Version May 2024
INTRODUCTION — Bone metastases are a common manifestation of distant relapse from many types of solid cancers, especially those arising in the lung, breast, and prostate [1]. Bone is the third most common organ affected by metastases, after the lung and liver. For hematologic malignancies, bone involvement can also be extensive in patients with multiple myeloma, and bone may be a primary or secondary site of disease involvement in patients with lymphoma. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)
Bone metastases represent a prominent source of morbidity [2,3]. Skeletal-related events (SREs) that are due to bone metastases can include pain, pathologic fracture, hypercalcemia, and spinal cord compression. Across a wide variety of tumors involving bone, the frequency of SREs can be reduced through the use of osteoclast inhibitors, such as bisphosphonates or denosumab. (See "Overview of cancer pain syndromes", section on 'Multifocal bone pain' and "Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma" and "Hypercalcemia of malignancy: Mechanisms", section on 'Osteolytic metastases' and "Clinical features and diagnosis of neoplastic epidural spinal cord compression" and "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors" and "Multiple myeloma: The use of osteoclast inhibitors".)
The incidence, distribution, clinical presentation, and diagnosis of adult patients with bone metastases is presented here. An overview of therapeutic options is provided separately, as are most detailed discussions of the mechanisms of bone metastases. Specific issues related to bone metastases in patients with prostate cancer, multiple myeloma, and primary lymphoma of bone (PLB) are discussed separately.
●(See "Overview of therapeutic approaches for adult patients with bone metastasis from solid tumors".)
●(See "Mechanisms of bone metastases".)
●(See "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on 'Patients with bone pain' and "Cancer pain management: Use of acetaminophen and nonsteroidal anti-inflammatory drugs", section on 'Efficacy'.)
●(See "Radiation therapy for the management of painful bone metastases", section on 'External beam radiation therapy' and "Radiation therapy for the management of painful bone metastases", section on 'Bone-targeted radioisotopes' and "Image-guided ablation of skeletal metastases".)
●(See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors" and "Multiple myeloma: The use of osteoclast inhibitors".)
●(See "Bone metastases in advanced prostate cancer: Clinical manifestations and diagnosis" and "Bone metastases in advanced prostate cancer: Management".)
MECHANISMS — The exact mechanism of bone metastasis is not fully understood. Multiple pathways have been implicated in the development of bone metastases. Bone undergoes constant remodeling, maintaining a dynamic balance between osteoclastic (resorptive) and osteoblastic (bone-forming) activity. As a metastatic focus (which is more often in the marrow than in cortical bone (see 'Distribution' below)) enlarges, osteoclastic and osteoblastic reactive changes occur simultaneously:
●Once cancer cells are established in the bone, interaction of the tumor cells, osteoblasts, and osteoclasts create a vicious cycle that increases bone turnover, leading to osteolytic destruction while promoting the survival of malignant tumor cells (figure 1). Activated osteoblasts stimulate production of the receptor activator of nuclear factor kappa B (RANK) ligand (RANKL), which interacts with RANK receptors to activate osteoclasts. These activated osteoclasts then resorb bone, which results in osteolysis with concomitant release of growth factors to induce tumor growth. The osteoblastic component of a lytic metastasis represents the reaction of normal bone to the metastatic process. (See "Mechanisms of bone metastases", section on 'Osteoblasts'.)
●The mechanism underlying predominantly osteoblastic metastasis is not well understood, but tumor factors, such as tumor-derived peptide endothelin-1 (ET-1), may be implicated in some solid tumors, such as prostate cancer [4]. (See "Mechanisms of bone metastases", section on 'Osteoblasts'.)
Osteolytic versus osteoblastic bone metastases — The mechanisms underlying bone metastases are reflected in the radiographic appearance; when bone-forming processes predominate, the lesions appear blastic, while if resorptive processes are dominant, the metastases appear lytic. Tumor type influences the predominance of osteolytic versus osteoblastic metastases (table 1). Osteolytic metastases are more likely to cause symptomatic complications, such as pathologic fractures, and thus, are more likely to manifest themselves earlier than osteoblastic metastases.
EPIDEMIOLOGY — Bone is one of the most common sites of distant metastases from cancer [2,5,6]:
●At postmortem, 70 to 90 percent of patients with breast or prostate cancer have some form of skeletal metastases [7,8].
●Among solid cancers, breast, prostate, lung, thyroid, and kidney cancer account for 80 percent of all skeletal metastases. However, many other primary malignant tumors can spread to bone, including, but not limited to, melanoma, lymphoma, sarcoma, and gastrointestinal malignancies, as well as uterine carcinomas.
●Skeletal lytic lesions are present at the time of diagnosis in approximately 60 percent of patients with multiple myeloma. Myeloma lesions are rarely sclerotic; when they are, they are often associated with the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal spike, skin changes) [9]. (See "POEMS syndrome", section on 'Osteosclerotic bone lesions' and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Imaging'.)
Due to the prevalence of bone metastases, ongoing improvements in systemic therapy that prolong the lives of patients with metastatic disease [10,11], and the fact that metastatic bone disease (especially fracture) is a major contributor to the deterioration in quality of life in patients with cancer [12,13], bone metastases represent a significant healthcare burden that is expected to increase in the coming years as an aging population develops malignancy [14,15].
CLINICAL PRESENTATION — Many metastatic bone lesions cause few or no symptoms and are diagnosed incidentally during the initial staging evaluation of the index cancer. In general, outside of a clinical trial setting, there is usually no reason to scan for bone metastases in the absence of symptoms unless routine laboratory studies indicate an elevated alkaline phosphatase or an elevated calcium level. In those cases, further evaluation with a fractionated alkaline phosphatase test (liver versus bone) would be indicated and could lead to further diagnostic imaging. Hypercalcemia might prompt further diagnostic evaluation as well. Hypercalcemia occurs more commonly in patients with osteolytic than with osteoblastic metastases. (See "Approach to the patient with abnormal liver biochemical and function tests", section on 'Elevated alkaline phosphatase' and "Diagnostic approach to hypercalcemia" and "Hypercalcemia of malignancy: Mechanisms".)
