Tumor-induced Osteomalacia due to a Phosphaturic Mesenchymal Tumor in the Cervical Spine: A Case Report and Literature Review
Keywords: Cervical spine, fibroblast growth factor-23, paraneoplastic syndrome, phosphaturic mesenchymal tumor-mixed connective tissue, tumor-induced osteomalacia
TIO is a rare paraneoplastic syndrome in which tumors, usually of mesenchymal origin and generally histologically benign, secrete molecules that induce renal phosphate wasting. One such molecule, fibroblast growth factor-23 (FGF-23) is a protein notorious for inhibiting renal tubular reabsorption of phosphate, thereby causing hypophosphatemia. Other accompanying abnormalities include inappropriately low blood levels of calcitriol, low-normal serum levels of calcium, and evidence of impaired bone mineralization. In most cases, the clinical symptoms and biochemical derangements resolve soon after complete resection of the lesion.
In this manuscript, we present the case of a 62-year-old man with TIO due to benign lesion involving C2 lamina. Histopathology revealed a PMT-MCT type. His symptoms significantly improved following a complete resection of the lesion and C2 hemilaminectomy and he continues to be disease free at 24 months follow-up. TIO is a rare disorder with over 200 cases reported. Most of them involve the appendicular skeleton and occasionally the craniofacial regions. To the best of our knowledge, only 18 cases of TIO localized to the spine have been so far reported with the present case being only the fifth involving the cervical spine [Table 1].,,,,,,,,
We discuss the management of TIO involving the axial skeleton and also present a review of literature.
This 62-year-old man presented with a 4-year history of backache, mild to moderate in intensity, aggravating on walking, and partially relieved with rest and analgesics. He also complained of proximal muscle weakness of 3 years with no specific pattern of progression. He also complained of truncal muscle weakness. At the time of presentation, he was unable to do his activities of daily living without the support of family members and was bed bound. However, he denied any sensory loss and bladder or bowel complaints. Only comorbid illness included systemic hypertension of 15 years controlled on medication. There was no history of similar illness in the family. He had received a course of teriparatide 1 year back in view of osteoporosis and multiple vertebral fractures.
On physical examination, the patient was alert and oriented. Cranial nerves II–XII were grossly intact. Motor strength was poor in proximal muscles in all extremities with good distal muscle power and intact sensations throughout. He had no focal or lateralizing neurological deficits.
On evaluation, we found low phosphate (1.3 mg/dl; normal range 2.5–4.5 mg/dl), normal calcium (8.5 mg/dl; normal range 8.1–10.4 mg/dl), normal PTH (79.3 pg/ml; normal range 16–87 pg/ml) and low-normal Vitamin D (35.9 ng/ml; normal range 25–50 ng/ml), low TmP/GFR (0.51; normal range 2.0–3.4 mg/dl), and elevated alkaline phosphatase (ALP) (702 IU/l; normal range 80–240 IU/l).
A skeletal survey revealed diffuse osteopenia (lumbar spine T score – 3.4; Z score – 2.7), multiple vertebral compression fractures, and pseudofracture of right femur. A 68-Ga DOTANOC PET-CT study revealed two nodules in the posterior cervical region at the level of C2 with increased radiotracer uptake [Figure 1]. It was isointense on T1W MRI of cervical spine and heterogeneously hyperintense on T2W sequence. On contrast enhanced MRI, it appeared as a well-defined lesion of heterogenous contrast enhancement abutting the left C2 lamina on its posterolateral aspect and infiltrating the substance of the overlying inferior oblique muscle without any restriction on DWI, suggesting a mesenchymal tumor [Figure 2]. A CT-guided biopsy confirmed the suspicion of a PMT – showing a spindle cell lesion with areas of fibrosis. The cells had small oval nucleus with indistinct cell margins. Immunohistochemically, the cells were positive for Bcl-2 (focal and weak) and MIC2 (focal and weak) but negative for SMA and CD34 [Figure 3].
Decision to excise the offending lesion was taken and a written informed consent obtained. Intraoperatively, on exposure of C1–C3 posterior elements, there was evidence of a grayish-white, moderately vascular, firm lesion attached to left C2 lamina, also involving the overlying obliquus capitis inferior muscle. All of the macroscopically visible tumor was excised with margins along with a left C2 hemilaminectomy. Care was taken to avoid injury to C1 nerve root and the horizontal part of vertebral artery within the suboccipital triangle. Rectus capitis muscles appeared normal and were left untouched.
