Musculoskeletal tumors are a diverse group of neoplasms that arise from various tissues of the musculoskeletal system, including bone, cartilage, muscle, and connective tissue. These tumors can be benign or malignant and can present in any age group.
The World Health Organization classifies musculoskeletal tumors (Table 1) as chondrogenic (cartilage forming), osteogenic (bone forming), fibrogenic, vascular, those derived from the notochord (an embryonic spinal structure), those with many osteoclastic cells, and hematopoietic neoplasms of bone. In addition, there is the large and important category of “other mesenchymal tumors of bone”, which includes more commonly seen conditions such as simple bone cysts, fibrous dysplasia, lipomas, and metastatic disease.
· Benign: chondroma; enchondroma; osteochondroma; chondroblastoma; chondromyxoid fibroma
· Malignant: chondrosarcoma
· Benign: osteoid osteoma
· Intermediate (locally aggressive): osteoblastoma
· Malignant: osteosarcoma
· Benign: fibroma, non-ossifying fibroma
· Intermediate (locally aggressive): desmoplastic fibroma
· Malignant: fibrosarcoma
Vascular tumors of bone
· Benign: hemangioma
· Malignant: angiosarcoma
Osteoclastic giant cell-rich tumors
· Benign: aneurysmal bone cyst; Non-ossifying fibroma
· Intermediate (locally aggressive): giant cell tumor of bone
· Malignant: giant cell tumor of bone, malignant
· Benign: benign notochordal cell tumor
· Malignant: chordoma
Other mesenchymal tumors of bone
· Benign: simple bone cyst; fibrous dysplasia; lipoma
· Malignant: adamantinoma of long bones; leiomyosarcoma; liposarcoma; bone metastases
Hematopoietic neoplasms of bone
· plasmacytoma of bone (myeloma); lymphoma; Hodgkin disease.
Table 1: The 2020 WHO Classification of Bone Tumors, with examples of benign and malignant lesions in each category.
Beyond considering the cell of origin, evaluating and classifying musculoskeletal neoplasia considers the grade and stage of the lesion. The grade represents the degree of aggressiveness of the lesion and is based primarily on histology, but also incorporates imaging features, such as the growth and destruction associated with the tumor. Grading is usually on a 0 to 3-point scale: benign (0), low grade, intermediate grade, and high grade (3). Grade predicts biological behavior and, thereby, assists in planning treatment. The stage of a tumor is based on its geographic location(s) in the body: that is; whether it is localized to one site, has spread to nearby tissues or organs (regional metastases) or has spread to distant sites (metastatic). These categories influence treatment decisions. A common way of describing the stage of a tumor is the TNM system provided by the AJCC (American Joint Commission on Cancer), where “T” is the size, “N” is the status of lymph node involvement, and “M” is the presence or absence of metastatic disease (local or distant). In musculoskeletal neoplasia, the Enneking Staging System provides another alternative and incorporates the tumor grade, its anatomical features, and the status of metastatic behavior.
Musculoskeletal tumors are rare. Indeed, a malignant lesion found in the bone is more likely to be a metastasis from another primary cancer than a primary bone lesion. Further, the most common oncologic condition that originates within the bone, multiple myeloma, is of blood cell, not bone cell, origin.
The incidence of musculoskeletal tumors varies according to tumor type and age group. Osteosarcoma is the most common primary bone cancer, followed by chondrosarcoma and Ewing sarcomas. The peak incidence of most malignant bone tumors is associated with a specific age group. For example, Ewing sarcoma, osteosarcoma, neuroblastoma, retinoblastoma, and rhabdomyosarcoma are the most common malignant lesions in patients under 20 years old, but relatively unlikely in adults over 40 years old.
In older patients, metastatic carcinoma, myeloma, and non-Hodgkin lymphoma are more likely than primary bone sarcoma. Benign lesions also have age predilections, with simple bone cysts and chondroblastomas typically occurring in skeletally immature individuals, and giant cell tumors occurring in skeletally mature individuals.
There are exceptions to the general rules of age distribution. For example, osteosarcoma has a second peak in adults older than 50 years who have Paget’s disease, as the Pagetic bone can undergo malignant transformation. Likewise, patients treated with radiation therapy or chemotherapy for other cancers are susceptible to developing bone malignancies at any age.
The clinical presentation of musculoskeletal tumors can vary depending on the type and location of the tumor. Patients may experience pain, swelling, or other non-specific complaints. A palpable mass may also be present due to the expansion of the tumor. Tumors can compress nearby structures, especially nerves, leading to local or distal symptoms.
When a musculoskeletal tumor grows within a bone, it can weaken the bone and make it more prone to breaking, even with minimal trauma. This condition is known as a pathological fracture. In some cases, a fracture without significant injury may be the first sign of a tumor's presence.