For symptomatic patients, pain is the most common symptom, and many patients with bone metastasis experience significant pain at some point in their disease course.
The characteristics and intensity of the pain may vary depending on the presence or absence of neuromas as part of tumor-induced bone remodeling, endosteal nerve compression by tumor, nerve injury from extension of the bone metastasis out of the bone, and location of the metastasis within the bone. The character of the pain may be somatic (ie, achy, sharp, well-localized), neuropathic (ie, burning, shooting, radiating), or both. It may be constant or exacerbated by movement of the joint or involved bone (so-called "incident" pain). Incident pain is particularly hard to treat in these patients because it comes on and remits suddenly and may be very severe. Neuropathic pain is often worse at night. A complication, such as invasion of adjacent structures, usually results in constant, progressively worsening pain. If the structure is the epidural space, producing compression of the spinal cord, the pain is likely to be worse at night and very intense. Sudden severe pain may be caused by a pathologic fracture, and prompt evaluation, especially in patients with a history of cancer, is necessary. Pathologic fractures are more likely to occur in osteolytic as compared with osteoblastic metastases. (See "Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma", section on 'Clinical presentation'.)
In the clinical setting, pain intensity is often measured simply by using a verbal rating scale (eg, "mild," "moderate," or "severe") or a numeric scale (eg, "how severe has your pain been, on average, during the past week, on a scale of 0 to 10 where 0 is no pain and 10 is the worst pain you can imagine?" (figure 2)). The classification of pain as mild, moderate, or severe using verbal or visual analog rating scales is arbitrary. Others have used the impact of pain on quality of life measures to propose a classification of pain intensity from bone metastases as mild (pain score of 1 to 5), moderate (pain score 6) or severe (pain score 7 to 10) [16].
Neurologic symptoms are not uncommon in patients with vertebral metastases, causing spinal cord compression or spinal instability. Symptoms of cord compression range from pain to neurologic deficits, including motor weakness and paralysis, sensory deficits, bowel and bladder dysfunction, and ataxia. Typically, the deficits result from soft tissue tumor compressing the spinal cord or cauda equina, rather than the pathologic fracture itself. Soft tissue expansion of bone metastasis and compression fracture may also cause nerve root impingement, leading to radiculopathy and pain. (See "Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma", section on 'Clinical presentation' and "Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma", section on 'Assessing spinal stability' and "Clinical features and diagnosis of neoplastic epidural spinal cord compression", section on 'Clinical features'.)
Distribution — In general, metastatic disease to the bone predominantly involves areas of red marrow, such as the skull, axial skeleton, or the medullary portion of the appendicular skeleton. Less commonly, metastases can be cortically-based surface lesions, although this almost always occurs in the appendicular, rather than the axial, skeleton [17,18]. The most common locations for metastatic disease are the vertebral column, sacrum, pelvis, and proximal femurs [19-21]. Within the spine, the lumbar segment is most frequently involved, followed by the thoracic and cervical segments.
The distribution of bone metastases may also be influenced by the specific type of primary malignancy. As an example, metastatic disease is distinctly unusual in anatomic sites distal to the elbow in the upper extremity and distal to the knee in the lower extremity (termed acrometastasis). When bone lesions in these locations are found to be due to metastatic carcinoma, lung and renal cell cancers are the most common primary sites [22,23].
DETECTION AND DIAGNOSIS — Detection of bone metastases is essential for accurate staging and optimal treatment. The goals of imaging are to identify sites of metastasis and to evaluate individual involved sites for the presence of, or the potential for, pathologic fracture and/or spinal cord compression. Imaging is also used to guide a biopsy, if deemed necessary. (See 'Diagnostic biopsy' below.)
Overview of the diagnostic approach — There is no consensus or universal standard approach for detection of osseous metastases in patients with cancer. The choice of imaging should be guided by the clinical presentation and the underlying histologic type of tumor since osteoblastic versus osteolytic patterns vary (table 1).
When a patient has a known malignancy and presents with progressive bone pain, focused imaging is indicated:
●For extremity lesions, radiographs of the affected area are recommended for initial evaluation. If there is no apparent lesion on radiograph, but the clinical suspicion is high then computed tomography (CT) or magnetic resonance imaging (MRI) should be done. Intravenous contrast is not required with either modality but could be helpful in MRI to evaluate for extraosseous soft tissue extension. Radiographs and cross-sectional imaging can help identify patients at risk for pathologic fracture, while cross-sectional imaging can better characterize disease extent and help with preoperative planning. (See "Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma", section on 'Radiographic studies'.)
●For cancer patients presenting with significant back pain, spinal MRI is indicated, even in the absence of any neurologic signs (ie, changes in sensation, weakness, or bowel or bladder dysfunction), to evaluate bone metastasis as well as to rule out epidural extension of tumor and spinal cord compression. The study should be performed with and without contrast as sequences obtained after intravenous contrast administration can be helpful to evaluate the paraspinal soft tissues and meninges. While evaluation of the extent of epidural disease, acuity of fracture development with potential edema, and metastatic osseous involvement is best evaluated with MRI, structural integrity of the bone is best evaluated with CT. MRI can also help differentiate between metastasis and other causes of back pain such as degenerative changes or infection. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression", section on 'Magnetic resonance imaging of the spine'.)
