What is Chondrosarcoma?

Chondrosarcoma is a malignant cancer whose tumor cells produce a pure hyaline cartilage that results in abnormal bone and/or cartilage growth. People who have chondrosarcoma have a tumor growth, or abnormal bony type of bump, which can vary in size and location. The term chondrosarcoma is used to define a heterogeneous group of lesions with diverse morphologic features and clinical behavior. Primary chondrosarcoma (or conventional chondrosarcoma) usually develops centrally in a previously normal bone. Secondary chondrosarcoma is a chondrosarcoma arising from a benign precursor such as enchondromas or osteochondromas.

Chondrosarcoma is the second most common primary bone cancer. The malignant cartilage cells begin growing within or on the bone (central chondrosarcoma) or, rarely, secondarily within the cartilaginous cap of a pre-existing osteochondroma (peripheral chondrosarcoma). There are several different types of chondrosarcoma, with names based on the type of cells identified when they are examined under a microscope (see next section for detailed descriptions).

It is important to understand the difference between a benign and malignant cartilage tumor. Chondrosarcoma is a sarcoma, or malignant tumor of connective tissue. A chondroma, also called exostosis or osteochondroma, is a benign bone tumor. Benign bone tumors are not sarcomas. Benign bone tumors do not spread to other tissues and organs, and are not life threatening. They are generally left alone or cured by surgical removal if they cause symptoms such as tenderness via pressure on surrounding muscles, tendons or nerves.

Malignant tumors arising from the skeletal system are rare, representing only about half of one percent of all new cancers. Approximately 2100 new cases of malignant bone cancers (sarcomas) occur in the United States each year (Unni, 1996). The most common type of bone cancer is osteosarcoma, which develops in new tissue inside growing bones. About one fourth of malignant bone cancers are chondrosarcomas.

What are the different kinds of chondrosarcoma?

The single most important factor to consider when evaluating the malignant potential of a chondrosarcoma is its "histologic grade", determined by the appearance of tumor material under the microscope (Donati et al., 2005; Lee et al., 1999; Marcove et al., 1977; Reith et al., 2003; Springfield et al., 1996; Wang et al., 2001). In addition to histologic grade (I-III, dedifferentiated, and mesenchymal, see Table 1), chondrosarcomas can be classified by their location within the bone (i.e., central, peripheral, periosteal) and body (i.e., axial skeleton versus appendicular skeleton), whether they are primary or secondary (i.e., arising de novo versus secondary to a pre-malignant but benign lesion such as an osteochondroma), or whether it fits into a specific histologic variant (i.e., clear cell, myxoid, mesenchymal, dedifferentiated). The lower grade variants of chondrosarcoma can often be quite difficult to differentiate from benign lesions because they have similar appearances on radiographic studies. Benign cartilage tumors, called enchondromas do not usually cause symptoms and never metastasize.

Molecular techniques to classify tumors, such as cDNA expression arrays may prove useful in the future but have yet to be substantiated in the clinical arena.

Conventional chondrosarcomas are divided into four histologic grades based upon their appearance under a microscope (Table 1). The grading is based primarily on nuclear size of tumor cells, nuclear staining (hyperchromasia, or darker staining of nuclear material) and cellularity (Evans et al., 1977).

Grade I (or "low grade") tumors most resemble normal cartilage, but may surround areas of lamellar bone (which is not seen in benign lesions), or show atypical cells including binucleate forms (cells with two nuclei instead of one), see Figure 1.

Grade II (or "intermediate grade") are more cellular with a greater degree of nuclear atypia, hyperchromasia and nuclear size (Schiller, 1985).

Grade III (or "high grade") tumors have significant areas of marked pleomorphism, large cells with more hyperchromatic nuclei than grade II, occasional giant cells and abundant necrosis. Mitoses are frequently detected.

Myxoid changes or chondroid matrix liquefaction is a common feature of chondrosarcomas particularly in Grade II and Grade III lesions. The vast majority of chondrosarcoma are Grade I or Grade II. Grade III is rare (Bjornsson et al., 1998).

The variant known as differentiated chondrosarcoma is less common. It is typically thought of as arising from one of the other three histologic subtypes or from a benign precursor. De-differentiated chondrosarcomas, along with mesenchymal chondrosarcomas, are highly malignant, particularly aggressive (i.e., rapidly growing and disturbing surrounding tissues) and carry with them a poor prognosis.

