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| SYMPOSIUM - METASTATIC SPINAL TUMORS |
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| Year : 2022 | Volume
: 5
| Issue : 2 | Page : 150-157 |
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Epidemiology, pathogenesis, clinical presentation, and diagnostic approach
Pratik Patel, Kshitij Chaudhary, Samir Dalvie
Spine Surgery Unit, Department of Orthopaedics, PD Hinduja National Hospital & Medical Research Centre, Mahim, Mumbai, Maharashtra, India
| Date of Submission | 11-Aug-2021 |
| Date of Decision | 18-Sep-2021 |
| Date of Acceptance | 24-Jan-2022 |
| Date of Web Publication | 08-Jun-2022 |
Correspondence Address:
Kshitij Chaudhary
Department of Orthopaedics, PD Hinduja National Hospital & Medical Research Centre, Veer Savarkar Marg, Mahim, Mumbai, Maharashtra
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/isj.isj_77_21
Spinal metastatis is a diagnostic and treatment challenge for the spine surgeon and must be addressed through multidisciplinary, multimodal, and individualized management. The presence of tumor cells in bone metastases results in homeostatic disruption between bone formation and remodeling and leads to osteolytic, osteoblastic, or mixed bone lesions. Spinal metastases are a significant cause for morbidity characterized by severe pain, impaired mobility, pathological fractures, spinal instability, and neurological involvement. Radiographs, magnetic resonance imaging, computed tomography, and positron emission tomography are widely used for the detection and staging of the disease. Histopathological examination is crucial to establish an oncological diagnosis. Our review focuses on epidemiology, pathogenesis, clinical presentation, and diagnosis of spinal metastasis. Keywords: Clinical presentation, diagnosis, epidemiology, metastasis, pathogenesis, spine
How to cite this article:
Patel P, Chaudhary K, Dalvie S. Epidemiology, pathogenesis, clinical presentation, and diagnostic approach. Indian Spine J 2022;5:150-7 |
| Introduction | |  |
Spinal metastasis has become a major public health problem worldwide and seriously affects patient’s quality of life. Spine metastases can cause pathological vertebral fractures and epidural spinal cord compression (ESCC) leading to severe axial pain and paralysis.[1]
Spinal metastasis can present as progression of known metastatic disease with a history of malignancy without prior metastases or without prior cancer diagnosis. Early diagnosis is essential in reducing pain, improving or preserving neurologic function, and maximizing quality of life. Spinal metastatic disease requires a multidisciplinary approach to achieve these goals. In this review article, we discuss the epidemiology, pathogenesis, clinical features, and diagnostic approach for metastatic spinal disease.
| Epidemiology | | |
About 50–70% of all cancer patients will have metastasis at the time of their death. Bone is one of the most common sites of metastasis, following liver and lung. The commonest site of bone metastasis is the spine, followed by the pelvis, proximal femur, and skull. Spinal metastases are most frequently encountered in the thoracic spine (70%), followed by lumbar (20%) and cervical spine (10%). Fifty percent of all spinal metastasis arise from prostate, breast, or lung.[1],[2] Renal, gastrointestinal, and thyroid sarcoma and melanoma are other malignancies that show predisposition for spinal metastasis. Lymphoreticular malignancies and multiple myeloma, although not strictly metastasis, have several common characteristics with other solid organ metastases. Spinal metastasis can occur in the vertebral column (85%) or paravertebral region (10–15%), or as epidural or intradural deposits (<5%).[1],[2] The anterior column is involved primarily, and the progressive invasion of the pedicle and lamina can occur as the lesion expands. Noncontiguous multiple lesions are found in 0–40% of patients.[1],[2] Wright et al. performed a global epidemiological comparison and found a higher incidence of colonic, liver, and lung carcinoma metastases in Asian countries, and more frequent presentation of breast, prostate, and melanoma metastases in the West.[3] However, there are no Indian studies that provide information on the incidence of spine metastasis in other common cancers or systemic malignancies.
| Pathogenesis | | |
Stephan Paget (1889) proposed that an organ would develop metastasis only when the seed (tumor cell) and the soil (organ) are compatible.[4] James Ewing proposed the mechanical theory of spread of tumor cells.[4] However, if Ewing’s theory that cancer spreads by pure mechanical factors was right, then spinal metastasis would occur in all types of tumors. We know that this is not true and that some tumors, like breast and prostate, have a special predilection for metastasizing to bone. In 1984, Hart and Fidler[5] disproved Ewing’s theory and conclusively proved the seed–soil theory of metastasis. Thus, the fact is that potentially metastatic cells from any tumor can reach the spine via the circulatory system, but the development of metastasis occurs only if the tumor cell has a special affinity for bone and in turn if the bone can provide a conducive environment for the tumor cells to grow.
