Pathologic Fractures

Prognosis

Patient survival after metastasis to bone varies greatly depending on the tumor type and sites of involvement. Mean survival ranges from 6 months, for those with lung carcinoma, to several years, for those with bone metastasis from prostate, thyroid, or breast carcinoma. Also, in breast cancer, prognosis after the development of bone metastasis is considerably better than that after progression into visceral sites. Coleman and colleagues found that the median survival of patients with advancement of breast cancer into the skeleton to be 24 months, compared with 3 months after relapse in the liver. The probability of survival was influenced by the development of metastasis to extraosseous sites. Breast cancer patients with metastatic disease confined to the skeleton had a median survival of 2.1 years compared with those with extraosseous metastatic disease, who had a median survival of 1.6 years. When examining lung cancer with skeletal metastasis, Sugiura and colleagues found a mean survival of 9.7 months and a median survival of 7.2 months. Approximately 70% of patients died within 1 year after the development of skeletal metastasis, and only 6% survived 2 years or more. The mean length of survival was substantially longer in patients with solitary skeletal metastasis versus patients with multiple site. The importance of the extent of bone metastasis can also be seen with renal cell carcinoma where a solitary site of bone metastasis treated aggressively with wide excision can confer a survival advantage compared with patients with multiple sites of disease or pathologic fracture.

Prognosis for guiding treatment decisions is very important but terribly difficult to estimate. This information is sought after to help set appropriate expectations for the patient, family, and medical staff. The goal is to maximize function and quality of life for the greatest amount of time. The data about cost, risk, and quality of life are often conflicting, but properly weighed could help define the most appropriate treatment for an individual with metastatic bone disease. Although no foolproof model exists to assist in the decision making for end-of-life orthopaedic care, there are several newer schemes that can be helpful. Forsberg and colleagues at Memorial Sloan Kettering Cancer Center developed a clinical decision-support tool that estimates patient survival at 1, 3, 6, and 12 months after surgery. This tool considers the presence of visceral metastases, lymph node involvement, number of bone metastases, histologic diagnosis, surgeon's estimation of survival, Eastern Cooperative Oncology Group (ECOG) performance status, preoperative hemoglobin, presence of pathologic fracture, and absolute lymphocyte count. An online version of this externally validated support tool can be found at www.pathfx.org . The authors suggest that patients with 1 month estimated survival receive hospice care, those with 3 months undergo less invasive surgery, and those with 6 months or more of predicted survival undergo maximally durable surgery. It is also advised to consider less tangible factors of the patient's psychosocial status and wishes of the family. For patients with metastatic cancer to the bony spine, a nomogram has been developed to assist in the estimation of survival of 30, 90, and 365 days. Primary carcinomas of lung, colon, rectum, bladder, esophagus, liver, and gastric system, as well as melanoma, had the poorest survival. Nathan and colleagues evaluated patients who had surgery for pathologic fractures to determine whether well-recognized prognostic parameters had value in determining the survival in this patient population. Median survival in their cohort was 8 months and 60% of the fracture-related consultations to the service underwent operative intervention of both pathologic fractures and impending fractures. Independent predictors for survival were diagnosis (or primary site of disease), ECOG performance status, number of bone metastases, presence of visceral metastases, and hemoglobin level. Patients with lung cancer fared the worst, and patients with renal cancer fared the best. At the end of their study, they concluded that justification for surgery on the basis of survival prognostication can be dangerously inaccurate and that more accurate prognostic indices are needed for patients undergoing surgery for bone metastases. Forsberg and colleagues attempted to tackle this issue by evaluating three different prognostic models to assist in the decision to offer surgery and also whether a more durable implant was appropriate based on the prediction of 3- and 12-month survival. Ultimately, the treating orthopaedic surgeon makes this difficult decision with input from the rest of the oncology team and careful consideration for the family's wishes and best interest of the patient.

The decision to pursue surgery, as well as the type of surgery, is strongly influenced by the expected survival of the patient and the need for surgical stabilization. Falsely optimistic survival estimates may influence patients and clinicians to pursue more aggressive therapies, rather than more conservative ones, and could result in a higher proportion of major perioperative complications and death. Conversely, falsely pessimistic survival prognoses could persuade a surgeon to choose a less invasive, less durable fixation technique that lacks sufficient biomechanical durability to outlast the patient and thus create a risk of reoperation.

