Definition and Epidemiology

The term bone tumor is broadly used and encompasses a wide variety of bone lesions. Bone tumors may be benign neoplasms of the musculoskeletal tissues, such as osteoblastoma or chondroblastoma (CBMA); a sarcoma, which is a malignant tumor of mesenchymal or neuroectodermal origin such as osteosarcoma and Ewing sarcoma; a tumor of vascular, hematopoietic, or lymphoid tissues, such as hemangioma, multiple myeloma, or lymphoma; or a metastatic cancer, which is a secondary tumor that arises from a cancer elsewhere in the body, such as breast or prostate. In addition, the term bone tumor may apply to hamartomas, which are abnormal growths of normal tissues, such as osteochondroma, and to non-neoplastic lesions of uncertain cause, such as aneurysmal bone cyst (ABC) and pigmented villonodular synovitis. Tumor mimics, such as bone lesions caused by gout, arthritis, and metabolic diseases, can also have the appearance of a bone tumor. Because so many disparate bone lesions may be described as bone tumors, clinicians should take care when informing patients that they may have a bone tumor.

The most common malignant tumor that originates in bone is multiple myeloma, with an incidence of 6.1 per 100,000. Approximately 20,000 adults are diagnosed with multiple myeloma each year, and 10,000 will die of the disease. The median age at diagnosis is 70 years.

Myeloma, lymphoma, and leukemia are lymphoproliferative disorders characterized by excess production of abnormal lymphocytes. Primary lymphoma of bone is a rare type of lymphoma that accounts for approximately 7% of all malignant bone tumors. Cancers that originate in connective tissues such as bone, tendons, or muscles are classified as sarcomas. Osteosarcoma, the most common bone sarcoma, originates from primitive mesenchymal bone-forming cells. Ewing sarcoma originates from cells that arise in the embryonic neural crest. Chondrosarcoma (CHSA)develops in primitive mesenchymal cartilage-forming cells.¹ Primary cancers of the bone account for less than 0.2% of all cancers. Osteosarcoma is the most common sarcoma, with an incidence estimated to be 1 in 1 million. After osteosarcoma, CHSA and malignant fibrous histiocytoma are the most common varieties of sarcoma. Approximately 3000 primary bone sarcomas are diagnosed each year in the United States. In children and teenagers younger than 20 years, the incidence of malignant bone tumors is 8.7 per million.²

In adults older than 40 years, metastatic deposits in bone from cancers elsewhere in the body are the most common cause of bone tumors. Approximately 70% of patients with advanced breast or prostate cancer and 15% to 30% of patients with kidney, lung, uterine, thyroid, stomach, rectal, bladder, and colon cancer will develop metastatic cancer in the bones.³ More than 350,000 people die with bone metastasis each year in the United States.³ Breast cancer has been found to be the most common primary tumor type (n = 4041). In the Medicare cohort (mean age 75.6 years; standard deviation [SD] = 7.8), 6427 (0.495%) patients were identified with metastatic bone disease. Breast (n = 1798) and prostate (n = 1862) cancers were the most common primary tumor types. It is estimated that 279,679 (95% confidence interval, 274,579 to 284,780) U.S. adults alive on December 31, 2008, had had evidence of metastatic bone disease in the previous 5 years. Breast, prostate, and lung cancers accounted for 68% of these cases.⁴

The incidence of benign bone tumors is difficult to estimate because many are left untreated and others are never discovered. In children, osteochondroma, nonossifying fibroma, and fibrous dysplasia (FD) are the most common benign bone tumors. In persons aged 20 to 40 years, giant cell tumor (GCT) and enchondroma are the most commonly diagnosed bone tumors.⁵ A recent study indicates that this incidence has not changed in past 30 years.⁶

Pathophysiology

In most cases, bone tumors arise from the deletion, addition, or modification of the tumor cell DNA or DNA-associated proteins. Genetic alterations have been identified in both benign and malignant bone and soft tissue neoplasms. These genetic and epigenetic anomalies disrupt the orderly growth, division, or senescence of cells by a number of mechanisms. One type of tumorigenesis is linked to the creation of a novel “fusion” gene. Approximately half of the fusion genes that have been identified in sarcomas belong to the FET family of transcription regulation genes. More than one molecular or genetic abnormality may be necessary for the development of cancer. The identification of precise markers and mechanisms of tumorigenesis in the laboratory has now benefited the clinician at the bedside in the form of highly specific diagnostic tests and treatments. The identification of specific chromosomal abnormalities allows definitive diagnosis of certain sarcomas using DNA probes. In addition, treatments that inhibit critical molecular abnormalities in bone tumors are now a reality. Outside the laboratory, researchers are examining large epidemiologic and genomic databases, seeking to apply “big data” techniques to the understanding and treatment of bone cancers.

