ONCOGENIC OSTEOMALACIA: THE SEARCH, TREATMENT, AND CURE OF A DEBILITATING TUMOR

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1 Case Report ONCOGENIC OSTEOMALACIA: THE SEARCH, TREATMENT, AND CURE OF A DEBILITATING TUMOR Christopher W. Lee, MD; Hannah Mathew, MD; Michael F. Holick, MD, PhD ABSTRACT Objective: To present a rare case of oncogenic osteomalacia, describe the breadth of potential clinical symptoms, and review the underlying pathophysiology of this disorder. Methods: We report a case of oncogenic osteomalacia cured by surgical resection of a mesenchymal tumor. Results: A 48-year-old, wheelchair-dependent man presented to a tertiary care academic hospital with progressive back pain and diffuse weakness. Biochemical evaluation revealed elevated alkaline phosphatase, marked hypophosphatemia, phosphaturia, vitamin D deficiency, and elevated fibroblast growth factor 23, results that are concerning for oncogenic osteomalacia. Subsequent imaging showed extensive loss of vertebral height, numerous fractures, and ultimately identified an area suspicious for tumor in the right mandible, with concurrent uptake on octreotide scan. Segmental resection of the right mandible revealed a calcifying mesenchymal tumor. Following surgery there was a normalization of biochemistries and dramatic improvement in the patient s symptoms. Submitted for publication December 19, 2017 Accepted for publication January 9, 2018 From the Boston University School of Medicine, Boston Medical Center, Department of Medicine, Section of Endocrinology, Diabetes, and Nutrition, Boston, Massachusetts. Address correspondence to Dr. Michael F. Holick, Boston University Medical Center, 85 East Newton Street, Building M-1013, Boston, MA MFHolick@BU.edu. DOI: /ACCR To purchase reprints of this article, please visit: Conclusion: Oncogenic osteomalacia is a rare and often confounding diagnosis. Identification may be aided by the relatively recently characterized hormone fibroblast growth factor 23. Identification of this paraneoplastic syndrome is critical, as surgical intervention has curative potential for possible debilitating symptoms. (AACE Clinical Case Rep. 2018;4:e300-e304) Abbreviations: 1,25(OH) 2 D = 1,25-dihydroxyvitamin D; 25(OH)D = 25-hydroxyvitamin D; FGF23 = fibroblast growth factor 23; ipth = intact parathyroid hormone; MRI = magnetic resonance imaging; TIO = tumor-induced osteomalacia INTRODUCTION Oncogenic osteomalacia, also referred to as tumorinduced osteomalacia (TIO), is a rare paraneoplastic syndrome. Its clinical presentation is highly variable, encompassing pain, fractures, and profound muscle weakness. These symptoms are a consequence of hypophosphatemia induced by excess fibroblast growth factor 23 (FGF23) secreted by a culprit tumor. While the clinical and biochemical diagnosis of TIO is relatively straightforward, subsequent localization of the culprit tumor is challenging, with cure contingent on complete resection of the mass. Here, we report a case of TIO where longstanding and debilitating weakness was resolved with the identification and resection of a mesenchymal tumor. CASE REPORT A 48-year-old, well-educated Haitian man presented to the hospital with several months of increasing back discomfort, painful leg spasms, debilitating fatigue, and e300 AACE CLINICAL CASE REPORTS Vol 4 No. 4 July/August 2018

2 Debilitating Oncogenic Osteomalacia, AACE Clinical Case Rep. 2018;4(No. 4) e301 progressive weakness of all 4 extremities. He also reported unrelenting dull, diffuse, achy pains in his joints and bones. On further review, he reported having been wheelchair dependent for 3 years without clear etiology. The patient s only medication was baclofen and he denied use of potentially phosphaturic medications such as tenofovir. On initial evaluation, the patient was afebrile and hemodynamically stable with a blood pressure of 129/76 mm Hg and heart rate of 71 beats per minute. He was a frail-appearing, wheelchair-bound man. Musculoskeletal exam revealed pectus excavatum, with 2/5 strength in the right lower extremity, 3/5 strength in the left lower extremity, and 4/5 strength in bilateral upper extremities. There was significant tenderness to palpation over the sternum, spinous processes, and bilateral tibias. Neurologic evaluation was unremarkable. Laboratory results revealed an alkaline phosphatase level of 599 U/L (normal range is 25 to 100 U/L), serum gamma-glutamyl transferase level of 39 U/L (normal