Bone metastases could potentially cause pain by any of multiple mechanisms, including endosteal or periosteal nociceptor activation (by mechanical distortion or release of chemical mediators) or tumor growth into adjacent soft tissues and nerves (16). There have been profound changes in the understanding of the physiology of bone pain. As cancer grows in bone, a wide range of inflammatory mediators is released. The cytokine expression of the tumor cells and their interaction with osteoclasts and osteoblasts determine the nature of the lesion (Fig. 1.1)). Osteoclast activity is regulated by a complex set of interactions. Activation of the osteoclast receptor nuclear factor-κB (RANK) leads to the downstream activation of nuclear factor-κB receptor ligand (RANKL), which leads to differentiation, activation, and survival of osteoclasts. Opposing this, the osteoblast-expressed protein osteoprotegerin (OPG), neutralizes RANKL and prevents the activation of RANK (17). Parathyroid Hormone (PTH) is involved in this interaction by upregulating RANKL and by inhibiting OPG gene expression. Recently it has been found that myeloma cells directly express RANKL and indicate that specific blockade of RANKL may be an effective treatment for myeloma bone disease (18). Osteoclastic activity has been shown to be increased by the expression of interleukin-6 and parathyroid hormone–related protein by the tumor (19).

Osteoblastic metastases can be caused by tumor-secreted endothelin-1 (ET-1), insulin-like growth factor, and a variety of other potential osteoblastic factors (20). Among these are the osteogenic factors released by the prostate and other cancer types, called bone morphogenic proteins (BMPs), which are part of the transforming growth factor (TGF)-β family (21, 22, 23). Paradoxically, the stimulation of osteoblasts can increase osteoclast function because osteoblasts are the main regulators of bone-destroying osteoclasts. Therefore, the expression of osteolytic and osteoblastic factors can produce mixed metastases or increased osteolysis.

The presence of bone metastases stimulates an upregulation of peripheral and central neural processes. Immunocytochemical studies from mouse models indicate alterations in the dorsal horn, including astrocyte hypertrophy and upregulation of dynorphin, that are quite different from those seen in inflammatory and neuropathy pains. In addition, in vivo electrophysiology of individual dorsal horn neurons have indicated a profound change and increased excitation within superficial and deep laminae (I and V, respectively). Additionally, there is an increase in the proportion of wide dynamic range (WDR) nerves in lamina I; this is correlated with an increased response to electrical and mechanical stimuli and parallels the development of hyperalgesia and allodynia (24).

Bone pain due to metastatic tumor needs to be differentiated from less common causes, among which the nonneoplastic causes include osteoporotic fractures (including those associated with multiple myeloma); focal osteonecrosis, which may be idiopathic or related to chemotherapy, corticosteroids (25), or radiotherapy (see subsequent text); and osteomalacia (26).

Bone pain may be focal, multifocal, or generalized. Multifocal bone pains are most commonly experienced by patients with
multiple bony metastases. A generalized pain syndrome is also rarely produced by replacement of bone marrow (27, 28, 29, 30). This bone marrow replacement syndrome has been observed in hematogenous malignancies (31, 32, 33) and, less commonly, in solid tumors (28). This syndrome can occur in the absence of abnormalities on bone scintigraphy or radiography, increasing the difficulty of diagnosis. Rarely, a paraneoplastic osteomalacia, which is associated with elevated levels of fibroblast growth factor 23 (34), can mimic multiple metastases (35).

The vertebrae are the most common sites of bony metastases. More than two thirds of vertebral metastases are located in the thoracic spine; lumbosacral and cervical metastases account for approximately 20% and 10%, respectively (36, 37). Multiple-level involvement is common, occurring in >85% of patients (38). The early recognition of pain syndromes due to tumor invasion of vertebral bodies is essential because pain usually precedes the compression of adjacent neural structures, and prompt treatment of the lesion may prevent the subsequent development of neurologic deficits. Several factors often confound accurate diagnosis; referral of pain is common, and the associated symptoms and signs can mimic a variety of other disorders, both malignant (e.g., paraspinal masses) and nonmalignant.

The two most important imaging modalities for the evaluation of bone pain are plain radiography and nuclear bone scan. In general, CT and MRI are reserved for situations in which the diagnosis cannot be discerned from clinical information and baseline tests in which there are specific diagnostic issues to be resolved that require special techniques.

