eMedicine Specialties > Orthopedic Surgery > Neoplasms

Metastatic Carcinoma

Author: Howard A Chansky, MD, Associate Professor, Department of Orthopedics and Sports Medicine, University of Washington Medical Center
Coauthor(s): John Eady, MD, Chief, Orthopaedic Surgery, Dorn VA Hospital, Columbia, SC 29209
Contributor Information and Disclosures

Updated: Jan 29, 2008

Introduction

Background

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 In males, cancers of the prostate and lungs make up 80% of the carcinomas that metastasize to bone. 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.³ 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.⁴ 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.

See also the following related topic in Medscape:
Resource Center Breast Cancer

See also the following related topics in eMedicine:
Bone Metastases
Vertebral Fracture

Pathophysiology

• 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.⁵

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.⁶

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.⁵ 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.⁴ 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.

Clinical

History

Although pain is an important symptom of musculoskeletal metastases, it is nonspecific. The pain pattern can be helpful if, in addition to being activity-related, it is present at rest and at night, especially in patients older than 50 years. However, this pain pattern can be present in patients with osteomyelitis and Paget disease, and in these instances, it is also is nonspecific.

Diagnostic factors

An orthopedic surgeon will be consulted in the following instances to help evaluate a patient with a suspicious bony defect.

• In the first instance, the surgeon is asked to help evaluate a patient a patient who has experienced a pathologic fracture or who has a known primary carcinoma as well as a bony defect.
• In the second, more worrisome instance, the surgeon is consulted in the evaluation of a patient whose bony defect was serendipitously found during the radiologic evaluation of another condition.

In the above instances, the orthopedist must perform 3 functions:

• Determine the cause of the bony defect.
  • In a limited number of patients, bony defects are often found serendipitously during radiographic evaluation of the affected part for other reasons. In these instances, the orthopedist is asked to determine if the discovered bony defect is a benign event requiring no further management or one that needs further investigation. The following are examples of such defects.
    • The stippled, calcific, benign-appearing enchondroma found in the proximal humerus during an evaluation of a patient for a rotator cuff tear
    • Bony physiologic changes in the intertrochanteric area of the proximal femur, which may be found on plain anteroposterior (AP) pelvic radiographs during evaluation of the pelvis for other reasons
    • An area of fibrous dysplasia, which may be observed on radiographs that have been taken of a patient involved in some traumatic event
  • It is often difficult to determine whether a bony defect found during a bone survey for metastatic disease is the result of that disease or of some other condition. For instance, a benign bone island, an area of osteopoikilosis or fibrous dysplasia, can produce a similar radiographic appearance. A bone biopsy is often required to determine the actual diagnosis of such a defect. If the patient has already been diagnosed as having a primary tumor, the management of the recently discovered bony defect is relatively uncomplicated.
  • When the diagnosis of the bony defect needs to be proven for therapeutic reasons, biopsy is appropriate. For example, the radiotherapist or oncologist may need confirmation that the recently discovered bony defect is the same as the primary tumor or that the bony site results from another condition. Bone biopsies can be accomplished in a number of ways, but for the diagnosis of bony metastases, the most appropriate and least invasive method for making a diagnosis is needle biopsy.
• Predict the probability of fracture.⁷
  • If the biopsy confirms that the bony defect has been caused by metastatic disease, the orthopedist must then decide if the defect fits the criteria for an impending fracture. The definition of an impending fracture is the presence of a bony defect that is likely to result in a pathologic fracture with physiologic loading (ie, activities of daily living). In this case, the orthopedist should determine the probability of fracture by examining plain radiographic findings and by conducting an interview with the patient. Quantitating the risk of fracture based on plain radiography alone is very subjective because the broad guidelines in the literature are based on small numbers of patients and, therefore, are limited in value. Using them can result in errors of judgment more than 50% of the time.
  • According to a 1995 report by Hipp and colleagues, useful criteria are as follows: defect geometry affecting load-bearing capacity, the histologic cell causing the defect (ie, blastic, lytic, or mixed), and the anatomic site (femoral neck vs greater trochanter).⁸ For instance, according to the study, the factor of risk for fracture of a normal proximal femur is approximately 0.4. The thinnest part of a cortical wall is the critical factor for predicting loss of strength. Central lesions with a 50% symmetrical loss of bone produce a 60% loss of bending strength. In patients who have eccentric bone loss, a 50% bone mass reduction results in a 90% reduction of bending strength. Therefore, a lesion located in areas that increase the risk factors to the bone must be considered.
  • Length of a bony lesion has been reported as critical only in torsional loads. The load-bearing capacity of bone apparently depends on: 1) the location of the defect with respect to the applied load, 2) the type of applied load, 3) the amount of bone loss, and 4) the condition of the remaining bone. The anatomic location of a bony lesion also is important. As the literature has shown, a drill hole that has been placed inappropriately in the lateral femoral shaft (at or below the level of the lesser trochanter) for fixation of a nonneoplastic femoral neck fracture results in a high risk of bone fracture with weight bearing through the lateral femoral cortical drill hold defect. Therefore, a similarly sized metastatic lesion in this area can be expected to create a similarly high fracture risk.
• Prophylactically fix a pathologic or impending fracture.
  • When a bony site displays radiographic and clinical evidence of an impending or already completed pathologic fracture, surgical stabilization is indicated. Most current literature supports the prophylactic fixation of impending fractures to minimize morbidity and protect function. In contrast, waiting for an impending fracture to occur increases morbidity and mortality and affects the patient's ability to regain function in as short a time as possible.
  • Because the life span of these patients is limited, the goal of management needs to be centered on returning as much function as possible as rapidly as possible.

See also the following related topic in eMedicine:
Bone Island

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