Chapter 12 Metastatic Evaluation
The incidence of metastatic spinal disease continues to rise, for two reasons: an increased capacity to detect metastatic lesions and improved survival of cancer patients.1 The optimal treatment of this disease requires an efficient yet thorough evaluation. Despite the ongoing evolution of surgical therapy, there is still controversy regarding the merits of surgery relative to non-surgical management with chemotherapy and radiation. The goal of the spine surgeon is to quickly and efficiently gather the information necessary to determine whether conservative non-operative management, preoperative adjuvant treatment, or initial surgical intervention is to be countenanced in the care of the patient with spinal metastases.
Our goal in this chapter is to navigate the landscape of metastatic spinal diseases that will inevitably be encountered by the surgical practitioner. This path must be enlightened by knowledge of the principles of clinical and surgical management of spinal metastatic disease. We will discuss these principles as we describe the presentation and the investigations necessary to evaluate these patients. In the end, when all the tests are complete and the images are obtained, the surgeon must decide on a course of action. We thus end with a brief discussion of treatment paradigms, including what we do at our institution.
Spinal metastatic lesions are quite common. Nearly 18,000 new cases2 with demonstrated secondary tumor spread represent almost 70% of all cancer patients each year.3,4 There are five possible pathways of metastasis to the spine: arterial, venous, direct extension, lymphatic, and leptomeningeal via cerebrospinal fluid (CSF). In anatomical distribution, the vast majority of metastatic spinal lesions are extradural, initially disseminating to the vertebral bodies (Figs. 12-1 and 12-2) and expanding subsequently in destructive fashion to eventually lie adjacent to the dura.5–7 Intradural metastases typically are found in patients with concomitant intracranial metastases. Drop metastases and leptomeningeal carcinomatosis are typically intradural extramedullary, originate via the CSF from an intracranial source, and exist as multiple discrete lesions or coat the dura and enmesh within nerve roots.7,8 Intramedullary metastases from hematological seeding of the spinal cord are exceedingly rare (Fig. 12-3).
Fig. 12-1 This is a 58-year-old breast cancer patient with estrogen receptor (ER) positive, human epidermal growth factor receptor-2 (HER-2) overexpressing metastases to the bone, lung, lymph node, liver, and brain. Lumbar magnetic resonance imaging (MRI) shows diffuse metastatic disease throughout the thoracic, lumbar, and S2 levels. Irregular pial gadolinium enhancement suggests metastatic subarachnoid disease spread.
Fig. 12-2 This patient is a 76-year-old man with metastatic hormone refractory prostate cancer. MRI of the thoracic spine shows diffusely abnormal bone marrow signal intensity throughout the spine, consistent with widespread metastatic disease to bone. There is an epidural metastasis at T4 causing central canal narrowing and compression of the thoracic spinal cord.
Fig. 12-3 Lumbar spine MRI of this 49-year-old man with metastatic renal cell carcinoma shows multiple, small, enhancing nodules in the cauda equina, consistent with subarachnoid tumor spread. In addition, a 1.5-cm intradural enhancing mass in the conus at the T12 level also can be seen.
Medulloblastomas,9–14 ependymomas,15,16 and gliomas14,17–19 are the primary tumors of the brain known to subsequently seed other central nervous system (CNS) locations via leptomeningeal dissemination.20,21 The location of secondary metastases from primary CNS tumors is usually intradural and extramedullary. Glioblastoma multiforme (GBM) is an exception, with sporadic reports describing metastases consistent with both intradural CSF seeding as well as hematogenous spread to the vertebral bodies and other extraneural locations.17–19 The more common leptomeningeal CSF seeding occurs primarily in children with tumors of the posterior fossa, affecting the entire neuraxis and thus requiring comprehensive evaluation of the brain and spinal cord with gadolinium-enhanced magnetic resonance imaging (MRI) studies.22 Treatment of leptomeningeal metastasis is typically palliative, with an expected patient survival of 6 months, and often halts further neurological deterioration until the patient succumbs to progression of systemic or intracranial disease. Treatment is a combination of intralumbar or intraventricular drug therapy with craniospinal radiotherapy and local radiation boost to solid portions of metastatic disease. Multiple, less common primary brain tumors have been reported to spread via CSF dissemination, including pineal germinoma23 and pineoblastoma, choroid plexus papilloma and carcinoma, hemangiopericytoma,24,25 ependymoblastoma,26 and retinoblastoma.27
In adults, secondary metastases typically originate from lung, breast, prostate, and hemopoietic tumors (multiple myeloma, lymphoma); renal cancer; melanoma; and sarcoma.3,4,28–31 In children, most spine metastases are caused by Ewing’s sarcoma and neuroblastoma; less common causes are sarcomas, Hodgkin’s lymphoma, and germ cell tumors.32 Extraneural tumors that subsequently spread to the spinal axis most commonly disseminate hematogenously to the bone as secondary metastases and extend to the epidural space via aggressive enlargement and bone lysis. Spread to the intradural space typically occurs as tertiary leptomeningeal metastases as a result of seeding via CSF pathways from secondary intracranial involvement (Fig. 12-3). Location in the intramedullary compartment is rare and believed to occur hematogenously.
Amongst all bony secondary metastases in the body, the spinal column is the most common site of spread,33 and it is also the initial site of spread in 12–20% of patients who present with spinal symptoms.7,34 Most metastatic spinal lesions originate from arterial hematological spread, but some, including prostate and renal metastases, also occur through the venous system in retrograde fashion via the valveless venous plexus described by Batson.35–37 Post-mortem studies also show that 15–40% of patients dying from disseminated cancer have vertebral epidural metastases38 and that, overall, extradural vertebral metastases increase in the caudal direction along the vertebral column. This is a volume-dependent relationship, corresponding to the greater volume of bone marrow within the larger vertebral bodies of the lumbar spine, followed by thoracic and then cervical vertebrae in marrow volume.28,30 Similarly, these lesions are found in the vertebral bodies 20 times more often than in the posterior elements because of the relative distribution of marrow volume.39 As a result, metastatic compression most often originates anterior to the thecal sac (Fig. 12-4). Symptomatic lesions, however, occur more often in the thoracic rather than the lumbar spine. A number of factors predispose the thoracic spine to increased risk of neurological deficit from tumor compression. The thoracic canal is small in dimension relative to the spinal cord, so there is less room for a tumor to expand before deficit onset.40 The spinal cord extends throughout the thoracic spine but only down to the second vertebra of the lumbar spine, and the spinal cord is more susceptible to neurological symptoms of compression than the roots of the cauda equina. The thoracic cord has a more tenuous blood supply. Finally, the thoracic spine with its natural kyphosis may be more prone to angular deformity with a pathological fracture, which would exacerbate the compression and mass effect from an expansile tumor anterior to the spinal cord (see Fig. 12-4).
Fig. 12-4 Spinal MRI of a 33-year-old African-American woman who underwent palliative radiation and steroid treatment for metastatic renal cell carcinoma shows abnormal signal intensity and enhancement within the T7 and L4 vertebral bodies compatible with metastatic disease. At the T7 level, the metastasis extends into the epidural space, effacing the anterior thecal sac.
Intradural extramedullary spinal metastases from extraneural sources most commonly occur as tertiary drop metastases from intracranial intradural secondary lesions, such as carcinomas of the lung, breast, melanoma, and hemopoietic tumors such as lymphoma and leukemia.41 These tumors begin in the brain and then subsequently seed the subarachnoid spaces and spread to other CNS locations, including the spine.20,21 The location of these tertiary CNS metastases is usually intradural and extramedullary (see Fig. 12-3), much like primary CNS tumors that spread to the spine via CSF dissemination. Once tumor cells enter the CSF, the entire neuraxis becomes affected, and comprehensive evaluation of the brain and spinal cord with gadolinium-enhanced MRI studies and CSF cytopathology is necessary.22 Treatment of leptomeningeal metastatic disease to the spine is palliative and requires a combination of intralumbar or intraventricular drug therapy and craniospinal radiotherapy with local radiation boost to solid portions. These lesions are often found on imaging and intraoperatively to be entangled within the nerve roots of the cauda equina as a diffuse meningeal covering, sometimes termed “sugar-coating,” with discrete areas of solid tumor interspersed.
Because of the small volume of the spinal cord in comparison to the mass of the spinal axis, hematogenous spread to the spinal cord is rare. Secondary intramedullary spinal cord metastases comprise approximately 0.5% of spinal axis metastases.6,7 The most common intramedullary metastases are lung and breast carcinomas, followed by hemopoietic tumors and melanoma, but all lesions that are metastatic to the brain have been reported in the spine.42–44 Treatment is via local radiotherapy, rather than surgical resection, in conjunction with systemic chemotherapy.
The non-metastatic differential diagnoses for spinal metastatic disease is broad but can usually be narrowed and eliminated with appropriate diagnostic evaluation through routine blood and neuroimaging studies. These non-metastatic diagnoses include benign primary bone tumors of the spine such as hemangioma, osteochondroma, osteoid osteoma, osteoblastoma, aneurysmal bone cyst, and giant cell tumor; degenerative spinal diseases, such as disc herniation, spondylosis, and stenosis; infectious disease, such as osteomyelitis, discitis and epidural abscess; vascular diseases, such as arteriovenous malformations (AVMs), dural arteriovenous (AV) fistulas, and cavernous malformations; and other conditions, such as epidural hematoma, transverse myelitis, and radiation-induced myelopathy. Biopsy is necessary to differentiate most primary bone tumors from metastases. Extruded spinal disc fragments have the same imaging properties as spinal discs in situ; they do not enhance, but scar tissue from past surgery can enhance. Extruded discs and spondylotic disease with stenosis may give the appearance of a mass lesion on myelography. Computed tomography (CT) scan of the appropriate spinal levels or the use of CT myelography will assist in the differentiation of bony spondylotic disease from metastatic lesions. The possibility of spinal infectious disease is more significant in this patient population because of diminished nutritional status and the effects of radiation and chemotherapeutic agents. Routine laboratory studies should include markers for infection. Imaging studies may not be able to clearly differentiate between infection and metastasis. In cases in which infection is suspected, a CT-guided biopsy may be required and should be sent for microbiology studies in addition to pathology. Most vascular lesions can be distinguished on MRI with the presence of characteristics such as flow voids or hemosiderin deposits, but highly vascularized metastases can have a similar appearance. Angiography is an indicated procedure in such instances both for diagnosis and to allow the option of embolization.
Severe axial spine pain is so commonly a manifestation of disseminated cancer that in the cancer patient, medical practitioners should treat it as a symptom of spinal metastasis until proven otherwise. Pain is by far the most common initial symptom, present in more than 90% of patients with metastatic spinal disease. The pain is usually severe, can be burning and dysesthetic, worsens at night, and is unremitting.40 This local pain may be caused by irritation of the periosteum, ligaments, or adjacent viscera. If the pain is more severe with movement and remits at rest, spinal stability must be evaluated because severe mechanical pain may be caused by extensive bone invasion and destruction.45 Radicular symptoms may be unilateral or bilateral. Paresthesias in the upper extremities may be reproduced with evaluation for Lhermitte sign, especially when cord compression is present. Nerve root irritation in the thoracic spine can be aggravated by sharp movements of the trunk, such as coughing or sneezing. When present, radicular symptoms may localize the lesion to a span of two to three vertebral levels before imaging.40 Leg pain may be present with compression of the cervical or thoracic spinal cord and is thought to arise from irritation of the anterolateral spinothalamic tract. Although the initial presentation is pain, as the lesion progresses, impingement on neurological structures eventually results in neurological deficits. Such deficits may begin as numbness and paresthesias but inevitably progress to weakness, sensory loss, bowel and bladder sphincter dysfunction, and ultimately paraplegia without appropriate intervention. Cervical and lumbar metastases are often symptomatic up to 6 months before the onset of neurological deficit, whereas thoracic lesions typically present with neurological compromise in conjunction with initial symptoms.46 Patients presenting with neurological deficit require urgent evaluation, and if the deficits are rapidly progressive, urgent surgical intervention may be indicated. Rapid progression and severe deficits indicate a poor prognosis.47
