Bone metastasis

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Bone metastasis
3D rendered CT of hip bone metastases.jpg
3D rendered CT scan of bone metastases of the hip bone, in a 60 year old woman with parotid gland cancer. Large lesions are seen on the ilium on the more distant side. Involvement of the vertebral column has caused a compression fracture.
Specialty Oncology

Bone metastasis, or osseous metastatic disease, is a category of cancer metastases that results from primary tumor invasion to bone. Bone-originating primary tumors such as osteosarcoma, chondrosarcoma, and Ewing sarcoma are rare; the most common bone tumor is a metastasis. [1] Bone metastases can be classified as osteolytic, osteoblastic, or both. Unlike hematologic malignancies which originate in the blood and form non-solid tumors, bone metastases generally arise from epithelial tumors and form a solid mass inside the bone. Bone metastases, especially in a state of advanced disease, can cause severe pain, characterized by a dull, constant ache with periodic spikes of incident pain. [2]

Contents

Types of lesions

Under normal conditions, bone undergoes continuous remodeling through osteoclast-mediated bone resorption and osteoblast-mediated bone deposition. [3] These processes are normally tightly regulated within bone to maintain bone structure and calcium homeostasis in the body. Dysregulation of these processes by tumor cells leads to either osteoblastic or osteolytic lesions, reflective of the underlying mechanism of development. [3] Typically, osteolytic metastases are more aggressive than osteoblastic metastases, which have a slower course. Regardless of the phenotype, bone metastases commonly show osteoclast proliferation and hypertrophy. [4]

Primary tumors

Signs and symptoms

Bone metastases can cause severe pain, bone fractures, spinal cord compression, hypercalcemia, anemia, spinal instability, decreased mobility, and rapid degradation in the quality of life for patients. [6] [7] Patients have described the pain as a dull ache that grows worse over time, with intermittent periods of sharp, jagged pain. [2] Even under controlled pain management, periods of breakthrough pain can occur rapidly, without warning, several times a day. [8] Pain may be worse at night and partially relieved by activity. [9] Metastases to weightbearing bones may become symptomatic early in the course of disease, as compared to metastases to the flat bones of the rib or sternum. [9]

Effects of bone metastasis

Major complications secondary to bone metastases are termed Skeletal-Related Events (SREs). [10]

Other symptoms include:

Sclerotic breast cancer metastases in the pelvis. ScleroticMets.PNG
Sclerotic breast cancer metastases in the pelvis.

Sources of bone metastases

Main sites of metastases for some common cancer types, with lung and breast routes to bones shown at shoulder level. Prostate cancer, the third major source, is not shown because of female model. Primary cancers are denoted by "...cancer" and their main metastasis sites are denoted by "...metastases". Metastasis sites for common cancers.svg
Main sites of metastases for some common cancer types, with lung and breast routes to bones shown at shoulder level. Prostate cancer, the third major source, is not shown because of female model. Primary cancers are denoted by "...cancer" and their main metastasis sites are denoted by "...metastases".
CT scan in the coronal plane of bone metastases of the hip bone, in a 60-year-old woman with parotid gland cancer. The more affected side is very irregular and sclerotic (visible as brighter in this presentation). CT of hip bone metastases.jpeg
CT scan in the coronal plane of bone metastases of the hip bone, in a 60-year-old woman with parotid gland cancer. The more affected side is very irregular and sclerotic (visible as brighter in this presentation).

