Tumor-induced osteomalacia

Abstract

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.

Keywords: 1,25-OH2-vitamin D, 1,25(OH)2D; CT, computerized tomography; FDG-PET/CT, fluorodeoxyglucose positron emission tomography with computerized tomography; FGF1, fibroblast growth factor 1; FGF23; FGF23, fibroblast growth factor 23; FGFR1, fibroblast growth factor receptor-1; FISH, fluorescence in situ hybridization; FN1, fibronectin-1; MAPK, mitogen-activated protein kinase; MRI, magnetic resonance imaging; PMT, phosphaturic mesenchymal tumor; PTH, parathyroid hormone; Phosphaturic mesenchymal tumors; SPECT, single-photon emission computed tomography; TIO, tumor-induced osteomalacia; TRP, tubular reabsorption of phosphate; TmP/GFR, tubular maximum reabsorption of phosphate to glomerular filtration rate; Tumor-induced osteomalacia.

Fig. 1

Skeletal consequences of tumor-induced osteomalacia. A) Chest PA radiograph showing significant loss of lung volume and an overall bell-shaped rib cage. B) Fracture in left ulnar shaft (arrow) C) Fracture in left distal fibula (arrow).

Fig. 2

Functional Imaging in Tumor-Induced Osteomalacia. Planar view of an FDG-PET (A) and FDG-PET/CT (B) showing hyper-metabolic lesion in T8 (arrows) consistent with a possible phosphaturic mesenchymal tumor.

Fig. 3

Anatomical Imaging in Tumor-Induced Osteomalacia. Axial images through the T8 vertebral body showing a right-sided lesion on a T2-weighted MR image (A) and a CT scan (B) (arrows) (Sciubba et al., 2009).

Fig. 4

Selective venous sampling to confirm location of phosphaturic mesenchymal tumor. FGF23 was measured at the indicated sites. While the data were suggestive of a lesion in the anatomical area of the T8/T7 vertebrae, they were not conclusive (e.g. levels in the left subclavian vein were high as well). Overall the findings were not considered to be diagnostic in that there was not a focal anatomical site that demonstrated a ratio > 1.6 over systemic circulation (Andreopoulou et al., 2011).

Fig. 5

Histological features of phosphaturic mesenchymal tumors (PMTs). Panel A depicts a low power view of the entire T8 vertebral body between the intervertebral discs (IVD), with a 0.5 cm PMT (dotted line), adjacent to preserved bone marrow (BM). A higher power view of the tumor (Panel B) showing typical findings seen in PMTs, including chondroid (“grungy”) matrix (CM), vascularity as demonstrated by abundant venous channels (*),and areas of lamellar bone (LB). Hematoxylin and eosin (H&E).

Fig. 6

Fibronectin-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. As such, the receptor has the potential to autodimerize, resulting in ligand independent signaling. It can also dimerize after FGF23 binding, thus signaling in a ligand-dependent fashion. Transduction continues through the extracellular signal–regulated kinase pathway (ERK1/2) and/or the mechanistic target of rapamycin (mTOR) pathway. If Klotho is also expressed by PMTs, it is possible that FGF23 could bind and signal in a Klotho-dependent manner. This signaling could lead to increased transcription, translation, and secretion of FGF23 by tumor cells via a feed-forward system. (Figure modified by Jason Berglund) (Minisola et al., 2017).

Fig. 7

Approach to localization of phosphaturic mesenchymal tumors (Minisola et al., 2017).

Fig. 8

Example of a positive result on selective venous sampling. A suspicious lesion had previously been identified in the fat pad of the left heel (Andreopoulou et al., 2011).