Constitutional symptoms, such as fatigue, malaise, unexplained weight loss, fevers, and night sweats, may also occur with musculoskeletal malignancies. Sometimes, tumors may be discovered incidentally during imaging studies performed for other reasons, especially in the case of benign or non-aggressive tumors.
Radiology plays a critical role in the diagnosis and management of musculoskeletal tumors. X-ray is often the first imaging modality and, in conjunction with the patient’s history and clinical findings, can usually lead to a diagnosis of a lesion involving the bone. Advanced imaging studies, including computed tomography (CT), magnetic resonance imaging (MRI), and positron emission topography (PET) scans, are used for evaluation of soft tissue musculoskeletal malignancies and can provide more detailed information regarding tumor extent and metastases for bony lesions.
When evaluating a radiograph of a suspected bone tumor, the first feature to note is the number of foci. Multiple lesions typically indicate osteomyelitis. However, bone islands, fibrous dysplasia, and enchondromatosis (a proliferation of enchondromas) are also associated with multiple lesions visible on x-ray.
The next considerations are the size and location of the lesion within the bone. Size is an important diagnostic criterion for some tumors. A tumor that would otherwise be classified as an osteoid osteoma becomes an osteoblastoma, for example, if larger than 1.5 cm. Even in cases where size of the lesion is not part of the diagnostic criteria, lesion size can indicate biological behavior. For instance, a thick cartilage cap on an osteochondroma (measuring more than 1.5 – 2.0 cm) suggests that it has transformed into a chondrosarcoma.
When considering the location of a lesion, two aspects are critical: the specific bone affected and the site within the bone where the lesion is found. Many bone tumors are associated with specific bones. For example, adamantinoma is classically found in the tibia, and osteoblastoma develops in posterior elements of spine. The site within the bone can be defined by longitudinal descriptors (e.g. diaphyseal, metaphyseal, or epiphyseal) and transverse descriptors (e.g. medullary, endosteal, cortical, or periosteal).
Other radiographic features indicative of aggressiveness include the margins of the lesion (also known as the “zone of transition” between the lesion and adjacent bone), and whether there is any periosteal reaction, mineralization or soft-tissue component associated with the lesion (Figure 1).
If a lesion has a so-called “geographic” or well-defined and narrow zone-of-transition or a sharp sclerotic margin, it is more likely to be benign. By contrast a non-geographic, poorly-defined, poorly-marginated infiltrative lesion with a wide zone-of-transition is more likely to be aggressive and malignant. Notably, osteomyelitis can have a non-geographic, poorly-defined, poorly-marginated, infiltrative appearance, reflective of aggressiveness but not malignancy.
The periosteum (the membrane on the cortex) can “react” to the bone lesion. Periosteal reactions have a variety of presentations on radiographs. A solid periosteal reaction of mature new bone deposited adjacent to the cortex, suggests a slow growing and less aggressive lesion: the solid reaction reflects the body’s ability to respond to the lesion with new bone growth. If the periosteal reaction is disorganized, showing hair-like or sunburst patterns, a more aggressive malignancy is likely. An “onionskin” or lamellar-appearing reaction indicates a lesion progressing with intermittent surges of growth.
There may also be reactions within the medullary canal, causing erosion of the inner surface of the cortex, known as endosteal scalloping. If the lesion is sufficiently slow-growing that the bone can form new tissue on the periosteal surface in response to the neoplasm, then the bone may expand in width. Simultaneous expansion of the cortex with endosteal scalloping may create a so-called “soap bubble” appearance. If the lesion is not slow-growing, it may simply break through the cortex and form an extra-cortical soft tissue mass.
Tumors may be lytic (due to stimulation of osteoclasts), sclerotic (due to stimulation of osteoblasts making new bone), or have a mixed pattern. The mineralization pattern of the matrix can help distinguish fibrous, osteoid or chondroid lesions. For example, a chondroid matrix (Figure 2) often has linear or lobular mineralization whereas a fluffy, cloudlike mineralization pattern suggests an osteoid matrix.
The presence of an extra-osseous soft-tissue mass suggests the presence of osteosarcoma, Ewing sarcoma, lymphoma, or infection.
CT scans are particularly useful in the evaluation of bone tumors as they provide high-resolution images of the bone structure (Figure 3). They can help identify the location, size, and extent of a bone tumor, as well as evaluate the involvement of adjacent soft tissues and organs. CT scans can also be used to guide a biopsy or other diagnostic procedures. CT scanning of the chest can be used as part of the staging workup of musculoskeletal tumors such as osteosarcoma, which are known to spread to the lungs.
