Metastases to Bone

Pathophysiology (Microenvironment)

Metastases to bone occur either by direct extension, hematogenous spread, or intraspinal involvement such as via subarachnoid spread for primary central nervous system neoplasms and lymphoma. In the absence of infection or sepsis, veins are better conduits for tumor metastasis to bone than arteries, because of the impervious nature of the arterial wall. The Batson vertebral plexus, a valveless, richly interconnecting venous plexus of the spine that communicates with the azygous venous system, receives venous drainage from the prostate, thyroid, breast, lung, and kidney and thereby provides a route of metastasis from these organs to axial bone, including the vertebral bodies, pelvis, skull, and proximal limb girdles. The much rarer arterial tree metastasis mechanism is most typically seen in the spread of pulmonary and renal carcinoma to the distal extremities below the elbow or knee. Bronchogenic carcinoma accesses the arterial system via the pulmonary vein. Lymphatics do not play a role in spread to bone, and an intraosseous lymphatic system has not been demonstrated. The liver intercepts some types of metastatic tumors, such as gastrointestinal stromal tumors, which therefore only rarely secondarily involve bone. Direct extension of tumor to bone is rare but includes Pancoast tumor to the adjacent ribs or vertebrae; soft tissue sarcomas with a propensity to involve bone, sarcomatoid or higher grade squamous cell carcinoma of skin especially of head and neck region ; and direct spread of tumor in a paravertebral lymph node to adjacent vertebra.

The formation of osseous metastases follows a complicated series of events that depends on the intrinsic properties of the primary malignancy and regulation by signaling pathways and molecular interactions. Basic steps from primary site to metastasis include local tumor invasion, intravasation, circulation survival, extravasation, colonization, and neovascularization; these steps occur at various rates for different primary malignancies. In the case of carcinoma, the neoplastic cells at the primary site must first become discohesive and break free from basement membrane to invade and enter a vascular structure, occasionally by acquiring mesenchymal properties via epithelial-mesenchymal transition (EMT). The E-cadherin cell adhesion molecule on tumor cells modulates release from the primary tumor into the bloodstream. Next, tumor cells must survive both intravascular transport and host immune system attacks. Bone is a particularly common site of subsequent extravasation due to the large gaps in the marrow vessel walls for hematopoietic precursors. Tumor cells attach to bone and target the endothelial layer via integrin cell adhesion molecules. Tumor cell survival in the bone microenvironment depends on cross-talk within the rich vascular milieu and the interaction of bone cells (osteoclasts, osteoblasts, stem cells) with the mineralized bone matrix and growth factors, including receptor activator of nuclear factor κβ ligand (RANKL) and transmembrane signaling receptors of the tumor necrosis factor (TNF) superfamily, such as TNF-α, runt-related transcription factor 2 (RUNX2), and transforming growth factor-beta (TGF-β). Continued tumor growth depends on successful replication and establishment of a tumor-specific blood supply. In general, it is estimated that fewer than 0.1% of cancer cells survive the transport process to the end organ.

An extensive and growing list of factors play a role in the homing of cancer cells to the bone marrow niche. EMT involves mesenchymal growth factors, including TGF-β, platelet-derived growth factor, epidermal growth factor (EGF), and hepatocyte growth factor. Hypoxia-inducible factor–α and TGF-β signals promote bone metastases independently by tumor-secreted chemokines such as CXCR4 that promote tumor cell homing to bone. Vascular endothelial growth factor stimulates tumor angiogenesis and increases osteoclastic and osteoblastic activity. Degradation of the local stroma (lysis of matrix) uses matrix metalloproteinases (MMPs; produced both by many cancer cells and fibroblasts), cathepsins (elevated in prostate carcinoma), urokinase-type plasminogen activator, CD26 dipeptidylpeptidase IV (produced by prostate carcinoma and CD34-positive marrow progenitor cells), and even prostate-specific antigen (PSA). Osteopontin has emerged as a glycophosphoprotein secreted by cancer cells and osteoblasts that has effects on cell-to-extracellular adhesion, especially along trabecular bone surfaces, chemotaxis, host immune suppression, and angiogenesis. The ability of breast cancer cells to form osteolytic metastases requires the production of osteoclast-activating factors, such as parathyroid hormone–related protein (PTH-rP), interleukins IL-11 and IL-6, TNF-α, and granulocyte–macrophage colony stimulating factor (GM-CSF). These first three factors in turn promote the secretion of RANKL that induces osteoclast formation, function, mobilization, and survival, part of the multifactorial process of bone destruction. GM-CSF directly promotes osteoclastogenesis. In lung cancer, PTH-rP accounts for hypercalcemia. Activated osteoclasts degrade the bone matrix, releasing cytokines that are normally stored in the bone matrix via TGF-β, bone morphogenetic proteins, insulin-like growth factors, and basic fibroblast growth factors. These factors, in turn, can act on the cancer cells and perpetuate a cycle of micrometastasis outgrowth. Osteoblastic bone metastases invoke tumor-secreted endothelin. The canonical Wnt pathway is also involved in bone formation with metastasis, especially prostatic carcinoma. Expression of these secreted factors would be unlikely to provide a selective advantage in another metastatic site or in the primary tumor, yet they are essential for the development of the osteolytic and osteoblastic lesions seen in bone. The bone marrow microenvironment is affected by multiple factors, including oxygen tension, pH, nutrient substrate, growth factors, calcium, and phosphorus, that enable circulating cancer cells to deposit, survive, and develop, making the skeleton, especially red marrow, the most common site for metastatic disease.

