Metastatic Tumors

Joseph H. Schwab

Metastatic disease to the spine is a common problem which will most often be diagnosed and managed locally without referral to a tertiary facility. Orthopedic surgeons are an important part of the multidisciplinary management necessary to address this complex disease process. The management of metastatic disease continues to evolve and the principles of care are different now compared to a decade ago. The purpose of this chapter is to review some of the accepted pillars of care for metastatic disease while giving an update to some of the changes that are ongoing within the field.

Relevant Anatomy

The spine is more likely to be afflicted with metastatic carcinoma than any other region of the skeleton. This is in part due to the surface area of the spine as well as the number of vertebral elements. However, the spine also has some unique anatomic features that may further predispose to the spread of carcinoma. One feature is the rich venous plexus that surrounds and supports the bony spine as well as the adjacent neurologic structures. This plexus is valveless and, like some of the arterial vessels in the spinal cord, it allows for antegrade and retrograde flow. In a relatively low-pressure system such as the venous system, one can imagine that variations in pressure may influence the flow. It is known that intrathoracic pressure can increase to levels above 250 mm Hg during a rigorous cough. Similarly, the Valsalva maneuver changes both intra-abdominal and intrathoracic pressure which can influence flow within the venous plexus surrounding the spine. The concept of malignant cells moving through this venous plexus as a result of changes in pressure supports the notion of metastatic spread focusing on embolization of tumor cells. However, the embolic theory of cancer is disputed and has been argued over for more than a century, with opponents maintaining the seed and soil hypothesis proposed originally by Paget in the late 1800s. In this theory, cells may pass through a tissue via the venous system but they will not grow there unless the environment is congenial to the cell. It is likely that the valveless venous system about the spine allows cells to come in contact with the vertebrae but the cells must have characteristics necessary to flourish there such as the ability to stimulate osteoclasts to resorb bone.

Pathogenesis

The seed and soil hypothesis has been supported by the advent of modern molecular biology which has shown that molecular changes within cells are responsible for their ability to grow, spread, and eventually become cancerous. Errors occur very commonly in normal cells and these errors are normally detected and corrected or, if the error is serious enough, the cell undergoes apoptosis. However, some cells develop an error such as a mutation which goes undetected. This error is not only undetected within the cell of origin but also by the immune system. The immune system is one of the major barriers to cells becoming malignant by destroying cells that do not present normal surface markers. Once a mutation takes hold of the cell it can lead the cell to divide into other cells that carry the mutation. Abnormal cells undergoing division can lead to further errors in the molecular biology of the cell leading to a colony of cells with multiple mutations. This is a key aspect of cancer metastasis. A colony of cells with randomly occurring mutations leads to a genetically heterogeneous population of cells. The reason that this is important is that this heterogeneity allows for a selection of cells that are particularly suited to survive unchecked by the host’s defense system. Most cells will be detected and cleared by the immune system. Others will not be able to grow or spread because they do not have the correct molecular composition. However, as further mutations occur, eventually one cell will be able to grow and spread out of its region of origin (the breast tissue, for instance) and into the blood stream or lymphatics. Even here most of the cells will not survive as they are exposed to the immune system in a much more robust way. Cells that gain access to the blood stream must also contend with significant turbulence within that system. The cells can be destroyed even by that turbulence alone. Cells uniquely qualified to reattach to the endothelium and/or grow through the endothelium have an advantage over those that do not, at least when one is considering metastatic carcinoma
(as opposed to blood dyscrasias). After cells have transgressed the endothelium they must be able to grow in their new environment. Cells must have the ability to grow through bone or somehow destroy bone in order to survive in the skeleton.

Crucial to the cancer cell surviving in bone is the osteoprotegerin/receptor activator of NF-κB and receptor activator of NF-κB-ligand (OPG/RANK/RANKL) system. Normally OPG and RANKL are produced and used as competing ligands for the receptor activator of NF-κB (RANK) on osteoclasts. Some cancer cells have been selected for their ability to circumvent this system. Several cancers including prostate and breast express components of the OPG/RANK system, and some studies have linked the expression of RANKL with tumor aggressiveness.

It is known that cancer cells must be able to directly or indirectly stimulate osteoclast resorption of bone. This is done via the RANK/RANKL system. Some cells express RANKL and they can directly stimulate osteoclasts without the need to go through osteoblasts. Myeloma cells express RANKL and therefore can stimulate bone resorption without first activating osteoblasts. This is in part why bone scans are negative in patients with myeloma. Bone scans require active osteoblasts to absorb the phosphate injected during such radiographic studies. If osteoblasts are not active, then the phosphate will not be absorbed from the blood stream. Myeloma cells have the ability to uncouple the RANK/RANKL system. Some cancer cells, such as myeloma cells, also express sklerostin. Sklerostin is normally produced by osteocytes and it inhibits the activity of osteoblasts. Blocking sklerostin stimulates osteoblast activity. Cells that can produce sklerostin inhibit bone formation and may allow more cancer cells to grow in areas that would normally be filled with new bone.

Epidemiology

Cancer is expected to surpass cardiac disease as the number one cause of death in the United States. Patients who die from cancer die from metastatic disease. Metastatic bone disease most commonly affects the spine. As the population continues to age, the number of patients with metastatic bone disease is expected to increase.

Women in the United States have a one out of eight chance of developing breast cancer and men have a one out of six chance of developing prostate cancer. Lung cancer is less common but still impacts 1 in 16 woman and 1 in 13 men. Lung and breast cancer accounted for over 100,000 deaths in women in 2013, whereas lung and prostate accounted for 117,000 deaths in men in 2013. Lung, breast, and prostate cancer all commonly spread to bone along with thyroid and renal cell carcinoma. Lymphoma and myeloma may also spread to the spine but do not represent true metastases, although they may be treated as such.

Treatment

Approaches to Management

The management of spinal metastasis is complex and requires the interaction and cooperation of spine surgeons, radiation oncologists, and medical oncologists. Care for these patients continues to evolve as these three disciplines advance. The complexity of these cases can be daunting and it may be useful to use an algorithm to assist in determining optimal approaches to care. The NOMS criteria include four domains: neurologic, oncologic, mechanical, and systemic. Each domain should be considered when evaluating patients with spinal metastases.

Neurologic

The neurologic domain includes elements such as pain, neurologic dysfunction, and spinal cord compression. Pain is the most common complaint of patients with spinal metastases and alleviating pain is a central goal in treating these individuals. Pain can occur from neurologic compression and chemical mediators induced by cancer cells. Neurologic compression includes both spinal cord compression and nerve root compression.

Figure 14.1 This T2-weighted MRI reveals a lesion centered in the vertebral body of L2 with extension into the spinal canal and neuroforaminae displacing the nerve roots to the contralateral side.

When radicular pain is occurring, it is typically from direct compression of the root from the tumor (Fig. 14.1). However, bony destruction can lead to pathologic fractures and vertebral body collapse, which may also result in neurologic compromise. The treatment of these two entities is very different and this distinction is elucidated
by careful history, physical examination, and evaluation of imaging studies.

Spinal cord compression is an imaging finding best seen on axial T2-weighted MRI. As with all imaging modalities they must be considered in conjunction with the patient’s history and physical examination. Patients with signs and symptoms of myelopathy warrant immediate attention whereas asymptomatic patients with spinal cord compression must be triaged based on their oncologic history.

Oncologic

The oncologic domain of the NOMS criteria encompasses two important points: the sensitivity of a patient’s tumor to radiation therapy as well as chemotherapy and the overall prognosis for survival.

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