Biology of Bone Metastases

Metastases can be characterized as either osteolytic or osteoblastic, which represent two extremes within a continuum where the dysregulation of normal bone remodeling occurs. Tumor cells can unbalance coupling in the bone microenvironment leading to bone formation or bone loss. Patients with skeletal metastasis can have either type of lesion or can have mixed blastic/lytic lesions. Specific cancers also have a predilection toward one type or the other. Breast cancer presents with predominantly osteolytic lesions, although 15% to 20% can be osteoblastic. In contrast, the lesions in prostate cancer are predominately osteoblastic. Only in multiple myeloma do purely lytic bone lesions develop.

With osteolytic metastasis, the destruction of bone is mediated by osteoclasts rather than tumor cells. Several osteoclastogenic factors have been implicated, including interleukin-1, interleukin-6, receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL), and macrophage inflammatory protein–1α. Parathyroid hormone–related peptide is also produced by most solid tumors and breast cancer cells and is most likely the factor that stimulates the formation of osteoclasts. The mechanism of formation of osteoblastic metastasis remains unknown, but factors such as endothelin-1, platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), urokinase, and prostate-specific antigen (PSA) are thought to be involved.

More than 100 years ago, Paget first noted that the spread of different cancers to distinct organs within the body was not random. He proposed an explanation for this and called it “the seed and soil hypothesis.” The “seed,” the cancer cell, which circulates in the bloodstream, can only “grow,” and metastasize, in particular compatible areas of the body, the “soil.” Not all cancers can grow on all “soil,” which leads to site-selected metastasis.

There are a series of inefficient steps that need to occur for a cancer cell to metastasize. The cell must detach and extravasate from the primary tumor; invade through the extracellular matrix and endothelium to enter the bloodstream; survive within the bloodstream; stop at a distant site by adhesion to the endothelium; intravasate again through the endothelium and additional extracellular matrix; and finally grow at a distant site. The primary tumor is a heterogeneous population of tumor cells with varying ability to metastasize; some of these cells express prometastatic genes that enable the cells to survive this process and metastasize to bone.

Hematogenous dissemination of cancer to bone is influenced by several factors. Batson described a high-flow, low-pressure, valveless plexus of veins that connects the visceral organs to the spine and pelvis. This vertebral venous system, referred to as “Batson's plexus,” runs parallel to the vertebral column and forms extensive anastomoses with the venous system of the vertebrae, pelvis, thorax, and brain. However, circulatory anatomy alone does not predict metastasis to bone. Bone receives 5% to 10% of the cardiac output, and as a consequence, most tumor cells that enter the circulation will pass through the bone marrow. Studies comparing perfusion criteria of various organs with metastatic frequency showed no correlation, as there are also other highly vascularized organs to which tumor cells rarely metastasize. Therefore it is probable that bone provides a particularly fertile microenvironment (“soil”) for the growth of tumor cells that survive the metastatic process and are able to reach it.

Examination: Clinical Features and Presentation

Pain is the most common presenting symptom of metastatic disease to bone. The pathophysiologic mechanism for this pain is poorly understood but includes tumor-induced osteolysis, cytokine and growth factor production, direct infiltration and irritation of endosteal nerve endings, mass effect causing periosteal stretch and elevated intraosseous pressures, stimulation of ion channels, and production of local tissue factors such as endothelin. The pain is usually well localized but can also be a diffuse ache, typically worse at night and not relieved by rest. Eventually the pain worsens with any weight-bearing activity and becomes functional pain. Functional pain is caused by the mechanical weakness of bone that can no longer support the normal stresses of daily activities. Functional pain is typically considered to be an indicator of bone at risk of pathologic fracture.

As a direct result of bone destruction and osteolysis seen with metastatic bone disease, hypercalcemia is a common metabolic complication. One breast cancer study found hypercalcemia in 17% of breast cancer patients with first-time recurrence in bone. Unrecognized, it can be a significant source of morbidity. The signs and symptoms are nonspecific and clinicians should always maintain a high index of suspicion. Mild hypercalcemia may cause unpleasant side effects related to dysfunction of the gastrointestinal tract, kidneys, and central nervous system. As the calcium levels increase, this can lead to renal insufficiency and calcification in the kidneys, skin, blood vessels, lungs, heart, and stomach. Severe hypercalcemia is a medical emergency, and death may ensue as a result of cardiac arrhythmias and renal failure. Hypercalcemia, in addition to acute renal failure, is a frequent first presentation in patients with multiple myeloma.