Development of bony metastasis is a multistep process. First, the cancer cells disengage from their primary site by loss of expression of E-cadherin, a cell-surface adhesion molecule, as seen in breast, prostate, colorectal, and pancreatic carcinomas. The disengaged cancer cells then spread contiguously or via hematogenous or lymphatic channels to distant organs. The vertebral venous plexus is thought to be a conduit for tumor cells to reach the spine.[6] Within the vascular or lymphatic system, the cancer cells must survive the immune system before they arrive at their final destination. At the distant site, the malignant cell must adhere to the basement membrane, invade the surrounding tissue, induce angiogenesis, and develop into a secondary mass. Disseminated tumor cells have the ability to reside within hematopoietic, osteoblastic, or vascular niches within the bone marrow, where they may sometimes enter a prolonged dormant state. Bone-derived growth factors—notably, transforming growth factor β—facilitate tumor growth.
The growth factor and cytokines released by the tumor cells activate both osteoclasts and osteoblasts. Receptor activator of nuclear factor-κB (RANK) is a receptor on osteoclast precursors. Its activation induces the formation and activation of osteoclasts. Receptor activator of nuclear factor-κB ligand (RANKL) is expressed on the surface of osteoblasts and marrow stromal cells. A soluble form of RANKL is produced by activated T cells. RANKL binds to RANK and induces the formation of osteoclasts. Osteoprotegerin (OPG) is a decoy receptor for RANKL that is present in the marrow. OPG binds to RANK and prevents its activation by RANKL, thus inhibiting osteoclasts [Figure 1].[2],[7] Metastases disrupt the OPG–RANKL–RANK signal transduction pathway. The balance of the interaction between OPG, RANK, and RANKL determines the nature of the lesion and its corresponding radiographic appearance, namely, osteolytic, osteoblastic, or mixed. Of note, there is an associated increase in osteoclastic bone resorption, even in osteoblastic lesions [Table 1].[8] Osteolytic metastases are more common and more likely to be associated with intractable bone pain, pathological fracture, and neural compression. | Figure 1: OPG–RANKL–RANK Pathway. RANKL is a potent inducer of osteoclast formation. Osteotropic factors (1,25-dihydroxyvitamin D3, PTH, prostaglandin E2, and interleukin-1) upregulate the expression of RANKL on the surface of stromal cells. RANKL then binds its receptor, RANK, on the surface of osteoclast precursors and induces their conversion to osteoclasts. OPG is a decoy receptor that binds to RANKL and prevents it from activating osteoclasts precursors. The ratio of RANKL (stimulator) to OPG (inhibitor) determines the level of osteoclastogenesis
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Bone metastases from breast cancer are predominantly osteolytic. Metastatic breast cancer cells produce factors like parathyroid hormone-related peptide (PTHrP) that shares molecular similarities with parathyroid hormone (PTH) and has the same effect on osteoclasts as PTH, which is stimulation of osteoclastogenesis via RANKL. The resorption of bone releases the reservoir of growth factors lying dormant in the bone, which induce the tumor cells to increase production of PTHrP inducing a vicious circle that leads to formation of osteolytic metastasis [Figure 2].[2],[7] | Figure 2: The vicious circle of osteolytic metastasis. Tumor cells secrete molecules that stimulate osteoclasts. Bone resorption induced by osteoclasts releases growth factors that are entrapped in the bone. These growth factors in turn increase tumor growth. This vicious cycle increases bone destruction and tumor growth
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Metastases from prostate cancer and some breast cancers are osteoblastic. Endothelin-1 is one of the factors implicated in breast and prostate cancers, which may induce a similar vicious cycle resulting in osteoblastic metastases.[2],[7]
| Clinical Presentation | | |
Spinal metastases represent a major source of morbidity from cancer. Morbidity from the same causes skeletal-related events (SREs), which are defined as a pathological fracture, spinal cord compression, necessity for radiation to bone (for pain or impending fracture) or surgery to bone, requirement for opiates, paraneoplastic syndrome, as well as hypercalcemia.[9],[10]
Pain
Pain is the most common presenting symptom in approximately 90% of patients with metastatic spinal disease.[11] It is important to distinguish tumor-related biologic pain from mechanical pain due to pathological fracture or instability. Tumor-related pain occurs as a result of periosteal stretching, venous engorgement, tumor growth, or tumor-induced inflammation and infiltration. It is a constant, dull ache that is often worse at night due to the normal diurnal variation in endogenous steroid levels. It does not get relieved even when lying flat in bed. Typically, it responds to nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, and radiation.