Epidural compression (EC) of the spinal cord or cauda equina is the second most common neurologic complication of cancer, occurring in up to 10% of patients (71). In a large retrospective series, 0.23% of patients with cancer had EC at the presentation of the disease and 2.5% of patients dying of cancer had at least one admission for malignant spinal cord compression (MSCC) in the 5 years preceding their death (72). Breast, lung, and prostate cancers each account for 20–25% of the epidural compression events occurring as complications (72, 73). EC is mostly caused by posterior extension of the vertebral body metastasis to the epidural space. Occasionally, EC is caused by tumor extension from the posterior arch of the vertebra or by infiltration of a paravertebral tumor through the intervertebral foramen.

Untreated, EC inevitably leads to neurologic damage. Effective treatment can potentially prevent these complications. The most important determinant of the efficacy of treatment is the degree of neurologic impairment at the time therapy is initiated. Seventy-five percent of patients who begin treatment while they are ambulatory remain so; the efficacy of treatment declines to 30–50% for those who begin treatment while they are markedly paretic and is 10–20% for those who are plegic (74). Despite this, delays in diagnosis are commonplace (75).

Back pain is the initial symptom in almost all patients with EC (71, 76), and in 10% it is the only symptom at the time of diagnosis (77). Because pain usually precedes neurologic signs by a prolonged period, it should be viewed as a potential indicator of EC, which can lead to provision of treatment at a time when a favorable response is most likely. Back pain, however, is a nonspecific symptom that can result from bony or paraspinal metastases without epidural encroachment, retroperitoneal or leptomeningeal tumor, epidural lipomatosis due to steroid administration (78), or a large variety of other benign conditions. Because it is infeasible to pursue an extensive evaluation in every patient with cancer who develops back pain, the complaint should impel an evaluation that determines the likelihood of EC and thereby selects patients appropriate for definitive imaging of the epidural space. The selection process is based on symptoms and signs and the results of simple imaging techniques.

The pelvis and hip are common sites of metastatic involvement. Lesions may involve any of the three anatomic regions of the pelvis (i.e., ischiopubic, iliosacral, or periacetabular region), the hip joint itself, or the proximal femur (92). The weight-bearing function of these structures, which is essential for normal ambulation, contributes to the propensity of the disease at these sites to cause incident pain with ambulation.

Acrometastases, metastases in the hands and feet, are rare and often misdiagnosed or overlooked (96). In the feet, the larger bones containing the higher amount of red marrow, such as the os calcis, or talus are usually involved (97, 98). Symptoms may be vague and can mimic other conditions, such as osteomyelitis, gouty rheumatoid arthritis, Reiter’s syndrome, Paget’s disease, osteochondral lesions, and ligamentous sprains.

Hypertrophic pulmonary osteoarthropathy (HPOA) is a paraneoplastic syndrome that incorporates clubbing of the fingers, periostitis of long bones, and, occasionally, a rheumatoid-like polyarthritis (99). Periosteitis and arthritis can produce pain, and tenderness and swelling in the knees, wrists, and ankles. The onset of symptoms is usually subacute and may precede the discovery of the underlying neoplasm by several months. It is most commonly associated with non–small cell lung cancer. Less commonly, it mat be associated with benign mesothelioma (100), pulmonary metastases from other sites (101), smooth muscle tumors of the esophagus (102), breast cancer (103), and metastatic nasopharyngeal cancer (104). Effective antitumor therapy is sometimes associated with symptom regression (105). HPOA is diagnosed on the basis of physical findings, radiologic appearance, and radionuclide bone scan (99, 106, 107).

Rarely, rheumatoid arthritis, systemic lupus erythematosus, and asymmetric polyarthritis may occur as paraneoplastic phenomena that resolve with effective treatment of the underlying disease (108). A syndrome of palmar plantar fasciitis and polyarthritis characterized by palmar and digital fibromatosis with polyarticular painful capsular contractions, has been associated with ovarian (109), breast (110) and gastric (111) cancers.

Persistent muscle cramps in patients with cancer are usually caused by an identifiable neural, muscular, or biochemical abnormality (112). In one series of 50 patients, 22 had peripheral neuropathy, 17 had root or plexus pathology (including 6 with leptomeningeal metastases), 2 had polymyositis, and 1 had hypomagnesemia. In this series, muscle cramps were the presenting symptom of recognizable and previously unsuspected neurologic dysfunction in 64% (27 of 42) of the identified causes (113). Cramps have been reported as an adverse effect of imatinib (114), goserelin (115), and vincristine (116).