Patient had an uneventful postoperative course and was discharged on the second postoperative day.
On follow-up, patient had a good clinical recovery. Serum phosphate was within normal range on the sixth postoperative day and was 3.5, 3.9, and 4.1 mg/dl at 3, 12, and 24-month follow–up, respectively. He started walking with support of a frame at 3 months and without support at 6 months post-op. Back pain gradually improved over a period of 12 months. On 24 months follow-up visit, patient had no e/o residual/recurrent disease [Figure 4] and could perform all his activities of daily living without difficulty and presently taking oral calcitriol supplementation alone.
Osteomalacia is the impaired mineralization of bone matrix proteins. Apart from calcium and vitamin D deficiency, osteomalacia may also occur with chronic hypophosphatemia. Tumor-induced osteomalcia is a syndrome of hypophosphatemia characterized by excessive secretion of FGF-23 by certain mesenchymal tumors.
TIO was first described by McCance in 1947 in a young girl who presented with vitamin D-resistant osteomalacia acquired at the age of 15 years. Prader and colleagues, in 1959, first described a “rachitogenic” substance secreted from a “giant cell tumor” in a rib as the basis of this disease in a 11.5-year old girl with rickets. FGF-23 is one such substances which inhibits reabsorption of phosphate in the proximal renal tubule. In addition, it inhibits the hydroxylation of 25 hydroxy vitamin D (25OHD) leading to decreased plasma levels of calcitriol.
Clinically, patients of TIO present with bone pains, insufficiency fractures, and proximal muscle weakness. In pediatric patients, the disease manifests as rickets and growth retardation. More commonly, it involves the appendicular skeleton or craniofacial regions. Involvement of axial skeleton is rare. To the best of our knowledge, only 18 cases, including the present case, have been reported thus far with the present case being only fifth reported case in cervical spine. In a literature review of all spinal cases of TIO, thoracic spine was found to be the most common site of involvement. Bone pain was the most consistent symptom (all cases) with no gender predilection of the disease (nine male and nine female patients). Diagnosis is often delayed due to small size and peculiar locations. In the present case, diagnosis with precise localization of tumor could be done after 4 years. This was similar to the findings of the literature review – mean duration of disease at diagnosis was 3 years 10 months.
Hypophosphatemia due to hyperphosphaturia is the most consistent lab finding, although nonphosphaturic variant has also been reported. Raised serum FGF-23 supports the diagnosis; however, it is not diagnostic as constitutive overexpression is seen in X-linked and autosomal-dominant hypophosphatemia rickets. Serum FGF levels were not done in the present case due to logistic issues. Other notable biochemical abnormalities include low serum vitamin D3 levels due to inhibition of one alpha hydroxylase by FGF-23, leading to fall in levels of serum phosphorus and a profound hypophosphatemia. This dual defect of renal phosphate wasting and impaired calcitriol synthesis is the cause of poor bone mineralization and fractures. Increased bone turnover results in raised serum ALP levels.
In addition to clinical and laboratory parameters, diagnosis and localization of a PMT relies on optimal imaging investigations. Chong and colleagues, in their review article, lucidly describe a stepwise approach in the utilization of imaging – first performing functional imaging – FDG-PET/CT,111 Indium octreotide scintigraphy, ideally combined with single photon emission CT and CT (SPECT/CT), and the more recently advocated 68Ga-DOTANOC PET/CT. There is evidence in favor of octreotide scintigraphy with SPECT/CT as the best initial study as it provides the combination of best specificity and sensitivity., Following identification of suspicious areas or when no lesions are identified on functional imaging, anatomic imaging X-rays, CT, and MRI may be carried out.
In this literature review of spinal cases of TIO, PET/CT was useful in localizing the tumor in almost all cases where the lesion could not be clinically localized. For others, MRI or CT specific to the clinical level could detect lesion in most cases. Chua et al. demonstrated the diagnostic value of FDG-PET in localizing oncogenic osteomalacia causing nonmesenchymal tumors in the setting of background postoperative changes, including bone grafting and metallic artifacts where MRI could not be used. Maehara et al. concluded that a 68-Ga DOTATOC PET/CT for somatostatin receptor imaging for localization of PMT is better than MRI or CT. Short tau inversion recovery whole body MRI has been found to be highly useful (although very costly) in detection of tumors causing oncogenic osteomalacia in various case reports.,,, In the present case, lesion at C2 level was detected using an 68-Ga DOTANOC PET/CT. Subsequent MRI and CT scan of the cervical spine revealed the anatomical extent of the lesion.