Finally, a patient may present with a pathologic fracture; this may be the first sign of metastatic bone disease. Breast, lung, renal, and thyroid cancers are the most common cancers that lead to pathologic fractures. Thirty-five percent of breast cancer patients with metastatic bone disease will sustain a fracture. Patients with bone metastases from prostate cancer usually do not sustain pathologic fractures because of the osteoblastic nature of the disease. However, those with castrate-resistant prostate cancer, where osteoblastic metastasis is common, do fracture greater than 20% of the time.

Diagnostic Evaluation

It is important to understand the differential diagnosis for an adult patient who presents with radiographic findings consistent with an aggressive-appearing skeletal lesion. These include metastatic bone lesions, multiple myeloma, lymphoma, primary malignant bone sarcoma, destructive benign bone lesions, and nonneoplastic conditions (e.g., infection, stress fracture, metabolic bone disease such as Paget disease or secondary hyperparathyroidism, and osteonecrosis). Knowledge of this differential diagnosis helps guide the diagnostic evaluation of an adult with an aggressive-appearing bone lesion.

In 2012 there were an estimated 1.64 million new patients with a diagnosis of cancer; of these, it is estimated that greater than 50% are likely to develop bone metastasis. In contrast, only 2890 of these new cases were of patients who presented with primary bone and joint malignancies. Therefore the chance that a solitary bone lesion is a metastatic carcinoma, especially in an individual older than 40 years of age, is approximately 500 times greater than the chance that it is a primary bone sarcoma.

Usually there are three types of patients who are ultimately diagnosed with skeletal metastasis. First is the patient with a remote history of cancer who seeks an opinion regarding an occult or painful osseous lesion. The second has a known cancer history and presents with a skeletal lesion found on routine staging studies. The third type of patient is found to have a skeletal lesion without a prior history of cancer. Regardless of how the patient presents, a thorough history and physical examination is essential to initiate the diagnostic workup. It is important to collect information about current symptoms, cancer history, constitutional symptoms, changes in bowel or bladder function, hematuria, smoking history, and exposure to chemicals, such as asbestos.

Laboratory studies are part of the diagnostic workup for a patient with a new bone lesion and, although usually not definitively diagnostic, may be helpful and offer clues that will help facilitate staging. Important laboratory values to evaluate include a complete blood count, urinalysis, and chemistry panel. Determination of the erythrocyte sedimentation rate and C-reactive protein are helpful; they are often elevated in individuals with infection, immunologic disorders, or marrow cell neoplasms such as lymphoma or Ewing sarcoma. Metabolic bone diseases such as osteomalacia, hyperparathyroidism, and rickets may be identified with abnormal serum or urine calcium and phosphorus levels. If multiple myeloma is suspected, serum and/or urine protein electrophoresis with immunofixation may confirm this diagnosis. These patients may also have impaired renal function secondary to the presence of Bence Jones proteins. There are also specific blood and tumor markers that can evaluate specific primary sites of disease, including thyroid function tests, PSA, carcinoembryonic antigen, α-fetoprotein, β-human chorionic gonadotropin, and cancer antigen–125. These known tumor markers lack specificity and their value usually lies in the assessment of response to therapy or tumor recurrence more so than in initial diagnosis.

Imaging

The clinical imaging evaluation of skeletal metastasis is usually accomplished in one of four ways: plain film radiography, radioisotope scanning, computed tomography (CT), and magnetic resonance imaging (MRI). More recently, positron emission tomography (PET) scans have been introduced as another imaging modality to assist in the staging of patients with diagnosed malignant tumors and to evaluate infections and other physiologic processes in the skeleton and soft tissues.

The most important initial imaging modality for evaluation of a bone lesion is a plain radiograph in two planes. It is important to image the entire bone involved, so as not to miss any discontinuous sites of disease. Plain radiographs can yield more information about a bone tumor than any other diagnostic modality, allowing the clinician to evaluate the anatomic site, the zone of transition between the tumor and the host bone, the internal characteristics of the tumor, and the nature of the matrix that it produces. One can look for aggressive features that include size of the tumor, cortical destruction, periosteal reaction, and pathologic fracture. The ability of plain radiographs to be used as a tool for early identification is poor as an approximately 25% loss of bone mineral is needed to enable detection.

