Abstract:Phosphaturic mesenchymal tumors typically cause paraneoplastic osteomalacia, chiefly as a result of FGF23 secretion. In a prior study, we identified FN1-FGFR1 fusion in 9 of 15 phosphaturic mesenchymal tumors. In this study, a total of 66 phosphaturic mesenchymal tumors and 7 tumors resembling phosphaturic mesenchymal tumor but without known phosphaturia were studied. A novel FN1-FGF1 fusion gene was identified in two cases without FN1-FGFR1 fusion by RNA sequencing and cross-validated with direct sequencing a… Show more
“…A very relevant finding in understanding PMTs tumorogenesis was the identification of fibronectin (FN1) and FGFR1 translocations that led to a FN1-FGFR1 fusion protein in 60% of studied PMTs by RNA sequencing or FGFR-specific fluorescence in situ hybridization (FISH) (Lee et al, 2015). Additional studies have confirmed this finding although in a smaller proportion of studied tumors (Berglund et al, 2017, Lee et al, 2016). The FN1-FGFR1 translocation is predicted to produce a chimeric protein that includes the FN1 extracellular domain, and the FGFR1 ligand-binding, transmembrane and intracellular signaling domains.…”
Section: Pathophysiologymentioning
confidence: 68%
“…Whether or not PMTs also express Klotho, in which case FGF23 could bind and signal in a Klotho-dependent manner, or if FGF23 is able to bind to the chimeric FN1-FGFR1 receptor and signal in a Klotho-independent manner, is not known.Fig. 6Fibronectin-fibroblast growth factor receptor 1 translocations in TIO.Depicted is the putative chimeric protein generated by the fibronectin-fibroblast growth factor 1 (FN1-FGFR1) translocations that were identified in a subset of the phosphaturic mesenchymal tumors that cause tumor-induced osteomalacia (Berglund et al, 2017, Lee et al, 2015, Lee et al, 2016). The chimeric protein includes the fibronectin extracellular autodimerization domain and the FGFR1 ligand binding, transmembrane and intracellular tyrosine kinase signaling domain.…”
Section: Pathophysiologymentioning
confidence: 99%
“…Depicted is the putative chimeric protein generated by the fibronectin-fibroblast growth factor 1 (FN1-FGFR1) translocations that were identified in a subset of the phosphaturic mesenchymal tumors that cause tumor-induced osteomalacia (Berglund et al, 2017, Lee et al, 2015, Lee et al, 2016). The chimeric protein includes the fibronectin extracellular autodimerization domain and the FGFR1 ligand binding, transmembrane and intracellular tyrosine kinase signaling domain.…”
Section: Pathophysiologymentioning
confidence: 99%
“…FGF1 protein is a crucial ligand for all FGFRs. It acts as a potent mitogen of fibroblasts and is involved in critical biological functions including development, morphogenesis, and angiogenesis (Lee et al, 2016). FGFR1 expression, as assessed by immunohistochemistry, has been demonstrated in 82% of PMTs, regardless of fusion status (Lee et al, 2016).…”
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome clinically characterized by bone pain, fractures and muscle weakness. It is caused by tumoral overproduction of fibroblast growth factor 23 (FGF23) that acts primarily at the proximal renal tubule, decreasing phosphate reabsorption and 1α-hydroxylation of 25 hydroxyvitamin D, thus producing hypophosphatemia and osteomalacia. Lesions are typically small, benign mesenchymal tumors that may be found in bone or soft tissue, anywhere in the body. In up to 60% of these tumors, a fibronectin-1(FN1) and fibroblast growth factor receptor-1 (FGFR1) fusion gene has been identified that may serve as a tumoral driver. The diagnosis is established by the finding of acquired chronic hypophosphatemia due to isolated renal phosphate wasting with concomitant elevated or inappropriately normal blood levels of FGF23 and decreased or inappropriately normal 1,25-OH2-Vitamin D (1,25(OH)2D). Locating the tumor is critical, as complete removal is curative. For this purpose, a step-wise approach is recommended, starting with a thorough medical history and physical examination, followed by functional imaging. Suspicious lesions should be confirmed by anatomical imaging, and if needed, selective venous sampling with measurement of FGF23. If the tumor is not localized, or surgical resection is not possible, medical therapy with phosphate and active vitamin D is usually successful in healing the osteomalacia and reducing symptoms. However, compliance is often poor due to the frequent dosing regimen and side effects. Furthermore, careful monitoring is needed to avoid complications such us secondary/tertiary hyperparathyroidism, hypercalciuria, and nephrocalcinosis. Novel therapeutical approaches are being developed for TIO patients, such as image-guided tumor ablation and medical treatment with the anti-FGF23 monoclonal antibody KRN23 or anti FGFR medications. The case of a patient with TIO is presented to illustrate the importance of adequate and appropriate evaluation of patients with bone pain and hypophosphatemia, as well as an step-wise localization study of patients with suspected TIO.
