Tumor-Induced Osteomalacia due to Sarcomatoid Non-Small Cell Lung Carcinoma Confounded by Drug-Induced Fanconi Syndrome

Abstract

Tumor-induced osteomalacia (TIO) is an exceedingly rare paraneoplastic condition characterized by hypophosphatemia, osteomalacia, fragility fractures, and fatigue. A 39-year-old man was assessed for hemoptysis, pathological rib fractures, and fatigue, and was found to have a chest mass with lung metastasis. Biopsy of the mass suggested high-grade epithelioid and spindle cell neoplasm. He was initially treated for soft tissue sarcoma with an ifosfamide-based regimen and developed Fanconi syndrome that resolved on cessation of ifosfamide. Serum phosphate remained low. A low tubular maximum reabsorption of phosphate to glomerular filtration rate ratio (TmP/GFR) indicated disproportionate phosphaturia, while a severely elevated fibroblast growth factor-23 (FGF23) level enabled a diagnosis of TIO. He was started on phosphate and calcitriol supplementation. Subsequent next-generation sequencing demonstrated a RET-fusion mutation, leading to reclassification of his malignancy to a sarcomatoid non-small cell lung carcinoma. He was switched to selpercatinib, a targeted RET-kinase inhibitor approved for locally advanced or metastatic RET-fusion-positive solid tumors. This induced tumor remission with subsequent normalization of his FGF23 levels and hypophosphatemia. Despite the presence of a confounding etiology like drug-induced Fanconi syndrome, persistence of hypophosphatemia should prompt a workup of TIO, especially in the presence of a tumor.

Keywords: Fanconi; burosumab; fibroblast growth factor-23; hypophosphatemia; selpercatinib; tumor-induced osteomalacia.

Figure 1.

A, Arrow highlights a left pleural based bass, measuring 5.0 × 2.6 × 4.4 cm. B, Numerous lung nodules, some with central cavitation, with some associated ground-glass opacification. C, Arrow highlighting one such nodule. Fluorodeoxyglucose positron emission tomography computed tomography (FDG PET CT) redemonstrated a now enlarged 6.8 × 6.9-cm left pleural-based mass (highlighted by arrow), with an standardized uptake value (SUVmax) of 19.6. D, FDG PET CT also demonstrated extensive FDG-avid osseous lesions. One such representative lesion (arrow) included here on the left ischium with an SUVmax of 15.8. E, Marked improvement in size of pleural mass (arrow) and F, lung nodules compared to prior images 8 weeks after selpercatinib (arrow highlighting area of improvement of a lung nodule).

Figure 2.

Phosphate is reabsorbed primarily in the proximal convoluted tubules by sodium-phosphate cotransporters (NaPi): NaPi-IIa and NaPi-IIc. Expression of these transporters is regulated by several hormones, including parathyroid hormone (PTH), calcitriol, and fibroblast growth factor (FGF) 23. Typically secreted by bone, FGF23 decreases NaPi expression, and therefore phosphate reabsorption, via binding of FGF receptor (FGFR) 1.