●Initiation of analgesic therapy is indicated to alleviate pain before the etiology is determined while testing is planned or underway. (See "Overview of cancer pain syndromes", section on 'Multifocal bone pain' and "Cancer pain management with opioids: Optimizing analgesia" and "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on 'Patients with bone pain'.)
●While analgesia is being addressed, additional skeletal imaging for further evaluation of bone metastasis can proceed. Our suggested approach to comprehensive skeletal evaluation is outlined in the table; the choice of technetium-99m (Tc-99m) skeletal scintigraphy (ie, bone scan), CT, MRI, 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) integrated with CT (FDG-PET/CT), or a combination of these imaging modalities depends on clinical presentation and/or primary cancer histology for those with a known cancer diagnosis who present with bone pain (table 2). However, in the situation where the patient needs emergent surgical evaluation for oncological emergency or complication (eg, symptomatic epidural spinal cord compression, spinal instability, or pathologic fracture of a weight-bearing bone with severe pain), comprehensive skeletal evaluation or staging workup may be deferred to allow prompt focused evaluation of the painful site followed by urgent intervention.
●The need for biopsy depends on whether surgery will be performed, whether clinical diagnosis using imaging evaluation is sufficient, and whether pathological diagnosis is required to confirm metastasis. For patients with no history of cancer, biopsy of skeletal abnormality may be necessary for pathologic diagnosis. For patients whose cancer is in remission, documentation of a pathologic diagnosis may be necessary especially if this is the first evidence of recurrence or disease progression. For patients with known history of stage IV malignancy or who are found to have other visceral metastasis on staging or restaging evaluation, clinical diagnosis with one or more imaging modalities may be sufficient to make a presumptive diagnosis of bone metastasis.
A stepwise approach to diagnosis and evaluation of osseous metastases in patients presenting with nonvertebral bone pain is outlined in the algorithm (algorithm 1); a separate algorithmic approach to diagnostic imaging is presented for patients with back pain (algorithm 2).
In general, for most patients with a known cancer capable of mixed lytic and blastic metastasis or pure blastic metastases (table 1), skeletal scintigraphy (bone scan) is indicated. For pure lytic tumors, such as multiple myeloma, a radiographic skeletal survey or whole body cross-sectional imaging (CT or MRI) is indicated to screen the skeleton. For patients with primarily lytic tumors, including metastatic Ewing sarcoma family of tumors (EFT), FDG-PET/CT is the recommended initial step. For patients with sclerotic multiple myeloma (the POEMS syndrome), as well as EFT with a sclerotic primary tumor and for all other patients with suspected bone metastases, bone scan is recommended. Integrated FDG-PET/CT may be the optimal diagnostic study for many solid tumors, especially if the purpose of imaging is to comprehensively evaluate both osseous and nonosseous metastases for the purpose of staging and/or re-staging. These recommendations are in keeping with the consensus-based guidelines of the NCCN [24]. (See "Clinical presentation, staging, and prognostic factors of Ewing sarcoma", section on 'Metastatic work-up' and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Skeletal surveys' and "POEMS syndrome", section on 'Osteosclerotic bone lesions'.)
Evaluation of a patient with no, or a remote, history of cancer is more complex and must include a search for the primary site; contrast-enhanced CT of the chest, abdomen, and pelvis tailored for visceral organ evaluation plus a bone scan or FDG-PET/CT may be used for comprehensive staging evaluation. In general, diagnostic evaluation should precede biopsy of suspicious bone lesions, particularly if a pathologic or impending pathologic fracture is present or suspected. If primary bone sarcoma is suspected, consultation with an orthopedic oncologist should be obtained, especially prior to biopsy so that the trajectory can be determined. However, if urgent surgical stabilization is needed, and the lesion is unlikely to represent a primary bone sarcoma, a more focused diagnostic evaluation can be performed, and tissue can be removed at the time of surgery to render a pathologic diagnosis. (See "Bone tumors: Diagnosis and biopsy techniques", section on 'Planning the biopsy' and "Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma", section on 'Patients with a remote or no history of cancer'.)
Specific imaging studies — Metastatic bone lesions can present with any radiographic appearance (lytic, blastic, or mixed), regardless of tumor type. However, there are some features that are typical of specific tumors (table 1 and image 1); these features may help in selecting appropriate imaging studies and facilitating radiographic interpretation of the abnormalities:
●Osteoblastic lesions are typically seen in prostate cancer (image 2)
●Metastases of lung, kidney, and thyroid cancers and bone involvement from multiple myeloma is almost always lytic (image 3)
●Mixed lesions are frequently seen in breast cancer
Radiographs — Radiographs are commonly used as an initial screen to evaluate symptomatic areas and to confirm findings seen with other imaging modalities. Because of poor sensitivity (44 to 50 percent [25,26]), workup for bone metastases cannot end with negative radiographs if the pretest probability of metastasis is high. Spine radiographs may be used to determine the mechanical alignment of the vertebrae and to evaluate for severe compression fracture. Patients with suspected mechanical instability should be urgently referred to a neurosurgeon. In some cases, radiographic skeletal surveys are still used as initial staging in multiple myeloma, although whole body CT and MRI are becoming favored modalities. (See 'Skeletal survey' below and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Skeletal surveys'.)
Bone lesions on radiographs may appear as areas of faint or absent density (reflecting osteolysis), as disrupted or absent trabecular structure, or as sclerotic lesions or rims. The limited contrast in trabecular bone makes radiographic detection more difficult than for lesions in cortical bone [27].
The typical radiographic appearance of a lytic metastasis is a permeative lesion of the diaphysis or metadiaphysis of a proximal long bone or bone of the axial skeleton (image 4). Osteoblastic lesions are usually sclerotic in appearance, sometimes admixed with lytic elements (image 1). In either case, a pathologic fracture line may be visible, and the normal anatomic alignment may be displaced (image 5).