Mechanical pain occurs due to intervertebral instability, pathological fractures, or impending vertebral fractures, i.e., lesions that have resulted in a significant bone destruction and are at a high risk for pathological vertebral collapse. Pathological fractures may sometimes be the first sign of metastatic bone disease. They are commonly associated with focal bone loss within lytic lesions arising from breast, lung, renal, and thyroid cancers. However, even in endocrine-resistant prostate cancer where osteoblastic metastases are typical, areas of osteolysis may compromise structural integrity, resulting in pathological fractures.[12] Mechanical pain is typically movement related as in changing positions from lying to sitting, from sitting to standing, and when turning in bed. It is also worse on prolonged sitting and standing but is relieved when lying immobile in the supine position. Mechanical pain does not get relieved with NSAIDs, steroids, chemotherapy, or radiotherapy. Significant pain necessitates surgical stabilization or percutaneous vertebral augmentation [Table 2].
Patients with no prior diagnosis of malignancy or a known primary malignancy without spinal metastasis, who present with severe nonmechanical back pain, should be screened using red flags [Table 3].[13] A thorough workup including hematological and radiological investigations must be done to diagnose the underlying condition.[9] | Table 3: Red flags in history and examination suggestive of metastatic spinal disease
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Neurological symptoms
Spinal cord compression can occur due to one or more of the following pathological processes: 1) compression by tumor tissue, 2) pathological fracture with retropulsed bone fragment, and 3) instability-related kyphosis or translation. Neurological symptoms may be radicular or myelopathic. Myelopathy presents as gait disturbance, spasticity, weakness, sensory loss, or sphincteric disturbance. Compression cauda equina may present with lower motor neuron type of paralysis.[1] Symptomatic ESCC is a surgical emergency. Ambulatory status prior to the intervention and the duration of loss of ambulation determine prognosis. Severe neurological deficits (paraplegia) of acute onset carry a poor prognosis.
Malignant hypercalcemia
Hypercalcemia is the most common metabolic complication of malignant disease, found in one-third of patients with advanced cancer (10–30%) and is associated with poor prognosis. It is frequently seen in squamous-cell lung carcinomas, breast cancer, kidney cancer, and hematological malignancies. Moderate to severe hypercalcemia leads to gastrointestinal dysfunction, and renal and central nervous system symptoms such as constipation, polyuria, polydipsia, and fatigue. In final stages, it may lead to cardiac arrhythmias and acute renal failure.[1]
| Investigations | | |
Imaging studies and biopsy are the next steps to establish diagnosis [Table 4]. Imaging includes conventional radiography, computed tomography (CT) scan, positron emission tomography (PET)/CT, and magnetic resonance imaging (MRI). Such studies allow diagnosis, oncological staging, determining treatment, and establishing a prognosis.[14]
Conventional radiographs
These are primary imaging modalities in the evaluation of suspected metastasis. Weight-bearing spine radiographs provide a precise assessment of alignment and stability as also pathological fracture. Serial radiographs can assess disease progression. Lesions cannot be detected on lateral radiographs until there is ≥30–50% of trabecular bone loss. Therefore, radiographs are not sufficiently sensitive to detect metastatic disease.[14] Winking owl sign (pediculolysis) is highly suggestive of metastatic disease [Figure 3]. | Figure 3: (X-ray lumbar spine)—winking owl sign—erosion of the right L2 pedicle in a patient with spinal metastases
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Computed tomography
CT provides excellent bony anatomic detail and degree of bone destruction while also evaluating spinal stability and quantitatively differentiating osteolytic and sclerotic components of the lesion. It also evaluates the integrity of the posterior vertebral wall prior to vertebroplasty. CT plays an important role for surgical planning of spinal instrumentation.[14],[15] Many patients with unknown primary get a CT chest–abdomen–pelvis as part of the workup. The same scan can be used to evaluate the spine after reformatting images. CT myelography is used in patients in whom MRI is contraindicated.
