En bloc spondylectomy for treatment of tumor-induced osteomalacia

Abstract

En bloc spondylectomy represents a radical resection of a spinal segment most often reserved for patients presenting with a primary extradural spine tumor or a solitary metastasis in the setting of an indolent, well-controlled systemic malignancy. The authors report a case in which en bloc spondylectomy was conducted to control a metabolically active spine tumor. A 56-year-old woman, who suffered from severe tumor-induced osteomalacia, was found to have a fibroblast growth factor-23–secreting phosphaturic mesenchymal tumor in the T-8 vertebral body. En bloc resection was conducted, leading to resolution of her tumor-induced osteomalacia. This case suggests that radical spondylectomy may be beneficial in the management of metabolically or endocrinologically active tumors of the spine.

OSTEOMALACIA is a metabolic bone disorder characterized by impaired mineralization of osteoid matrix in mature bone. Hereditary and acquired forms of osteomalacia are recognized. Acquired forms include renal tubulopathy (Fanconi type) and FGF-23–secreting PMTs. When caused by the latter, it is referred to as oncogenic osteomalacia or tumor-induced osteomalacia. Tumor-induced osteomalacia is characterized by bone pain, multiple fractures, renal phosphate wasting, decreased levels of serum vitamin D3, and elevated serum FGF-23.^10,12,21

In this case report, we illustrate the presentation and treatment of a patient with a PMT of the spinal column. Because this patient presented with severe osteomalacia and multiple skeletal fractures due to the metabolic activity of her tumor, she underwent an en bloc spondylectomy to attain oncological and metabolic control. Pathological analysis of the spine lesion revealed a PMT, a rare type of tumor that causes tumor-induced osteomalacia. Since undergoing resection, the patient has experienced resolution of her osteomalacia. Although en bloc spondylectomy is generally reserved for slow-growing primary tumors of the spinal column to facilitate local control and longer disease-free survival, such aggressive surgery may prove beneficial for patients with endocrinologically or meta-bolically active spinal lesions.

Case Report

History and Presentation.

This 56-year-old woman presented to our neurosurgery spine clinic for consultation regarding resection of an FGF-23–secreting tumor in the T-8 vertebral body. Five years prior to this presentation, she had experienced a minor fall in her bathtub, sustained multiple rib fractures, and developed persistent back pain, difficulty walking, and bilateral hip fractures. Osteoporosis was initially diagnosed and treated with teriparatide, but the patient’s symptoms progressively worsened and she became disabled and unemployed. Subsequent evaluation noted hypophosphatemia (1.9 mg/dl [normal range 2.5–3.5 mg/dl]), and elevated PTH (132.0 pg/ml [normal range 16.0–87.0 pg/ml]). The low phosphorus level was believed to be secondary to hyperparathyroidism, and a thyroid ultrasound scan revealed a right lobe hypoechoic mass approximately 8-mm in size. She was presumed to have osteoporosis due to primary hyperparathyroidism and underwent a right hemithyroidectomy and resection of 3 parathyroid nodules. However, the pathological analysis of her thyroid and parathyroid glands revealed only hyperplastic changes with no evidence of parathyroid adenoma or carcinoma.

Unfortunately, the patient’s osteomalacia and hypophosphatemia persisted. She was referred to the National Institutes of Health for evaluation, where it was discovered that she had markedly elevated levels of serum FGF-23 (404 pg/ml [normal range 10–50 pg/ml]). Evaluation using MR imaging, whole body PET-CT, and octreotide uptake scan revealed a lesion of the T-8 vertebral body (Fig. 1 upper). Interestingly, this lesion did not enhance on the octreotide scan, but did enhance on PET-CT.

Fig. 1.

Axial images through the T-8 vertebral body showing a right-sided lesion on a T2-weighted MR image (upper) and a CT scan (lower).

On presentation to our neurosurgical clinic, the patient had signs of severe osteoporosis and complained of diffuse bone pain throughout her axial skeleton. On physical examination, the patient was alert and oriented. Cranial nerves II–XII were grossly intact. Motor strength was graded as 5/5 (full strength) in all extremities and sensation was intact throughout. She had no focal or lateralizing neurological deficits.

The patient’s preoperative laboratory studies revealed a normal serum ionized calcium level of 1.28 mg/dl (normal range 1.1–1.4 mg/dl), total calcium level of 2.20 mmol/L (normal range 2.2–2.6 mmol/L), low phosphorus level of 1.2 mg/dl (normal range 2.5–3.5 mg/dl), elevated alkaline phosphatase level of 222 IU/L (normal range < 140 IU/L), elevated PTH level of 98.6 pg/ml, and normal thyroid stimulating hormone level of 1.48 μIU/ml (normal range 0.5–5.0 μIU/ml). The patient also demonstrated a 1,25-dihydroxy vitamin D level < 10 pg/ml (normal range 22–67 pg/ml).