Some bone cancers arise from an inherited tumor gene such as the retinoblastoma (RB1) gene. The cells of normal individuals have two intact RB1 genes on chromosome 13, and both genes must be defective for cancer to develop. Affected individuals inherit one defective copy of the RB1 gene from a parent; the other mutates during fetal development. These children develop retinoblastoma in childhood and they are at high risk for osteosarcoma, small cell lung cancer, and synovial sarcoma as adults.⁷

A small number of malignant bone tumors are caused by chronic diseases. Approximately 5% of patients with widespread Paget disease of bone (see Chapter 182 develop sarcoma in the affected bones, usually osteosarcoma. Patients with long-standing infection in the bone (see Chapter 185 are at risk for development of a malignant tumor, including squamous cell carcinoma, at the site of the draining infection. The data on exposure to chlorinated dioxin contaminants in the herbicide Agent Orange have not provided consistent evidence of an increased cancer risk in exposed individuals.⁸ Other factors, such as genetic polymorphisms, which are known to increase the risk of developing non-Hodgkin lymphoma, may play a role.⁹

Clinical Presentation

Bone tumors are likely to be discovered in an ambulatory setting such as a primary care office. There are three distinct patterns of clinical presentation depending on whether the tumor is latent, active, or aggressive (Box 172-1). Latent bone tumors, such as nonossifying fibroma in children and enchondroma in adults, do not grow appreciably over time and do not cause bone pain or symptoms. These tumors are usually discovered as incidental findings during an evaluation for a musculoskeletal injury. In latent bone tumors, the radiographs show that the lesion is not growing and is not causing any damage to the bone. A careful history and physical examination combined with the x-ray findings are often enough to verify that the injured ligament, bone, or tendon is the source of the pain, not the tumor. In general, no workup or treatment for the tumor is needed other than repeat radiographs in 6 to 12 months to verify that the lesion is not clinically significant. In some cases, latent bone tumors may be large enough to create a real or perceived risk of pathologic fracture. In these cases referral for risk assessment is recommended. Careful analysis of the radiographs and other imaging studies is used to calculate the risk of pathologic fracture and decide on the need for prophylactic fixation.¹⁰

Active bone tumors are usually (but not always) benign. These tumors grow slowly and will locally invade and weaken the bone. Examples of active tumors include ABCs and unicameral bone cysts (UBCs), CBMAs, chondromyxoid fibromas (CMFs), and FD in children; and FD, GCT, and human CHSA in adults. In the primary care setting, the patient reports months of mild, gradually increasing pain with minimal loss of function and no obvious abnormalities on physical examination. In these patients, pain after an injury may be the reason the patient visits the primary care provider (PCP), but a careful history will reveal that the pain was present and gradually increasing before the injury. This is an important distinction because it establishes that the tumor is the source of the pain, not the injury. In active bone tumors, the radiographs show that the tumor is slowly growing. There will be evidence of local damage and a corresponding response from the involved bone. Referral of these cases to a specialist is recommended. These patients will require a regional skeletal workup and a biopsy before treatment. Most of these tumors are benign, and as a result many can be treated by thorough curettage of the tumor cavity followed by packing with bone graft, bone cement, or other material to restore the bone integrity.

Aggressive bone tumors are likely to be malignant and typically are discovered after months of progressively severe pain and a mass or swelling of the limb or joint. Examples of aggressive bone tumors include osteosarcoma, lymphoma, Ewing sarcoma, and metastatic adenocarcinoma. Constitutional symptoms are unusual in aggressive bone tumors, but fever and leukocytosis may occur in Ewing sarcoma and lymphoma. In the early stages the pain may mimic a musculoskeletal injury or a sprained joint, but as time goes on the pain changes. The pain becomes less activity related and more constant and may occur at night. There is swelling or a mass near a large joint such as the knee, hip, or shoulder. In active bone tumors, the radiographs show a permeative lesion that has clearly been growing and has damaged the bone, invaded the soft tissues, and prompted a vigorous local response such as a periosteal reaction. Careful history taking will allow the clinician to distinguish the pain of an aggressive bone tumor from typical pain of musculoskeletal origin, even at a relatively early stage. Patients with chordoma, a type of sarcoma that has a predilection for the sacrum, may come to their health care provider with persistent low back pain, constipation, or difficulty with defecation. Digital rectal examination reveals a mass growing out of the sacrum, which can block the rectum. Patients with active bone tumors require prompt referral to a specialist. A complete workup, including computed tomography (CT) scan of the chest and a whole body bone scan, is required. These tumors have a significant risk of being malignant sarcomas, which are treated by combination therapy including aggressive surgery, chemotherapy, and occasionally radiation.

Adults who have been treated for cancers of the breast, prostate, lung, thyroid, kidney, or some gastrointestinal sites are at risk of bone metastasis, even years after the completion of the treatment. The metastasis may initially manifest as a musculoskeletal ache or stiffness in the back, shoulder, hip, or chest wall. These patients should receive regular follow-up monitoring for bone metastasis.

