Tumor-induced osteomalacia with IgG4-related lymph node disease

To the Editor: A 60-year-old man presented with progressively worsened limb weakness of 4 years duration, which had rendered him wheelchair-bound since May 2018. The patient also had muscle and joint pain and numbness. He had a history of type 2 diabetes, hypertension, and gout, no family history of bone disease. He took diabetic peripheral neuropathy treatment but the symptoms kept progressing. On admission, the patient was well developed and in normal body shape. Physical examination was unremarkable except for all-sided weakness. Laboratory evaluation showed hypophosphatemia with notable elevated urinary phosphorus loss. Other laboratory abnormalities were elevated alkaline phosphatase levels, mild insufficient vitamin D status, and mild elevated parathyroid hormone. After bone scintigraphy failed to localize an osseous tumor, whole-body positron emission tomography (PET)/computed tomography (CT) using 18F-fluorodeoxyglucose (18F-FDG) and the radiolabeled somatostatin analog 68Ga-DOTATATE were performed to make clear diagnosis of oncogenic hypophosphatemic osteomalacia. Both of the examinations revealed a suspicious mass in subcutaneous tissue around the umbilicus and enlarged right axillary lymph nodes [Figure 1A and 1B].Figure 1: Whole-body SSTR (68Ga-DOTATATE)-PET scan and 18F-FDG-PET scan revealing focally increased tracer uptake at umbilicus and right axillary (pointed by the arrows; A and B). Histologic examination of umbilicus mass showing spindle-shaped tumor cells with oval nuclear and eosinophilic cytoplasm, and scattered cloud-like calcium deposits (hematoxylin and eosin staining, original magnification ×200; C). Immunohistochemistry of the enlarged right axillary lymph nodes showing that IgG4-positive rate of IgG-positive plasma cells being about 70%, and more than 100 cells being positive for IgG4 cells per high powered field of biopsy sample (original magnification ×200; D). Graph illustrating the trends in serum phosphate levels over time (day.month.year; E). Serum phosphate showed subsequent and steady recovery after surgical removal of the tumor. FDG: fluorodeoxyglucose; PET: positron emission tomography; SSTR: somatostatin receptor.The patient was subjected to surgery for resection of the subcutaneous mass and enlarged right axillary lymph nodes after obtaining written informed consent. The subcutaneous mass was red, round-shaped without necrosis. It displayed spindle-shaped cells with oval nuclear and eosinophilic cytoplasm, and characteristic scattered cloud-like calcium deposits under histologic examination. No atypical cells, abnormal mitotic activity, or necrosis were observed [Figure 1C]. On the basis of its morphologic and immunohistochemical features, the tumor was diagnosed as a phosphaturic mesenchymal tumor. Interestingly, histologic examination of lymph nodes revealed immunoglobulin G (IgG) 4-positive plasma cells >100 cells per high-power field, and the IgG4-positive rate was up to 70% of IgG-positive plasma cells in intra-follicular zones [Figure 1D]. Supplemental laboratory testing demonstrated elevated IgG4/IgG ratio, thus an IgG4 lymph node disease could be diagnosed. The patient was released from the hospital after a rapid recovery of serum phosphorous [Figure 1E] and urinary phosphorus loss. He reported normal serum phosphorous and significantly improved symptoms during our one and a half months follow-up. Tumor-induced osteomalacia (TIO) is a rarely seen tumor-related disease with characteristics of hypophosphatemia and abnormal urinary phosphate wasting. The increased level of fibroblast growth factor 23 (FGF23), a circulating phosphaturic hormone produced by tumors leads to decreased renal phosphate reabsorption through reduction of the sodium-phosphate co-transporter expression in the proximal renal tubule. Clinically, patients suffering from TIO may develop weakness, fatigue, bone, muscle pain, and fractures. Tumors resulting in TIO are often too small to localize by conventional radiologic methods. In the case that anatomical imaging (CT or magnetic resonance imaging) fail to detect the tumors, scintigraphy with a radiolabeled somatostatin analog (111indium octreotide scintigraphy or 68Ga-DOTATATE PET/CT) with or without 18F-FDG PET/CT is recommended. Selective venous sampling with FGF23 should be taken into consideration when other tests come to nothing. IgG4-related diseases (IgG4-RD) is a fibro-inflammatory condition involving multiple organs characterized by storiform fibrosis, increased serum IgG4 level, and inflammatory infiltrate with IgG4-rich plasma cells. It was reported that patients with IgG4-RD had higher risks of solid and hematologic malignancies than the general population.[1,2] Furthermore, history of malignancy may be related to subsequent IgG4-RD development.[3] However, the connection between IgG4-RD and malignancy still remains unclear. Some studies claimed no connection between IgG4-RD and malignancy. A Japanese prospective study found that the incidence of total malignancies in IgG4-RD patients was similar to that in the general population.[4] Pathogenesis of IgG4-RD and TIO are totally different as immunity-related and FGF-23 related. We speculate that there is no association between TIO and IgG4-RD in this patient. Here, we presented a 60-year-old man who had suffered from severe clinical manifestations of TIO due to a mesenchymal tumor in the umbilicus and was discovered an IgG4 lymph node disease accidentally. In this case, the tumor was identified by 68Ga-DOTATATE PET/CT and surgical removal of the tumor resulted in significant relief of symptoms and hypophosphoremia. When meeting with unexplained bone pain and fatigue, TIO should always be taken into consideration and scintigraphy with a radiolabeled somatostatin analog should be applied early when routine examination failed to detect tumors. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the article. The patient understands that his name and initial will not be published and due efforts will be made to conceal the identity of the patient, although anonymity cannot be guaranteed. Acknowledgements The authors thank Yun-Feng Han for whole-body positron emission tomography scan with radiolabeled somatostatin analog of the patient. Funding This work was supported by a grant from the National Natural Science Foundation of China (No. 81670754).