Additional three-dimensional imaging of a metastatic bone lesion is typically not needed, unless more precise definition of the soft tissue component is helpful in preparation for surgical or radiation treatment. In these cases, CT scan or MRI can then be obtained. Once a skeletal lesion is identified, a bone scan is also typically warranted to evaluate the patient for other bony sites of disease. It should be noted that bone scans identify osteoblastic activity, and disease processes, such as multiple myeloma, with minimal osteoblastic activity, may not demonstrate sites of involvement on whole body bone scanning. Myeloma requires a skeletal survey to define extent of skeletal involvement

PET/CT is an emerging technology that has a high sensitivity for identifying tumors; however, its specificity is quite low. It has been found to be superior to bone scan in detecting bone involvement in various malignancies, and because tracer uptake is not restricted to the skeleton, it has become the mainstay of staging in several malignancies. It can detect lytic, blastic, and mixed lesions because it identifies the presence of tumor directly by measuring metabolic activity. This method allows for earlier detection of metastatic foci than other studies that indirectly identify tumor by highlighting bone loss as a result of the presence of tumor. It is also much more sensitive than bone scintigraphy, especially in the detection of myeloma or renal cell carcinoma, which are predominantly osteolytic. Studies have compared PET/CT scans to whole body bone scans and found that PET/CT has increased specificity and sensitivity and overall better metastatic lesion detection. However, skeletal scintigraphy, or whole body bone scan, still remains the most commonly used diagnostic imaging modality for the evaluation of the entire skeleton for bony metastases, which is likely due to familiarity with its use compared with the more limited availability and relatively high cost of PET scans. However, with the recent surge in interest, gradually increasing availability, and increasing spectrum of applications for PET scans, this is rapidly changing, and PET/CT is likely to replace whole body bone scanning to assess tumor involvement in the skeleton, viscera, and brain. It is important to note that PET/CT remains inferior to chest CT in examining the lungs.

Understanding that many patients with skeletal metastasis are older than 40 years of age, present with a destructive and painful bone lesion, and have an unknown primary, Rougraff and colleagues developed a diagnostic protocol to assist the orthopaedic surgeon who will have the task of determining the presence of metastatic cancer and the primary site of malignancy. By obtaining an adequate history and physical, routine laboratory analysis, plain radiographs of the involved bone and chest, whole body bone scan, and CT scan of the chest, abdomen, and pelvis with oral and intravenous (IV) contrast, they were able to identify the primary tumor site in patients with metastatic cancer to bone in 85% of patients. In the event that workup for an aggressive bone lesion demonstrates only a solitary site with no obvious primary, an MRI with and without IV contrast should be done before biopsy of this lesion.

Biopsy

A biopsy is performed once all of the workup has been done and the data necessary to assist in the diagnosis have been collected. There are several reasons why it is critical to conduct a staging workup before the biopsy. First, the tumor may be a primary sarcoma of bone and an ill-planned biopsy could compromise the ability to perform a limb-sparing procedure and to obtain high-quality imaging studies. Second, there may be another site of disease that is easier to biopsy and associated with less morbidity. Third, preoperative embolization may be helpful to prevent bleeding during biopsy or treatment, such as in the case of presumed thyroid, liver, and renal cell metastases. Fourth, an unnecessary biopsy can be avoided if the diagnosis can be made based on laboratory analysis alone, such as with multiple myeloma. Fifth, histologic analysis alone identified the primary site of disease in only 3% of patients due to poor differentiation of cancer tissue. Sixth, an accurate diagnosis is more likely with the combined information from laboratory studies, imaging results, and histopathology.

There are multiple ways to perform a biopsy and specific guidelines on how to do so. Biopsy techniques include fine-needle aspiration, image-guided core-needle biopsy, and open incisional biopsy. Proper oncologic principles should always be followed irrespective of technique. The advantages of fine-needle aspirations or core-needle biopsy are that general anesthesia is not required, they are less morbid procedures, and they reduce the potential for contamination of the tumor site. The main disadvantage is a potential for sampling error due to the smaller tissue obtained and possibility of inaccurate diagnosis. When performing an open incisional biopsy, the incision should be as small as possible, should be oriented in a longitudinal fashion with minimal disruption of the surrounding tissues, and should avoid major neurovascular structures and joints. The location of the biopsy must be chosen cautiously, so it can be excised en bloc with the tumor, if necessary. It is important to maintain hemostasis throughout the procedure using electrocautery and bone wax to minimize contamination and tumor cell spillage.