MRI scans (Figure 4) are particularly useful in the evaluation of soft tissue tumors as they provide detailed images of the soft tissue structures. They can help identify the location, size, and extent of a soft tissue tumor. MRI can provide detailed information about the bone structure, including the bone marrow, cortical bone, and periosteum. It can also help identify the degree of bone destruction caused by the tumor, as well as its relationship to adjacent soft tissues and organs, notably the neurovascular bundles near the lesion.MRI can also be used to evaluate the response of the tumor to treatment, such as chemotherapy or radiation therapy.
Positron Emission Tomography (PET) scans are useful in evaluating the metabolic activity of tumors. PET scans can help differentiate between benign and malignant tumors and identify the spread of cancer to other parts of the body.
Ultrasound can be useful in the evaluation of soft tissue tumors, particularly in the extremities. It can help identify the location, size, and extent of a soft tissue tumor and can also be used to guide biopsy procedures.
Often the combination of patient age and radiographic appearance provides sufficient information to arrive at a diagnosis. Nevertheless, there are many instances in which a biopsy is needed.
Tissue specimens can be obtained by fine needle aspiration, core biopsy, and open techniques. An open biopsy is term incisional if a sample is removed; an excisional biopsy removes the entire lesion, or at least the grossly appreciable disease.
Fine needle biopsy is a quick and minimally invasive procedure that can be guided by palpation in a superficial location or, if necessary by ultrasound or CT. Fine needle biopsy is often used in conjunction with cytology but may not provide enough tissue for a definitive diagnosis. As true of any biopsy approach, there is a risk of sampling error (i.e., the tissue sample is not representative of the tumor as a whole).
Core needle biopsy attempts to increase diagnostic accuracy by using a larger gauge needle to remove a cylinder-shaped sample of tissue, but still carries a risk of sampling error. Core biopsy may not be suitable for tumors adjacent to organs and neurovascular bundles, even with image guidance.
Open biopsy utilizes a small incision to remove a larger sample of tissue from the tumor for analysis and might even be able to remove the entire tumor if it is small enough (i.e. an excisional biopsy). An open biopsy is of course a more invasive procedure with its attendant complication risks.
A biopsy will, foremost, identify the type of tumor that is present. Examination of the sample includes noting the degree of differentiation of the tumor cells and whether they are actively dividing. (The ratio of the number of cells undergoing mitosis to the number of cells not undergoing mitosis, the so-called mitotic index, quantifies that parameter.) The shape, size, and arrangement of the cells can help determine the type of tumor that is present. For example, large and irregularly shaped cells with a high degree of nuclear pleomorphism are indicative of a high-grade sarcoma. Gene profiling may also predict drug treatment efficacy. Special stains, such as immunohistochemistry, can identify specific proteins or markers that are associated with particular types of tumors.
In addition to examining the cells themselves, the pathologist will also look at the extracellular matrix surrounding the cells, i.e. the presence of collagen fibers, or demonstrating the presence of mucin or other substances within the matrix that may be characteristic of particular types of tumors. Additional molecular testing of the biopsy sample looks for specific genetic mutations or alterations that may be associated with particular tumors. For example, the presence of a specific translocation involving the EWSR1 gene can help confirm a diagnosis of Ewing sarcoma.
Disease Course: Treatment and Prognosis
The surgical management of bone and soft tissue tumors remains the mainstay of treatment. The surgical options available for the management of bone and soft tissue tumors are curettage (scraping out the tumor from within the bone), marginal resection (cutting out the tumor and a small layer of surrounding normal tissue), wide resection (removal, but with an additional, larger layer of normal tissue around the tumor mass), and amputation. Wide resection is also referred to as a limb-sparing or limb-salvage approach. The choice of surgical option depends on the location, size, and aggressiveness of the tumor, as well as the patient's age, general health, and functional goals.
Curettage can be used to treat benign bone tumors and some low-grade malignant tumors (Figure 5). After the tumor is removed, the cavity is filled with bone cement or bone graft. Curettage is often used in combination with adjuvant therapies such as cryotherapy, phenolization, or high-speed burring to ensure that all neoplastic cells are destroyed. In cases where the tumor has caused significant damage to the bone, bone grafting may help restore the structural integrity of the bone. Internal fixation may be needed to help support the bone and prevent fracture. Curettage is a less invasive procedure compared to resection but has a higher local recurrence rate. This approach may preserve function, particularly around joints.
Resection is a surgical option for aggressive bone and soft tissue tumors. Resection involves the removal of the tumor along with a margin of normal tissue. The extent of the resection depends on the type, size, and location of the tumor as well as the grade (aggressiveness) of the neoplasm.
