare malignancy, accounting for a small fraction of primary bladder cancers and showing a marked female predominance. The histogenesis of CCA remains controversial, with evidence supporting both Müllerian and urothelial origins, and recent molecular studies have identified frequent ARID1A and TP53 mutations, further complicating its classification. Clinically, CCA often presents with hematuria and lower urinary tract symptoms, but its rarity and overlapping features with other glandular and clear cell lesions pose significant diagnostic challenges. Epidemiologically, while bladder cancer is more common in men, CCA disproportionately affects women and is often diagnosed at an advanced age. Risk factors for bladder cancer include chronic inflammation, prior pelvic radiation, and prolonged immunosuppression, with glucocorticoid therapy recently implicated in increasing the risk of invasive bladder tumors. The prognosis of CCA is generally poorer than that of conventional urothelial carcinoma, attributed to its aggressive behavior and higher stage at diagnosis. This report presents a case of high-grade CCA of the bladder in an elderly female with a long history of rheumatoid arthritis and Sjögren syndrome under chronic immunosuppressive therapy, followed by a review of the current literature on the clinicopathologic, molecular, and therapeutic aspects of this rare entity.

Case Presentation: An 82-year-old Mongoloid female with a history of rheumatoid arthritis and Sjögren syndrome, treated with glucocorticoids and immunomodulators for over 10 years, presented with gross hematuria and dysuria for 3 days. Laboratory evaluation revealed hematuria and anemia (hemoglobin: 10 g/dl). Abdominal sonography identified a 2 cm bladder tumor. The lesion was completely resected via bipolar transurethral resection of bladder tumor (TURBT). Bilateral retrograde pyelography showed no filling defects. Histopathology demonstrated high-grade clear cell adenocarcinoma (CCA) of the urinary bladder, with invasion into subepithelial connective tissue but no detrusor muscle or angiolymphatic invasion.

Discussion: CCA of the urinary bladder is a rare malignancy, predominantly affecting women, and is characterized by aggressive behavior and poor prognosis. Most patients present with hematuria and a bladder mass, often at advanced age. Histologically, CCA displays abundant clear cytoplasm and tubulocystic, glandular, or solid patterns, with immunoprofiles typically positive for CK7 and CA125. The pathogenesis remains debated, with evidence supporting Müllerian differentiation in many cases, especially in females. Recent molecular studies have identified frequent ARID1A and TP53 mutations, with rare TERT promoter alterations, suggesting a link to chronic inflammation and urinary stasis rather than progression from intestinal metaplasia or urothelial carcinoma. Epidemiological data indicate that prolonged systemic glucocorticoid therapy increases the risk of bladder cancer, particularly invasive and high p53-expressing tumors, implicating impaired immune surveillance in carcinogenesis. This is clinically relevant in patients with autoimmune diseases receiving long-term immunosuppression, as in this case. Differential diagnosis includes nephrogenic adenoma, metastatic clear cell carcinoma, and other glandular neoplasms, requiring integration of clinical, radiologic, and immunohistochemical findings for accurate classification. Treatment is primarily surgical, with TURBT as initial management for non-muscle invasive disease. However, due to the high-grade and aggressive nature of CCA, early radical cystectomy is recommended for muscle-invasive or recurrent tumors. Adjuvant chemotherapy and radiotherapy have limited efficacy and should be considered on a case-by-case basis. Prognosis is generally poorer than other bladder carcinomas, attributed to higher stage at diagnosis and aggressive histology.

Conclusions: Bladder clear cell adenocarcinoma is a rare, aggressive tumor with female predominance and poor prognosis. Long-term immunosuppression, particularly glucocorticoid therapy, may increase bladder cancer risk. In patients with autoimmune disease presenting with hematuria, bladder cancer should be included in the differential diagnosis. Early recognition and aggressive surgical management are essential to optimize outcomes.