Soft tissue sarcomas arising from fat, fibrous tissue, or skeletal muscle are the most common tumors involving the skeletal muscles. The skeletal muscle is one of the most unusual sites of metastasis from any malignancy (117, 118). The sarcomas occur disproportionately at sites of prior muscle trauma (119). Lesions are usually painless but may present with persistent ache.

Among 183 patients with new-onset chronic headache as an isolated symptom, investigation revealed underlying intracerebral tumor in 15 cases (121). The prevalence of headache in patients with brain metastases or primary brain tumors is 60–90% (122, 123). The headache is presumably produced by traction on pain-sensitive vascular and dural tissues. Patients with multiple metastases and those with posterior fossa metastases are more likely to report this symptom (124). The pain may be focal, overlying the site of the lesion, or generalized. Headache has lateralizing value, especially in patients with supratentorial lesions (125). Posterior fossa lesions often cause a bifrontal headache. The quality of the headache is usually throbbing or steady, and the intensity is usually mild to moderate (125).

Among children, clinical features predictive of underlying tumor include sleep-related headache, headache in the absence of a family history of migraine, vomiting, absence of visual symptoms, headache of <6 months’ duration, confusion, and abnormal neurologic examination findings (126).

The headache is often worse in the morning and is exacerbated by stooping, sudden head movement, or Valsalva’s maneuvers (cough, sneeze, or strain) (125). In patients with increased intracranial pressure, these maneuvers can also precipitate transient elevations in intracranial pressure called plateau waves, which may also be spontaneous and can be associated with short periods of severe headache, nausea, vomiting, photophobia, lethargy, and transient neurologic deficits (127, 128). Occasionally, these plateau waves produce life-threatening herniation syndromes (127, 128).

Leptomeningeal metastases, which are characterized by diffuse or multifocal involvement of the subarachnoid space by metastatic tumor, occur in 1–8% of patients with systemic cancer (129). Non-Hodgkin’s lymphoma and acute lymphocytic leukemia both demonstrate a predilection for meningeal metastases (129); the incidence is lower for solid tumors alone. Among solid tumors, adenocarcinomas of the breast and small cell lung cancer predominate (130).

Leptomeningeal metastases present with focal or multifocal neurologic symptoms or signs that may involve any level of the neuraxis (129, 131, 132). More than one third of patients present with evidence of cranial nerve damage, including double vision, hearing loss, facial numbness, and decreased vision (131, 132); this is particularly true among patients with underlying hematologic malignancy (132). Less common features include seizures, papilledema, hemiparesis, ataxic gait, and confusion (133). Generalized headache and radicular pain in the low back and buttocks are the most common pains associated with leptomeningeal metastases (132). The headache is variable and may be associated with changes in mental status (e.g., lethargy, confusion, or loss of memory), nausea, vomiting, tinnitus, or nuchal rigidity. Pains that resemble cluster headache (134) or glossopharyngeal neuralgia with syncope (135) have also been reported.

The diagnosis of leptomeningeal metastases is confirmed through analysis of the CSF, which may reveal elevated pressure, elevated protein level, depressed glucose level, and/or lymphocytic pleocytosis. Ninety percent of patients ultimately show positive cytology, but multiple evaluations may be required. After a single lumbar puncture (LP), the false-negative rate may be as high as 55%; this falls to only 10% after three LPs (131, 136, 137). The sensitivity and specificity of CSF cytology is enhanced by the use of fluorescence insitu hybridization (FISH) (138, 139) or immunocytochemical techniques (140). Tumor markers, such as lactic dehydrogenase (LDH) isoenzymes (131), carcinoembryonic antigen (141),
β₂-microglobulin (141), and tissue polypeptide antigen (142), may help delineate the diagnosis. Flow cytometry for detection of abnormal deoxyribonucleic acid content may be a useful adjunct to cytologic examination (143).

Gadolinium-enhanced MRI of the neuroaxis can assist in identifying leptomeningeal metastases. When headache is the presenting feature, gadolinium-enhanced MRI examination of the brain is the initial imaging investigation, especially if signs of cranial nerve involvement are present (144, 145). If this is nondiagnostic and if the pain distribution indicates spinal involvement, the sensitivity is enhanced by performing an examination of the whole spine. There is evidence that gadolinium-enhanced spinal MRI may be positive in almost 50% of patients without clinical findings related to the spinal region and in 60% of patients with negative CSF cytology (146). Additionally, findings of contrast enhancement of the basilar cisterns, parenchymal metastases, hydrocephalus without a mass lesion, or spinal subarachnoid masses or enhancement may all have therapeutic implications (129).