Common Clinical Scenarios

There are common clinical circumstances in which a primary care physician is called on to evaluate the potential for a bone tumor.

Medical History and Physical Examination

The evaluation of a bone tumor begins with a thorough history and physical examination.¹¹ In addition to the general medical history, the patient’s cancer risk factors and personal cancer history must be elicited. Tobacco use as well as the status of cancer screening examinations, such as prostate examination and breast self-examination and mammography, should be documented. Patients who were treated for cancer in the past may consider themselves cured, and as a result they may not volunteer their cancer history unless carefully prompted. A thorough health history is often the most efficient way to identify the origin of the bone tumor. In taking the history of present illness, the provider should endeavor to establish the precise chronology of the pain. Patients may ascribe the pain from a bone tumor to a minor injury or accident. However, closer questioning will often reveal that the pain was present before the injury.

The general physical examination may reveal a systemic condition that might be associated with bone tumors, such as a growth disturbance, anemia, or cachexia. The focused musculoskeletal examination should assess the entire region of the body involved in the problem, not just an isolated part. The shoulder, hip, and knee cannot be comprehensively examined with the patient’s clothing left on, and an incomplete examination may contribute to delay in making the correct diagnosis. The examiner should look for the presence of warmth or inflammation, a mass, loss of full joint motion, or lymphadenopathy. Subtle abnormalities are easy to identify by comparing the findings in the affected region with those in the corresponding normal region. Even large lesions that are deep seated in the shoulder, pelvis, or thigh may be difficult to identify by palpation. However, they can be easily seen if the examiner visually compares the normal and the abnormal sides of the body from a short distance away.

Diagnostics

Screening laboratory examinations have a very limited role in the initial diagnostic evaluation of a patient with a suspected bone tumor. Specific diagnostic test-s are still very valuable. Laboratory tests are used in a targeted way (Table 172-1). For example, the widespread use of prostate-specific antigen (PSA) as a prostate cancer screening tool has been reduced or eliminated in favor of risk-adjusted screening by age. A similar targeted approach applies to all bone tumors. A patient with suspected multiple myeloma should have serum protein electrophoresis tested to identify secretion of tumor paraproteins. However, patients with high-grade sarcoma may have entirely normal laboratory findings. Bone lesions caused by infection are associated with an elevated or normal white blood cell count, an elevated erythrocyte sedimentation rate (ESR), and elevated C-reactive protein. In certain sarcomas, a definitive diagnosis can be made from pathognomonic molecular markers that can be identified by the pathologist in the biopsy material.

TABLE 172-1

Diagnostic Tests for Bone Tumors

Method	Best for	Expected Result	Precautions
Plain radiograph	Evaluation of suspected tumor after physical examination and history	Benign: well circumscribed, sclerotic margin Aggressive: poorly circumscribed permeative destruction of bone	Soft tissue lesions not detected, no abnormality seen in early metastasis
Hematology: complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein	Differentiation of tumor from infection, evaluation of suspected hematologic malignant neoplasm (e.g., myeloma, lymphoma)	Lesions caused by infection: elevated white blood cell count, elevated ESR	Most benign bone tumors do not cause alterations in CBC, ESR, or C-reactive protein
Blood chemistry	Evaluation of prognosis (e.g., osteosarcoma), confirmation of diagnosis (e.g., Paget disease)	Elevated alkaline phosphatase and ionized calcium levels	Some bone tumors do not cause alterations in blood chemistry
Specific blood tests	Index of tumor activity in specific cancers (e.g., prostate-specific antigen [PSA] in prostate cancer)	Dependent on type of cancer (e.g., prostate cancer with metastasis will show abnormal PSA levels)	Not useful as an initial screening tool
Urinalysis	Confirmation of specific diagnostic entity (e.g., Bence-Jones protein for myeloma, hematuria in renal cell carcinoma)	Elevated secretion of tumor paraproteins	Not diagnostically useful for benign bone tumors
Technetium 99m (99mTc) bone scan	Determination of presence and location of multiple bone metastases in cancer	Abnormally elevated tracer uptake in areas of possible metastatic deposits in bone (“hot spots”)	False-positive results from old fracture, arthritis, infection, and other nontumor causes
Computed tomography	Evaluation of lesions in complex bones, such as pelvis or spine	Extent of bone destruction, quantitative risk of pathologic fracture	Substantial radiation dose
Magnetic resonance imaging	Soft tissue lesions, hematologic malignant neoplasm (e.g., lymphoma), staging of lymph nodes	Tumors invisible on other imaging techniques (e.g., early metastasis from breast cancer)	False-positive results from injury, infection, smoking, and metabolic diseases
Positron emission tomography (PET)	Assessment of effectiveness of treatment for bone tumors	High absorption of tracer by cancer cells	Role in staging and diagnosis of bone tumors is not well defined, some tumors are PET negative

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