Radiographs may also be useful to assess the extent of cortical compromise and the risk of pathologic fracture in a tubular bone. The extent of cortical compromise seen on radiography is an important indicator of the risk of a pathologic fracture in tubular bones (table 3). (See "Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma", section on 'Long bones'.)
Compression fractures in vertebral bodies lead to a collapse of the endplates (image 6). However, it may be difficult to distinguish vertebral collapse related to tumor from osteoporotic vertebral collapse on radiographs; MRI may be needed. (See "Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma", section on 'Cross-sectional imaging'.)
In general, radiographs are more specific, but less sensitive, for bone metastases than bone scan or FDG-PET scan [27,28]. Considerable bone destruction (an estimated 30 to 75 percent reduction in bone density) must be present before a lesion is evident on radiographs [29]. One exception is that radiographs are more sensitive than bone scan for purely lytic metastases (eg, multiple myeloma, some renal cell metastases). (See 'Bone scan' below and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Imaging'.)
Computed tomography or magnetic resonance imaging — CT or MRI of the body part of concern may be required to evaluate the following: suspected complete or impending pathologic fractures; suspected epidural spinal cord or cauda equina compression; metastatic bone disease involving the shoulder, spine, or pelvis because of the complex anatomy; or a strong clinical suspicion of bone metastases when other imaging exams are equivocal [30]. Exams to evaluate the entire skeleton for metastasis (ie, whole-body low-dose CT and MRI) are discussed below. (See 'Low-dose, whole-body computed tomography' below and 'Whole-body magnetic resonance imaging' below.)
Choice of modality is tailored to anatomic site of concern and clinical indication [31]. However, in general, MRI can better evaluate the bone marrow and adjacent soft tissues, while CT can still be helpful in treatment planning. CT is usually performed without intravenous contrast. MRI can also be performed without intravenous contrast; however, postcontrast images can help evaluate extraosseous tumor extension into the adjacent soft tissues.
CT is used to diagnose bone metastases if MRI is contraindicated (eg, MRI incompatible pacemaker), or the site of concern is included in a CT obtained to evaluate for extraosseous metastases (eg, torso CT). To assess the integrity of the bone cortex at a site with a known bone metastasis, CT is preferred.
●CT demonstrates superior bony detail compared with radiographs and can detect osteolytic and osteoblastic metastases within the bone marrow before there is destruction sufficient to become evident on radiography (image 7) [32,33]. When compared with bone scan, CT demonstrates similar sensitivity. In a meta-analysis of various imaging modalities for the diagnosis of bone metastases in a variety of malignancies, on a per-lesion basis, the sensitivity and specificity of CT were 77 and 83 percent; the corresponding values for bone scan were 75 and 94 percent, respectively [34].
●CT enables high-resolution visualization of the bone cortex. This can aid in the diagnosis of a complete pathologic fracture and in the assessment of fracture risk using newer technology, such as CT-based structural rigidity analysis. (See "Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma", section on 'CT-based structural rigidity analysis'.)
●Other benefits from CT compared with radiography are that it shows associated soft tissue disease and provides three-dimensional reconstruction of images, which is helpful for planning radiotherapy (RT) or surgery.
●CT involves faster image acquisition than MRI and may be more readily available. However, the soft tissue contrast of CT is inferior to MRI. Therefore, if spinal cord compression, nerve impingement, or adjacent muscle or joint involvement is suspected, MRI should be used.
On the other hand, MRI is more sensitive than CT to detect metastases, allows better delineation of the extent of tumor, and is particularly useful for patients with spine metastases to evaluate the extent of medullary and extraspinal disease. MRI may distinguish benign from malignant compression fractures [27,33-42]:
●MRI demonstrates greater accuracy than CT or bone scan and comparable accuracy to FDG-PET/CT in diagnosis of skeletal metastases [34]. On a per-lesion basis, the sensitivity and specificity of MRI, FDG-PET/CT, CT, and bone scan are 91 and 96 percent, 94 and 97 percent, 75 and 94 percent, and 77 and 83 percent, respectively. To specifically evaluate the spine for metastases, MRI is the most accurate modality [42].
●Standard MRI protocols for evaluation of bone metastasis include T1- and T2-weighted imaging without contrast and, often times, postcontrast images. Normal bone marrow usually contains a high percentage of fat and has high signal intensity on T1-weighted images (that do not have fat-saturation). Metastatic lesions display decreased signal on T1-weighted sequences, reflecting the replacement of normal fatty marrow with water-containing tumor; conversely, on T2-weighted images, metastases usually have a higher signal than surrounding normal bone marrow. Metastases usually enhance avidly with contrast in comparison with the surrounding normal tissue.
●MRI with and without contrast should be used when spinal cord compression and/or epidural disease/nerve root impingement is suspected because of the excellent soft tissue resolution. It also shows the presence of spinal cord edema and other abnormalities in the spinal cord. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression", section on 'Imaging protocol and timing'.)
●MRI can be used to help distinguish a pathologic fracture from an insufficiency fracture by evaluating for an underlying bone marrow replacing lesion [43]. This is particularly relevant in the spine and pelvis, both common locations for insufficiency fractures and metastatic disease. The most common discriminating feature of a pathologic fracture is a well-defined, low-signal T1-weighted abnormality around the fracture, indicating an underlying tumor [44]. Diffusion-weighted imaging with measurement of the apparent diffusion coefficient of the marrow at the fracture site is highly accurate in discriminating benign from pathologic fractures (sensitivity and specificity >90 percent for both) and is often added to conventional imaging [45,46]. However, the added value of this technique has not yet been demonstrated. (See "Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma", section on 'Cross-sectional imaging'.)
