Chronic Renal Failure causing Brown Tumors and Myelopathy

April 1999 Volume 90 Number 2

Case Reports and Technical Notes

Igor Fineman, M.D., J. Patrick Johnson, M.D., Pier–Luigi Di–Patre, M.D. and Harvinder Sandhu, M.D.
 
Divisions of Neurosurgery and Neuropathology, University of California, Los Angeles School of Medicine, Los Angeles, California; and Department of Surgery, Orthopedics, Cornell University Medical College, New York, New York

Brown tumors (osteoclastomas) are histologically benign lesions that are caused by primary or secondary hyperparathyroidism. Secondary hyperparathyroidism is a frequent complication of chronic renal failure. Skeletal brown tumors are relatively uncommon, and brown tumors that involve the spine are considered very rare. The authors present the case of a 37–year–old woman with systemic lupus erythematosus and hemodialysis–dependent anuric renal failure, in whom spinal cord compression developed due to a brown tumor and pathological fracture at T–9. The patient underwent transthoracic decompressive surgery and spinal reconstruction in which cadaveric femoral allograft and instrumentation were used. Brown tumors of the vertebral column require surgical treatment if medical therapy and parathyroidectomy fail to halt their progression or if acute neurological deterioration occurs. In patients with renal failure bone healing is delayed and there is an increased risk that healing will fail because the metabolic derangements can result in severe osteoporosis. Surgical reconstruction of the spine may require the use of augmentation with instrumentation and aggressive treatment of hyperparathyroidism to achieve successful outcomes.

KEY WORDS.   brown tumor, hyperparathyroidism, spinal reconstruction, osteoclastoma, osteitis fibrosa

BROWN tumors, or osteoclastomas, are erosive bony lesions caused by increased osteoclastic activity and peritrabecular fibrosis (that is, osteitis fibrosa). They arise as complications of primary or secondary hyperparathyroidism, and the latter occurs in the majority of patients with chronic renal failure (CRF). 17, The incidence of skeletal brown tumors in patients with CRF ranges from 1.5 to 13%, and these lesions occur most often in the pelvis, ribs, and the mandible. 6, 9, 11 – 14, Involvement of the vertebral column is rare, and only seven cases of symptomatic brown tumors that involve the spine have been reported to date. 1, 2, 5, 15, 16, 18,

Patients who harbor brown tumors are typically treated by medical management of their hyperparathyroidism, 3, 17, whereas surgery in which a subtotal or total parathyroidectomy is performed may be necessary in cases of advanced or refractory disease. 1, 5, 10, 18, Brown tumors of the spine that cause neurological symptoms due to pathological fractures or tumor mass may require emergency surgical management.18

We present a patient in whom a brown tumor involved the thoracic spine, and we review of the radiological findings, metabolic pathophysiology, and the medical and surgical treatment options.

Case Report

A 37–year–old woman with a 10–year history of hemodialysis–dependent anuric renal failure secondary to systemic lupus erythematosus presented with sudden onset of lower thoracic pain, rapidly progressive bilateral lower–extremity weakness, and left–lower extremity numbness after suffering a lifting injury. She was initially evaluated at another hospital, where her sensory deficits improved after bedrest and intravenous dexamethasone therapy. Her lower thoracic pain and leg weakness persisted, but there were no episodes of bladder or bowel incontinence. A magnetic resonance (MR) image reportedly revealed multiple thoracic spinal lesions and a T–9 vertebral body fracture that caused the spinal cord to become compressed. The patient was transferred to our institution to undergo further treatment.

 
Examination.

On physical examination mild tenderness to palpation and percussion over the lower thoracic spine were noted. Strength and muscle tone were normal throughout, except for her quadriceps and hip flexors (4+/5 power). Deep tendon reflexes were normal, and plantar responses were flexor. Sensation was intact to light touch and pinprick, but her lower–extremity proprioception and vibratory sensation were moderately impaired. Sphincter tone and sensation were normal.