At the time of neurosurgical evaluation, a CT scan indicated a mixed sclerotic and lytic lesion measuring 1.4 × 1.8 cm in the right T-8 vertebral body with some erosion and expansion of the bone cortex (Fig. 1 lower). The lesion was noted to abut the pedicle but did not significantly invade the lamina. Multiple healed or healing bilateral rib fractures were also observed.

Operative Procedure.

With informed consent, the decision was made to resect the T-8 vertebral body via an en bloc spondylectomy procedure followed by spinal reconstruction to remove all metabolically active tissue. The operative procedure began with an incision from approximately T-5 to T-11. Pedicle screw instrumentation was then placed bilaterally in the vertebral bodies of T-5, T-6, T-7, T-9, T-10, and T-11. Dissection was performed laterally for approximately 6 cm. Next, the rib heads from the proximal attachment of the vertebral bodies of T-7 and T-8 were resected bilaterally. A laminectomy of T-7 and T-9 was subsequently performed. The pedicles of T-8 were then cut bilaterally using a wire saw, and the posterior elements of T-8 were removed in 1 piece. This removed piece included the spinous process, bilateral lamina, superior and inferior articulating processes, bilateral pars, bilateral transverse processes, and bilateral pedicles. Radical discectomies were performed at the T7-8 and T8-9 levels, allowing the T-8 vertebral body to be freed from the rest of the spine (Fig. 2). At this point, the vertebral body was rotated around the thecal sac and removed. A titanium expandable cage was placed in the position of the T-8 vertebral body and was packed with recombinant human BMP-2 matrix (Medtronic). Titanium rods were placed to connect the instrumented levels. There were no intraoperative complications, and the patient was transferred to the intensive care unit in stable condition, both hemodynamically and neurologically.

Fig. 2.

Illustration of posterior approach to thoracic en bloc spondylectomy. Following resection of posterior elements and stabilization of spine with a pedicle screw and rod construct, the vertebral body is separated from the spine via radical discectomies and the specimen is rotated out of the patient (green arrow).

Histological Analysis.

Intraoperative frozen histological analysis of the lesion suggested a vascular mesenchymal neoplasm morphologically consistent with a PMT. The lesion appeared completely excised. Tumor cells focally stained for S100 protein and CD31 highlighted vessels. However, stains for actin, HMB-45, melan, and keratin were all negative. All of these features supported a diagnosis of PMT. Permanent pathology specimens also were consistent with a PMT (Fig. 3).

Fig. 3.

Photomicrographs of histopathological specimens of the resected lesion showing features consistent with a PMT. Tumor cells are observed within the surrounding bone trabeculae. Additional stains (not shown here) found that tumor cells focally stained for S100 and CD31 highlighted vessels, consistent with PMT. H & E, original magnification 100 (left) and 400 (right).

Postoperative Course.

A postoperative CT scan revealed placement of posterior instrumentation from T-5 through T-11 and proper placement of the titanium cage at T-8. The patient’s postoperative course was initially complicated by an infection at the surgical site, requiring readmission to the hospital at 2 weeks. This wound infection was concluded to be superficial and the patient was treated using intravenous vancomycin alone. Three days later, the patient was discharged with instructions to continue ampicillin-sulbactam for 2 weeks. At 14 months postoperatively, the patient’s laboratory study results have returned to, and remained at, normal levels, including FGF-23. At last follow-up, the patient was neurologically stable without any problems related to her instrumentation or local regrowth of tumor. A postoperative follow-up CT scan revealed intact instrumentation without construct failure or osteolysis secondary to use of recombinant human BMP-2. The presence of bone fusion was not yet visible (Fig. 4).

Fig. 4.

Sagittally reconstructed postoperative CT scan showing placement of the interbody cage, pedicle screws, and rods following T-8 en bloc spondylectomy. No osseous fusion mass is apparent.

Discussion

Osteomalacia is a condition characterized by inadequate mineralization of bone. It is most commonly caused by vitamin D deficiency, and can be associated with hypocalcemia and hypophosphatemia. Other causes include calcium deficiency without vitamin D deficiency, disorders of vitamin D metabolism, and long-standing hypophosphatemia that can be seen in tumor-induced osteomalacia mediated by tumor production of FGF-23.^2,11,20 Clinically, osteomalacia presents with diffuse bone pain, especially in the spine, pelvis, and ribs, as well as proximal muscle weakness.¹⁸ Radiographically, it is distinguished by the radiolucency of the skeleton, a decrease in bone cortical thickness, and the presence of pseudofractures.^2,4 Depending on the cause, treatment consists of some combination of vitamin D, calcium, and/or phosphate supplementation.²