Particularly among patients with multiple myeloma, MRI is the gold-standard method for assessing bone marrow infiltration of the spine, predicting the risk of vertebral fracture, and distinguishing benign versus malignant etiologies [47]. (See "Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma", section on 'PET/CT plus MRI' and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'CT, MRI, and PET'.)
MRI is sensitive to movement and artifact due to metallic objects, which may obscure evaluation. In addition, patients with implantable devices may not be able to undergo MRI. Patients with severe claustrophobia also may not tolerate this study unless it is performed using conscious sedation or, in patients who are not candidates for conscious sedation, under general anesthesia.
Whole-body skeletal evaluation
Bone scan — Tc-99m skeletal scintigraphy, generally referred to as a "bone scan," is the most widely used method to detect bone metastases because it provides visualization of the entire skeleton within a reasonable timeframe and at a reasonable cost. 99m-Tc-methylene diphosphonate (99mTc-MDP) is the most commonly used tracer. It accumulates in areas of increased osteoblastic activity, provides a total skeletal examination, and is reliable for detecting metastases in diseases like prostate and breast cancers (image 8).
Among patients with a variety of malignancies, including breast, lung, and prostate cancer, bone scan is reasonably sensitive (79 to 86 percent) and specific (81 to 88 percent) for the diagnosis of bone metastases [34,48,49]. However, bone scan is less sensitive for detecting tumors with little to no osteoblastic activity (such as multiple myeloma) and for aggressive lesions with rapid bone destruction because it detects osteoblastic activity resulting in new bone formation. Bone lesions associated with multiple myeloma are only "hot" on bone scan in approximately 20 percent of cases. Lytic lesions can be detected as "cold spots" on bone scan, but these subtle findings may be overlooked.
The addition of single-photon tomography (SPECT) to bone scan improves the diagnostic accuracy over bone scan alone but does not improve sensitivity for purely lytic lesions; it is not routinely used [34,50-54].
Skeletal survey — Because of poor sensitivity, skeletal survey radiographs are uncommonly used in screening for bone metastases. While they have typically been used in workup of patients with plasma cell dyscrasias, low dose whole-body CT and MRI are becoming more favored modalities. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Skeletal surveys'.)
Positron emission tomography (PET) scanning — Metabolic imaging with FDG-PET, without or with integrated CT, has high sensitivity and specificity for diagnosis of distant metastases, including the bone. Integrated FDG-PET/CT is increasingly utilized in clinical staging and restaging evaluation for metastatic disease, including osseous metastasis from solid tumors and multiple myeloma.
For some malignancies (ie, lung and breast cancer), FDG-PET is more specific than bone scans for detection of bone metastases, although it is possibly less sensitive (especially for osteoblastic foci) and clearly more expensive [55-63]. As an example, in a meta-analysis of 13 studies directly comparing FDG-PET versus bone scan for detection of bone metastases in patients with breast cancer, the following was found [64]:
●On a per-patient basis, the pooled sensitivity and specificity rates for FDG-PET were 53 and 100 percent; the corresponding values for bone scan were 88 and 96 percent, respectively.
●On a per-lesion basis, pooled sensitivity and specificity rates for FDG-PET were 83 and 95 percent; the corresponding values for bone scan were 87 and 88 percent, respectively.
The addition of integrated FDG-PET/CT may improve sensitivity and is a major evaluation tool for cancer staging:
●In a study of 29 consecutive women with newly diagnosed breast cancer who underwent both integrated FDG-PET/CT and bone scan, the sensitivity and specificity rates for FDG-PET/CT on a per-lesion basis were 96 and 92 percent, while the corresponding values for bone scan were 76 and 95 percent, respectively [65]. For the 16 lesions without a CT correlate, the sensitivity of FDG-PET was only 77 percent. The majority of bone metastases were mixed osteolytic/osteoblastic (48 of 70 or 69 percent).
●In a meta-analysis of 17 articles comparing integrated FDG-PET/CT, FDG-PET alone, MRI, and bone scan for diagnosis of bone metastases in patients with lung cancer, the per-patient pooled sensitivity and specificity rates for FDG-PET/CT were 92 and 98 percent, respectively; the corresponding rates for FDG-PET alone were 87 and 94 percent, while for bone scan, they were 86 and 88 percent, respectively [48].
A major benefit of FDG-PET over bone scan is its ability to screen for distant metastases at sites other than bone [66,67]. Because of this, consensus-based guidelines from the NCCN recommend integrated FDG-PET/CT to evaluate for distant metastases at all sites, including bone, for patients with newly diagnosed non-small cell and small cell lung cancer [24]. (See "Overview of the initial evaluation, diagnosis, and staging of patients with suspected lung cancer", section on 'Suggested approaches to diagnostic evaluation and radiographic staging' and "Pathobiology and staging of small cell carcinoma of the lung", section on 'Staging workup'.)
Integrated FDG-PET/CT may also be useful for assessing the whole skeleton in those patients with metastatic thyroid cancer, where the propensity for purely lytic bone metastases renders the bone scan insensitive (table 1 and image 1 and image 7), and possibly in renal cell and head and neck cancer, in which lytic bone metastases predominate [68,69]. NCCN consensus-based guidelines suggest that integrated PET/CT be considered for the staging of patients with anaplastic thyroid cancer, as well as to evaluate potential distant metastases from a variety of primary head and neck cancer sites, but continue to recommend bone scan as a screen for metastatic osseous disease in renal cell cancer [24]. (See "Overview of the diagnosis and staging of head and neck cancer", section on 'Evaluation for distant metastases' and "Clinical manifestations, evaluation, and staging of renal cell carcinoma", section on 'Staging studies' and "Anaplastic thyroid cancer", section on 'Imaging'.)
