Bone tumors may present with various signs and symptoms, including pain, mass, and limb deformity. The incidence of primary malignant bone tumors is approximately 3,600 cases annually in the United States. Benign bone tumors are estimated to be 100 times more common than malignant bone tumors, although the true prevalence is unknown. The most common presenting symptom of a malignant bone tumor is pain, often associated with a mass, and occasionally pathologic fracture. Patients with benign bone tumors may present with incidental findings noted on radiographs, painful mass/lesion, or pathologic fracture.¹

The patient’s age must be considered when determining the differential diagnosis. Diagnoses for pediatric patients differ significantly from those for young and older adults (Table 1). Common bone tumors in pediatric patients include nonossifying fibromas, unicameral bone cysts, aneurysmal bone cysts, osteosarcoma, and Ewing sarcoma. By comparison, in a patient older than 40 to 50 years, bone lesions are more commonly metastatic carcinoma, multiple myeloma, lymphoma, chondrosarcoma, and secondary osteosarcomas.

It is imperative to obtain a detailed history evaluating the location of the symptom(s), onset and duration, rate of growth, alleviating or exacerbating factors, pain history, trauma history, and infection history. In general, pain related to benign entities is relatively mild, often related to activity and relieved by NSAIDs. If the bony lesion is active or aggressive, such as aneurysmal bone cyst or giant cell tumor, it may cause progressive pain or fracture. In contrast, malignant bony lesions usually cause pain that is more severe and unresponsive to anti-inflammatory treatments. Patients often characterize the pain as dull, deep, or achy that is present with activity but also at rest and at night. An associated soft-tissue mass may cause distal extremity swelling or nerve compression with neurologic symptoms.

The history should also include questions regarding constitutional symptoms, such as fever, chills, night
sweats, unintentional weight loss, fatigue, lymphadenopathy, breast or other palpable masses, and diphosphonate use. Approximately 20% to 30% of patients with Ewing sarcoma present with fever.² In adults, metastatic disease to bone is vastly more common than primary bone malignancies, and a carcinoma or hematopoietic malignancy may present with a painful lesion or pathologic fracture. Any personal history of cancer, even diagnosed several decades prior, is a risk factor for metastatic bone disease. It is also important to identify any history of radiation, as there is a late risk of radiation-associated sarcomas. A prolonged history of diphosphonate use is a risk factor for impending or completed atypical femoral fractures, which are considered pathologic even though not neoplastic.

Physical examination can identify additional signs associated with the patient’s symptoms. The location, approximate size, and proximity to important structures should be noted. Palpation can reveal if the mass is soft, firm, or hard and if it is mobile or fixed. It is often possible to discern whether a soft-tissue mass is superficial or deep to the fascia by asking the patient to tense their muscles in the extremity; if the mass remains mobile, it is superficial, whereas if it becomes more immobile, it is below the fascia. A careful neurovascular assessment distal to the lesion is critical. For incidentally noted bone lesions, physical examination can diagnose the true problem that prompted medical attention. For example, if a patient presents with shoulder pain and radiographs reveal an enchondroma of the proximal humerus but the examination is consistent with subacromial impingement, the bone lesion can be designated an incidental finding, and the patient can be treated for rotator cuff pathology. The patient should also be examined for signs of systemic diseases and syndromes; for example, café-au-lait cutaneous lesions may indicate McCune-Albright syndrome, or clubbing of the fingertips may result from a pulmonary parenchymal process such as lung cancer. Other findings, such as lymphadenopathy and solid organ masses (particularly breast), may also be detected on physical examination and used to direct further diagnostics.

Similar to bone tumors, the prevalence of benign soft-tissue masses far exceeds malignant diagnoses; however, most soft-tissue sarcomas are painless, making them diagnostic challenges. Rhabdomyosarcoma is the most common malignant soft-tissue sarcoma in children, whereas undifferentiated pleomorphic sarcoma, liposarcoma, fibrosarcoma, and leiomyosarcoma are more common soft-tissue sarcoma subtypes in adults.

The history should include onset, duration, temporality, alleviating and exacerbating factors, and associated symptoms. Distal paresthesias may suggest a nerve sheath tumor or nerve compression. Masses or symptoms that fluctuate with activity may suggest a vascular or cystic component; inflammatory lymph nodes can also vary in size over time. In a patient who taking an anticoagulant medication, a growing mass might be an acute or chronic hematoma, although in these situations, malignancy must also be considered and ruled out.