Bone is the third most common location for metastasis, after the lung and liver. [12] While any type of cancer is capable of forming metastatic tumors within bone, the microenvironment of the marrow tends to favor particular types of cancer, including prostate, breast, and lung cancers. [3] In prostate cancer, bone metastases tend to be the only site of metastasis. [2] The most common sites of bone metastases are the spine, pelvis, ribs, skull, and proximal femur. [9]

Common primary tumors

Mechanism

Initial Seeding

Many cancers spread to bone, but not all bones are implicated in cancerous metastasis. The microenvironment of differing bone types is thought to play a role in its predisposition to tumor seeding. [13] For example, trabecular bone rich in red marrow and bone subject to frequent turnover are more likely to be seeded [13] at premetastatic niches formed by interactions between cancerous cells and bone substrate [14] Tumor cells are then attracted to the metastatic niche in the bone. However, the characteristics of these niches have yet to be fully elucidated. [14] Initial seeding can occur prior to the discovery of the primary tumor. [14]

Vascular Seeding

The pathogenesis of bone metastasis via the vasculature is hypothesized to be related to the Batson vertebral vein plexus, a longitudinal valveless system connected to the breast, lung, kidney, thyroid, and prostate gland that extends from the sacrum to the skull. [15] The most common locations of metastases are the pelvis, vertebral bodies, ribs and ends of long bones. [15]

Dormancy

Once established, the tumor cells can remain dormant on the bone microenvironment, radiologically undetectable, for many years. [14] The triggers which eventually awaken metastatic tumor cells are an active field of study as they could elucidate mechanisms of controlling dormancy. [14]

Tumor Cell-Bone Interactions

Tumor cells may have paraneoplastic effects, such as via the secretion of Prostaglandin E, TGF-alpha, TGF-beta, TNF, and interleukins to increase bone resorption. The destruction of bone affected by bone metastases are caused by osteoclast-mediated osteolysis. [15] The uncoupled regulation of osteoclasts and osteoblasts leads to malformation of the bone. [2] Lytic bone lesions may also lead to the pathogenesis of hypercalcemia in cancers that have spread to bone [16]

Diagnosis

Skeletal Radiography

A plain film x-ray of the entire body can identify bone metastasis. However, the sclerotic or osteolytic lesions must be at least 1 cm in diameter. [14] A combination of X-ray, CT and MRI scans may be most sensitive in the diagnosis of cancerous bone metastasis. [14]

Radionuclide Bone Scan

A radionuclide bone scan or scintigraphy can identify bone metastasis. Technetium-99m–labeled bisphosphonate attaches to calcium at sites of active bone formation. [14] Bone scans are more sensitive and can identify lesions earlier than plain radiographs. [14] However, these methods are less effective at identifying purely osteolytic lesions and will also highlight other areas of bone formation, such as those caused by trauma or inflammation unrelated to cancer. [14] Additionally, bladder activity may mask the detection of certain pelvic lesions. [14]

CT Scan

A CT scan can detect bone metastases before they present with symptoms in patients diagnosed with tumors that are high-risk for spread to the bone. Even sclerotic bone metastases are generally less radiodense than enostoses, and it has been suggested that bone metastasis should be the favored diagnosis between the two for bone lesions lower than a cutoff of 1060 Hounsfield units (HU). [10] If a biopsy is indicated, a CT scan is often used to localize the lesion before biopsy. [14]

MRI

MRIs can be used to detect bone metastasis with a sensitivity of 82-100% and a specificity of 73-100%.

PET Scan

Positron emission tomography (PET) with fluorine 18–labeled fluorodeoxyglucose ( 18 F-FDG) is a powerful diagnostic tool to visualize the activity of bone metastasis. [14] Bone metastases on PET scan are usually multiple, irregularly distributed foci of increased tracer uptake without relationship to a single anatomic structure. [14] A PET scan can directly identify tumor cells with significant metabolic rate. However, it is a costly procedure and device availability may be limited. [14]

Bone Markers

Due to the high rate of bone turnover, metabolites are theorized to be capable of detecting bone metastasis. [14] Use of bone markers for detection and screening is an active field of research, though radiographic evidence remains the gold standard. [14] However, once the presence of a bone metastasis has been established, tumor metabolic markers can provide useful diagnostic and prognostic information. [14]