Because of the overall lower incidence of lytic bone metastasis in patients with breast and prostate cancer, bone scan remains the standard diagnostic study in these patients.
Other settings where integrated FDG-PET/CT may be preferred over bone scan range from multiple myeloma with a single site of bone involvement or smoldering myeloma, rapidly progressive metastases that are associated with minimal reactive bone formation [70] for the staging of lymphomas that are routinely avid for radiolabeled glucose (eg, diffuse large B cell lymphoma, Hodgkin lymphoma (image 9)), and for staging the bone in Ewing sarcoma with a lytic primary tumor. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Imaging'.)
Integrated PET/CT scanning may be of particular utility in differentiating benign versus malignant fractures, particularly in patients with multiple myeloma, in whom the nature of the spine fracture may be more difficult to determine due to the presence of concomitant osteoporosis. (See "Clinical presentation, staging, and prognostic factors of Ewing sarcoma", section on 'Metastatic work-up' and "Pretreatment evaluation and staging of non-Hodgkin lymphomas", section on 'Positron emission tomography (PET)' and "Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma", section on 'PET scan'.)
In addition to FDG-PET/CT, there is growing evidence that integrated PET/CT scanning using 18-fluorine sodium fluoride (NaF PET/CT) may offer increased sensitivity and specificity in evaluating metastatic bone disease compared with Tc-99m-based bone scan in a wide variety of clinical settings [71-80]. NaF is a bone-targeting agent for evaluating osseous metastasis, approved by the US Food and Drug Administration (FDA) as a tracer agent for bone scintigraphy to define areas of osteoblastic activity, independent of cancer type. NaF PET/CT has improved image quality compared with Tc-99 bone scan; a meta-analysis showed sensitivity and specificity of 96.2 and 98.5 percent, respectively, compared with 57 and 98 percent for Tc-99 bone scan [81]. While the use of F-18 NaF PET/CT has been increasing in clinical practice, there are only limited data suggesting clinical superiority over FDG-PET/CT. However, NCCN guidelines endorse NaF PET/CT as an option if there are equivocal results on bone scan for men with unfavorable intermediate-risk, high-risk, very high-risk prostate cancer and women with advanced breast cancer [24]. (See "Clinical features, diagnosis, and staging of newly diagnosed breast cancer", section on 'Assessing the extent of local disease' and "Initial staging and evaluation of males with newly diagnosed prostate cancer", section on 'PET imaging using PSMA-based radiotracers'.)
Gallium Ga-68 DOTATATE PET/CT is somatostatin-receptor-based imaging and may be considered for staging evaluation for metastatic workup including bone metastasis for pheochromocytoma, medullary carcinoma, and neuroendocrine tumors [82]. (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Somatostatin receptor-based imaging techniques' and "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms", section on 'Somatostatin-receptor-based imaging' and "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging", section on 'Radiologic evaluation' and "Clinical presentation and diagnosis of pheochromocytoma", section on '68-Ga DOTATATE PET'.)
Prostate-specific membrane antigen (PSMA)-PET tracers are the radiopharmaceuticals that target PSMA on the surface of prostate cells. The FDA has approved F-18 piflufolastat (F-18 DCFPyL), flotufolastat F-18, and Ga-68 PSMA-11 as the PSMA-PET tracers for prostate cancer imaging. Given the increased sensitivity and specificity of PSMA-PET tracers for detecting micrometastatic disease, the updated NCCN guidelines now recommend PSMA PET/CT, as an alternative to standard imaging of bone and visceral metastasis from prostate cancer for initial staging and at the time of PSA progression. (See "Initial staging and evaluation of males with newly diagnosed prostate cancer", section on 'PET imaging using PSMA-based radiotracers' and "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation", section on 'Ga-68 and F-18 PSMA PET/CT'.)
Additional radiopharmaceuticals that are designed to image tumor antigen expression, angiogenesis, and amino acid transport are also being tested for PET applications and may have a future role in those tumor types that are hypometabolic (eg, prostate cancer) and, thus, are not optimally imaged with the current standard FDG-PET/CT [49,83-85].
Low-dose, whole-body computed tomography — As a screening test for bone metastases in patients with solid tumors, CT has lower sensitivity than bone scan, whole-body MRI, and FDG-PET for detection of skeletal metastases [25,34,86]. As an example, in a meta-analysis comparing FDG-PET, CT, whole-body MRI, and bone scan for diagnosis of bone metastases, on a per-patient bases, sensitivity and specificity rates for CT were 73 and 95 percent, respectively; the corresponding rates for bone scan were 86 and 81 percent, while for FDG-PET they were 90 and 97 percent, respectively [34].
However, one setting in which whole-body, low-dose CT may have utility is in patients with multiple myeloma as an alternative to skeletal survey [87-90]. A meta-analysis concluded that higher detection rates could be achieved with low-dose multidetector CT (MDCT) compared with whole-body radiography in patients with multiple myeloma [91].
Whole-body magnetic resonance imaging — Whole-body MRI has the potential to detect more destructive bone lesions in the axial skeleton (particularly the spine) than bone scan [39,92,93] or, among patients with multiple myeloma, whole-body radiographs [91,94-96]. However, on a per-patient basis, whole-body MRI is less sensitive and less specific than FDG-PET/CT and less sensitive than bone scan [48]. Furthermore, with the current generation of scanners, whole-body MRI is generally not clinically practical in most centers because it would require over one hour of table time for image acquisition. However, whole-body MRI techniques are rapidly advancing with the potential for faster acquisition times and may replace other means of imaging bones, such as bone scan, in the future [97].