range is 11 to 58 U/L), serum phosphorus level of 1.4 mg/dl (normal range is 2.7 to 4.5 mg/dl), serum calcium level of 9 mg/dl (normal range is 8 to 10.5 mg/dl), 25-hydroxyvitamin D (25(OH)D) level of 18 ng/dl (normal range is 30 to 100 ng/dl), 1,25-dihydroxyvitamin D (1,25(OH) 2 D) level of 16 pg/ml (normal range is 18 to 72 pg/ml), intact parathyroid hormone (ipth) level of 136 pg/ml (normal range is 11 to 90 pg/ml), fractional excretion of phosphorus of 26% (normal range is 10 to 20%), and FGF23 level of 277 RU/mL (normal levels are <180 RU/mL) (Table 1). Complete blood count and basic metabolic panel were within normal limits. X-rays of the lumbosacral spine revealed numerous vertebral compression fractures. Successive magnetic resonance imaging (MRI) and computed tomography scans showed diffuse loss of vertebral height and numerous fractures involving the sacrum, iliac bones, ribs, and right scapula. A bone scan demonstrated focal uptake in the right mandible and the left foot, as well as uptake in the bilateral costochondral junctions with a beaded appearance (Fig. 1). Subsequent X-rays of the mandible were unremarkable, however, left foot X-rays revealed nondisplaced fractures of the bases of the third and fourth metatarsals. Given the fractures observed in the left foot and concern for a locally destructive tumor, an MRI scan of the left foot was performed, however, no focal tumor was visualized. An outpatient octreotide scan revealed a single abnormal focus of increased uptake localized to the right mandible (Fig. 2) with a right mandibular mass of 1.5 cm confirmed on dedicated neck MRI scan (Fig. 3). The patient was started on ergocalciferol at 50,000 IU weekly, calcitriol at 0.25 μg twice daily, calcium carbonate at 1,250 mg twice daily, and sodium phosphate at 250 mg 4 times daily. Over a 4-month period, the patient s serum phosphorus persisted at values less than 1.8 mg/dl (normal Table 1 A Comparison of the Relevant Laboratory Results Before and After Operation* Reference range Before operation 1 day post Laboratory value 2 weeks post 4 weeks post Albumin g/dl Total protein g/dl Total bilirubin mg/dl Alanine aminotransferase 9-67 u/l Aspartate aminotransferase u/l Alkaline phosphatase u/l Gamma glutamyl transferase u/l 39 N/A N/A N/A Calcium mg/dl Phosphorus mg/dl Magnesium mg/dl hydroxyvitamin D ng/dl 18 N/A 52 N/A 1,25-dihydroxyvitamin D pg/ml 16 N/A Intact parathyroid hormone pg/ml Fractional excretion of phosphorus 10-20% 26 N/A N/A N/A Fibroblast growth factor 23 <180 RU/mL N/A Abbreviation: N/A = not available. *Basic metabolic panel and complete blood count remained normal during the course of treatment. ^Off of phosphorus and calcitriol supplementation since the day of operation.

3 e302 Debilitating Oncogenic Osteomalacia, AACE Clinical Case Rep. 2018;4(No. 4) Fig. 1. Bone scans revealing uptake in the right mandible (white arrow), bilateral costochondral junctions (white arrowheads), and left foot (white circle). Fig. 2. Octreotide scan revealing a single abnormal focus of increased uptake localized to the right mandible (white arrow). range is 2.7 to 4.5 mg/dl) despite confirmed adherence to all medications including aggressive phosphorus repletion. Ultimately, segmental resection of the right mandible revealed a calcifying mesenchymal tumor with tumor-free margins. In the immediate postoperative period, phosphate supplementation and calcitriol were discontinued. On postoperative day 1, the patient s FGF23 normalized to 55 RU/mL (normal levels are <180 RU/mL) and at the patient s week 2 postoperative office visit, labs revealed a normalized serum phosphorus of 2.9 mg/dl (normal range is 2.7 to 4.5 mg/dl) off of phosphorus supplementation, serum calcium of 9.5 mg/dl (normal range is 8 to 10.5 mg/dl), 25(OH)D of 52 ng/dl (normal range is 30 to 100 ng/dl), 1,25(OH) 2 D of 494 pg/ml (normal range is 18 to 72 pg/ml), ipth of 132 pg/ml (normal range is 11 to Fig. 3. Neck magnetic resonance imaging scan revealing a 1.5-cm, right mandibular mass (white arrow). 90 pg/ml), and an FGF23 of 44 RU/mL (normal levels are <180 RU/mL). In the weeks following surgery, the patient had dramatic recovery of strength, improvement in bone pain, and regained his ability to walk. He was closely monitored in the endocrine clinic for 1 month post operation after which he returned to Haiti permanently. During this month the patient continued to display improvement in his laboratory values (Table 1). DISCUSSION TIO was first reported in 1947 by Dr. Robert McCance. While best known for contributions in the fields of newborn physiology, nutrition, metabolism, and survival at sea after