Untreated leptomeningeal metastases cause progressive neurologic dysfunction at multiple sites, followed by death in 4–6 weeks. Current treatment strategies, which include radiation therapy to the area of symptomatic involvement, corticosteroids, and intraventricular or intrathecal or systemic chemotherapy, are of limited efficacy, and in general, patient outlook remains poor (133, 147, 148).

Base of skull metastases are associated with well-described clinical syndromes (149), which are named according to the site of metastatic involvement: orbital, parasellar, middle fossa, jugular foramen, occipital condyle, clivus, and sphenoid sinus. Cancers of the breast, lung, and prostate are most commonly associated with this complication (149, 150), but any tumor type that metastasizes to bone may be responsible. When base of skull metastases are suspected, axial imaging with CT (including bone window settings) is the usual initial procedure (149). MRI is more sensitive for assessing soft tissue extension, and CSF analysis may be needed to exclude leptomeningeal metastases.

As noted, specific cranial neuralgias can occur from metastases in the base of skull or leptomeninges. They are most commonly observed in patients with prostate and lung cancer (158, 159). Invasion of the soft tissues of the head or neck or involvement of sinuses can also eventuate in such lesions. Each of these syndromes has a characteristic presentation. Early diagnosis may allow effective treatment of the underlying lesion before progressive neurologic injury occurs.

Headache and facial pain in patients with cancer may have many other causes. Unilateral facial pain can be the initial symptom of an ipsilateral lung tumor (175). Presumably, this referred pain is mediated by vagal afferents. Facial squamous cell carcinoma of the skin may present with facial pain due to extensive perineural invasion (176). Patients with Hodgkin’s disease may have transient episodes of neurologic dysfunction that has been likened to migraine (177). In some cases this may be a reversible posterior leukoencephalopathy syndrome (RPLS), which is characterized by headache, conscious disturbance, seizure, and cortical visual loss with neuroimaging finding of edema in the posterior regions of the brain (178).

Headache may occur with cerebral infarction or hemorrhage, which may be due to nonbacterial thrombotic endocarditis or disseminated intravascular coagulation. Headache is also the usual presentation of sagittal sinus occlusion, which may be due to tumor infiltration, hypercoagulable state, or treatment with L-asparaginase (179). Headache due to pseudotumor cerebri has also been reported to be the presentation of superior vena caval obstruction in a patient with lung cancer (180). Tumors of the sinonasal tract may present with deep facial or nasal pain (181).

Radiculopathy or polyradiculopathy may be caused by any process that compresses, distorts, or inflames nerve roots. Painful radiculopathy is an important presentation of epidural tumor and leptomeningeal metastases (see preceding text).

The ventral rami of the upper four cervical spinal nerves join to form the cervical plexus between the deep anterior and lateral muscles of the neck. Cutaneous branches emerge from the posterior border of the sternocleidomastoid. In the cancer population, plexus injury is frequently due to tumor infiltration or treatment (including surgery or radiotherapy) of neoplasms in this region (185). Tumor invasion or compression of the cervical plexus can be caused by direct extension of a primary head and neck malignancy or by neoplastic (metastatic or lymphomatous) involvement of the cervical lymph nodes (185). Pain may be experienced in the preauricular (greater auricular nerve) or postauricular (lesser and greater occipital nerves) regions or the anterior neck (transverse cutaneous and supraclavicular nerves). Pain may refer to the lateral aspect of the face or head or to the ipsilateral shoulder. The overlap in the pain referral patterns from the face and neck may relate to the close anatomic relationship between the central connections of cervical afferents and the afferents carried in the cranial nerves V, VII, IX, and X in the upper cervical spinal cord. The pain may be aching, burning, or lancinating and is often exacerbated by neck movement or swallowing. Associated features can include ipsilateral Horner syndrome or hemidiaphragmatic paralysis. The diagnosis must be distinguished from EC of the cervical spinal cord and leptomeningeal metastases. MRI or CT scan of the neck and cervical spine is usually required to evaluate the etiology of the pain.

The two most common causes of brachial plexopathy in patients with cancer are tumor infiltration and radiation injury. Less common causes of painful brachial plexopathy include trauma during surgery or anesthesia, radiation-induced second neoplasms, acute brachial plexus ischemia, and paraneoplastic brachial neuritis.