Laboratory results demonstrated that serum levels were remarkable for creatinine of 7.2 mg/dl (normal range 0.5–1.2 mg/dl), phosphate of 6.1 mg/dl (normal range 2.6–4.2 mg/dl), and calcium of 10.5 mg/dl (normal range 8.4–10 mg/dl), Westergren sedimentation rate of 90 mm/hour (normal range 0–20 mm/hour), and parathyroid hormone (PTH) of 456 pg/ml (normal range 10–55 pg/ml).

Plain radiographs obtained in the thoracic spine revealed a 50% compression fracture of the T–9 vertebra, as well as severe generalized osteopenia with blurring of the trabecular markings. On skeletal–survey radiographs a 5 X 2–cm lytic lesion at the mid–shaft of the left femur, multiple lytic rib lesions, and profound osteopenia of the hands with a lytic lesion in the distal left fourth metacarpal were revealed. Computerized tomography scanning of the spine revealed a lytic soft–tissue mass with enroachment into the spinal canal at T–9 (Fig. 1). An MR image obtained in the thoracic spine revealed a "bubbly" lesion of the T–9 vertebral body with a retropulsed bony and soft–tissue mass that severely narrowed the spinal canal and compressed the spinal cord (Fig. 2). The lesion appeared hyperintense on T2–weighted MR imaging sequences (Fig. 2) and slightly hypointense on T1–weighted images (data not shown). The majority of the T–7 vertebral body was similarly involved, as were multiple other sacral, thoracic, and cervical vertebral bodies, laminae, and spinous processes; however, these smaller lesions did not cause significant neurological compression.

The clinical diagnosis was consistent with brown tumor associated with renal failure and secondary hyperparathyroidism, although a tissue biopsy sample had not been obtained preoperatively. Because of the patient's acute neurological deterioration and risk of further spinal cord injury, a surgical decompressive procedure was indicated. The T–7 vertebral body was considered to be at high risk for subsequent collapse, which necessitated reconstruction of both T–7 and T–9 vertebral bodies. Because the lesions primarily involved the vertebral bodies and the posterior spinal elements were intact, the patient would need to undergo anterior decompressive surgery in which vertebral body reconstruction would be required.

 
Operation.

A left lateral thoracotomy revealed that the T–7 and T–9 vertebral bodies were almost completely replaced by a soft brownish–red tissue debris, and examination of a frozen section confirmed the diagnosis of brown tumor. The entire T–7 and T–9 vertebral bodies were removed by performing sharp curettage, thus allowing spinal canal decompression. The adjacent vertebrae were noted to be severely osteoporotic. Bone screws were placed in the T–6, T–8, and T–10 vertebral bodies in the coronal plane to provide distraction for graft placement and subsequent graft compression. Femoral allografts were filled with autogenous bone that was harvested from the iliac crest and placed into the T–7 and T–9 vertebral body defects after careful decortication of the end plates. Spinal instrumentation, consisting of a single rod that connected the bone screws, was placed to provide additional compression on the grafts.

On postoperative motor examination the patient was noted to have fluctuating motor responses in the lower extremities, and a computerized tomography scan revealed that the T–7 graft was malpositioned with a 3–mm compromise of the spinal canal. She was returned to the operating room to undergo graft repositioning, and following reexploration, her neurological status returned to its preoperative baseline level.

 
Histological Findings.

Histological examination of the T–7 and T–9 surgical specimens was conducted by performing hematoxylin and eosin staining of formalin–fixed, paraffin–embedded tissue, and it revealed hypercellular bone marrow with focal areas of fibrosis. The most significant histological features were the presence of numerous giant cells and microfoci of hemosiderin deposition (Fig. 3). Between the giant cells were sheets of plump fibroblasts and a rich vascular network. The microscopic appearance of the lesion confirmed the diagnosis of brown tumor or giant cell tumor of hyperparathyroidism.

 
Postoperative Course.

One–year postoperatively the patient was walking independently with a cane, and her bone grafts were well incorporated (Fig. 4). She also underwent a subtotal parathyroidectomy in the interim, which normalized her serum PTH and calcium levels.