“…A very relevant finding in understanding PMTs tumorogenesis was the identification of fibronectin (FN1) and FGFR1 translocations that led to a FN1-FGFR1 fusion protein in 60% of studied PMTs by RNA sequencing or FGFR-specific fluorescence in situ hybridization (FISH) (Lee et al, 2015). Additional studies have confirmed this finding although in a smaller proportion of studied tumors (Berglund et al, 2017, Lee et al, 2016). The FN1-FGFR1 translocation is predicted to produce a chimeric protein that includes the FN1 extracellular domain, and the FGFR1 ligand-binding, transmembrane and intracellular signaling domains.…”
Section: Pathophysiologymentioning
confidence: 68%
“…Whether or not PMTs also express Klotho, in which case FGF23 could bind and signal in a Klotho-dependent manner, or if FGF23 is able to bind to the chimeric FN1-FGFR1 receptor and signal in a Klotho-independent manner, is not known.Fig. 6Fibronectin-fibroblast growth factor receptor 1 translocations in TIO.Depicted is the putative chimeric protein generated by the fibronectin-fibroblast growth factor 1 (FN1-FGFR1) translocations that were identified in a subset of the phosphaturic mesenchymal tumors that cause tumor-induced osteomalacia (Berglund et al, 2017, Lee et al, 2015, Lee et al, 2016). The chimeric protein includes the fibronectin extracellular autodimerization domain and the FGFR1 ligand binding, transmembrane and intracellular tyrosine kinase signaling domain.…”
Section: Pathophysiologymentioning
confidence: 99%
“…Depicted is the putative chimeric protein generated by the fibronectin-fibroblast growth factor 1 (FN1-FGFR1) translocations that were identified in a subset of the phosphaturic mesenchymal tumors that cause tumor-induced osteomalacia (Berglund et al, 2017, Lee et al, 2015, Lee et al, 2016). The chimeric protein includes the fibronectin extracellular autodimerization domain and the FGFR1 ligand binding, transmembrane and intracellular tyrosine kinase signaling domain.…”
Section: Pathophysiologymentioning
confidence: 99%
“…FGF1 protein is a crucial ligand for all FGFRs. It acts as a potent mitogen of fibroblasts and is involved in critical biological functions including development, morphogenesis, and angiogenesis (Lee et al, 2016). FGFR1 expression, as assessed by immunohistochemistry, has been demonstrated in 82% of PMTs, regardless of fusion status (Lee et al, 2016).…”
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome clinically characterized by bone pain, fractures and muscle weakness. It is caused by tumoral overproduction of fibroblast growth factor 23 (FGF23) that acts primarily at the proximal renal tubule, decreasing phosphate reabsorption and 1α-hydroxylation of 25 hydroxyvitamin D, thus producing hypophosphatemia and osteomalacia. Lesions are typically small, benign mesenchymal tumors that may be found in bone or soft tissue, anywhere in the body. In up to 60% of these tumors, a fibronectin-1(FN1) and fibroblast growth factor receptor-1 (FGFR1) fusion gene has been identified that may serve as a tumoral driver. The diagnosis is established by the finding of acquired chronic hypophosphatemia due to isolated renal phosphate wasting with concomitant elevated or inappropriately normal blood levels of FGF23 and decreased or inappropriately normal 1,25-OH2-Vitamin D (1,25(OH)2D). Locating the tumor is critical, as complete removal is curative. For this purpose, a step-wise approach is recommended, starting with a thorough medical history and physical examination, followed by functional imaging. Suspicious lesions should be confirmed by anatomical imaging, and if needed, selective venous sampling with measurement of