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J Thorac Cardiovasc Surg 2007;134:803-805
© 2007 The American Association for Thoracic Surgery
Brief Communication |
Division of Thoracic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
Received for publication March 22, 2007; revisions received May 3, 2007; accepted for publication May 22, 2007. * Address for reprints: Steven J. Mentzer, MD, Room 259, Brigham & Women’s Hospital, 75 Francis S, Boston MA 02115. (Email: smentzer{at}partners.org).
A previously healthy 32-year-old man had a 9-month history of progressive rib, pelvic, and foot pain. Skeletal radiographs and bone scintigraphy revealed multiple fractures of the ribs, pelvis, and right foot.
Blood testing demonstrated low plasma phosphate levels (1.5 mg/dL; normal 2.4–5.0 mg/dL) but normal calcium (9.2 mg/dL; normal 8.8–10.5 mg/dL) and immunoreactive parathyroid hormone levels (39 pg/mL; normal 11–80 pg/mL). A 24-hour urine collection demonstrated phosphaturia (1593 mg/24 hours; normal 500-1200 mg/24 hours), suggesting a phosphate wasting disorder. Since 25 vitamin D (34 ng/mL; normal 20–57 ng/mL) and 1,25 vitamin D (19 pg/mL; 18–62 pg/mL) levels were within normal limits, a recently recognized disorder of paraneoplastic fibroblast growth factor (FGF)–23 production was investigated. Serum immunoassays for FGF-23 were initially found to be high normal (173 RU/mL; normal <180 RU/mL), but levels obtained the day of surgery were elevated (432 RU/mL).
As part of a systemic soft tissue and skeletal survey for an FGF-23 secreting tumor, a chest computed tomographic scan demonstrated an expansile and destructive lesion in the right posterior eighth rib (Figure 1, A). A fine needle aspiration biopsy revealed benign spindle cells with osteoclast-like cells and hemosiderin deposition.
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Histopathologic examination of the mass revealed a spindle cell proliferation with features of an aneurysmal bone cyst (Figure 1, D). In the context of elevated FGF-23 levels, the histopathologic features were consistent with those of a phosphaturic mesenchymal tumor. Postoperatively, phosphate (4.5 mg/dL), urine phosphate (1066 mg/24 h), and FGF-23 (FGF-23 <50 RU/mL to undetectable) levels normalized and remain normal 6 months postoperatively.
Acquired "fragile bone syndromes" reflect abnormalities in calcium and phosphate metabolism. The primary regulators of calcium and phosphate homeostasis are vitamin D and parathyroid hormone. Vitamin D deficiency—whether a result of dietary insufficiency (ricketts), malabsorbtion, renal dysfunction or drug interactions—demonstrates a low level of the active form of vitamin D (1,25-dihydroxy vitamin D3; Calcitriol). In contrast, hyperparathyroidism will reflect an elevated immunoreactive parathyroid hormone level. In patients with normal vitamin D and parathyroid hormone serum levels, bone wasting may be due to a paraneoplastic etiology.
The constellation of an identifiable tumor and bone wasting has been referred to as oncogenic osteomalacia. Although the first report described a chest wall tumor, 104 of the 109 cases reviewed by Folpe and associates1
were found in the extremities, head, or neck. Isolated case reports have described tumors in the lung, mediastinum, thoracic spine, and rib.1 In a study of patients with oncogenic osteomalacia, Jonsson and colleagues2 have described 5 of 6 patients with markedly elevated levels of FGF-23.
With an improved understanding of their biologic activity, recent classification systems have described the tumors associated with oncogenic osteomalacia as phosphaturic mesenchymal tumor, mixed connective tissue variant or PMTMCT.3 Common to these tumors is a paraneoplastic syndrome associated with marked phosphaturia. PMTMCT tumors are locally expansile and destructive, but rarely associated with metastatic disease. When the primary tumor is not identifiable by conventional radiographic imaging, octreotide scanning may be useful to localize the site of the lesion.4
When an FGF-23 secreting tumor is identified, surgical resection is the treatment of choice. Preoperative therapy with octreotide has been advocated as a strategy to suppress the production of FGF-23 and minimize perioperative metabolic complications. Consistent with other reports, the margins of this tumor were readily assessed at surgery and a complete resection was obtained with limited morbidity.
The present case illustrates an improved understanding of both the etiology of oncogenic osteomalacia and the biology of tumor-associated angiogenesis. Recent studies have suggested that most cases of oncogenic osteomalacia are paraneoplastic syndromes associated with FGF-23 production.2 FGF-23 is a member of the FGF molecular family. FGF family members are involved in a variety of biologic processes including morphogenesis, tissue repair, and tumor growth and invasion. In this patient, the excessive production of FGF-23 may have contributed an autocrine effect; that is, FGF-23 may have contributed not only to pathologic posphaturia, but also to neovascularization and tumor progression.5 Regardless of the biologic effects, the paraneoplastic production of FGF-23 provides a useful serum marker for both diagnostic confirmation and postresectional surveillance.
References
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