Incidence and Demographics

Metastatic tumors are diagnosed 25 to 35 times more frequently than primary osseous neoplasms. Incidence is increasing due to longer survival resulting from improvements in the management of the primary disease; at least 400,000 people in the United States each year are reported to have bone metastases. However, the true incidence of metastatic disease to bone is difficult to ascertain because pathologic examination of the entire skeleton is rarely performed at autopsy. It has been estimated that 350,000 patients die each year in the United States with skeletal metastases.

It is generally well accepted that any new osseous lesion in an adult older than 40 years of age should be considered a potential metastasis until proven otherwise. Although metastases are more common in older patients, metastatic disease is well described in the pediatric population. There is no sex predilection.

In adults, five primary carcinomas (prostate, thyroid, breast, lung, and kidney) account for 80% of bone metastases. Prostate accounts for 60% of metastases in males; 90% of men with high-grade prostatic adenocarcinoma have bone metastases. In females, breast accounts for 70% of bone metastases; 80% of women with advanced-stage breast cancer have bone metastases. HER2-positive patients develop bone marrow metastases earlier than HER2-negative patients. Time to development of bone marrow metastasis is significantly shorter in multicentric breast carcinomas with perinodal infiltration. The thyroid and kidney are the most common solitary bone metastases, and kidney and lung metastases can enter the arterial system to distal extremities. Liver and pancreas carcinomas and malignant paraganglioma are also osteotropic. Melanoma seldom metastasizes to bone, representing approximately 5% to 7% of cases, and may include spindle cell and amelanotic variants. When the site of origin remains occult after initial clinical and radiographic workup, a lung primary is ultimately diagnosed in approximately 50% of cases. Bone may be the first site of presentation of malignancy in up to 15% of cancer patients and, in 20% to 60% of patients, a primary lesion may never be found.

In children, neuroblastoma, medulloblastoma, osteosarcoma, and Ewing sarcoma are the most common malignancies to metastasize to bone. Exceedingly rare are renal clear cell sarcoma and rhabdomyosarcoma metastases to bone, the latter with multiple lytic lesions. Metastases in neuroblastoma may manifest as multiple symmetrical or solitary lesions, involving skull, ribs, long bone, spine, and pelvis.

Localization and Clinical Manifestations

The axial skeleton, where “red marrow” is located, is a much more common metastatic site than the appendicular skeleton. Thoracic vertebrae are the most common site for metastasis overall; in adults, the proximal femur is the most common site for pathologic fracture due to metastasis. Tumors arising in the lung apex (Pancoast tumor) or other locations within the lung or mediastinum may extend directly into the ribs and cervical vertebra. Aggressive skin or soft tissue tumors that may also directly invade bone include higher grade sarcomatoid squamous cell carcinoma, especially of the head and neck, epithelioid sclerosing fibrosarcoma, and synovial sarcoma. The pelvis may be affected by bladder urothelial (transitional cell) carcinoma or rectal adenocarcinoma, the lower thoracic and lumbar vertebrae by pancreatic cancer, and the base of skull by nasopharyngeal carcinoma. Metastases are more common in the proximal than distal extremities. Metastatic disease rarely involves the bones of the hands and feet, but when it does occur, tumors most commonly originate in the lung, kidney, or colon. Metastases are generally multiple but can be solitary, particularly in cases of metastatic renal cell carcinoma or thyroid carcinomas. Prognosis depends on the type of primary malignancy and other sites of disease; breast cancer patients have a better outcome with bone metastases alone than in the setting of concurrent visceral metastases, whereas bone metastases in prostate carcinoma or malignant paraganglioma currently have an absolutely dismal prognosis.

