While the mechanism of metastasis to the spine remains incompletely understood, several theories have been proposed in the literature. For instance, the mechanical hypothesis of Ewing suggests that the bony trabeculae of the vertebral bodies present an ideal site for lodging of metastatic emboli secondary to the low-flow state within the venous sinusoids (15). Alternatively, Paget’s theory suggests that there are unique anatomic and biologic factors allowing selective tumor adherence in certain tissues (16). Fidler also defined three principles for metastasis to occur: first, the primary tumor must contain tumor cells and normal host cells, including fibroblasts, leukocytes, and epithelial cells; second, the metastatic process must selectively allow cells to invade and embolize to distant sites; and, finally, metastasis is only successful if there is communication between normal host cell responses and the metastatic cells (17). Regardless of the theory, it is clear that tumor invasion requires cell adhesion to normal tissue, local proteolysis, and cell migration.

The route of spread is most commonly through the venous system, although direct extension from adjacent neoplasms into the vertebral bodies or into the spinal canal through the neuroforamina may occur. In addition, arterial and lymphatic spread may contribute to tumor deposits within the spine. The perivertebral venous plexus, as described by Batson (18), is a series of valveless channels allowing bidirectional flow and may be a potential source of metastatic spread to the lumbar spine. Through this route, increased intra-abdominal or intrathoracic pressure diverts venous flow into the epidural space from the pelvic or azygous system and subsequently into the vertebral trabeculae. Seeding of the axial skeleton or epidural space, and rarely intradural structures, is possible with this shunting of venous flow. Constans et al. (7) have classified four principal types of metastatic lesions based on the site of seeding and the relationship to the vertebral body, posterior elements, and spinal cord or thecal sac. This classification scheme includes complex or associated lesions (83.5%) responsible for both bony and neural compression, primarily bony metastases (10.3%), epidural masses (5.0%), and intradural lesions (1% to 2%).

The vertebral body is the primary site of seeding of metastatic deposits in the cervical spine. These deposits may be osteolytic or osteoblastic (19). The establishment of tumor deposits within the vertebrae allow for cancellous bone destruction through multiple mechanisms, including direct tumor cell bony lysis or osteoclastic activation. Osteoclasts are activated by tumors through processes involving receptor activator of nuclear factor kappa B (RANK) and its ligand RANKL. RANKL is directly able to activate precursor cells to differentiate into osteoclasts. Tumors may directly secrete RANKL or increase RANKL production by host cells via production of signaling proteins (17). Trabecular erosion ensues, causing biomechanical weakening of the vertebra and increases the risk for pathologic collapse. Asdourian et al. have described the pathogenesis of vertebral body collapse and etiology of spinal canal compromise in a series of patients with metastatic breast cancer, subsequently relating this to the development of spinal deformity (13,20). The mechanism of osteoblastic metastasis remains poorly understood (17).

The manifestations of collapse vary within the cervical spine and differ in the upper cervical and subaxial regions. In the subaxial cervical spine, vertebral body collapse may lead to a kyphotic deformity with or without posterior cortical wall retropulsion. Neurologic dysfunction may result from spinal cord or anterior spinal artery compression caused by tumor or bone displacement into the epidural space, or by tenting of the dural sac over an acute angular deformity. Pathologic fracture may also develop without significant angular deformity if the cervical lordosis is maintained. In this situation, as the line of weight bearing passes posterior to the vertebral body, collapse occurs symmetrically in an axial direction with or without epidural space involvement (13). Although the intervertebral disk is usually resistant to tumor encroachment, the weakened vertebral end plates may allow for disk collapse into the vertebral bodies. The presence of disk space collapse associated with vertebral body destruction may cause cervical metastatic disease to be confused with diskitis, requiring advanced imaging studies for differentiation between these pathologic processes (21).

The occipitoatlantoaxial complex is an anatomically and biomechanically unique area. Metastatic involvement in this area is rare and may involve the lateral masses of C1 and the body or posterior elements of C2 (22). The spinal canal area at the C1-C2 level is large, and neurologic signs generally develop from mechanical instability rather than from slow, direct tumor spread. Destruction of the lateral masses may lead to a painful rotatory instability unlike the angular kyphosis and flexion instability of subaxial vertebral body involvement. A kyphotic deformity may develop, however, from destruction of the C2 spinous process with subsequent detachment of the paraspinal musculature from its insertion (22).

Patients with cervical spine metastatic disease may present with varied clinical signs and symptoms. The most common symptoms include local nonmechanical or referred pain, mechanical pain secondary to pathologic fracture or instability, and neurologic deficits resulting from nerve root and spinal cord compression (23,24). Rao et al. (9) also identified 11% of patients presenting with cervical lesions that were asymptomatic and were recognized only through routine screening studies (9).

Pain is the predominant symptom in most patients with metastatic disease of the cervical spine with localized, unremitting discomfort reported in 89% to 93% of cases (9,25). The nonmechanical pain due to tumor infiltration is commonly described as progressively worsening in severity, unrelated to physical activity, and often presenting at night causing sleep interruption. Pain may be unilateral or bilateral with referred pain to the upper trapezia1 and shoulder area. In a patient with a previous history of known carcinoma, a new onset of nonmechanical neck pain is more concerning for metastatic disease than cervical spondylosis and should prompt appropriate evaluation. Studies have suggested that cervical metastases may appear up to 29 months after the initial diagnosis of the primary neoplasm (9,25).