The history should include inquiry into constitutional symptoms, a personal or family history of cancer, and syndromes associated with soft-tissue masses. For example, neurofibromatosis results in multiple tumors and risk of malignancy, and 5% to 10% of desmoid tumors are associated with familial adenomatous polyposis.³ A history of traumatic brain injury may lead to heterotopic ossification, and chronic renal failure can be associated with tumoral calcinosis.⁴

Physical examination can suggest a tumor’s size and depth to fascia. It is important to note whether the mass itself and the overlying skin are mobile. Any areas of compromised skin where the tumor is threatening to fungate may influence decisions about secondary coverage and preoperative or postoperative radiation. Peripheral nerve sheath tumors or masses compressing nerves can have a positive Tinel sign. Highly vascular lesions may
have a bruit or thrill on auscultation. Regional lymph node metastases can occur in rhabdomyosarcoma, synovial sarcoma, angiosarcoma, epithelioid sarcoma, and clear cell sarcoma; therefore, evaluation for lymphadenopathy should be performed.

Radiographs are the first step in the workup of bone tumors because they are accessible, quick, and inexpensive. In any potentially malignant case, orthogonal views of the whole bone as well as the joints above and below the symptomatic area should be obtained and closely examined. In combination with the history and physical examination, radiographic characteristics can typically lead to a narrow differential diagnosis. Enneking described the following factors that can be determined from radiographs: (1) skeletal maturity; (2) tumor location; (3) what the tumor is doing to the bone; (4) the bone’s response; and (5) if the tumor is producing any matrix. Patient age, skeletal maturity, and the location of the bone lesion can suggest certain pathologies. For example, Ewing sarcoma and chondrosarcoma are common in flat bones, whereas osteogenic osteosarcomas are common in the distal femoral and proximal tibial metaphyseal regions (Table 2). It is important to note whether the lesion is located in the epiphysis, metaphysis, and diaphysis, as well as the medullary, cortical, or periosteal spaces. Other relevant questions include: Are there polyostotic lesions? Is the tumor destroying cancellous and/or cortical bone? Is the lesion expanding the cortex? Features of containment, that is, a narrow zone of transition and a reactive or sclerotic rim, suggest an indolent process. In contrast, features such as a wide zone of transition, moth-eaten or permeative destruction, cortical expansion and erosion, or an associated soft-tissue mass suggest an aggressive process. The presence of irregular periosteal reaction such as lamellated, spiculated, interrupted patterns (eg, perpendicular/sun-burst, Codman triangle) is suggestive of an aggressive underlying process (Figure 1 shows multiple types of aggressive periosteal reactions in a primary lymphoma of bone). Finally, the type of matrix produced can strongly influence the differential diagnosis; for example, a bone-forming aggressive bone lesion in a pediatric patient is very likely an osteosarcoma.

For soft-tissue masses, radiographs are useful to determine whether there is a mineralized or osseous component, such as myositis ossificans or an osteochondroma with an associated bursa. If calcifications are present, the pattern may suggest certain pathologies such as phleboliths for hemangiomas and peripheral calcification for myositis ossificans. Most soft-tissue tumors cannot be fully seen on radiograph, so additional imaging is warranted.

Ultrasonography is quick, relatively inexpensive, does not require sedation, and does not involve exposure to ionizing radiation.⁵ It is useful for characterizing superficial soft-tissue tumors, particularly in children. If a soft-tissue mass is not palpable on physical examination, ultrasonography is useful to determine whether a defined mass is present. Doppler ultrasonography can provide information regarding intralesional vascular flow and the degree of vascularity. Ultrasonography can also identify lipomas and differentiate cystic from solid components of a lesion.

Axial imaging can be very useful in evaluating bone tumors when radiographs do not provide sufficient information (eg, seeing occult lesions, determining location in axial or flat bones). CT can further characterize bony involvement, tumor matrix, periosteal reaction, and pathologic fractures.⁶ CT can assess bone loss to help determine pathologic fracture risk⁷ as well as assist with preoperative planning. CT with and without contrast can also be an acceptable alternative imaging modality for soft-tissue masses for patients who cannot undergo MRI. CT is also routinely used for systemic staging. In patients with a bone or soft-tissue sarcoma, a chest CT should be obtained to evaluate for pulmonary metastases (Figure 2). For myxoid liposarcoma, which has a propensity for extrapulmonary metastases such as the retroperitoneum and axial skeleton, CT of the chest, abdomen, and pelvis and MRI of the whole spine or whole body have been suggested for staging and surveillance.⁸ For patients with suspected metastatic carcinoma,

CT of the chest, abdomen, and pelvis should be obtained to evaluate for solid organ masses and to assess disease burden.

