Radiotherapy is applied in various tumors, either as a primary or adjuvant treatment with surgery or chemotherapy. Radiation may cause damages to the skeletal system, depending on the age and health of the patient, size and location of the radiation field, and dose and fractionation of the beam [5]. Doses > 4000 cGy have been reported to be usually required to cause this irreversible bone injury, and the rate of necrosis was up to 50% with dose of > 7500 cGy [5]. Previous cervical ORN cases have been reported with a cumulative dose of 3000–6000 cGy [4]. Our patient received a total of 3500 cGy of focused radiotherapy and 14 doses at 250 cGy for the treatment of T3 N0 M0 gallbladder carcinoma, which is in the line with previously published reports.
During the past century, several theories have been proposed about the pathogenesis of ORN. The pathophysiology of ORN was believed to be a radiation-induced metabolic and homeostatic deficiency. In 1983, Marx proposed the “three H” hypothesis to describe post-radiation injury, which has been the most widely accepted hypothesis [6]. It is characterized by the formation of hypoxic, hypovascular, and hypocellular tissues. It was hypothesized that radiation-induced injury caused bone to be unable to increase its metabolic and nutritional requirements and thus to replace the normal collagen and cellular components lost through routine wear. This results in tissue breakdown and necrosis. In addition, in 2004, a new theory for the pathogenesis of ORN was reported [7] and revealed that damage to bone is caused by radiation-induced fibrosis. Cells in bone are damaged as a result of acute inflammation, free radicals, and chronic activation of fibroblasts by a series of growth factors. The destruction of cells, accompanied by vascular thrombosis, leads to local ischemia, necrosis of micro-vessels, and tissue breakdown.
ORN is clinically described as a chronic disorder with a slow onset. It begins with an acute phase response to radiation that consists of bone marrow edema and mild surrounding soft tissue inflammation. ORN gradually progresses to the chronic phase, which includes vascular damage that leads to a combination of osteitis and discitis. ORN of the jaw has been reported to commonly present within 2 years after radiation treatment but has been described to present up to 20 to 30 years after the initial radiotherapy [8]. In addition, we reviewed that the mean time to onset of previous cervical ORN cases was 112 months, and the longest time was even up to 42 years [4, 7,8,9,10,11,12]. The onset time of spinal ORN seemed even longer than that of ORN of the mandible or maxilla. In this case, the occurrence time of lumbar ORN was around 2 years after radiotherapy. Compared with previous spinal ORN cases, the present case seemed to have a relatively earlier onset time.
The classification of ORN proposed by Marx is widely acceptable [13]. He describes three types of ORN. Type 1 ORN develops shortly after radiation treatment as the synergistic effect of surgical trauma and radiation injury. Type 2 ORN occurs within a few years after the radiation due to progression of endarteritis and vascular occlusion. This type of ORN always follows a traumatic event and rarely occurs before 2 years after treatment, commonly occurring after 6 years. Type 3 ORN occurs spontaneously without traumatic events between 6 months and 3 years after radiotherapy. This type is associated with immediate cellular damage and death due to radiotherapy. In this case, the patient had ORN 2 years after radiotherapy without a traumatic factor, so the classification of ORN was type 3 according this classification system. In the previous cervical ORN cases reported, type 3 ORN occurred most frequently (29/31, 93.5%), followed by type 1 ORN (2/31, 6.5%) [4, 7,8,9,10,11,12].
The most common presenting symptom of ORN is pain. As shown in this case, the only symptom present was chronic back pain. Khorsandi reported that all patients with cervical spine ORN presented with neck pain [12]. However, as ORN progresses, spinal kyphosis and instability can also lead to neurological compression and induced myelopathy or radiculopathy. In our review, most patients (18/31, 58%) with cervical ORN presented with symptoms of neurological injury at the end stage [4, 7,8,9,10,11,12]. Nevertheless, the common symptom of back pain is often overlooked as numerous etiological factors influenced. Patients with spinal ORN do not have any severe neurological symptoms and can be treated conservatively most of the time, as they mainly present pain, for which analgesics are adequate. This is the main reason why most patients with spinal ORN are not identified until complications occur.