4 Debilitating Oncogenic Osteomalacia, AACE Clinical Case Rep. 2018;4(No. 4) e303 shipwreck (1), in 1947 he described a case of a child with osteomalacia, which he attributed to vitamin D resistance (2). In 1959, Dr. Andrea Prader encountered a similar case of a young child with rickets, but further recognized that there was likely a specific substance causing the severe vitamin D deficiency as the patient was cured with the resection of a rib tumor (3). Only in the early 2000s was the causative substance isolated and identified as FGF23 (4). TIO is classically caused by small, slow-growing benign tumors of mesenchymal origin, however tumors of various histologic appearances have also been described including both benign and malignant tumors such as hemangiopericytomas, osteosarcomas, and giant cell tumors (5). Currently, a few hundred cases of primary TIO have been identified in the literature (6). Since the initial identification of FGF23, it has been discovered that inactivating mutations of the phosphateregulating endopeptidase homolog X chromosome-linked gene, implicated in X-linked hypophosphatemia, resulted in increased levels of FGF23. Deletion of FGF23 from mice with this inactivating mutation reversed their hypophosphatemia, abnormally low 1,25(OH) 2 D, and osteomalacia (7). FGF23 is secreted by bone osteocytes (7) and osteoblasts (8), and is involved in the control of serum phosphorus concentration by altering vitamin D metabolism and phosphorus handling in the kidneys. FGF23 decreases the expression of 25-hydroxyvitamin D-1α-hydroxylase and increases the expression of 25-hydroxyvitamin D-24- hydroxylase thereby decreasing both 1,25(OH) 2 D and 25(OH)D, respectively (9). This decrease in 1,25(OH) 2 D results in decreased intestinal absorption of phosphorus. In the kidneys, the proximal renal tubules are the site of 70% of freely filtered phosphorus reabsorption via type 2 sodium-phosphate co-transporters (10). In the renal proximal tubule cells, FGF23 binds to the FGF23-receptor and the transmembrane protein Klotho, downregulating the expression of type 2 sodium-phosphate co-transporters, resulting in renal phosphate wasting (10). Hypophosphatemia can manifest as diverse symptoms including mild neuropathy, altered mentation, seizures, coma, anemia, cardiomyopathy, cardiac arrhythmias, and respiratory failure (11). Common etiologies of hypophosphatemia include chronic alcoholism, use of phosphate binders or phosphaturic medications, chemotherapeutic agents, and vitamin D deficiency. TIO is a unique cause of hypophosphatemia, and careful history and medication reconciliation must be undertaken prior to its diagnosis to exclude the aforementioned etiologies. TIO should be suspected in patients with hypophosphatemia who have low 1,25(OH) 2 D, elevated fractional excretion of phosphorus, and elevated FGF23 levels. To aid in assessing this relatively rare diagnosis, experts have constructed an algorithmic approach for localization of tumors in TIO, including techniques such as octreotidesingle-photon emission computed tomography, positronemission tomography with 2-deoxy-2-[fluorine-18]fluoro- D-glucose integrated with computed tomography, MRI, gallium-68 dotatate scan, and selective venous sampling (to identify the culprit tumor in cases of TIO with multiple identified tumors) (12,13). The diagnosis is confirmed by symptom and biochemical resolution following tumor identification and resection. The treatment of choice in cases of TIO is widemargin resection of the culprit tumor (6). Abnormalities in phosphate wasting and vitamin D metabolism typically resolve within a few days following surgical intervention and clinical symptoms resolve within a few weeks after surgery (12). However, the responsible tumor is not always identified in cases of TIO. In such cases, medical therapy with phosphorus supplementation and calcitriol is critical to prevent the potentially debilitating effects of hypophosphatemia (6). There are also case reports of successful use of radiofrequency ablation for incompletely resected tumors or in cases where surgical morbidities were deemed too great (14-16). Additionally, there is a potential role for the use of a monoclonal antibody against FGF23 in cases of unidentified tumors. KRN23, a monoclonal