FINAL DIAGNOSIS: BROWN TUMOR (GIANT CELL TUMOR OF HYPERPARATHYROIDISM)
Involvement of the spine by brown tumor with subsequent cord compression is extremely rare and usually occurs in the setting of primary hyperparathyroidism. Only four cases of brown tumors with spinal cord compression in patients with end stage renal disease (ESRD) and secondary hyperparathyroidism have been reported (1-4).
Brown tumors typically occur in the medullary shafts of long bones, ribs, mandible, metacarpals and pelvis (5). The incidence of brown tumors in patients with ESRD and secondary hyperparathyroidism is 1.5% (6) to 1.7% (5). Histologically they are characterized by numerous giant cells, arranged in clusters or diffusely, in a background of mononuclear oval to spindle stromal cells. Vascularity is high and hemosiderin deposition may be abundant. Brown tumors may be histologically indistinguishable from giant cell tumor of the bone and correlation with clinical and radiographic studies are essential in making the correct diagnosis. The presence of "tunneling" bone resorption in bone uninvolved by tumor strongly favors the diagnosis of brown tumor over giant cell tumor of the bone.
Brown tumor is an extreme form of osteitis fibrosa cystica, which in turn is a manifestation of renal osteodystrophy. The term renal osteodystrophy is used to define the skeletal complications of ESRD which are in essence a disorder of bone remodeling. The major pathogenetic mechanism leading to secondary hyperparathyroidism is deficiency of 1a, 25-dihydroxycholecalciferol (1a,25-dihydroxyvitamin D3) with resulting hypocalcemia and phosphate retention, leading to increase in parathyroid hormone (PTH) production and secretion from the parathyroid glands. Increased PTH secretion and expression of numerous other factors (such as IL-1, TNF-a, IL-6 and IL-11) and their receptors in ESRD leads to activation of bone remodeling towards bone resorption which results in osteopenia and decrease in bone mass (7). Our understanding of the regulatory mechanisms of calcium -responsive PTH secretion has been advanced by the recent cloning of the calcium-sensing receptor (CaR) from the chief cells of the parathyroid (8). CaR belongs to the G protein-coupled receptor superfamily. It "senses" the extracellular concentration of calcium and initiates the downstream events that lead to up- or downregulation of PTH production and secretion. Mutations of the CaR receptor are responsible for three familial disorders of calcium homeostasis. Two of those disorders, familial benign (hypocalciuric) hypercalcemia and neonatal severe hyperparathyroidism, are due to a loss of CaR function. The third disorder, familial (hypercalciuric) hypocalcemia, is due to a gain of CaR function (9). It is interesting that in acquired hyperparathyroidism the levels of CaR protein are reduced suggesting that reduction of CaR expression may be important in the reduced suppression of PTH in acquired hyperparathyroidism. Agonists of the CaR prevent the development of secondary hyperparathyroidism in nephrectomized rats and are promising new agents for the management of human renal osteodystrophy, and are currently on clinical trials (9).
Five histological forms of renal osteodystrophy have been described and correlate with the underlying pathophysiological mechanism. Osteitis fibrosa is the most common form occurring in varying severity in 50% of patients with ESRD (10). It is characterized by an increase number of osteoclasts, peritrabecular fibrosis and "tunneling" resorption of trabeculae. Brown tumors are an exaggerated form of "local" osteitis fibrosa. Osteomalacia is a second form, occurring in 7% of patients with ESRD (10) and is characterized by increased osteoid and defective mineralization. It is usually caused by inhibition of mineralization by deposition of aluminum at the mineralization front. Elimination of aluminum from the dialysate has dramatically decreased the incidence of osteomalacia. Combination of osteitis fibrosa and osteomalacia is found in 13% of patients with ESRD (10) and constitutes the third form named mixed disease. A mild form of osteitis fibrosa is present in 3% of patients with ESRD (10), constitutes the fourth form and is known as mild disease. The last histological form is adynamic renal bone disease which occurs in 27% of patients with ESRD (10) and is characterized by absent remodeling and hypocellular bone. The pathogenesis of this form is poorly understood. It is usually found in patients whose secondary hyperparathyroidism is well controlled, or in patients who have been overtreated with vitamin D and calcium or those who have aluminum intoxication or diabetes mellitus. A certain degree of PTH hypersecretion may be necessary in patients with ESRD and correction of PTH levels to normal levels may contribute to the pathogenesis. Other factors such as overproduction of suppressors of bone formation (such as IL-11 and IL4) and decreased production of activators of bone formation (growth factors) have been implicated in the pathogenesis of adynamic renal bone disease.
Management of renal osteodystrophy aims at controlling the levels of serum phosphate, calcium and PTH (7). Institution of low-phosphate diet and administration of phosphate binders, careful monitoring of dialysate calcium and administration of oral calcium and use of vitamin D preparations (such as calcitriol) are the main therapeutic regimes. Parathyroidectomy is reserved for patients with refractory secondary hyperparathyroidism. Renal transplantation provides the best treatment of renal osteodystrophy and of the myriad other medical complication in patients with ESRD.
Given the paucity of cases of brown tumor resulting is spinal cord compression, the best method of clinical management is not known. In this patient, the posterior elements of the vertebrae were resected to decompress the spinal cord. As the thoracic spinal column has additional structural support from the rib cage the column may remain stable. However, since brown tumor is still present in the T2 vertebral body, the patient may require surgical stabilization if progressive kyphosis develops. Close follow-up is thus required.
Contributed by Zissimos Mourelatos MD, Herbert Goldberg MD, Grant Sinson MD, Dianna Quan MD and Ehud Lavi MD, PhD