In patients with suspected or newly diagnosed myeloma, particularly those with a solitary bone lesion or smoldering myeloma, MRI has become the gold-standard imaging method for early detection of bone marrow involvement (in addition to bone destruction, fracture, and spinal cord/nerve compression) [47]. Where whole-body MRI is not available, MRI of the spine and pelvis can be used as it detects approximately 90 percent of focal lesions. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'CT, MRI, and PET'.)
Differential diagnosis — The differential diagnosis of a lytic bone abnormality includes primary malignant bone tumors, bone metastases from distant primary sites, as well as several benign bone lesions. Radiography, as discussed in the above section, may assist in the differential diagnosis (table 4).
Primary malignant bone tumors that may appear as lytic lesions include primary bone sarcoma (osteosarcoma (image 10), chondrosarcoma (image 11), fibrosarcoma, Ewing sarcoma of bone (figure 3 and image 12 and image 13), solitary plasmacytoma of bone [SPB] (image 14 and image 15 and image 16), and primary lymphoma of bone [PLB] (image 17)). Most of these primary bone tumors have a characteristic radiographic appearance, although biopsy is generally needed to establish the histologic diagnosis. (See "Bone tumors: Diagnosis and biopsy techniques", section on 'Differential diagnosis'.)
"Benign" bone tumors that can present as lytic lesions (table 4) include hemangioma, various types of cysts, lipomas, eosinophilic granuloma, enchondroma, osteoid osteoma, nonossifying fibroma, and giant cell tumor of bone. (See "Nonmalignant bone lesions in children and adolescents" and "Giant cell tumor of bone" and "Radiologic evaluation of knee tumors in adults" and "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis", section on 'Lytic bone lesions'.)
The modified Lodwick-Madewell Grading System is a method to categorize lytic bone lesions into those that have a low, moderate, or high risk for malignancy based upon patterns of bone destruction as seen on radiographs [98]. This system is best applied to lesions of the long bones; it may be difficult to apply to calvarial and/or spine lytic bone lesions. Grade I lesions represent lesions with low risk of malignancy, and include well-defined geographic lesions with a sclerotic rim (IA) and geographic lesions with a sharp margin without a sclerotic rim (IB). Grade II lesions are geographic lesions with ill-defined margins, while grade III lesions include those with a moth-eaten or permeative appearance, indicating a high risk of malignancy.
The differential diagnosis of a sclerotic or blastic bone lesion is narrower. A bone island, also known as an enostosis, is a focus of compact bone located in cancellous bone (image 18). This is a benign entity that is usually found, incidentally, on imaging studies that may mimic an osteoblastic metastasis; CT attenuation measurements can aid in the distinction [99]. Other benign conditions that may present as a solitary sclerotic bone lesion are calcifying enchondroma, osteoid osteoma (image 19), bone infarct, fibrous dysplasia, Paget disease of bone, and vertebral venous congestion in patients with thrombosis of the superior vena cava [100]. (See "Clinical manifestations and diagnosis of Paget disease of bone" and "Nonmalignant bone lesions in children and adolescents".)
Diagnostic biopsy — Definitive diagnosis of bone metastasis requires histologic examination of biopsy material. However, tissue diagnosis may not be needed for all patients:
●If a primary tumor is known, a skeletal lesion with a typical appearance on imaging studies (either lytic or osteoblastic (table 1)) may be presumed to be metastatic, especially if there are multiple lesions and the radiographic appearance is typical. However, because of the dire prognostic implications of metastatic disease, the possibility that the finding could represent a benign lesion (21 percent in one study of 482 patients with a single known primary malignancy who underwent biopsy of a suspicious bone lesion [101]) and the outside possibility of a second occult primary malignancy (estimated to occur in 3 percent of cases in this same study [101]), histologic confirmation of an initial site of bone metastasis is recommended. Of course, it is neither feasible nor desirable to confirm each metastatic lesion by biopsy.
If a patient has a history of cancer without prior documentation of bone metastases and a confirmatory diagnosis of metastatic disease is all that is required, needle biopsy can be an excellent method to acquire enough tissue simply to document the presence of metastatic disease. CT-guided fine needle aspiration biopsy (FNA) is easy to perform and accurate in this setting [102,103]. Core biopsy has higher diagnostic accuracy for determining the type, grade, and specific diagnosis of musculoskeletal tumors but may not be needed. An example of a situation in which this would be particularly helpful would be in the case of a patient with a remote estrogen receptor positive (ER+), progesterone receptor positive (PR+), and Her-2-neu positive invasive ductal breast cancer who now presents with bony metastases after a long disease-free interval. Potential hormonal therapy options for bone-only metastatic disease in this setting would be guided by knowing the molecular profile of the metastases. Open biopsy is rarely, if ever, needed. (See "Bone tumors: Diagnosis and biopsy techniques".)
●For patients with an unknown primary cancer who present with a bone metastasis, and initial staging evaluation fails to delineate the primary malignancy, a biopsy is generally indicated to both confirm the malignant nature of the bone lesion and to provide histologic information about likely primary sites. Identification of the primary tumor may permit patients to benefit from therapy that is tailored to the specific type of malignancy. However, biopsy of the metastatic deposit may or may not indicate the most likely source of the primary malignancy, even when sophisticated histologic techniques are used [104,105]. In this setting, an FNA biopsy may not provide sufficient information to guide in the evaluation of a possible primary site, and a core biopsy may be needed in order to permit immunohistochemical evaluation.
In the past, this scenario prompted the performance of elaborate imaging evaluations in an attempt to locate the primary site, but with limited success. It is now recommended that the diagnostic work-up be selectively chosen based upon the history, the patient's sex, the clinical findings, and laboratory tests. The topic of neoplasms of unknown primary site is discussed in detail separately. (See "Overview of the classification and management of cancers of unknown primary site".)