MRI is useful to evaluate intramedullary and extramedullary masses, providing anatomic detail, neurovascular invasion or proximity, medullary involvement or edema, and matrix character. When a primary bone sarcoma is suspected, it is important to communicate with the radiologist so that the image will include the entire affected bone to identify any skip metastases. MRI permits local staging by defining tumor size, extracompartmental extent, and proximity to adjacent structures. Intravenous gadolinium contrast can assist with the diagnosis as well as identify the best areas for biopsy placement. Moreover, a 2019 radiology study of 130 adults with nonmetastatic soft-tissue sarcomas identified three MRI characteristics that were predictive of high-grade, metastasis-free survival and overall survival: necrosis, heterogeneity on T2 sequences, and peritumoral contrast enhancement.⁹

With increased availability of whole-body MRI, the role of this imaging modality for staging of primary bone tumors is under investigation but thus far is not being used routinely. A 2021 study in patients with osteosarcoma and Ewing sarcoma found no significant differences between whole-body 18F-fluorodeoxyglucose positron emission tomography/CT, technetium Tc-99 methylene diphosphonate skeletal scintigraphy, and whole-body MRI in sensitivity, specificity, positive predictive value, and negative predictive value in detecting skeletal metastases.¹⁰

Whole-body bone scans are most commonly used in the workup and staging of primary and secondary bone malignancies to detect polyostotic disease. By identifying areas of the skeleton with high turnover, bone scans can identify additional lesions that might be optimal for tissue biopsy. In the setting of primary bone tumors, bone scans can evaluate for skip as well as distant metastases. For patients with metastatic carcinoma, bone scans quantify the burden of osseous disease and identify other lesions at potential risk of fracture. Hematopoietic malignancies may have lesions that are not detectable on bone scans, so skeletal surveys or low-dose, whole-body CT scans are more appropriate for diseases such as multiple myeloma.

Positron emission tomography CT is useful in monitoring response to systemic therapy.¹¹ It is also used to monitor conditions such as neurofibromatosis, because it has a role in distinguishing malignant transformation.¹²

A biopsy is often needed to establish or confirm a diagnosis and must be performed before treatment. Ideally, this should be performed or directed by the surgeon who will be definitively treating the patient because the biopsy technique and approach have prognostic and
therapeutic implications. Unplanned excision of sarcomas leads to increased local disease recurrence, need for advanced soft-tissue reconstruction, and amputation.¹³,¹⁴ Moreover, patients with unexpected positive margins have worse oncologic outcomes of local recurrence-free survival and cause-specific survival.¹⁵

All local imaging and staging studies should be completed before the biopsy, as these data help form a differential diagnosis and may identify an optimal area of the tumor to sample. In general, there is very little utility in fine-needle aspiration for musculoskeletal lesions because the diagnoses require examination of tissue architecture. Thus, biopsy procedures are typically core needle, incisional, or excisional. Core biopsies are minimally invasive and can be performed with image guidance (Figure 3). Incisional open biopsies are performed in the operating room and can yield a larger amount of tissue; the surgical principles of biopsy must be followed to avoid contamination of the surrounding tissues, which could compromise oncologic and survival outcomes. Excisional open biopsies are appropriate for small, superficial soft-tissue lesions that can be easily removed with a wide margin.

The workup of a bone lesion is presented in Figure 4.

Based on the biopsy, it is often possible for specialty-trained musculoskeletal pathologists to determine grade; however, there is the potential for sampling error. There are several grading systems available; commonly, the American Joint Committee on Cancer system is used: grade 1, well differentiated; grade 2, moderately well differentiated; grade 3, poorly differentiated; and grade 4, dedifferentiated. Grading has prognostic implications because higher grade tumors tend to be more clinically aggressive with increased growth and incidence of metastases.¹⁶

Although many musculoskeletal pathologies can be determined by hematoxylin and eosin stains, immunohistochemistry and molecular diagnostics are increasingly used to determine and verify diagnoses. For example, up to 95% of giant cell tumors of bone have a H3F3A gene mutation; both primary and malignant versions can be verified by immunohistochemistry staining with antibodies against H3.3 G34W/R/V.¹⁷

There are several staging systems to describe benign and malignant bone and soft-tissue tumors. Enneking described staging systems for benign and malignant bone tumors, and these systems were adopted by the Musculoskeletal Tumor Society (MSTS). The other commonly used system for malignant bone tumors and malignant soft-tissue tumors was developed by the American Joint Committee on Cancer. None of the staging systems are comprehensive; there is debate regarding true prognostic variables; however, they provide a framework that is useful for prognostication and management.

Benign bone tumors have varied biologic activity, and the Enneking staging system reflects those differences. Stage 1 tumors are latent tumors, which are typically asymptomatic and found incidentally. If observed over time, these lesions remain stable and may even regress; examples include nonossifying fibromas, enchondromas, and osteochondromas. Questionable lesions should be followed, and if there is a clinical or radiographic suggestion of more aggressive behavior, the surveillance interval should be shortened, with consideration of advanced imaging and potentially a biopsy. Stage 2 tumors are active and can be mildly symptomatic. These lesions can grow slowly and cause cortical expansion or plastic deformation; examples include osteoid osteoma, chondromyxoid fibroma, and unicameral bone cysts. Stage 3 tumors are aggressive and can display rapid growth with cortical destruction and an associated soft-tissue mass. These lesions are more
likely to present with pathologic fractures than latent or active tumors. Osteoblastoma, giant cell tumor, and aneurysmal bone cyst are examples of aggressive benign bone tumors.