On histopathology, majority of the tumors (13 out of 18) were phosphaturic mesenchymal tumors. Osteoblastoma, osteosarcoma, hemangiopericytoma, and plasmacytoma were the other causes of oncogenic osteomalacia in this review. In 2004, Folpe et al. did a comprehensive review of mesenchymal tumor-associated oncogenic osteomalacia and concluded that most of these cases belong to a single histopathologic entity of PMT-MCT variant. These tumors are mostly benign with low cellularity, myxoid change, bland spindled cells, distinctive “grungy”-calcified matrix, fat, HPC-like vessels, microcysts, hemorrhage, osteoclasts, and an incomplete rim of membranous ossification, although malignant hypercellular variants with cytological atypia are also known to occur. Weidner and Cruz studied four PMT-MCT tumors immunohistochemically and three of these tumors revealed only vimentin immunoreactivity within the primitive-appearing tumor cells. All other reagents (desmin, S-100 protein, leu-M 1, chromogranin, cytokeratin, neuron-specific enolase, leukocyte common antigen, and factor VIII-related antigen) were nonreactive in tumor cells. The tumor cells in the present case had similar findings on immunohistochemistry [Figure 3].
A complete surgical resection of the lesion with wide margins to ensure biochemical remission and prevent recurrences is the therapy of choice.,, There is evidence in literature which suggests that for phosphaturic mesenchymal tumors arising from bone, intralesional procedures may not be sufficient and wide resection should be performed wherever possible. Care should be taken to make all cuts in the bone outside the tumor margin to ensure minimal spillage., Sciubba et al. and Meng et al. have suggested en bloc spondylectomy for these tumors. In regions where resection with wide margins is technically difficult, intralesional excision should be considered. Nakamura and colleagues performed an intralesional excision and demonstrated successful bony union with noninstrumented fusion using iliac struts in a patient with tumor of C5 vertebra. They found no evidence of local recurrence or metastasis after a 5-year follow-up.
In addition, a key point is that osteomalacia may predispose to nonunion or delayed union; hence, rigid internal fixation with multiple fixation points and augmented pedicular screws should be considered and effective postoperative bracing can be helpful.,
In the previously reported cases in spine, persistent serum abnormalities were reported in all 3 cases where a subtotal tumor excision was performed and in only 1 of the 15 cases where a gross total excision was done [Table 1]. In eight cases of fusion following tumor excision in the spine (out of a total of 18 cases), only one in the cervical spine has been a noninstrumented fusion [Table 1].
Fusion was not necessary in the present case as a complete excision with margins could be achieved with hemilaminectomy. Following surgery, serum phosphate levels usually return to normal within a week and symptomatic improvement is seen over a period of 3–6 months.,
Radiotherapy is the therapeutic option for unresectable tumors or for incompletely resected tumors.,,
For patients with no clear documented evidence of tumor with symptomatic hypophosphatemic osteomalacia/rickets, medical management is advised.,, It includes phosphorus and calcitriol supplementation. However, it is not effective in long term and patients should be monitored for potential complications of hyperparathyroidism, hypercalcemia, and nephrolithiasis.
Other proposed treatment options include radiofrequency ablation for small bony tumors in critical locations and a new treatment approach using cinacalcet, a calcium sensing receptor agonist.
Serum phosphate and FGF-23 levels correlate with recurrence of disease and can be used for postoperative screening. FGF-23, although a more direct marker of tumor activity, is expensive and logistically demanding. The test was not performed in the present case due to its unavailability at our center. The patient did not show any symptomatic, radiological, or biochemical evidence of tumor recurrence at 18-month follow-up.
TIO due to a PMT-MCT in the spine is exceedingly rare. This manuscript presents a case of this tumor in the cervical spine which is only the fifth reported case in this region. The patient had a drastic improvement in terms of clinical and biochemical parameters following complete resection and continued to be disease free at 24 months follow-up. The manuscript also includes an exhaustive literature review of all the published cases of TIO due to a tumor in the spine to the best of our knowledge.
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There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]