Tumor-Induced Osteomalacia with IgG4-Related Lymph Node Disease
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by hypophosphatemia and abnormal urinary phosphate wasting. It is caused by tumors that secrete fibroblast growth factor 23 (FGF23), a phosphaturic hormone that reduces renal phosphate reabsorption by downregulating the sodium-phosphate co-transporter in the proximal renal tubule. Clinically, patients with TIO often present with symptoms such as muscle weakness, fatigue, bone pain, and fractures. The tumors responsible for TIO are typically small and difficult to locate using conventional imaging techniques, making diagnosis challenging. In this case, we present a 60-year-old man with TIO caused by a phosphaturic mesenchymal tumor, who was also incidentally found to have IgG4-related lymph node disease.
The patient, a 60-year-old man, had been experiencing progressively worsening limb weakness for four years, which had rendered him wheelchair-bound since May 2018. He also reported muscle and joint pain, as well as numbness. His medical history included type 2 diabetes, hypertension, and gout, but there was no family history of bone disease. Despite receiving treatment for diabetic peripheral neuropathy, his symptoms continued to progress. On admission, the patient appeared well-developed and in normal body shape. Physical examination revealed generalized weakness but was otherwise unremarkable.
Laboratory evaluation revealed several abnormalities, including hypophosphatemia with notable urinary phosphorus loss. Other findings included elevated alkaline phosphatase levels, mild vitamin D insufficiency, and mildly elevated parathyroid hormone levels. Initial bone scintigraphy failed to localize an osseous tumor. To further investigate, whole-body positron emission tomography (PET)/computed tomography (CT) using 18F-fluorodeoxyglucose (18F-FDG) and the radiolabeled somatostatin analog 68Ga-DOTATATE were performed. Both imaging modalities identified a suspicious mass in the subcutaneous tissue around the umbilicus and enlarged right axillary lymph nodes.
Following written informed consent, the patient underwent surgical resection of the subcutaneous mass and the enlarged right axillary lymph nodes. The subcutaneous mass was red and round-shaped, without necrosis. Histologic examination revealed spindle-shaped cells with oval nuclei and eosinophilic cytoplasm, along with characteristic scattered cloud-like calcium deposits. No atypical cells, abnormal mitotic activity, or necrosis were observed. Based on these morphologic and immunohistochemical features, the tumor was diagnosed as a phosphaturic mesenchymal tumor.
Interestingly, histologic examination of the lymph nodes revealed immunoglobulin G (IgG) 4-positive plasma cells, with more than 100 cells per high-power field. The IgG4-positive rate was up to 70% of IgG-positive plasma cells in the intrafollicular zones. Supplemental laboratory testing demonstrated an elevated IgG4/IgG ratio, confirming the diagnosis of IgG4-related lymph node disease.
Post-surgery, the patient experienced a rapid recovery of serum phosphorus levels and a reduction in urinary phosphorus loss. During a follow-up period of one and a half months, the patient reported normal serum phosphorus levels and significant improvement in symptoms.
TIO is a rare condition, and the tumors responsible for it are often small and difficult to detect using conventional imaging techniques. In cases where anatomical imaging (CT or magnetic resonance imaging) fails to identify the tumor, functional imaging with radiolabeled somatostatin analogs, such as 111indium octreotide scintigraphy or 68Ga-DOTATATE PET/CT, is recommended. Selective venous sampling for FGF23 may also be considered when other diagnostic methods are inconclusive.
IgG4-related disease (IgG4-RD) is a fibro-inflammatory condition that can affect multiple organs. It is characterized by storiform fibrosis, elevated serum IgG4 levels, and inflammatory infiltrates rich in IgG4-positive plasma cells. Some studies have suggested that patients with IgG4-RD may have an increased risk of solid and hematologic malignancies compared to the general population. However, the relationship between IgG4-RD and malignancy remains unclear, with some studies finding no significant association. The pathogenesis of IgG4-RD is distinct from that of TIO, with IgG4-RD being immunity-related and TIO being FGF23-related. In this case, we speculate that there is no direct association between the two conditions.
This case highlights the importance of considering TIO in patients presenting with unexplained bone pain and fatigue. Early use of functional imaging with radiolabeled somatostatin analogs is crucial for diagnosing and localizing the tumor. Surgical removal of the tumor typically results in significant symptom relief and normalization of serum phosphorus levels.
In summary, we present a case of TIO caused by a phosphaturic mesenchymal tumor in a 60-year-old man, who was also found to have IgG4-related lymph node disease. The tumor was successfully localized using 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT, and surgical resection led to significant clinical improvement. This case underscores the importance of early and accurate diagnosis of TIO and the potential for incidental findings of other conditions, such as IgG4-RD, during the diagnostic process.
doi.org/10.1097/CM9.0000000000000188
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