 
Discussion
Overview of Brown Tumors

Contrary to a name that suggests otherwise, brown tumors are a nonneoplastic process. On radiographic evaluation their multifocal involvement may be misconstrued as metastatic disease; however, the clinical history of renal failure and secondary hyperparathyroidism (or primary hyperparathyroidism) usually establishes the diagnosis. 8, Brown tumors are known to occur only in the setting of hyperparathyroidism, and they rarely affect the spinal column. In a review of the literature we found that seven symptomatic brown tumors involving the spine have been reported, only two of which were caused by renal failure and secondary hyperparathyroidism. 1, 2,

Primary hyperparathyroidism is caused by solitary parathyroid adenomas in 85% of the cases. Less frequently, it results from glandular hyperplasia that is associated with multiple endocrine neoplasia (types I and II). The incidence of parathyroid carcinoma accounts for less than 5% of cases of primary hyperparathyroidism. Treatment of primary hyperparathyroidsm usually involves performing a total or subtotal parathyroidectomy. 1,

Secondary hyperparathyroidsm, as in the case presented here, is a frequent complication of CRF, particularly in dialysis–dependent patients. 1, 2, 11, 12, 17, The goals of prevention and treatment of brown tumors in patients with CRF include normalizing blood levels of calcium and phosphate to reverse skeletal abnormalities and prevent extraskeletal deposition of calcium and phosphate. 3, 17, If medical therapy fails to halt the progression of brown tumors, a subtotal or total parathyroidectomy is generally performed to reduce the serum levels of PTH. 1, 5, 10, 18,

Brown tumors most commonly involve the pelvic bones, ribs, and extremities; it is unclear why the vertebral column is affected less frequently. On gross inspection, brown tumors appear as reddish–brown friable masses that replace normal bone; histologically, they consist primarily of a mass of fibrous tissue, macrophages, and hyperactive osteoclasts. 4, When brown tumors involve the spinal column, they can cause either slowly progressive symptoms due to mass effect or acute spinal cord compression due to pathological fractures. 1, 2, 5, 15, 16, 18, Although parathyroidectomy has been performed to treat slowly progressive symptoms, spinal decompressive surgery in which reconstruction is performed is required in patients with acute neurological deterioration. 18,

 
Pathophysiology of Chronic Renal Failure and Secondary Hyperparathyroidism

Renal osteodystrophy is a complication of CRF and may be viewed as four clinical processes: osteitis fibrosa, osteomalacia, osteosclerosis, and osteoporosis. 17 In osteitis fibrosa (that is, peritrabecular fibrosis) a brown tumor mass results from secondary hyperparathyroidism that is manifested by hyperplasia of the parathyroid chief cells in which elevated serum PTH levels and osteoclast activation are produced. The pathogenesis of secondary hyperparathyroidism is linked to five main abnormalities encountered in CRF: 1) phosphate retention, 2) altered metabolism of calcitrol (vitamin D), 3) skeletal resistance to PTH, 4) impaired degradation of PTH, and 5) altered feedback regulation of PTH by calcium. Phosphate retention reduces the concentration of ionized calcium in extracellular fluid due to the increased binding of ionized calcium by phosphate. There is also decreased renal production of vitamin D in response to increased serum phosphate concentration and decreased calcium mobilization from bone because of the direct effects of phosphate on bone.

Serum PTH levels are further elevated by a reduced production of vitamin D. Elevated levels of phosphate inhibit the activity of the hydroxylase that is required for conversion of 25(OH)D3 to 1,25(OH)2D3 (that is, calcitrol, the active form of vitamin D), which is necessary for intestinal absorption of calcium. This leads to further decreased serum levels of ionized calcium and subsequent hyperstimulation of the parathyroid glands.

Skeletal resistance to PTH in patients with renal failure is responsible for the additional reduction in serum ionized calcium. This results in further upregulation of parathyroid PTH production as an attempt to maintain adequate serum levels of ionized calcium.