In this case report, we described a patient at our institution who was treated with en bloc spondylectomy for osteomalacia secondary to a PMT. Phosphaturic mesenchymal tumors are a diverse group of rare benign tumors, usually of soft-tissue or bone origins, that produce peptides with metabolic activity. Phosphaturic mesenchymal tumors are classified into 4 subgroups: mixed connective tissue tumors, osteoblastoma-like tumors, nonossifying fibroma-like tumors, and ossifying fibroma-like tumors.²¹ The peptides produced by these tumors cause renal phosphate wasting, hypophosphatemia, and vitamin D-resistant osteomalacia, and are known as phosphatonins. One of these peptides that is hypersecreted in PMTs is FGF-23, a gene product that is constitutively active in hereditary hypophosphatemic rickets and leads to marked bone demineralization in mice.^7,15,16 Parathyroid hormone levels are commonly elevated in patients with PMTs, a change that reflects the normal physiological response to the low serum levels of vitamin D3. The tumor-induced osteomalacia and other symptoms observed with PMTs frequently precede identification of the offending lesion by months to years, a scenario that was observed in our patient.^5,12 Phosphaturic mesenchymal tumors are very rare, but, when present, can lead to debilitating complications and years of suffering. However, these lesions should be considered in patients with severe osteomalacia and hypophosphatemia, and elevated serum FGF-23 levels.

Vertebrectomy and en bloc spondylectomy are the most commonly used surgical techniques for resection of mass lesions of the spine. Vertebrectomy or corpectomy for spine tumor resection traditionally refers to intralesional removal of tumorous tissue, along with varying amounts of neighboring bone and soft tissues that may be contaminated by local tumor spread.⁸ When vertebral body metastases are surgically treated due to neural compromise, fracture, deformity, and/or pain refractory to nonsurgical treatment, vertebrectomy may be performed in conjunction with reconstruction of the spine. Because surgery for metastatic spine disease is generally considered a palliative procedure, and the progression of the systemic malignant disease is believed to be the primary factor affecting overall survival, vertebrectomy is not designed to remove all cancerous spine tissue in a gross-total fashion.^3,14

En bloc spondylectomy, on the other hand, represents a more radical type of vertebral body resection in which the entire vertebral body is removed with a clear margin of tissue, in an attempt to thoroughly remove all local cancerous tissue without contaminating neighboring structures.¹⁹ Although more technically demanding and more destructive to the local anatomy, en bloc spondylectomies are generally reserved for primary tumors of the spine that have low metastatic potential but high likelihood of local spread (such as chordomas and chondrosarcomas),^22,23 the latter of which may affect overall patient survival. In this way, spondylectomies can improve outcomes and in some cases produce a cure.^1,6,9,13

Although PMTs are generally benign, intralesional vertebrectomy was not performed in this patient due to concern for inadequate metabolic control of her tumor-induced osteomalacia. Rather, a radical en bloc spondylectomy was performed in an attempt to remove all metabolically active tumor. Thus far, this patient has experienced remission of her symptoms and improvement of her osteomalacia. Of note, en bloc spondylectomy has been previously used for the treatment of metastatic and primary lesions with specific histopathological features. For instance, such radical spine resections have been shown to be more effective than radiation therapy alone for metastatic renal cell carcinomas of the spine.¹⁷ Specifically, in patients with a solitary renal cell carcinoma metastasis to the spine, systemic disease progression can be quite indolent following nephrectomy and en bloc spondylectomy. In this way, radical resection of metastatic lesions may improve overall clinical outcome.

It should also be noted that the decision was made to place BMP-2 in the resection bed to facilitate fusion in a patient with substantially poor bone quality. Placement of BMP in this manner is currently considered an off-label use by the US FDA. Furthermore, use of commercially available BMP in a region potentially containing active tumor cells is currently a relative contraindication according to the FDA. The risks and benefits of using BMP in this special circumstance were discussed at length with the patient prior to surgery. Imaging and serological markers currently show no signs of local or distant tumor recurrence. Follow-up CT scans also did not demonstrate osseous fusion in the resection bed (Fig. 4). However, this result was not unexpected given the severe degree of preoperative osteomalacia. As her condition continues to improve and her osteomalacia corrects, osseous fusion may yet be achieved.

Conclusions

Phosphaturic mesenchymal tumors are quite rare, but sometimes produce metabolically active components, primarily FGF-23, that can have destructive effects on the body, including osteomalacia. In such cases, en bloc spondylectomy may be considered a reasonable option for functional control of an endocrinologically or metabolically active lesion.

Abbreviations used in this paper:

BMP

bone morphogenic protein

FGF-23

fibroblast growth factor-23

PMT

phosphaturic mesenchymal tumor

PTH

parathyroid hormone