antibody against FGF23, has been shown in a phase I clinical trial to increase serum phosphorus levels in patients with X-linked hypophosphatemia and so there may be a role for such therapy in patients with TIO given its similar pathophysiology to that of X-linked hypophosphatemic rickets (17). With regards to our patient, 2-week postoperative labs revealed a significantly increased 1,25(OH) 2 D of 494 pg/ml (normal range is 18 to 72 pg/ml) and an ipth of 132 pg/ml (normal range is 11 to 90 pg/ml). These values were improving by the patient s 4-week postoperative clinic visit: 1,25(OH) 2 D of 252 pg/ml (normal range is 18 to 72 pg/ml) and an ipth of 106 pg/ml (normal range is 11 to 90 pg/ml) (Table 1). We believe that the 1,25(OH) 2 D had a robust increase in the postoperative period from a rebound effect due to sudden cessation of the inhibitory hormone FGF23 (from removal of the tumor). The 1,25(OH) 2 D was trending towards the normal range by 4 weeks post operation. In terms of the patient s ipth, we believe that the pre-operative elevated ipth was due to secondary hyperparathyroidism from vitamin D deficiency. In the immediate postoperative period, ipth actually increased but began to trend towards the normal range as vitamin D status improved which was evidenced by the patient s postoperative labs. Finally, it is remarkable what a dramatic increase the patient s phosphorus levels had (off of phosphorus supplementation), rising to 4.5 mg/dl (normal range is 2.7 to 4.5 mg/dl) by 4 weeks post operation. CONCLUSION TIO is a notable paraneoplastic syndrome due to an excess of FGF23 secretion from often surreptitious tumors

5 e304 Debilitating Oncogenic Osteomalacia, AACE Clinical Case Rep. 2018;4(No. 4) with consequent hypophosphatemia, myopathy, and osteomalacia. The disorder is important to recognize as surgical removal of the offending tumor can rapidly reverse the biochemical and clinical manifestations of the disease. DISCLOSURE The authors have no multiplicity of interest to disclose. REFERENCES 1. Breathnach CS, Moynihan JB. Robert Alexander McCance, and his forays into experimental medicine with Elsie Widdowson. Ulster Med J. 2014;83: McCance R. Osteomalacia with Looser s nodes (Milkman s syndrome) due to a raised resistance to vitamin D acquired about the age of 15 years. Q J Med. 1947;16: Prader A, Illig R, Uehlinger E, Stalder G. Rickets following bone tumor [in German]. Helv Paediatr Acta. 1959;14: Yamashita T, Yoshioka M, Itoh N. Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. Biochem Biophys Res Commun. 2000;277: Hautmann AH, Hautmann MG, Kölbl O, Herr W, Fleck M. Tumor-induced osteomalacia: an up-to-date review. Curr Rheumatol Rep. 2015;17: Chong WH, Molinolo AA, Chen CC, Collins MT. Tumorinduced osteomalacia. Endocr Relat Cancer. 2011;18:R53-R Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD. Pathogenic role of Fgf23 in Hyp Mice. Am J Physiol Endocrinol Metab. 2006;291:E38-E Masuyama R, Stockmans I, Torrekens S, et al. Vitamin D receptor in chondrocytes promotes osteoclastogenesis and regulates FGF23 production in osteoblasts. J Clin Invest. 2006;116: Shimada T, Hasegawa H, Yamazaki Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res. 2004;19: Baia LC, Heilberg IP, Navis G, de Borst MH; NIGRAM investigators. Phosphate and FGF-23 homeostasis after kidney transplantation. Nat Rev Nephrol. 2015;11: Subramanian R, Khardori R. Severe hypophosphatemia. Pathophysiologic implications, clinical presentations, and treatment. Medicine (Baltimore). 2000;79: Chong WH, Andreopoulou P, Chen CC, et al. Tumor localization and biochemical response to cure in tumor-induced osteomalacia. J Bone Miner Res. 2013;28: Minisola S, Peacock M, Fukumoto S, et al. Tumour-induced osteomalacia. Nat Rev Dis Primers. 2017;3: Hautmann AH, Schroeder J, Wild P, et al. Tumor-induced osteomalacia: increased level of FGF23 in a patient with a phosphaturic mesenchymal tumor at the tibia expressing periostin. Case Rep Endocrinol. 2014;2014: Tarasova VD, Trepp-Carrasco AG, Thompson R, et al. Successful treatment of tumor-induced osteomalacia due to an intracranial tumor by fractionated stereotactic radiotherapy. J Clin Endocrinol Metab. 2013;98: Hesse E, Rosenthal H, Bastian L. Radiofrequency ablation of a tumor causing oncogenic ostemalacia. N Engl J Med. 2007;357: Carpenter TO, Imel EA, Ruppe MD, et al. Randomized trial of the anti-fgf23 antibody KRN23 in X-linked hypophosphatemia. J Clin Invest. 2014;124: