Secondary Bone Tumors

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CHAPTER 42 Secondary Bone Tumors

Jesse T. Torbert, Edward J. Fox, Harish S. Hosalkar, Kingsley R. Chin, Carol A. Dolinskas, Richard Daniels, Richard D. Lackman

INTRODUCTION

Approximately 10% of all cancer patients develop clinically significant spinal metastases.¹ Metastatic spine tumors are 40 times more frequent than all primary bone tumors combined.² In autopsy series, vertebral body metastases were found in over one-third of patients dying of cancer.³ The most common cancers to metastasize to the spine are breast, lung, prostate, and renal carcinomas (Table 42.1). Lymphoid cancers, including lymphoma and myeloma, are systemic diseases and common sources of spinal involvement. However, many authors do not consider these lesions true spinal metastases, and they are not included in many clinical series. When lymphoma and myeloma are included, they represent 8% and 5% of secondary spine tumors, respectively.⁴

Table 42.1 The Most Common Primary Cancers that Metastasize to the Spine ^4,¹¹

Primary Malignancy	Percentage of all Metastatic Spine Lesions
Breast	21–30
Lung	13–19
Prostate	7–10
Renal	6–12
Gastrointestinal	4–7
Thyroid	5
Various other cancers	9
Cancers of unknown origin/primary	10–15

Although spinal metastases can occur in all age groups, the risk of metastatic spread to the spine coincides with the relatively high cancer risk period of 40–65 years of age.⁵ The average time between diagnosis of primary cancer and occurrence of spinal metastases varies widely (lung: 4 months; prostate: 22 months; breast: 86 months).⁶ Like most metastatic disease, metastatic spine tumors are rare in children. Exceptions to this are Ewing’s sarcoma and osteosarcoma (from other skeletal sites), neuroblastoma, and rhabdomyosarcoma.⁷

The spine can be divided into anterior elements and posterior elements (Fig. 42.1). Anterior elements consist of the vertebral body, and the posterior elements include the remainder of the vertebra (pedicles, transverse processes, laminae, and spinous process). Metastases involving the spine are located in the bony vertebral column 85% of the time,⁸ and the anterior elements of the spine are 20 times more likely to be involved than the posterior elements.⁹ Other metastases involving the spine may be located in the paravertebral region and less often in the epidural space.

Fig. 42.1 This axial view of a vertebra illustrates the anterior elements and posterior elements.

The thoracic spine is most frequently invaded by metastases, followed by cervical, then lumbar segments.¹⁰ It has been suggested that the distribution of metastases to the spine is roughly proportional to the height of each segment, with the cervical spine hosting 24% of metastases, thoracic 48%, lumbar 26%, and sacral 2% (Fig. 42.2).¹¹

Fig. 42.2 This view of the spinal column demonstrates the approximate distribution of metastases within the spine.

Early diagnosis is critical in both primary and secondary tumors of the spine. Unlike primary tumors, the early diagnosis and treatment of secondary tumors will not prevent metastatic disease. However, much of the significant morbidity related to spinal metastases can be lessened with early intervention. For instance, the best predictor of neurologic outcome after radiotherapy is the neurologic function prior to treatment; patients with severe neurologic deficit before radiation are unlikely to improve.¹² In addition, patients undergoing surgery for neurologic symptoms had much better outcomes if they were ambulatory prior to surgery.¹³ Neoplastic paraplegia not only reduces a patient’s quality of life, it results in decreased life expectancy and a large economic cost to society.

The primary treatment goals in metastatic spine disease are to preserve/improve quality of life, alleviate pain, preserve/improve neurologic function, prevent/correct spinal instability, and optimize local tumor control as well as treatment of primary malignancy. Treatment options include various medications, external bracing, chemotherapy, radiation therapy, vertebroplasty/kyphoplasty, radiofrequency ablation, embolization, and surgery. Due to the many goals and modes of therapy, treatment of a patient with spinal metastatic disease requires a multidisciplinary approach, which often includes a pain specialist, medical oncologist, interventional radiologist, spine surgeon, physical medicine/rehabilitation specialist, social worker, and hospice care.

EXPLANATION OF ANATOMIC LOCATION

It is thought that the highly vascular, sinusoidal nature of the red marrow within vertebral bodies makes them particularly susceptible to seeding of metastatic cells. Moreover, retrograde venous flow into the internal vertebral plexus (Batson’s plexus)¹⁴ has historically been implicated in the spread of metastases to the spine. The internal vertebral plexus, a network of valveless veins in the vertebral canal, travels outside the dura from the foramen magnum to the coccyx. Due to the lack of valves, a rise in intrathoracic or intra-abdominal pressure can cause venous blood from the azygous system and the pelvic venous plexus to enter the internal vertebral plexus, allowing seeding of metastatic emboli from various organs. Drainage of the breast through the azygous vein and the prostate through the pelvic venous plexus predisposes the spine to metastatic processes from these areas. Drainage of the lung through the pulmonary vein, and colon through the portal system, tend to result in more diffuse embolic patterns.¹⁵ Oeppen et al. published a case report of a patient with renal vein involvement of renal cell carcinoma with spinal metastases that centered on the basivertebral veins at three contiguous levels in the low thoracic spine. Magnetic resonance imaging (MRI) demonstrated tumor in the intervertebral veins, which link the azygous system to the internal vertebral plexus.¹⁶ This case was highly suggestive of vertebral metastases due to retrograde venous spread through the internal vertebral plexus. Oge et al. described a case of a broken pacemaker lead tip migrating from the common iliac vein to a vein within the internal vertebral plexus at the level of L5.¹⁷ Due to the lack of valves and lengthy nature of the internal vertebral plexus, metastatic lesions occur at multiple noncontiguous levels in approximately 25% of cases.¹⁸ Some authors disagree with the Batson’s plexus theory and instead believe that arterial hematogenous spread to the marrow of the vertebral body results in the characteristic growth of tumors in the vertebral body, which eventually grow to directly or indirectly impinge the spinal cord (Fig. 42.3).¹⁹

Fig. 42.3 This axial view of a vertebra (with the superior half of the vertebral body cut away) shows the relationship of the intervertebral, basivertebral, and the anterior, and posterior veins of the internal vertebral plexus.

CLINICAL PRESENTATION

As mentioned previously, the early diagnosis of secondary spinal tumors is essential. Symptoms suggestive of spine involvement in a patient with a prior malignancy must be taken seriously. Also, a high index of suspicion is necessary in those patients without known malignancies. The clinician must be thoroughly familiar with the symptoms that are typically present in patients with metastatic spine tumors, which are often the same presenting symptoms as in primary tumors of the spine. A careful history characterizing the character and timeline of symptoms is important in the diagnosis and direction of their work-up. Likewise, elements of the history can dictate the treatment plan. A proper history provides a baseline to evaluate the course of the disease and the effect of therapy and includes a summary of prior treatment (chemotherapy, radiation, prior surgery).

Pain

As in primary spinal tumors, the first indication of spinal metastases is most often due to the pain produced by these tumors. Back pain is so common, and is typically such an early symptom of spinal metastases, that it may lead to recognition of a previously undiagnosed primary malignancy, such as lung carcinoma or prostatic cancer. Back pain is the first symptom of a spinal metastasis in 90–97% of cases.^11,¹³ The presence of back or neck pain in a child with a cancer is caused by metastatic disease in approximately half of patients, and of these patients with spinal metastatic disease, spinal cord compression is present in approximately one-third.²⁰ Pain often precedes other neurologic symptoms by weeks or months. In 42 patients undergoing surgery for metastatic disease of the spine, the median time from onset of back pain to appearance of neurological signs was 7 months with a range of 0–72 months.²¹ In addition, back pain may be present before a radiographic lesion can be detected.

Metastatic disease to the spine can manifest in back pain in various ways and is often multifactorial (Table 42.2). When possible, it is important to determine the mechanism of back pain because the treatment may vary depending on the mechanism. Local pain is produced by an intraosseous mass effect of the tumor or local stretching/distortion of the periosteum due to tumor destruction. In addition, this pain may be produced and exacerbated by inflammatory mediators. Local pain is persistent, often worse at night, and not typically affected by movement. Low-dose steroids (decadron 12 mg daily) often relieve the pain. In addition, local pain is often relieved by treatment of the underlying tumor with radiation or surgery.²² Axial pain, which is mechanical in nature, evolves from a structural abnormality of the spine and may indicate instability. Axial pain may be produced by axial loads on the spine; therefore, in such cases, it is exacerbated by motion and alleviated by rest. Radicular pain may develop from nerve root compression by tumor epidural extension and is worse with motion. It is often positional, alleviated by one position and exacerbated by another. Cauda equina syndrome, caused by compression of the nerve roots below the conus medularis, may exhibit lumbar and sacral radicular pain as well as paresthesias and weakness. Symptoms are often asymmetric. Some patients may develop a combination of radiculopathy and axial pain resulting from instability and neuroforaminal compression. Myelopathic pain is due to direct compression of the spinal cord either by tumor or bone. Recumbency often makes myelopathic pain worse; this is thought to be due to the distention of the internal venous plexus. Steroids often reduce myelopathic pain by reducing vasogenic edema.

Table 42.2 Types and Characteristics of Back Pain Found in Tumors of the Spine ^22,^24,¹⁰²

In general, pain from tumors commonly mimics the pain produced by nontumorous disorders. It is therefore necessary for the clinician to have a high index of suspicion when dealing with back pain, even if the patient does not present with the characteristic types of pain associated with spinal tumors. In a patient with known malignancy, back pain should be considered spinal metastases until proven otherwise.

Neurologic impairments

Neurologic manifestations other than pain often begin with radiculopathy, followed later by myelopathy due to spinal cord compression.²² Progression of symptoms can be gradual, but acute deterioration may occur as a result of spinal instability. Acutely worsening symptoms in patients with spinal metastases requires emergent attention. Along with pain, radiculopathy in the cervical and lumbar regions causes weakness in the arms and legs, respectively. Radiculopathy due to lesions in the thoracic spine may cause pain in a band-like pattern in the corresponding dermatomes along the thorax and abdomen. Objective sensory loss is rare when a single nerve root is involved due to the overlap from neighboring roots. Cauda equina syndrome may present with loss of sensation in the buttocks and legs, unilateral or asymmetric leg weakness, hypotonia, decreased reflexes, early bladder and bowel incontinence, and lumbosacral radicular pain.

Myelopathy, which occurs in 20% of adult patients with spinal metastases,²³ often begins as hyperreflexia below the level of the compression. This can progress to weakness, proprioceptive sensory loss, loss of pain and temperature sensation, urinary and fecal incontinence, impotence, and even paralysis. Eighty percent of patients with spinal cord compression will have weakness or paralysis.²⁴ Impaired proprioception, sphincter function,²⁴ and ability to ambulate²⁵ indicate more serious neurologic damage when affected, and they are less likely to be recovered with treatment. In addition, patients tend to underestimate the loss of bladder and bowel control and sometimes discount them as symptoms of other medical problems, such as prostatic hypertrophy or side effects of chemotherapy.

Other symptoms

As with any suspected malignancy, constitutional symptoms such as fatigue, fever, and unexpected weight loss must be included in a careful review of symptoms. If suspicious of a metastatic lesion in the spine, the physician should inquire about symptoms of possible primary cancers. A family history of cancer may also be helpful in elucidating the diagnosis of a patient with a suspected metastatic lesion. Red flags that suggest malignancy of the spine are presented in Table 42.3.

Table 42.3 Elements of the Presentation that are Worrisome for Spinal Malignancy

Red Flags
History of prior malignancy
Back pain worse at night/pain that wakes patient from sleep
Consistent progression of pain
Pain unchanged during rest or activity
Acute neurologic deterioration
Presence of a mass
Presence of constitutional symptoms

PHYSICAL EXAMINATION

The examination in a patient with possible metastatic disease to the spine is similar to that in a patient with a suspected primary tumor (see previous chapter). A complete examination of the spine and its neurologic function should be performed on any patient with a suspected spine tumor. One may cautiously attempt to elicit Lhermitte’s sign. Lhermitte’s sign is defined as a subjective electric shock-like sensation traveling down the spinal column and through the upper and lower limbs that occurs with neck flexion. This finding was encountered in 15% of patients with symptomatic spinal metastases, and all lesions associated with this finding were in the thoracic spine.²⁶ In addition, careful examination of the neck, breasts, lungs, abdomen, and prostate can often reveal a potential source for metastatic spinal tumors. Identification of lymphadenopathy in the cervical, axillary, and inguinal lymph nodes can suggest leukemia, lymphoma, or other systemic malignancy. A rectal exam, including stool guaiac and assessment of sensory, motor, and reflex components, may be informative. Careful palpation of the extremities, rib cage, and iliac crests for painful areas can alert the examiner to other sites of bony metastatic disease.

WORK-UP

Laboratory studies

The laboratory work-up in a patient with a suspected tumor of the spine can be involved, especially if an undiagnosed primary malignancy is suspected. A complete blood count (CBC) with a differential is important when working up any suspected malignancy. Elevated erythrocyte sedimentation rates (ESR) and C-reactive protein (CRP) levels signal that an inflammatory process is involved, but cannot consistently differentiate an infectious process from a malignancy. Lactate dehydrogenase (LDH) levels can be elevated in sarcomas, and LDH isoenzymes 2 and 3 can suggest a diagnosis of lymphoma.²⁷ In order to check for liver cancer, alpha fetoprotein (AFP) levels are often obtained in patients with hepatitis C or those who are heavy drinkers. Carcinoembryonic antigen (CEA) is a marker of adenocarcinomas such as colonic, rectal, pancreatic, gastric, and breast.²⁸ Prostate specific antigen (PSA) levels can help diagnose prostate cancer. A thyroid panel can help eliminate the suspicion of a rare thyroid primary, and parathyroid hormone (PTH) can be ordered to look for hyperparathyroidism. An elevated PTH level may lead to diagnosis of a brown tumor of the spine, which can be mistaken for metastatic disease. The diagnosis of multiple myeloma can be confirmed by the identification of monoclonal proteins in the serum or urine via serum protein electrophoresis (SPEP) or urine protein electrophoresis (UPEP); however, up to 3% of patients may have negative serum and urine electrophoresis.⁴ A chemistry panel can be used to assess kidney function and allows calcium and phosphate levels to be followed to detect and avoid the development of malignant hypercalcemia associated with metastatic lysis of bone. An elevated alkaline phosphatase level can also provide evidence for a neoplastic bone disease.

X-ray

The sensitivity is low for early metastatic involvement of the spine; however, plain films should be obtained initially, as in the work-up of primary tumors of the spine. Of patients with spinal metastases that underwent autopsy, 48% had no visible lesions on plain films, and 26% had negative X-rays despite gross involvement by tumor.³ The high false-negative rate can be partly attributed to the amount of cancellous bone (50%)²⁹ that must be destroyed before becoming radiographically evident. Paraspinal tumors invading through the neural foramen may produce no radiographic abnormality. Therefore, the work-up of a spinal tumor does not end with a negative plain film. Despite low sensitivity, plain films are inexpensive and can offer information not provided by MRI and other imaging modalities.

Pedicle erosion is one of the more common X-ray findings in the thoracic and lumbar spine. The absence of one pedicle, which normally appears as an ovoid margin of dense cortical bone, gives the appearance of a ‘winking owl’ on the anteroposterior radiograph. This is a manifestation of pedicle erosion due either to a bony spine lesion or a lesion extrinsic to the vertebrae. Pedicle involvement is typically seen early because of the predominant cortical bone content. Pathological compression fractures may be seen, but may be distinguished from benign compression fractures unless pedicle erosion, other cortical erosion, or a soft tissue mass is associated with the fracture. Neoplastic vertebral body lesions typically spare the disc spaces, which can differentiate them from osteomyelitis.

Flexion and extension studies, performed with caution, may be warranted if instability is suspected. The presence of instability is demonstrated by 25% translation of vertebral elements or >50% collapse, and is an indication for operative treatment.

Bone scan

Bone scanning (skeletal scintigraphy) utilizes a disphosphonate compound, tagged with technetium 99m, which, after intravenous injection becomes incorporated into bone by osteoblastic activity. Bone scanning provides images of the entire body in a fairly short period of time. It is a fairly sensitive technique for the detection of bone metastases and can detect these lesions earlier than plain films; however, its one weakness is low specificity. Bone scans demonstrate areas of osteoblastic activity, and the radionuclide accumulates at sites of fracture, infection, degenerative disease, bone metastases, and benign tumors such as some hemangiomas and fibrous dysplasia. The pattern of uptake is frequently helpful in deciding if uptake is likely to represent metastatic disease. False-negative bone scans are often due to destructive activity that exceeds reactive or blastic activity, as in multiple myeloma, aggressive tumors, and in tumors which are confined to the medullary cavity and do not affect the cortex.³⁰ Also, paraspinal tumors that invade the epidural space through the intervertebral foramen are often missed on bone scan.

Computed tomography

Computed tomography (CT) provides the best images of bone architecture and readily detects small areas of bone destruction or blastic change, although MRI is more effective in detection of lesions before changes in bone structure can be demonstrated. In the past it was not considered a good screening tool for lesions in the spine, but with multidetector scanners, the entire spine can be scanned in great detail in under 5 minutes. Using bone and soft tissue windows, both bone and paraspinal lesions are readily detected. The images can be reconstructed into any plane for the evaluation of bone alignment and extent of compression in a compression fracture. CT imaging can also provide the spine surgeon with an image of remaining bone in an abnormal vertebra, a factor in the feasibility of fixation. CT imaging is also valuable for planning and guiding percutaneous biopsies of vertebral lesions. CT imaging of the spine is especially useful in those patients who cannot undergo MRI (claustrophobic, cannot lie flat for long periods of time, or have implanted devices liable to be affected by magnetic field).

Myelography (conventional and CT-myelography)

Myelography is an invasive procedure with inherent risks. Before MRI, conventional myelography was the gold standard for detection of cord compression and intrinsic cord lesions, but it has been largely replaced by MRI scanning, and by CT-myelography when MRI is contraindicated. Myelography may fail to reveal secondary sites of epidural spinal cord compression and has been shown to be less sensitive in diagnosing spinal tumors than MRI.³¹ CT-myelography, like conventional myelography, involves the instillation of contrast into the dural sac, but the amount of contrast used is much less due to the enhanced ability of CT to depict subtle contrast differences. By employing various window settings for the images, details of the paraspinal structures, bone, and dural sac contents are well demonstrated. Both conventional and CT-myelography may be used when metallic fixation devices have been placed in and around the spine and MRI is unable to provide adequate images. This problem is becoming less frequent with the increased use of titanium spinal hardware.

Magnetic resonance imaging

Magnetic resonance imaging detects spinal and paraspinal pathology better than any other imaging technique. It reliably depicts changes in the water content of structures, and thus most pathology, before changes in gross architecture occur. Pathology is detected by employing imaging sequences that emphasize various components of tissues such as fat, fluid, and vascularity. MRI is the only noninvasive technique able to visualize pathology within the spinal cord and clearly depicts the degree of cord compression, as well as the process causing the compression. MRI defines lesions in the vertebrae as well as disc pathology and is the best method to diagnose discitis and paraspinal infections. MRI is also more reliable than other techniques in separating benign compression fractures from pathologic fractures of the vertebral bodies. This distinction is made by analyzing signal intensity changes in the bone and paraspinal space as well as by evaluating the shape of the vertebrae and integrity of the cortical margins. MRI reveals bone metastases earlier than bone scintigraphy and depicts foci of osteolytic and osteoblastic activity equally. Most bone metastases are readily detected without the use of gadolinium-based intravenous contrast (most are easily demonstrated on T1-weighted and fat-suppressed T2-weighted images without contrast).³² Contrast actually may obscure metastases to bone as enhancement may cause the signal in the lesion to increase to that of normal bone marrow on T1-weighted scans.³³

Limitations of MRI include the relatively long time needed to acquire a complete imaging sequence (at least 1 hour to study the entire spine in detail), degradation of the images by patient motion and by implanted metal such as fixation devices, the need for the patient to be able to lie flat and supine for the study, and contraindications such as pacemakers, various other implanted electronic devices, brain aneurysm clips of uncertain composition, and claustrophobia.

Positron emission tomography

The most common radiotracer used in clinical positron emission tomography (PET) imaging is fluorine-18-fluoro-2-D-deoxyglucose (18F-FDG), which accumulates in areas of high glycolysis and membrane transport of glucose, both known to be increased in malignant tissue. Unlike the agent used in bone scanning, 18F-FDG may detect bone marrow-occupying lesions before cortical involvement occurs, thus detecting bone metastases before they can be found on bone scans. Sclerotic metastases, however, as found in some breast and prostate cancers, are less likely to be detected by PET as these lesions have lower glycolytic rates and are less cellular than lytic metastases.³⁴ 18F-FDG is not specific for tumors and may accumulate at sites of infection but is less likely to be detected at sites of degenerative change than technetium 99m, the agent used in bone scans. Therefore, it is somewhat more specific for tumors. PET also demonstrates metastases in soft tissue throughout the body, resulting in additional diagnostic value. In addition to detecting spine tumors, PET may also be useful in distinguishing malignant lesions from benign.

Biopsy

When a lesion is identified by radiologic means, it is often necessary to establish a histologic diagnosis for purposes of treatment. Biopsy is vital when the patient without a known primary possesses a spinal lesion that is suspicious for malignancy. In a patient with a previously diagnosed malignancy who presents with a new, solitary spinal lesion, biopsy of the spinal lesion is always required to confirm diagnosis before treatment with radiation, chemotherapy, or surgery. Benign spine lesions can develop in a patient with a known malignancy, and spine metastases may arise from a primary tumor unrelated to a previously diagnosed cancer. Therefore, the proper histological diagnosis of the spinal lesion helps avoid misdiagnosis and erroneous treatment.

Types of biopsy

As discussed in the preceding chapter, there are two types of biopsy commonly used for spinal lesions: percutaneous, guided biopsy and open, surgical biopsy. Both fluoroscopic-guided and CT-guided percutaneous biopsies can be utilized, and both are effective. The accuracy of CT makes it superior when dealing with small, deep-seated lesions, especially in the cervical and thoracic regions.³⁷ CT allows better selection of the optimal location to sample tissue. For lesions visible via fluoroscopic monitoring, fluoroscopic-guided biopsy offers real-time positioning of the needle. Open biopsy maximizes tissue retrieval, providing the highest diagnostic success rate; however, it is typically reserved for failed percutaneous biopsies due to the increased morbidity of the open procedure and greater risk of wound contamination with tumor. Regardless of which method is used, the goal is to obtain an adequate amount of tissue while minimizing complications.

Biopsy success rate

Accurate diagnosis of tumorous and nontumorous lesions using CT-guided biopsy is achieved greater than 90% of the time.³⁷^–³⁹ In lesions with central necrosis, the ability to obtain the correct diagnosis may be enhanced by obtaining tissue from the periphery of the lesion. In paucicellular aspirates, a cell block can be prepared or additional tissue, such as a core biopsy, can be obtained. If histology yields only peripheral blood in an obviously destructive mass, biopsy can be repeated, by directing the needle/device at a slightly different area of the lesion.³⁹ If indicated, corticosteroids should only be administered after biopsy due to their lytic effect on certain tumors, including leukemia. This lytic effect can lead to a nondiagnostic biopsy.