Additionally, because parathyroid hormone is metabolized in the liver and the kidney, decreased renal function of end–stage renal disease may be responsible for increased serum levels of PTH due to slowed catabolism.

Lastly, feedback regulation of PTH production in the parathyroid gland caused by serum calcium is altered in cases of advanced renal disease that result from decreased sensitivity to calcium; this, in turn, leads to further increases in serum levels of PTH.

 
Skeletal Changes Due to Secondary Hyperparathyroidism

Aggressive bone resorption by hyperstimulated osteoclasts leads to osteitis fibrosa. Microscopically, this appears as microfractures and microhemorrhages with hemosiderin–filled macrophages and osteoclasts that become dispersed throughout fibrous tissue within the marrow spaces (Fig. 3). Progression of focal bone resorption and fibrosis results in macroscopically visible cysts that coalesce to form brown tumors. The extensive involvement of bones with brown tumor may weaken them sufficiently to result in pathological fractures. Concurrent osteomalacia and osteoporosis seen in CRF increase the risk of pathological fractures and impaired bone healing despite aggressive medical treatment of brown tumors.

 
Management of Secondary Hyperparathyroidism and Brown Tumors Involving the Spine

Initial treatment of secondary hyperparathyroidism is directed at controlling serum phosphate by restriction of dietary phosphorus intake and phosphate–binding antacids, and adequate calcium intake should be ensured with oral calcium supplements. 3, 17, If skeletal disease develops despite these measures, vitamin D (and metabolites) should be administered. The continued progression of bone lesions, hypercalemia, intractable pruritus, or extraskeletal calcifications should indicate treatment in which a subtotal or total parathyroidectomy is performed. 1, 10,

Among the seven cases reported in the literature of brown tumor involving the spine, two were successfully treated by a parathyroidectomy and immobilization. 1, 5, One case involved a brown tumor that had destroyed the patient's C–5 vertebral body, whereas another patient harbored a brown tumor that caused posterior spinal cord compression by invading the T–2 lamina and spinous process without causing significant spinal instability. 1, 5, In both cases a parathyroidectomy procedure was able to halt the progression of the brown tumor, and sufficient remodeling of the remaining vertebra occurred.

In the majority of reported cases, acute spinal cord compression due to a brown tumor and an associated pathological fracture resulted in paraplegia or severe neurologic deficit. 2, 15, 16, 18, These patients require prompt surgical intervention, because neither medical therapy nor parathyroidectomy can achieve rapid spinal cord decompression. However, they may subsequently require a parathyroidectomy to correct their metabolic pathophysiology and provide an optimum physiological environment for bone healing.

Surgical treatment of a vertebral brown tumor requires resection of the tumor that causes neurological compression. Reconstructive surgery in which bone grafting and instrumentation are used is necessary if spinal instability is present. Spinal reconstruction in these patients is potentially more difficult because of the severe osteoporosis and impaired bone healing. The use of instrumentation and structural bone grafts, as in the case presented here, provides immediate stability during the prolonged healing process. Vertebral body defects in the cervical and upper thoracic region may be replaced with iliac tricortical grafts, but femoral allografts are more appropriate for the lower thoracic and lumbar spine regions. 7, In addition, concurrent medical or surgical treatment of the secondary hyperparathyroidism is essential to promote bone fusion.

Although brown tumors of secondary hyperparathyroidism are most prevalent in patients receiving hemodialysis treatment, renal transplant patients may remain susceptible to them. 6, However, brown tumors that are discovered after renal transplantation likely began developing in the altered metabolic environment that exists prior to transplantation.

With improvements in the medical care of patients with renal failure and the dearth of organs for transplantation, the number of dialysis–dependent patients, and consequently the incidence of brown tumors, may be expected to increase. A high index of suspicion of brown tumors should exist for dialysis–dependent patients in whom secondary hyperparathyroidism and new onset of neurological symptoms are related to spinal column lesions.

 
 
Acknowledgments:

The authors wish to thank Samantha Phu for her assistance in the preparation of this manuscript.

 
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Manuscript received November 10, 1998.
Accepted in final form December 28, 1998.