Magnetic resonance imaging
MRI is the imaging modality of choice for evaluating spinal metastasis due to exceptional ability to identify the cause of cord compression with resultant implications on management.[15] T1-weighted images and short tau inversion recovery (STIR) images are most suitable to pick up lesions [Figure 4]. Gadolinium enhancement may be required to evaluate soft tissue, epidural extension, and the spinal cord. MRI of the entire spine helps detect skip lesions. MRI can also help in differentiating malignant and benign causes of vertebral collapse. MRI also helps determine the severity of ESCC (Bilsky grades). The proximity of epidural tissue to spinal cord has implications in planning stereotactic radiosurgery. Dynamic contrast-enhanced MRI perfusion scan is an alternative to digital subtraction angiography (DSA) to determine tumor vascularity and treatment response to radiosurgery.[16] MRI also helps in differentiating between malignant and benign (osteoporotic vertebral compression fracture) causes of vertebral collapse. MRI findings of malignant pathological fracture are presence of convex posterior border body, abnormal signal intensity of the pedicle or posterior element, epidural involvement, paraspinal involvement, and multiple lesions in one or more vertebral bodies.) Findings suggestive of osteoporotic vertebral compression fracture are low signal intensity band on T1- and T2- weighted images, normal bone marrow, high signal intensity in STIR, absence of signal abnormality of the pedicle or posterior arch elements, and multiple fracture lines due to compression and fluid sign (Kummel lesion).[17] | Figure 4: MRI of metastatic carcinoma: A (T1), B (STIR), and C and D (Axial)—diffuse T1 hypo-intensity and STIR hyperintensity are seen involving D2 and D3 vertebral bodies and posterior elements. Pathological fractures of the T2 and T3 vertebrae are seen with convexity of the posterior margin. Note the expansile spinous processes. There is severe ESCC with intramedullary signal changes
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Digital subtraction angiography
Preoperative embolization of spinal metastases is an adjunct to surgery to reduce perioperative bleeding, especially in cancers that are known to have hypervascular metastasis such as renal, thyroid, liver, and carcinoid tumors. The positive predictive value of hypervascular tumors on MRI is 77–94%. However, 33–79% of metastases predicted to be hypovascular by MRI findings are diagnosed hypervascular on DSA. Consequently, the final decision on preoperative embolization is based on the preoperative DSA tumor blush, which is considered the ‘‘gold standard’’ for determining tumor vascularity.[16]
Bone scan
Technetium bone scintigraphy plays an important role in staging and management of patients with metastatic bone disease. In the absence of PET scan facilities, bone scan combined with CT chest–abdomen–pelvis can provide useful information.[18] Its limitations include difficulty in picking up osteoblastic lesions, pure osteolytic lesions (myeloma), and avascular sites. Bone scan has a sensitivity of 87.5%, specificity of 92.9%, and accuracy of 90.4% for detection of metastasis.[14]
Positron emission tomography–computed tomography
PET is deeply integrated in modern clinical oncology as a pivotal component for diagnostic workup. PET combined with CT or MRI provides better anatomic localization, disease extent, biopsy site, and status of disease progression and response to chemotherapy.[14] It is not only used to identify primary cancer site but also useful for staging of disease by revealing skeletal and visceral metastases.
Biopsy
Biopsy provides confirmatory diagnosis of metastasis in a patient with known or unknown primary tumor and determines the nature of a solitary bone lesion. Percutaneous CT-guided biopsy has an overall success rate of 77–97%.[19] Immunohistochemistry examination enables identification of multiple receptors, which aid in identifying the primary site of tumor and help orient a more specific therapeutic strategy.[8] Oncologic diagnosis is of utmost importance to determine treatment and prognosis.