Treatment

The goals of treatment for bone metastases include pain control, prevention and treatment of fractures, maintenance of patient quality of life, and local tumor control. [9] Optimal treatment requires a multidisciplinary team of physicians, including medical and radiation oncologists, orthopedic surgeons, radiologists, nuclear medicine physician, palliative medicine specialists, and more. [14] Assessment of treatment is determined by multiple factors, including performance status, pain score, impact on quality of life, and overall status of clinical disease. [14] Important therapies include external-beam radiotherapy, targeted radioisotope therapy, image guided tumor ablation chemotherapy, and bone-targeting chemotherapeutic agents such as Bisphosphonates and Denosumab. Orthopedic interventions such as internal fixation or spinal decompression may be necessary in the case of loss of structural stability due to bone destruction. [14]

Pain management

The World Health Organization's pain ladder was designed for the management of cancer-associated pain. The original ladder details the management of pain using a sequence of analgesic medications, starting with non-steroidal anti-inflammatory medications and progressing to weak and strong opioids [17]

Other treatments include corticosteroids, radiotherapy, and radionucleotides. [2] Percutaneous osteoplasty involves the use of bone cement to reduce pain and improve mobility. [18] In palliative therapy, the main options are external radiation and radiopharmaceuticals. [19]

Thermal ablation techniques are increasingly being used in the palliative treatment of painful metastatic bone disease. Although the majority of patients experience complete or partial relief of pain following external radiation therapy, the effect is not immediate and has been shown in some studies to be transient in more than half of patients. [20] For patients who are not eligible or do not respond to traditional therapies ( i.e. radiation therapy, chemotherapy, palliative surgery, bisphosphonates or analgesic medications), thermal ablation techniques have been explored as alternatives for pain reduction. Several multi-center clinical trials studying the efficacy of radiofrequency ablation in the treatment of moderate to severe pain in patients with metastatic bone disease have shown significant decreases in patient reported pain after treatment. [21] [22] These studies are limited, however, to patients with one or two metastatic sites; pain from multiple tumors can be difficult to localize for directed therapy. More recently, cryoablation has also been explored as a potentially effective alternative as the area of destruction created by this technique can be monitored more effectively by CT than radiofrequency ablation, a potential advantage when treating tumors adjacent to critical structures. [23]

A Cochrane review of calcitonin for the treatment of metastatic bone pain suggests calcitonin yields no significant benefit in the reduction of bone pain or improvements in quality of life. [24]

Bone-Targeted Agents

Bone-Targeted Agents (BTAs) including Bisphosphonates and Denosumab, can interrupt osteoclast-mediated osteolysis. [14] Osteoclast inhibitors, most frequently used in the treatment of osteoporosis, can allow for bone healing and delay complications. [14] BTAs have been shown to decrease the incidence of Skeletal Related Events (SREs) like pathological fractures, thereby decreasing the need for surgical intervention or pain medication. [14]

Prognosis

Many cancers are predisposed to metastasize to bone. [12] The list below details the likelihood of a cancer, if in a stage of advanced metastasis, to have spread to bone at time of death: [25]

Given the high incidence of breast, lung and prostate cancer, these patients account for > 80% of patients with bone metastases. [14]

For patients with advanced metastatic disease involving the bone, median survival from the time of diagnosis of a bone metastasis varies by primary tumor type. A list is included below: [25]

See also

Related Research Articles

<span class="mw-page-title-main">Prostate cancer</span> Male reproductive organ cancer

Prostate cancer is the uncontrolled growth of cells in the prostate, a gland in the male reproductive system just below the bladder. Early prostate cancer usually causes no symptoms. As the tumor grows, it can damage nearby organs causing erectile dysfunction, blood in the urine or semen, and trouble urinating. Some tumors eventually spread to other areas of the body, particularly the bones and lymph nodes. There, tumors cause severe bone pain, leg weakness or paralysis, and eventually death.

<span class="mw-page-title-main">Metastasis</span> Spread of a disease inside a body

Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, are metastases (mets). It is generally distinguished from cancer invasion, which is the direct extension and penetration by cancer cells into neighboring tissues.

