Thymoma with hypercalcemia and membranous nephropathy

Thymoma is a rare mediastinal tumor originating from thymic epithelial cells.1 The incidence of a paraneoplastic syndrome (PNS) with thymoma is approximately seven times higher than that with thymic carcinoma, with type B2 thymoma being the most common histological pattern.2 Hypercalcemia is the most common PNS in patients with malignant tumors,3 accounting for 30% of all cases.4, 5 The next most common PNSs in thymoma are myasthenia gravis and pure red cell regeneration disorder6; membranous nephropathy (MN) is unusual in thymoma. Hypercalcemia often leads to tubulointerstitial nephritis.7, 8 However, whether this MN is directly related to secondary autoimmune disease caused by thymoma remains unknown. A 62-year-old man was admitted on May 23, 2022, because of hypercalcemia that resulted in elevated creatinine levels. The patient was diagnosed with diabetes 17 years earlier and also had coronary heart disease, hypertension, and chronic obstructive pulmonary disease for 2 years. Approximately 3 months before this admission, owing to persistent hypercalcemia and a mediastinal mass, 18F-fluorodeoxyglucose positron emission tomography was performed. The findings revealed lymph node enlargement in the mediastinum and bilateral hilar regions with increased glucose metabolism. Additionally, reactive changes were observed in lymph nodes adjacent to the bilateral neck, bilateral axilla, intra-abdominal region, retroperitoneum, and pelvic cavity. These findings strongly indicated Castleman's disease. On admission to the hospital, the patient presented with dyspnea, reduced urine output, and edema. He had pale skin, moist rales in both lungs, and moderate edema in both lower extremities. The following measurements were recorded: creatinine: 330 μmol/L, serum calcium: 3.09 mmol/L, 24-h urinary protein: 1613 mg/24 h, intact parathyroid hormone (PTH): 1.07 pmol/L, and 25 hydroxyvitamin D: 11.29 ng/mL. Because multicentric Castleman disease was not ruled out, a lymph node biopsy was performed; however, the histopathological findings of the right inguinal region did not correspond to those of Castleman's disease. Subsequently, octreotate positron emission tomography/computed tomography (CT) was performed and indicated that imaging agents were concentrated in the anterior mediastinal soft tissue, with a maximum standardized uptake value of 3.1 (Figure 1). After a CT-guided biopsy of the anterior mediastinal mass, thymoma type A was considered. Despite gradually increasing the calcitonin dose to 200 IU/day, the patient's blood calcium levels continued to rise. On June 11, zoledronic acid 4 mg was administered (Supporting Information: Figure S1). The patient underwent anterior mediastinal mass resection at another hospital, and the postoperative pathology revealed thymoma type AB, which had locally invaded the capsule and surrounded adipose tissue. The corrected diagnosis was type AB thymoma, Tumor, Node, Metastasis, stage II (Masaoka staging system). Other diagnoses comprised coronary artery atherosclerotic heart disease, hypertension, diabetes, and chronic renal failure. Despite undergoing surgery, the patient's creatinine levels failed to return to normal, and the 24-h proteinuria gradually increased. When proteinuria reached 3036 mg/24 h, a renal biopsy was performed. Pathological findings suggested stage II MN complicated with diabetic nephropathy and chronic tubulointerstitial lesions (Supporting Information: Figure S2). Conservative treatment was administered, the proteinuria resolved completely after 6 months, and the albumin level also returned to normal. Owing to renal insufficiency, the patient recently underwent radiotherapy at another hospital. Thymoma is often associated with autoimmune PNS and is rarely associated with chronic glomerulonephritis. MN is a relatively rare PNS of thymoma.9 During the initial stages of our patient's illness, differentiating multicentric Castleman disease was challenging because of the presence of generalized lymphadenopathy (short-axis diameter of the enlarged lymph nodes >1 cm) accompanied by anemia, decreased serum albumin levels, renal insufficiency, proteinuria, emaciation, fatigue, edema, and pleural effusion. Therefore, we adopted a strategy of lymph node biopsy, suggesting reactive hyperplasia of lymphoid tissue, which was not consistent with the pathology of Castleman's disease. Interestingly, no abnormal glucose metabolism was observed at the lymph node biopsy site. A subsequent octreotide scan did not reveal imaging agent accumulation in the lymph nodes, whereas a mediastinal mass biopsy revealed a thymoma. We considered that thymoma caused abnormal reactive hyperplasia of the lymph nodes and after surgery, chest CT confirmed further reduction in the size of the lymph nodes, confirming the diagnosis of thymoma. Glomerular lesions are rarely associated with thymoma. Typically, these lesions manifest subsequent to thymoma therapy.10 Since 1998, eight cases of thymoma/myasthenia gravis combined with MN have been reported, and more than half of the cases did not demonstrate a direct association between thymoma and MN.10-14 Hypercalcemia often leads to chronic interstitial nephritis, typically accompanied by low-grade proteinuria, and rarely by nephrotic-range proteinuria.15 Our patient's proteinuria level continued to increase even after achieving control of blood calcium levels. Given the consistency between the patient's clinical appearance and resolution of the proteinuria and the discovery and removal of the anterior mediastinal mass, we believe that this patient's MN was secondary to thymoma. The thymus remains active throughout adulthood, independent of age, and may be crucial for immune reconstruction and regulation.16 Thymic dysfunction may be an important cause of PNS. Tumor-induced hypercalcemia may result from humoral hypercalcemia, osteolysis, overproduction of vitamin D analogs or calcitriol by tumor cells, or ectopic production of PTH. The proportion of hypercalcemia caused by PTH-related peptides varies from 32% to 80% in patients with malignant tumors.17-19 In our patient, PTH-related peptide was not detected, and serum intact parathyroid hormone and 25-dihydroxyvitamin D levels decreased, indicating that humoral hypercalcemia was most likely. The result of phospholipase A2 receptor antibody testing was negative. The proteinuria reached its peak after thymoma resection, and then gradually decreased and eventually resolved completely. As the primary disease resolved, glomerulonephritis also resolved; therefore, the patient's MN was considered a PNS associated with thymoma. Hypercalcemia appears to be the primary cause of elevated creatinine levels. However, even after controlling the serum calcium level, creatinine levels did not return to normal in our patient. Autoantibodies resulting from immunological dysregulation may have contributed to the dense deposits observed in both subepithelial tissue and basement membranes. In conclusion, thymoma is associated with various forms of PNS. MN and hypercalcemia secondary to thymoma are rare. Persistent unrelieved albuminuria and renal impairment may indicate concomitant glomerulonephritis. All authors have made a significant contribution to this paper. Mengmeng Li and Yuxin Xie drafted the manuscript. Zebin Wang, Jianbo Liang, and Yueqiang Wen revised the manuscript. All authors contributed to the article and approved the submitted version. The authors thank the patient and his family. They also thank Guilin Peng and Peilan Zhou, the First Affiliated Hospital of Guangzhou Medical University. The authors declare no conflict of interest. Guangzhou key discipline of urology, Grant/Award Number: 2021-LCYJ-04. The study involving human participants was reviewed and approved by the Ethics Committee of the Second Affiliated Hospital of Guangzhou Medical University (IRB approval number 2022-hg-ks-21). The patients provided written informed consent to participate in this study. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article. The data in this study is not publicly available owe to the primary data is kept confidential. 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