FGF23. If the tumor is not localized, or surgical resection is not possible, medical therapy with phosphate and active vitamin D is usually successful in healing the osteomalacia and reducing symptoms. However, compliance is often poor due to the frequent dosing regimen and side effects. Furthermore, careful monitoring is needed to avoid complications such us secondary/tertiary hyperparathyroidism, hypercalciuria, and nephrocalcinosis. Novel therapeutical approaches are being developed for TIO patients, such as image-guided tumor ablation and medical treatment with the anti-FGF23 monoclonal antibody KRN23 or anti FGFR medications. The case of a patient with TIO is presented to illustrate the importance of adequate and appropriate evaluation of patients with bone pain and hypophosphatemia, as well as an step-wise localization study of patients with suspected TIO.
Rationale:Phosphaturic mesenchymal tumor (PMT) is a new tumor entity of soft tissue and bone tumor recently accepted by the World Health Organization, which typically causes the paraneoplastic syndrome of tumor-induced osteomalacia (TIO). The majority of PMTs follow a benign clinical course and local recurrence occurs in < 10% of cases, malignant PMTs with distant organ metastasis are extremely uncommon.Patient concerns:We reported a 41-year-old woman who was diagnosed with PMT 10 years ago with a repeated recurrence and pulmonary metastasis.Diagnoses:Based on clinical manifestations, MRI scan, serum biochemical indicators evaluation, followed by histopathological examination, the patient was diagnosed as malignant PMT with pulmonary metastasis.Interventions:The patient was treated with calcium, phosphorus, and vitamin D after surgical resection and measured the serum ion concentrations every 3 months.Outcomes:The patient had a favorable outcome for 10 months without recurrence.Lessons:PMTs lack of characteristic histological morphology, some recurrence cases may appear benign morphologically; the malignant PMTs are easily overlooked. Patients with PMT should be carefully evaluated and monitored, in order to early identify its malignant potential.
Key Clinical MessagePhosphaturic mesenchymal tumor (PMT) is a rare disorder primarily affecting the extremities. It is notable for its correlation with hypophosphatemic osteomalacia and high FGF23 serum levels, which results in renal phosphate wasting and clinical symptoms associated with low serum phosphorus. We presented a patient with a 5‐year history of progressive osteomalacia who recently experienced a major pathological bone fracture. Laboratory findings showed a persistent low serum phosphate, normal calcium, elevated alkaline phosphatase activity, high parathyroid hormone levels, and increased renal excretion of phosphate. According to ultrasonography and nuclear imaging, there was no evidence of parathyroid adenoma. During further diagnostic assessment, a sinonasal cavity tumor was found and resected. Histologically, the tumor was composed of bland spindle cell proliferation in the background of a calcified matrix with foci of osteoid formation, hemangiopericytoma‐like (HPC‐like) vasculature, and osteoclast‐like giant cells. Tumor cells showed variable positivity for SMA, but CD34, S100, CD99, Melan‐A, p63, and desmin were all nonreactive. Regarding the clinical context, histological and immunohistological findings, a final diagnosis of tumor‐induced osteomalacia (TIO) secondary to a PMT was made. After surgery, laboratory results returned to normal, clinical symptoms disappeared, and the patient did not experience a recurrence during a six‐month follow‐up.
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