<span class="mw-page-title-main">Bone tumor</span> Medical condition

A bone tumor is an abnormal growth of tissue in bone, traditionally classified as noncancerous (benign) or cancerous (malignant). Cancerous bone tumors usually originate from a cancer in another part of the body such as from lung, breast, thyroid, kidney and prostate. There may be a lump, pain, or neurological signs from pressure. A bone tumor might present with a pathologic fracture. Other symptoms may include fatigue, fever, weight loss, anemia and nausea. Sometimes there are no symptoms and the tumour is found when investigating another problem.

<span class="mw-page-title-main">Osteosarcoma</span> Cancerous tumour in a bone

An osteosarcoma (OS) or osteogenic sarcoma (OGS) is a cancerous tumor in a bone. Specifically, it is an aggressive malignant neoplasm that arises from primitive transformed cells of mesenchymal origin and that exhibits osteoblastic differentiation and produces malignant osteoid.

<span class="mw-page-title-main">Interventional radiology</span> Medical subspecialty

Interventional radiology (IR) is a medical specialty that performs various minimally-invasive procedures using medical imaging guidance, such as x-ray fluoroscopy, computed tomography, magnetic resonance imaging, or ultrasound. IR performs both diagnostic and therapeutic procedures through very small incisions or body orifices. Diagnostic IR procedures are those intended to help make a diagnosis or guide further medical treatment, and include image-guided biopsy of a tumor or injection of an imaging contrast agent into a hollow structure, such as a blood vessel or a duct. By contrast, therapeutic IR procedures provide direct treatment—they include catheter-based medicine delivery, medical device placement, and angioplasty of narrowed structures.

Spinal tumors are neoplasms located in either the vertebral column or the spinal cord. There are three main types of spinal tumors classified based on their location: extradural and intradural. Extradural tumors are located outside the dura mater lining and are most commonly metastatic. Intradural tumors are located inside the dura mater lining and are further subdivided into intramedullary and extramedullary tumors. Intradural-intramedullary tumors are located within the dura and spinal cord parenchyma, while intradural-extramedullary tumors are located within the dura but outside the spinal cord parenchyma. The most common presenting symptom of spinal tumors is nocturnal back pain. Other common symptoms include muscle weakness, sensory loss, and difficulty walking. Loss of bowel and bladder control may occur during the later stages of the disease.

<span class="mw-page-title-main">Osteoprotegerin</span> Mammalian protein found in Homo sapiens

Osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor (OCIF) or tumour necrosis factor receptor superfamily member 11B (TNFRSF11B), is a cytokine receptor of the tumour necrosis factor (TNF) receptor superfamily encoded by the TNFRSF11B gene.

<span class="mw-page-title-main">Invasive carcinoma of no special type</span> Medical condition

Invasive carcinoma of no special type (NST) is also referred to as invasive ductal carcinoma or infiltrating ductal carcinoma(IDC) and invasive ductal carcinoma, not otherwise specified (NOS). Each of these terms represents to the same disease entity, but for international audiences this article will use invasive carcinoma NST because it is the preferred term of the World Health Organization (WHO).

<span class="mw-page-title-main">Spinal cord compression</span> Medical condition

Spinal cord compression is a form of myelopathy in which the spinal cord is compressed. Causes can be bone fragments from a vertebral fracture, a tumor, abscess, ruptured intervertebral disc or other lesion.

<span class="mw-page-title-main">RANKL</span> Mammalian protein found in Homo sapiens

Receptor activator of nuclear factor kappa-Β ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiation factor (ODF), is a protein that in humans is encoded by the TNFSF11 gene.

<span class="mw-page-title-main">Cryoablation</span> Process using extreme cold to destroy tissue

Cryoablation is a process that uses extreme cold to destroy tissue. Cryoablation is performed using hollow needles (cryoprobes) through which cooled, thermally conductive, fluids are circulated. Cryoprobes are positioned adjacent to the target in such a way that the freezing process will destroy the diseased tissue. Once the probes are in place, the attached cryogenic freezing unit removes heat from ("cools") the tip of the probe and by extension from the surrounding tissues.

