Tumour-induced Osteomalacia Secondary to a Sarcoma

Tumour-induced osteomalacia (TIO), is a rare paraneoplasatic syndrome found in >95% of benign tumours that secrete fibroblast growth factor 23 - a phosphaturic circulating hormone. A rare case of a TIO secondary to a sarcoma, in a 21-year old man with history of bone fractures and distinctive physical and biochemical characteristics is presented and discussed.

Oncogenic osteomalcia, also known as tumour-induced osteomalacia (TIO), is a rare paraneoplasatic syndrome with around 350 reported cases. 1 TIO initial symptoms are nonspecific and include fatigue, bone pain, muscle weakness, weight, and height loss, and later bone deformity and fractures. It is characterised by hypophosphatemia, hyperphosphaturia, elevated alkaline phosphatase, and low serum 1-25(OH) vitamin D. Pathophysiologically, TIO is caused by tumours that secrete fibroblast growth factor 23 (FGF-23), a phosphaturic circulating hormone.
TIO tumours are usually benign (in >95% of cases), however, they are a diagnostic challenge owing to their small size (usually less than 1 cm), which makes them difficult to localise.
The differential diagnoses are genetic causes such as X-linked hypophosphatemic rickets, autosomal dominant and recessive hypophosphatemia, Dent's disease, idiopathic hypercalciuria, and hereditary hypophosphatemic rickets with hypercaliuria. 2 Ten cases of TIO in the literature have been reported to be secondary to sarcomas, however, all of them were reported before it was known that the secreted molecule by these tumours was FGF-23, hence the diagnosis remained 'uncertain'. Herein, we report the case of a 21-year-old male with a TIO associated with spindle cell sarcoma.

Case report
A 21-year-old man presented for evaluation of a pathological femur fracture. The patient had been otherwise healthy until age 18, when he noted onset of lower back pain after soccer practice, which was exacerbated by exercise and improved when being resting. This pain was progressive and he started noticing a loss of height. Over the next several months he experienced sudden, intense lower back pain and was diagnosed with a femur neck fracture.
He had surgery with internal fixation, and stayed mainly in bed for the next 6 months. During this time, he recognised a growing tumour (around 2 cm) in the inner thigh of his right leg. This tumour progressively grew until it was around 4 x 10 cm. During this time he also lost height (going from 1.75 m to 1.65 m) and weight (losing 15-20 kg in total), and noticed kyphosis in the thoracic spine and sternum protrusion. While he was walking, he fell and suffered a pathologic right femoral fracture. On physical examination, his vital signs at presentation were normal and he was noted to have kyphosis, sternum protrusion, and no Harrison's sulcus or pain at rib palpation (see Figure 1). Interestingly, a 4 x 10 cm tumour was noticed in the inner thigh of his right leg (rigid consistency, with rough edges, partially mobile and not painful). The neurologic evaluation and strength were unremarkable.
A biochemical evaluation ( Table 1)  Tumour-induced Osteomalacia Secondary to a Sarcoma Resection of the lesion revealed a spindle cell sarcoma with areas of necrosis and nuclear atypia that showed tendency to collagenation, and although it did not form malignant osteoid, cells were positive in immunohistochemistry for osteonectin, which suggests osteoblastic and osteogenic origin with high-grade fibroblastic osteosarcoma being the best fit option, and whose association with hyperphosphaturia is very rare. The neoplasm was in touch with resection borders.
After surgery the patient persisted with low levels of phosphorus, and adjuvant chemotherapy was started with six cycles of adriamycin and cisplatin, with a consequent normalisation of phosphorus levels (2.7 mg/dl).

Discussion
The first patient with TIO was reported in 1947 by   is not found, usually we must continue with medical treatment with phosphorus supplementation and vitamin D. Overall, the tumour prognosis is good, however, in our patient, due to the diagnosis of sarcoma, close follow-up will be mandatory.

Conclusion
TIO, which is currently not frequently suspected, generally occurs when the disease is advanced and the patient has experienced multiple fractures and other complications. Usually they are benign tumours however, as in our case, a small proportion of them can be malignant. q