En bloc resection refers to a surgical technique in which a tumor or a portion of bone is removed intact, generally with a rim of surrounding soft tissues, rather than being dissected out piece by piece (Figure 6). The goal of en bloc resection is to minimize the risk of leaving behind any residual tumor cells and to prevent the spread of tumor cells into adjacent tissues. During en bloc resection, the tissues removed may include nearby muscles, nerves, and blood vessels, adding morbidity to the procedure in exchange for more complete removal of intermediate to high grade tumor cells and a lower incidence of local recurrence. While en bloc resection offers the advantages of reduced risk of local and systemic spread of disease, it is a more complex and technically demanding surgical technique that requires specialized training and experience.
Limb-sparing surgery involves the removal of the tumor while preserving as much of the affected limb as possible. This approach is typically used for musculoskeletal tumors that are sufficiently localized and have not spread to other parts of the body (metastasized). The goal of limb-sparing surgery is to remove the entire tumor while preserving function, mobility, and a higher quality of life than amputation offers. The surgical procedure for limb-sparing typically involves a combination of tumor resection, bone reconstruction, and soft tissue repair. In some cases, the surgeon may use a bone graft or a metal implant to replace the removed bone. Following surgery, the patient may require physical therapy and rehabilitation to regain strength, range of motion, and function. Advantages of limb-sparing include the preservation of the affected limb and improved functional outcomes at the cost of a longer recovery time compared to amputation. Disease-free survival is the same with amputation and a well-executed limb-sparing procedure.
The choice between limb-sparing and amputation depends on several factors, including the type and stage of the tumor, its location, the patient's age and overall health, and the potential for retaining functional outcomes. In general, limb-sparing surgery is preferred whenever possible, as it allows for the preservation of the affected limb and better functional outcomes.
Prophylactic internal fixation of long bones affected with progressive metastatic disease can reduce the incidence and morbidity of sustaining a fracture. The prediction of impending pathological fracture is based upon the degree of cortical destruction caused by the tumor, and the presence of activity-related pain. Another crucial factor to consider is the precise location of the lesion within the bone. Areas that experience particularly high forces with weight-bearing, the calcar region of the proximal femur, for example, are at higher risk of fracture and thus may be treated prophylactically more readily.
Radiation therapy is a non-surgical treatment option for musculoskeletal tumors that can be used alone or in combination with surgery and chemotherapy. Radiation therapy works by preferentially damaging the DNA of highly active cancer cells (with less impact on surrounding normal tissues). This prevents the tumor cells from dividing, growing and metastasizing. The targeted radiation can be delivered externally, using a machine called a linear accelerator that directs high-energy radiation beams at the tumor from outside the body, or internally, using a radioactive source that is implanted directly into or near the tumor.
One of the challenges of radiation therapy for musculoskeletal tumors is that bone and soft tissues have different radiation sensitivity. Bones are more resistant to radiation than soft tissues and, therefore, require a higher radiation dose to achieve the same level of tumor cell death. This increases the risk of radiation-induced bone complications such as osteoradionecrosis and pathologic fractures. To minimize complication risk, radiation therapy is usually delivered in a series of daily treatments over several weeks to allow healthy tissues to recover between treatments. The radiation dose and schedule are carefully planned by a team of radiation oncologists and medical physicists based on specific characteristics of the tumor and the patient's health.
In addition to killing cancer cells, radiation therapy can also cause side effects, such as skin irritation, fatigue, and damage to surrounding healthy tissues. The severity and duration of these side effects depend on the dose and duration of radiation therapy, as well as the patient's individual sensitivity and overall health.
Chemotherapy is commonly used in the treatment of musculoskeletal tumors to kill cancerous cells, reduce the size of the tumor, or prevent spread to other parts of the body. Chemotherapy can be used as adjuvant therapy, neoadjuvant therapy, or palliative therapy depending on the stage and type of musculoskeletal tumor.
Adjuvant chemotherapy is given after the surgical removal of the tumor, to kill any remaining cancer cells that may not be visible on imaging or may have spread to other parts of the body. It can reduce the risk of local recurrence, metastatic disease and improve overall survival. Adjuvant chemotherapy is commonly used for high-grade bone and soft tissue sarcomas, as these tumors are more likely to spread to other parts of the body.
Neoadjuvant chemotherapy is given before surgery, to shrink the tumor and make it easier to remove. It can also help determine the tumor's responsiveness to chemotherapy, which can guide the choice of further treatment after surgery. Neo-adjuvant chemotherapy is commonly used for locally advanced or difficult to resect tumors, to improve the chances of successful surgical removal.
Palliative chemotherapy is given to relieve symptoms and improve quality of life in patients with advanced or metastatic tumors, by slowing tumor growth to reduce symptom severity. Palliative chemotherapy may be given in combination with other treatments, such as radiation therapy, to maximize patient comfort.