<span class="mw-page-title-main">Denosumab</span> Human monoclonal antibody

Denosumab is a human monoclonal antibody for the treatment of osteoporosis, treatment-induced bone loss, metastases to bone, and giant cell tumor of bone.

<span class="mw-page-title-main">Metastatic liver disease</span> Medical condition

A liver metastasis is a malignant tumor in the liver that has spread from another organ affected by cancer. The liver is a common site for metastatic disease because of its rich, dual blood supply. Metastatic tumors in the liver are 20 times more common than primary tumors. In 50% of all cases the primary tumor is of the gastrointestinal tract; other common sites include the breast, ovaries, bronchus and kidney. Patients with Colorectal cancer will develop liver metastases during the disease

<span class="mw-page-title-main">Metastatic breast cancer</span> Type of cancer

Metastatic breast cancer, also referred to as metastases, advanced breast cancer, secondary tumors, secondaries or stage IV breast cancer, is a stage of breast cancer where the breast cancer cells have spread to distant sites beyond the axillary lymph nodes. There is no cure for metastatic breast cancer; there is no stage after IV.

<span class="mw-page-title-main">Brain metastasis</span> Cancer that has metastasized (spread) to the brain from another location in the body

A brain metastasis is a cancer that has metastasized (spread) to the brain from another location in the body and is therefore considered a secondary brain tumor. The metastasis typically shares a cancer cell type with the original site of the cancer. Metastasis is the most common cause of brain cancer, as primary tumors that originate in the brain are less common. The most common sites of primary cancer which metastasize to the brain are lung, breast, colon, kidney, and skin cancer. Brain metastases can occur in patients months or even years after their original cancer is treated. Brain metastases have a poor prognosis for cure, but modern treatments are allowing patients to live months and sometimes years after the diagnosis.

Breast cancer metastatic mouse models are experimental approaches in which mice are genetically manipulated to develop a mammary tumor leading to distant focal lesions of mammary epithelium created by metastasis. Mammary cancers in mice can be caused by genetic mutations that have been identified in human cancer. This means models can be generated based upon molecular lesions consistent with the human disease.

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<span class="mw-page-title-main">Osteolytic lesion</span>

An osteolytic lesion is a softened section of a patient's bone formed as a symptom of specific diseases, including breast cancer and multiple myeloma. This softened area appears as a hole on X-ray scans due to decreased bone density, although many other diseases are associated with this symptom. Osteolytic lesions can cause pain, increased risk of bone fracture, and spinal cord compression. These lesions can be treated using biophosphonates or radiation, though new solutions are being tested in clinical trials.

A pre-metastatic niche is an environment in a secondary organ that can be conducive to the metastasis of a primary tumor. Such a niche provides favorable conditions for growth, and eventual metastasis, in an otherwise foreign and hostile environment for the primary tumor cells. This concept demonstrated the fundamental role of the microenvironment in regulating tumor growth and metastasis. The discovery of the pre-metastatic niche has fostered new research regarding the potential treatment of metastases, including targeting myeloid derived suppressor cells, and stromal cell plasticity including fibroblasts and pericytes and perivascular smooth muscle cells and (attempts to stop the flow of vesicles from primary tumors to pre-metastatic niches in secondary organs and different combinations of microenvironment targeted therapies.

References

  1. ↑ MedlinePlus Overview bonecancer
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  11. ↑ List of included entries and references is found on main image page in Commons: Commons:File:Metastasis sites for common cancers.svg#Summary
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  24. ↑ Martinez-Zapata, MJ (2012). "Calcitonin used to treat metastatic bone pain". Cochrane Database Syst Rev. 2006 (3): CD003223. doi:10.1002/14651858.CD003223.pub2. PMC   9676422 . PMID   16856000.
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