A sudden onset of pain with minimal trauma or applied force to the neck may indicate a pathologic fracture, although deformity associated with an acute fracture is rare. Deformity in the lower cervical spine is usually a slowly developing angulation from anterior and middle vertebral body collapse. Destruction of the C2 spinous process with detachment of the insertion of the paraspinal musculature may lead to a progressive feeling of head “heaviness” and an inability to hold the head upright without assistance (22).

Neurologic dysfunction is estimated to occur in 5% to 10% of patients with metastatic spine disease and may present with variable intensity and rapidity of onset. Although uncommon, cervical radiculopathy may result from tumor metastasis into the epidural space, neural foramen, or from retropulsion of weakened bony fragments secondary to tumor invasion. Patients typically describe a burning, dysesthetic pain radiating in a specific dermatomal pattern suggestive of nerve root involvement. Weakness and sensory and reflex deficits may also accompany the primary symptom of pain. Spinal cord compression with symptoms and signs of myelopathy may also develop and become a presenting feature of cervical metastatic disease. Motor deficits are often initial presenting features, most likely from the anterior epidural space being invaded by tumor from the vertebral body. Long tract signs, including lower extremity spasticity, difficulty with ambulation, myelopathic hand syndrome (26), and intrinsic hand muscle atrophy, may be seen. Sphincter disturbance is usually a late finding of spinal cord compression and portends a poor prognosis for eventual recovery of function (27).

The initial evaluation of patients with persistent or nonmechanical neck pain includes plain radiographic examination. This is especially important in a patient with a previous history of known cancer in whom the possibility of metastasis must be considered (19). One drawback of plain radiographs is that they require 30% to 50% demineralization before detecting a destructive process within the vertebral body, thereby limiting their sensitivity as a
screening tool. Due to this limitation, up to 60% of patients with metastatic spinal disease may not have evidence of spinal involvement on plain radiographs (28,29).

For patients with known primary cancer, bone scintigraphy is an excellent screening test for identifying metastatic lesions. Skeletal metastases maybe seen on bone scans 3 to 18 months prior to appearing on plain radiographs (30). However, the use of bone scans to detect metastatic lesions in the spine has limitations including the lack of specificity, inability to provide detailed description of the anatomy of the area being investigated, and inability to show evidence of neural compression. Although bone scans are sensitive in determining the presence of a high bone turnover state, they cannot differentiate whether the process is from spondylosis, infection, healing fracture, or tumor. In addition, bone scans may not be positive in pathologic processes such as in myeloma in which osteoclastic activity far outweighs osteoblastic bone production. The main indications for this test in a patient with known cervical metastatic disease are to identify skip lesions within the spine and to evaluate the appendicular skeleton for possible impending fractures.

The use of more advanced neurodiagnostic studies such as computed tomography (CT), either alone or combined with water-soluble myelography (CT myelography), and magnetic resonance imaging (MRI) has become commonplace in the evaluation of spinal metastases. Often, there is a role for the use of both of these studies in determining the degree of bony and soft tissue involvement, including spinal cord compression.

MRI has several advantages over CT myelography, such as detailed evaluation of spinal cord compression, identification of intramedullary cord signal change, and direct visualization of bone marrow changes that are consistent with pathologic processes. In addition, MRI can provide information at multiple spinal levels and can be used as a screening study with sagittal plane evaluation of the entire spinal column.

Metastatic lesions to the vertebral bodies replace normal marrow fat with tumor tissue that can be detected on MRI scanning. The use of gadolinium (gadopentetate dimeglumine) on TI-weighted images may further enhance tumor tissue, providing additional differentiation of neoplastic structures. The characteristics of marrow replacement also allow MRI to differentiate metastases from infectious processes (2). Bone marrow signal in tumor and infection show diminished intensity on TI-weighted views and increased intensity on T2-weighted sequences. When bone marrow is replaced by tumor, multiple focal defects are often delineated including involvement of the posterior elements, whereas in the case of infection, marrow alterations are typically located adjacent to the vertebral end plates and absent from the posterior bony column.

Positron emission tomography (PET) is a useful tool in patients with recurrent spinal metastases. PET gives functional information based on tissue uptake of a biologic marker (such as¹⁸F-fluorodeoxyglucose). It can differentiate active, recurrent tumor from nonspecific inflammatory changes or tissue necrosis secondary to prior surgery or radiation (31,32). PET images alone lack the anatomic detail seen with CT and MRI. However, unlike CT and MRI, PET does not create artifact in patients with metallic implants. This artifact can create indistinct tumor margins when planning radiation treatment. Gwak et al. (32) showed that PET co-registered with CT can be especially useful for planning stereotactic radiosurgery in patients with prior spinal surgery, leading to reduced overall tissue volume subject to radiation.

For patients with spinal metastases of unknown primary origin, further evaluation to find the primary tumor site includes a chest radiograph, CT scan of the chest, abdomen, and pelvis, bone scintigraphy, and mammography for women (33).