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Tumor‐induced osteomalacia in an adolescent with an undifferentiated embryonal sarcoma of the liver

To the Editor: Tumor-induced osteomalacia (TIO) is an uncommon paraneoplastic syndrome usually associated with nonmalignant mesenchymal tumors.1 It consists of rickets, hypophosphatemia, and renal phosphate wasting causedbya tumor-secretedhormone: fibroblast growth factor 23 (FGF-23).2 We present an adolescent with ametastatic undifferentiated embryonal sarcoma of the liver (UESL) who developed TIO. A 16-year-old female presented with a 3-month history of abdominal pain, weight loss, and intermittent fever. Examination revealed an abdominal mass in the right upper quadrant, and laboratory tests showed normal beta-human chorionic gonadotropin and alphafetoprotein (AFP) levels and intact liver function. Magnetic resonance imaging revealed a 11.5 × 8 × 10.5 cm heterogeneous mass involving liver segments V and VI. An ultrasonography-guided biopsy confirmed the diagnosis of UESL and chest computed tomography (CT) showed two lesions of 9 and 3 mm in the right middle lobe suggestive of metastatic disease. The plan was that she receive neoadjuvant chemotherapywithdoxorubicin and ifosfamidebefore complete resection of the tumor and adjuvant therapy afterward. Routine laboratory test previous to chemotherapy revealed serum phosphate level 1.3 ng/dL (normal 2.5-4.9 ng/dL), calcium 8.2 ng/dL (normal 8.4-10.2 ng/dL), 25-hydroxyvitamin D (25(OH)D) 10.3 ng/mL (normal 20-40 ng/mL), parathyroid hormone (PTH) 252 pg/mL (normal 15-65 pg/mL), and alkaline phosphatase 178 UI/L (normal 44-147UI/L). Due to the need to start treatment, tubular function tests were obtained just after the first course of ifosfamide and because of intensive fluid and diuretic therapy, some results could be interfered. Tubular reabsorption of phosphate (TRP) value was 30% and tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR) was 0.16 mmol/L, suggesting renal tubular phosphate loss. B-2-Microglobuline was<2mg/L (normal<0.2mg/L). Personal history of bone pain or pathologic fractures was negative and there were no rickets or hypophosphatemic disorders family history either. At this point, serum levels of FGF-23 were >446.0 RU/mL (normal <145 RU/mL) and confirmed suspected diagnosis of TIO. She initially required intravenous phosphate replacement and after reaching normal levels, she received oral phosphate (2300 mg/day elemental phosphorus), calcium, cholecalciferol, and calcitriol supplements. As the tumor gradually decreased, the need for supplementation diminished. After two courses of chemotherapy, response assessment showeda20%decrease in livermass. Phosphate, calcium, and calcitriol supplements could be discontinued at this moment, when 25(OH)D and PTH levels were normal. TRP and TmP/GFR values also normalized to 87% and 1.6 mmol/L, respectively. After the third course of chemotherapy, FGF-23 levels decreased to 108.7 RU/mL. TIO is a rare paraneoplastic disorder in pediatric population. The average age of diagnosis is 40-45 years, however, more than 10 children cases were described.3,4 Responsible tumors, known as phosphaturic mesenchymal tumors (PMT), are typically benign, small, and of mesenchymal origin.5 The most common sites include extremities and acral sites, but soft tissue organs like the liver had not been reported to be involved yet.3 In our case, the tumor was an UESL, an aggressive mesenchymal tumor that occurs predominantly in children between 6 and 10 years of age. Its presentation is uncommon after 15 years of age andmetastatic lesions at diagnosis are rare.6,7 Diagnosis is highly suspicious in a young child with a rapidly growing liver mass, normal AFP, and an apparently cystic lesion on CT but solid on ultrasound study. It is sometimes misdiagnosed as other types of liver sarcomas due to nonspecificmorphological features and lack of unique immunohistochemical markers.6 Despite its aggressive nature, UESL is a potentially treatable disease with multimodal management and supportive therapy including nonstandardized chemotherapy regimens and surgery.8 AhighFGF-23 level in a patient with normal renal function, hypophosphatemia, and with or without osteomalacia, is suggestive of PMT. This is based on the assumption that the responsible tumor is the major or only source of FGF-23.9 FGF-23 increases phosphate transport into the urine by reduction of the expression levels of sodium-dependent phosphate transporters, resulting in inhibiting tubular phosphate reabsorption.3 It also decreases the activity of 1-α-hydroxylase,which converts inactive vitamin D to active 1,25-dihydroxyvitamin (1,25(OH)2D), and increases the activity of the 24-hydroxylase, which catabolizes the degradation of 1,25(OH)2D, leading to decrease of intestinal phosphate absorption.1,10 Therefore, the overproduction of FGF-23 enhances phosphate renal and intestinal wasting, and causes chronic hypophosphatemia that eventually contributes to osteomalacia or rickets. Differential diagnosis includes inherited and acquired hypophosphatemic disorders: X-linked hypophosphatemic rickets, autosomal dominant or recessive hypophosphatemic rickets, vitamin D deficiency, phosphorus deficiency, or Fanconi syndrome.3 Ifosfamide is a well-known agent to cause renal tubular electrolyte disorders, which can occur during infusion or any time throughout treatment.11 Normal value of β2-microglobuline and no other signs suggestive of