A general physical examination, followed by a detailed musculoskeletal examination, should be performed for all patients with possible metastatic spinal disease. With detailed musculoskeletal and sensory examinations performed to clearly assess the patient’s neurological status at the time of presentation, further neurological decline can be properly evaluated in the context of both ideal patient care and medicolegal documentation. Spine tenderness is often present with palpation on the spinous processes overlying the metastatic lesions.48 In addition, the general examination should emphasize the anatomical locations of primary tumors that commonly metastasize to bone and spine. These would include cervical, axillary and inguinal lymph nodes, breasts, chest, abdomen, and prostate. Lesions that compress the cervical and thoracic spinal cord produce the myelopathic findings of upper motor neuron deficits, such as weakness and spasticity. Limbs feel heavy, objects are dropped by the hands, and legs buckle with standing or ambulation. Wasting of intrinsic hand muscles may occur with lesions that affect the anterior horn neuronal cell bodies. Spasticity findings include increased deep tendon reflexes, clonus, extensor plantar responses, and Beevor sign with upward deviation of the umbilicus on abdominal contraction. Lesions above the conus also can result in bowel constipation, priapism, reflex ejaculations, spastic sphincters, and initially urinary retention followed by overflow incontinence and then intermittent emptying. In contrast, conus and cauda equina lesions produce lower motor neuron deficits without myelopathy. Conus lesions result in lower extremity weakness, absent extensor plantar responses, hypotonia, saddle anesthesia, and eventually loss of sphincter tone and incontinence. Cauda equina compression similarly produces decreased tone in the lower extremities, either unilateral or bilateral lower extremity weakness, and like conus lesions can result in flaccid incontinence of bowel and bladder and impotence from sacral root dysfunction.
Other more specific findings may be found depending on the location of the lesion and should be rigorously documented before initiation of treatment to prevent a lack of clarity with regard to deficit onset. Dorsal column dysfunction from posterior compression may result in deficits of position sense, vibration, and fine touch. Because of the anatomical layering of sensory fibers, extramedullary lesions often produce greater loss peripherally than proximally, with the reverse being true for intramedullary lesions. Intramedullary lesions also may produce a segmental pattern of sensory loss with sacral sparing. Tumors that compress the cord from a lateral to medial direction can produce Brown-Séquard’s syndrome, which is classically an ipsilateral decrement in corticospinal motor function, dorsal column sensory function, and contralateral spinothalamic pain and temperature loss. Lesions in the upper cervical spine may cause respiratory dysfunction from intercostal muscle weakness. Lesions of low cervical and high thoracic segments may produce Horner’s syndrome, with ipsilateral ptosis, miosis, anhidrosis, and enophthalmos. Eruption of herpes zoster may occur from posterior root irritation at the level of metastatic disease.48 If the history and physical examination suggest an acutely worsening neurological condition, emergent surgical intervention is warranted.
Routine laboratory studies should be performed for all patients with suspected metastatic disease. A chemistry panel to assess for electrolyte imbalances is important in this patient population undergoing multimodal therapy for cancer. Potential metabolic derangements from tumor lysis; metastatic organ involvement, including kidney and liver; and bony invasion with osteolysis and bone resorption make the knowledge of serum sodium, potassium, blood urea nitrogen, creatinine, calcium, phosphate, magnesium, liver enzymes, and coagulation times important for patient management and for any contemplation of surgical intervention.49,50 A complete blood count, erythrocyte sedimentation rate or C-reactive protein, albumin, and transthyretin are important to evaluate the nutritional and immunological status for cancer patients subject to chemotherapy and radiation treatment. Electrocardiograms are necessary if the patient is older or if electrolyte abnormalities, such as hypercalcemia, exist.