●An impending or complete pathologic fracture in a patient with a solitary bone lesion, with or without a history of cancer, should never be fixed without a tissue diagnosis. Should the lesion prove to be a primary mesenchymal malignancy (eg, osteosarcoma, chondrosarcoma), the surgical repair could jeopardize not only the opportunity for limb salvage, but also the possibility of cure. If the biopsy is to be done in advance by an interventional radiologist, discussion with the physician performing the biopsy is very important as the biopsy should be performed in a location that will permit excision of the biopsy tract should a primary sarcoma be diagnosed. Collaboration with an orthopedic oncologist is advised in this setting. (See "Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma", section on 'Diagnostic biopsy'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neoplastic epidural spinal cord compression" and "Society guideline links: Management of bone metastases in solid tumors".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Bone metastases (The Basics)")
SUMMARY
●Clinical presentation
•Bone metastases are a common manifestation of distant relapse from many types of solid cancers, especially lung, breast, prostate cancer, and multiple myeloma. Metastatic bone disease is a prominent source of morbidity and a major contributor to deterioration in quality of life. Skeletal-related events (SREs) attributed to bone metastases include pain, pathologic fracture, hypercalcemia, and spinal cord compression. (See 'Introduction' above.)
•Most patients with metastatic bone disease will develop significant pain at some point. Neurologic symptoms may arise if spine metastases cause spinal cord compression or spinal instability. Patients with osteolytic bone metastases may also present with hypercalcemia. (See 'Clinical presentation' above.)
●Diagnostic approach
•The goals of imaging are to identify sites of metastasis and to evaluate individual involved sites for the presence of, or potential for, complications such as pathologic fracture and spinal cord compression, and to guide the biopsy, if deemed necessary. (See 'Detection and diagnosis' above.)
•The choice of imaging should be guided by the clinical presentation and the underlying histologic tumor type. In general, cross sectional imaging of the affected body part may be required for the evaluation of suspected pathologic fractures; disease extent; suspected epidural spinal cord compression or spinal instability; metastatic bone disease involving the shoulder, spine, or pelvis because of the complex anatomy; or a strong clinical suspicion of bone metastases when other imaging exams are equivocal. Choice of modality (computed tomography [CT], magnetic resonance imaging [MRI]) is tailored to the anatomic site of concern and the clinical indication. MRI is particularly useful for patients with spine metastases to allow evaluation of the extent of medullary and extraspinal disease, and spinal cord and nerve root compression. For suspected or newly diagnosed multiple myeloma, MRI is the gold-standard imaging for skeletal and marrow abnormality. (See 'Computed tomography or magnetic resonance imaging' above.)
Our suggested diagnostic approach is outlined in the algorithms (algorithm 1 and algorithm 2), and summarized as follows (see 'Overview of the diagnostic approach' above):
-For patients with a known cancer diagnosis presenting with back pain, spinal MRI without and with contrast is indicated, especially for evaluation of bone metastasis and spinal cord compression (algorithm 2). Postcontrast images are acquired to evaluate for tumor spread into the paraspinal soft tissue. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression", section on 'Magnetic resonance imaging of the spine'.)
-For patients with nonvertebral bone pain, initial evaluation should include a radiograph of the affected area. If a complete or impending pathologic fracture is suspected, cross-sectional imaging with contrast-enhanced CT or MRI without and with contrast can identify patients who may need surgical stabilization (algorithm 1). (See "Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma", section on 'Radiographic studies'.)
-Subsequent whole-body skeletal evaluation is generally the next step to screen the rest of the skeleton for bone metastases, for both vertebral and nonvertebral metastases. 99m-technetium-methylene diphosphonate skeletal scintigraphy, generally referred to as a "bone scan," is the most widely used method to detect bone metastases because it provides visualization of the entire skeleton within a reasonable timeframe. (See 'Bone scan' above.)
However, the whole-body radiographic bone survey (typically with low-dose CT or whole body MRI) is preferred for staging of patients with multiple myeloma because of poor sensitivity of bone scan in this situation (table 2). (See 'Radiographs' above and 'Skeletal survey' above.)
•Metabolic imaging with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) integrated with CT (FDG-PET/CT) is often utilized for initial staging of patients with Ewing sarcoma and a lytic primary tumor, and for those with rapidly progressive metastases associated with minimal reactive bone formation. FDG-PET/CT is also commonly used for staging and/or restaging of solid cancers when the goal is to screen for both osseous and nonosseous metastases (table 2). PET/CT using novel PET tracers such as Ga-68 DODATATE for neuroendocrine tumors or Ga-68 PSMA-11 for prostate cancer are increasingly used as an alternative to standard imaging. (See 'Positron emission tomography (PET) scanning' above.)
•Differential diagnosis of metastatic bone disease includes primary bone sarcomas (osteosarcoma, chondrosarcoma, fibrosarcoma, and Ewing sarcoma of bone), solitary plasmacytoma of bone (SPB), and primary lymphoma of bone (PLB). Benign bone tumors that can present as lytic lesions include hemangioma, various types of cysts, lipomas, eosinophilic granuloma, enchondroma, nonossifying fibroma, and giant cell tumor of bone. Benign conditions that may present as a solitary sclerotic bone lesion include a bone island (enostosis), calcifying enchondroma, osteoid osteoma, bone infarct, fibrous dysplasia, and Paget disease of bone. (See 'Differential diagnosis' above.)
•Definitive diagnosis of bone metastases requires histologic examination of biopsy material. However, tissue diagnosis may not be needed for all patients. If a patient has a history of cancer without prior documentation of bone metastases and a confirmatory diagnosis of metastatic disease is all that is required, needle biopsy is an appropriate choice. (See 'Diagnostic biopsy' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Thomas F DeLaney, MD, who contributed to an earlier version of this topic review.
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