Enchondromas, which are benign cartilage tumors, are usually found incidentally, most commonly in the bones of the hand and feet (Enneking, 1983). Radiographically they appear as small cartilage nests (usually <5cm in diameter) with multiple intralesional calcifications. Occasionally, very mild endosteal scalloping will occur, however true cortical invasion and the involvement of adjacent soft tissues is rare (Enneking, 1983). Histologically, islands of normal hyaline cartilage are found surrounded by lamellar bone. On rare occasion, enchondromas will become symptomatic, or lead to pathologic fracture, and will require surgical treatment.

Juxtacortical chondrosarcoma arises on the surface of bone and is histologically identical to conventional intramedullary chondrosarcoma.

Chondrosarcomas may also be classified by their histologic sub-type. These sub-types include clear cell, mesenchymal, and de-differentiated. Clear cell chondrosarcomas are low-grade tumors with significant amounts of glycogen. They typically involve the proximal portion of femur, tibia or humerus. Histologically, cells have abundant clear cytoplasm embedded in a loose hyaline cartilaginous matrix and an infiltrative growth pattern. Radiographs show a lytic defect at epiphyseal end of long bones that is sharply demarcated with sclerotic margins. They carry a low recurrence rate and a good prognosis with wide resection.

Mesenchymal chondrosarcomas are highly aggressive tumors that are radiographically and histologically distinct from conventional and dedifferentiated types. They are eccentrically located in bone and commonly extend into soft tissues. This variant of chondrosarcoma is characterized by a bimorphic pattern that is composed of highly undifferentiated small round cells (similar to Ewing’s Sarcoma) and islands of well-differentiated hyaline cartilage. This tumor usually affects young adults and teenagers and shows a widespread distribution in skeleton. The craniofacial bones, the ribs, the ilium and the vertebrae are the most common site (Bertoni et al., 1983). The treatment is radical surgery combined with chemotherapy.

De-differentiated chondrosarcomas represent about 10% of all chondrosarcomas. The most common sites of involvement are pelvis bones, femur and humerus. This tumor is a distinct variety of chondrosarcoma containing two clearly defined components: a well-differentiated cartilage tumor (enchondroma or chondrosarcoma grade I and II) juxtaposed to a high grade non-cartilaginous sarcoma. They are most often found in the femur, pelvis, or humerus bones, although they may also occur in the head, spine, breast, and prostate. Histologically there is a typical abrupt transition between the two components, cartilaginous and non-cartilaginous; both tumor components are evident in varying proportions. The malignant non-cartilaginous component is most frequently malignant fibrous histiocytoma, osteosarcoma or fibrosarcoma, although other malignant tumors have been reported as the differentiated component. The cartilaginous and non-cartilaginous components are often adjacent, and the term "collision of two tumors" has been applied to this lesion. Radiographically the tumor produces an ill defined, lytic, intraosseous lesion associated with cortical disruption and extension into the soft tissues.

Who gets chondrosarcoma?

Most chondrosarcomas are low-grade lesions. They are typically seen in adults in their late 20s to 60s. They occur more commonly in men than women. Chondrosarcoma is not contagious. It cannot be passed on to another person by exposure to a chondrosarcoma patient. Although specialists are not yet certain what causes chondrosarcoma, there are several factors that put people at a higher risk.

Certain hereditary conditions may make people more susceptible to chondrosarcomas. These include Ollier's Disease, Maffucci Syndrome, Multiple Hereditary Exostoses (MHE, a.k.a., osteochondromatoses), and Wilms Tumor. People affected by these conditions are at a higher risk because they usually develop several benign bone tumors (sometimes called bone spurs in the case of MHE), which have a higher chance of becoming malignant. People with these hereditary conditions who experience sudden growth spurts or increases in hormone production, such as pregnancy, have a slight increased risk of a benign bone tumor changing into a chondrosarcoma. These patients should be followed by a bone tumor specialist for all of their lives.

However, most patients with chondrosarcoma do not have any of these genetic conditions. Adults with Paget's disease, a non-cancerous condition characterized by abnormal development of new bone cells, may be at increased risk for chondrosarcoma. When chondrosarcoma occurs in children and young adults, it is often in patients who have had radiation or chemotherapy treatments for other conditions.

Recently, genetic studies have shown that there are specific locations on chromosomes where the genetic information for chondrosarcoma resides (Bovee et al., 2005; Sandberg, 2004). