Metastatic Carcinoma 

Approximately 1.2 million patients present with cancer each year in the United States. Of these, approximately 600,000 persons have metastases to bone. In contrast, 2,700 patients per year develop primary bone sarcoma.

In addition, the age range of patients with sarcoma is different from that of individuals with carcinoma of bone; most metastatic bone lesions occur in adults older than 50 years, while most sarcomas occur in adolescents or young adults (< 30 y). Therefore, a bone-occupying mass in an adult is much more likely to be a focus of metastatic carcinoma than to be a primary sarcoma of bone; however, in a patient with a bone lesion with no documentation of metastatic disease, caution is warranted to ensure the correct diagnosis.

In females, the breasts and lungs are the most common primary disease sites; approximately 80% of cancers that spread to bone arise in these locations.^{[1, 2, 3, 4, 5]} In males, cancers of the prostate (see image below) and lungs make up 80% of the carcinomas that metastasize to bone.^[6] The remaining 20% of primary disease sites in patients of both sexes are the kidney, gut, and thyroid, as well as sites of unknown origin.

Most patients with metastatic bone disease survive for 6-48 months. In general, patients with breast and prostate carcinoma live longer than do persons with lung carcinoma.^{[7, 8]} Patients with renal cell or thyroid carcinoma have a variable life expectancy.

The orthopedic surgeon has 2 major tasks to perform when treating patients who develop bone metastases.^[9] The first task is to biopsy a bony lesion of unknown origin, which may be found during evaluation/staging studies or as a result of a patient's symptoms.

The orthopedic surgeon's second task is to manage the stabilization of impending or already completed pathologic fractures of bones in a critical area, such as an upper or lower extremity, the pelvis, or the spine. In one study of patients with breast carcinoma, 19% of the patients developed a pathologic fracture or hypercalcemia as the first sign that the carcinoma had spread to bone. Moreover, 10% of the patients suffered spinal cord compression, and 9% of them experienced bone marrow failure. It is important to develop strategies that emphasize maintenance of function, including ambulation, in these patients for the remainder of their lives and to intervene when possible before a fracture occurs. The associated morbidity and mortality rate is greater when intervention is delayed.

Previously, the 2 main theories of how tumor cells metastasize and grow in bones were Paget's fertile soil hypothesis and Ewing's circulation theory. However, a substantial amount of work has more clearly defined the metastatic process to bone. Bone metastases occur in a predictable distribution. In order of frequency, the most common locations include the following:

• Spine
• Pelvis
• Ribs
• Proximal limb girdles

The red marrow theory, combined with knowledge about the cytokine stimulation of metastases, provides an excellent explanation of how this distribution occurs.

Metastases distal to the knee and elbow are extremely uncommon, but approximately 50% of these acral metastases are secondary to primary lung tumors. Carcinomas, such as those of the breast and prostate, rarely exhibit such a distinct pattern.

Bone destruction, secondary to metastases, is clearly caused by the activation of osteoclasts rather than by the direct destruction of bone by tumor cells. In 1995, Mundy and Yoneda described the cellular events necessary for the success of the metastatic process, including the attachment of tumor cells to the basement membrane, the production of proteolytic enzymes by tumor cells (such as metalloproteinases, which are enzymes that disrupt basement membranes), and the migration of tumor cells through the basement membranes into surrounding tissue, especially the arteriolar network.^[10]

Once in the bloodstream, these tumor cells must be capable of surviving the intravascular killer T cells; they must also successfully attach to the basement membrane of the vessel at the distant site, break it down, and migrate into the surrounding tissues. Because these cells cannot survive further than 100 mm away from a capillary, they must also produce angiogenesis factors to stimulate capillary ingrowth.

Needless to say, something must attract these tumor cells to a specific site in the body, but that process is not as clear. Type I collagen, a byproduct of bone resorption, has been shown to be a chemotactic factor that attracts tumor cells to bone. Cell adhesion molecules, such as laminin, E-cadherin, and integrins, also have been identified as substances that facilitate the attachment of metastatic cells to basement membranes.

Once at the distant site, destruction of the host bone must be accomplished. Tumor cells are also able to up-regulate osteoclasts through the production of RANK ligand, a potent stimulator of osteoclastic activity. This substance recruits and activates osteoclasts in order to destroy trabecular and cortical bone. RANK ligand and other chemotactic factors, as noted above, up-regulate osteoclasts for the degradation of bone, producing pockets or holes in the bone in which the tumor cells to grow.

Another important substance that stimulates bone resorption is parathyroid hormone – related peptide (PTHrP). This substance is expressed by breast carcinoma cells, as well as by oat cell tumors of the lung, and is a potent stimulant of osteoclasts. In 1996, Guise and colleagues reported elevated PTHrP levels in the bone marrow plasma (as compared with serum plasma levels) in rats with tumors.^[11]

An interesting concept, reported in 1995 by Mundy and Yoneda, is that myeloma cells are especially adapted to producing bone destruction through direct stimulation of osteoclasts.^[10] During the resorption process, the osteoclasts release interleukin-6, which is a major regulatory factor in the growth of myeloma cells. Additional myeloma cells further stimulate increased osteoclastic production in a continuous feedback mechanism. This enhances survival of the tumor cells and further destruction of the bone.

The process by which bone metastases develop appears to be the following:

• Cells from the primary site must, through the process of neovascularization or through migration to the nearest blood vessel, attach to the basement membrane of the vessel wall and produce proteolytic enzymes that disrupt the basement membrane.
• The cells then migrate through the basement membrane and float away in the bloodstream to a distant site. If they survive the journey to the distant site, the tumor cells attach to the basement membrane of the vessel wall using proteolytic enzymes (integrins/cadherins). After disrupting the receptor site basement membrane, they migrate into the substance of the distal host tissue. Producing the chemotactic factors noted above, as well as RANK ligand, these cells stimulate osteoclast activity to produce bone resorption.
• A feedback relationship, such as that present in myeloma cells, then produces continued osteoclast stimulation for bone resorption and tumor cell growth, providing for continued growth and survival of the metastatic cells. This, in turn, progressively destroys cancellous and cortical bone at the distant osseous site.

This osteoclastic bone resorption can be modified by bisphosphonates; these substances are presently being used in the management of metastatic breast carcinoma and multiple myeloma.^[9] Future research and modification of RANK ligand will produce additional substances that can further arrest or retard bone destruction by metastatic disease.

Other intriguing research is being conducted in the area of angiogenesis inhibition. Presently, such efforts are being directed at patients with GI tumors. Additional research in the areas of combined large vessel embolization and microscopic angiogenesis inhibition needs to be done.

Frequency

United States

See Background.

Mortality/Morbidity

In general, once skeletal metastases are present, patient survival is dramatically shortened. For example, the 5-year overall survival rate for people with prostate cancer is 93%, but once skeletal metastases are present, the average survival time is only 29 months. However, patients are surviving and remaining active for longer periods as treatment protocols improve. These factors make the orthopedic surgeon's task in prophylactic or reconstructive surgery more challenging. In addition, perioperative complications are greater in this population.

• The perioperative mortality rate is approximately 8%.
• The perioperative infection rate is approximately 4% and increases in previously irradiated sites.

Age

Most patients with skeletal metastases are older than 50 years.