Bone metastases typically have a significant impact on quality of life; complications include pain, pathologic fracture, spinal cord and nerve root compression (paralysis), hypercalcemia, and marrow suppression (anemia). Pain is one of the most common presenting symptoms and one of the most significant clinical consequences associated with skeletal metastases, but the relationship between pain and osseous metastatic disease is not well understood. In a study examining the relationship between pain and scintigraphic abnormalities in patients with breast or prostate carcinoma, Palmer and colleagues found that 20% of patients with osseous metastases reported no pain and 36% of patients with breast cancer reported pain without a scintigraphic abnormality. In this same study, there was poor correlation between site of the scintigraphic abnormality and a complaint of pain; however, it was noted that lumbar spine lesions were most likely to be reported as painful (45%). In another study, patients with prostate cancer and pain had metastases 47% of the time, but in patients with breast cancer, metastases were more common in patients without pain than in patients with pain (70% versus 30%). Therefore, lack of pain does not exclude the diagnosis of osseous metastatic disease, and pain in and of itself is a poor predictor of metastatic disease.

Hypertrophic osteoarthropathy, characterized by woven to woven-lamellar periosteal new bone formation of the long and short tubular bones, is occasionally associated with clubbing and joint swelling. It is most common in metastatic pulmonary carcinoma (3% to 10% of patients) (see Radiologic Features of Metastatic Disease, Periosteal Reaction on Imaging).

Hypercalcemia of malignancy is a paraneoplastic syndrome occurring in 10% of patients with cancer. It is most commonly associated with bone metastatic disease but may be present without osseous metastases. Symptoms and signs include confusion, coma, muscle weakness, polyuria and polydipsia, nausea and vomiting, and dehydration. Hypercalcemia is considered a medical emergency and carries a very poor prognosis; median survival is only 3 months following recognition of hypercalcemia. By definition, parathyroid hormone is not elevated. Instead, hypercalcemia is due to PTH-rP, which shares many of the biologic effects of native parathormone and which is detectable in 80% to 90% of patients with hypercalcemia of malignancy. A number of additional osteolytic cytokines produced by tumor cells have been implicated, including TNF, TGF-β, procathepsin D, IL-1 and IL-6, CSF, and prostaglandins of the E series. The combination of osteolytic bone metastases and hypercalcemia is most suggestive of squamous cell carcinoma of lung.

Radiology of Osteolytic Metastases

Lytic metastases are not specific as to the site of origin of the primary tumor and may span the range from geographic to permeative bone destruction ( Fig. 17-1 ). Metastases that are commonly “lytic” include primary renal cell carcinoma, breast carcinoma, thyroid neoplasms, pulmonary tumors, uterine cancers, pheochromocytoma/paraganglioma, melanoma, rarely gastrointestinal tumors (colorectal), hepatocellular carcinoma, squamous cell carcinoma of skin, head and neck tumors, and vascular neoplasms. These tumors are lytic because they produce an osteoclast-activating factor. These factors include prostaglandins, TGF-α, PTHrP, TNF, and lytic enzymes. The two most common primary tumors causing lytic metastases are from the breast and lung. Lytic lesions with marked expansile remodeling of bone (a “blowout” pattern) are somewhat more specific for renal cell and thyroid carcinomas (which may show marked hypervascularity), although the pattern also may be seen with breast and lung carcinomas ( Fig. 17-2 ). A mixed lytic/blastic pattern is seen in up to 25% of lytic metastases as a response to bone loss, particularly with breast, lung, and gastrointestinal tract primary tumors. The amount of lytic destruction needed before a lesion becomes evident on radiographs depends on the specific location of the lesion within bone. Cortical or intracortical lesions are readily evident even when the lesions are very small. On the other hand, intramedullary lesions without cortical involvement can be quite large before they are readily detectable on radiographs, particularly in the spine, where greater than 50% to 75% of vertebral body destruction may be necessary for detection.