Blood investigations
Basic routine blood tests include complete blood count with differential count, metabolic profile, coagulation profile, renal and liver function test, and bone metabolic profile (calcium, phosphorus, alkaline phosphatase). In addition, specific tests such as prostate-specific antigen and serum protein electrophoresis may be indicated.
| Diagnostic Approach | | |
Spinal metastases represent a clinical challenge in both diagnosis and treatment. The primary tumor pathology, extent and control of metastatic disease, and the functional status of the patient are the strongest predictors of survival. Careful physical examination along with imaging studies aids in making the diagnosis. Through examination of neck swelling, breast swelling, per rectum examination, skin lesion and any soft tissue swelling in the body helps to form the diagnosis of primary tumor.
The diagnostic strategy differs for patients with differing clinical presentations:
- (1) For patients with established metastatic spinal disease who present with typical imaging findings, the treatment generally proceeds without biopsy [Figure 5].
- (2) Patients with a history of primary tumor without prior spinal metastases require further evaluation prior to treatment, with PET–CT scan and biopsy for staging and confirming the diagnosis [Figure 6].
- (3) About 10–20% of cancers will present as symptomatic spinal metastasis without a prior diagnosis of cancer [Figure 7]. Through history and physical examination are very important and can help in identifying the primary tumor. Patients who present with rapidly deteriorating neurology or severe deficit have limited time for workup. Ideally, PET–CT scan must be done to look for a primary, if it can be arranged quickly enough. Alternatively, a quick search can be made with CT chest–abdomen–pelvis. It is important to assess vascularity of tumor using dynamic contrast MRI or angiography before intervention is planned. Patients who present without neurological deficit should undergo PET–CT scan before CT-guided biopsy. Histological diagnosis of solitary lesions is paramount to differentiate them from primary spinal tumors (e.g., chondrosarcoma). Intralesional surgery prior to histological diagnosis will make such lesions incurable. If no identifiable primary site can be found after thorough work up, then metastasis has truly unknown primary disease.
 | Figure 5: Algorithm for workup of a patient with prior spinal metastasis and a known primary tumor presenting with new symptomatic spinal metastasis
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 | Figure 6: Algorithm for workup of a patient presenting with spinal metastasis with known primary tumor but without prior spinal metastasis
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 | Figure 7: Algorithm for workup of a patient presenting with spinal metastasis without a known primary tumor diagnosis
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In patients with an unknown diagnosis, high-grade ESCC, and an unstable fracture, the unknown tumor should be presumed radioresistant and the critical concept of immediate decompression and fixation is the right call baring medical contraindications. Even if the tumor is multiple myeloma or conversely chordoma, the surgeon’s obligation is to get the patient out of trouble and then do meaningful radiation and/or chemotherapy. In principle, delaying effective surgical therapy to establish a radiosensitive diagnosis or conversely, a tumor traditionally requiring en bloc excision jeopardizes neurological function and does not impact local tumor control.[20]
| Conclusion | | |
Spinal metastatic disease is common in patients with cancer and results in serious morbidity and disability. Cancers of the prostate, lung, breast, and kidney are the most frequent tumors to metastasis to the spine. The seed–soil theory of metastasis explains why these tumors show a great predilection for skeletal metastasis. The presence of tumor cells in spine results in a disruption of the homeostasis between bone formation and remodeling, thereby producing osteoblastic, osteolytic, and mixed lesions. Understanding the molecular mechanisms involved in pathogenesis helps researchers develop new target molecules that can help reduce the tumor burden. Spinal metastasis can present as a diagnostic challenge that requires multidisciplinary team including spine surgeon, oncologist, and interventional radiologist. Currently, PET/CT is widely employed to search for the primary tumor and oncological staging. Biopsy is mandatory in nonemergent situations, for any suspicious spinal lesions in patients without a primary diagnosis of cancer or those in whom the lesion is the first sign of metastasis.
Ethical policy and institutional review board statement
Not applicable.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3], [Table 4]
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