Given the history of gallbladder carcinoma in our patient and the site of the lesion at the lumbar spine, differentiation from recurrent or metastatic disease was essential, as the throacolumbar spine is the leading site of spinal metastasis, and the diseases require very different management strategies. Usually, no special signs of ORN are observed on radiography, but dynamic radiography also plays an important role to demonstrate spinal kyphosis and instability caused by the lesion of the spinal ORN [12]. In this study, radiography or dynamic radiography was not conducted before the MRI arranged. It is a limitation of this case report. MRI, CT, and PET scan have been demonstrated to be useful imaging tools for the diagnosis of ORN but have also revealed limitations in distinguishing metastatic or recurrent lesions from radiation-induced injury. The hypointense areas on T1WI and T2WI that corresponded to the intervertebral vacuum cleft sign suggested ORN [5]. Mut proposed that MRI of ORN demonstrates T1 hypointensity with variable T2 signal [14]. The signal changes in the intervertebral disk on MRI were useful for the differential diagnosis of ORN from metastatic disease, as the intervertebral disk was mostly not involved in spinal tumor. Khorsandi reported that the intervening disk space had a hypointense signal on T1WI and T2WI in three of four cases [11], while Wu et al. reported that the hypointense signal on T1WI and hyperintense signal on T2WI of the intervertebral disk indicated discitis, an important signal of end-stage spinal ORN [5]. In our case, the signal changes on MRI were variational as the progress of spinal ORN. Thus, further study on MRI findings of spinal ORN is essential for understanding the natural history of spinal ORN. Alhilali also suggest that besides MRI findings, bony sclerosis is a useful CT imaging feature for differentiating ORN from recurrent tumors [15]. In addition, PET scan has been shown to be a promising method for discriminating between radiation-induced change and tumor recurrence. Dholam reported that differential diagnosis between ORN and bony metastasis may be possible with low FDG uptake of ORN on PET scan [16]. However, the inflammatory response associated with ORN may be interpreted as a false-positive strong uptake, and false-positive PET scan results have been reported in post-radiotherapy patients [16]. The specificity of the examination in distinguishing the etiology is approximately 85% [17]. Utility of single photon emission computed tomography (SPECT) using various radio-pharmaceuticals has been reported to diagnose ORN and differentiate it from metastasis. Deshpande found that TI-201 SPECT clarified 75% (three of the four) of the false-positive PET to be ORN. Thus, SPECT may be used to reduce false-positive rates and improve specificity [18]. Owing to the lack of specificity of imaging studies in the differential diagnosis from recurrent tumors, bone biopsies may be invasive in special cases but can be useful for making a definite diagnosis of ORN.
Besides differentiation from metastatic disease, differential diagnosis from pyogenic spondylitis or spinal tuberculosis was necessary. Firstly, patients with pyogenic spondylitis or spinal tuberculosis were more frequently associated with constitutional symptoms such as fever, shivers and loss of body weight. Secondly, Kim found that pyogenic spondylitis was commonly associated with high white blood cell counts, high fraction of neutrophils, elevated C-reactive protein and erythrocyte sedimentation rate [19], whereas they may be normal or slightly elevated in ORN. In addition, paravertebral abscess was a specific imaging feature for pyogenic spondylitis or spinal tuberculosis on CT or MRI, however, in ORN, less paraspinal soft tissue was involved.
Treatment of spinal ORN is comprehensive, and strategies have included orthosis, medication (anti-inflammatory analgesic, clodronate, and corticosteroids), hyperbaric oxygen therapy, surgery, and new treatment combinations of pentoxifylline and tocopherol. Orthosis is essential for patients with spinal ORN to support the physical loading of the spinal column, relieve pain, and prevent spinal deformity. The most common symptom of patients with spinal ORN was back pain, and painkillers such as non-steroidal anti-inflammatory drugs are necessary. Some reports have recommended clodronate for ORN owing to its effect on osteoclast inhibition, but evidence supporting its usefulness is insufficient [6]. In addition, hyperbaric oxygen therapy was reported to be an excellent adjunct treatment for ORN, as it stimulated angiogenesis, fibroblast, and collagen formation [20]. Khorsandi also reported that hyperbaric oxygen therapy is associated with significantly improved clinical and radiographic outcomes for a patient with cervical ORN [11]. Surgery for spinal ORN is indicated when kyphosis or instability is progressive and leads to spinal cord compression. The surgical principles for spinal ORN are debridement of necrotic tissue, decompression of neural structures, and reestablishment of spinal alignment and stability using a structural graft [4]. Anterior spinal surgery was also recommended owing to its advantages of excellent removal of necrotic bone, direct spinal cord decompression, and good fusion bed preparation in an irradiated surgical area. In the previous cervical ORN cases reported, the surgical rate for ORN was 52% (16/31), indicating that most patients with spinal ORN cannot be cured with conservative treatment [4, 7,8,9,10,11,12]. In our case, the patient was successfully treated conservatively. This implied that ORN of the cervical spine may easily cause neurological complications as compared with that of the lumbar spine. Moreover, the pathogenesis of ORN is caused by radiation-induced fibrosis, as proposed in the new theory mentioned earlier. New therapies have been developed that include pentoxifylline, a vasodilator that inhibits fibrosis, and tocopherol (vitamin E) to reduce the damage caused by free radicals [7].
In this case, an interesting finding was the adjacent vertebral fractures that occurred after ORN was cured following trauma. During the healing of ORN, bony sclerosis may cause increased strength and decreased elasticity of the vertebrae. It may increase the risk of adjacent vertebral fracture, similarly to the biomechanical mechanism of the adjacent vertebral fracture after percutaneous kyphoplasty.
In summary, ORN of the spine is a rare complication of radiotherapy. We present a case of lumbar ORN after radiotherapy for gallbladder carcinoma, which was successfully treated conservatively. ORN is described clinically as a chronic disease with a slow onset. The most common presenting symptom of ORN is pain. However, as ORN progresses, spinal kyphosis and instability lead to neurological compression, and induced myelopathy or radiculopathy. Treatment of spinal ORN is comprehensive, and the surgical rate for spinal ORN was relatively high, indicating that most patients with spinal ORN cannot be cured with conservative treatment.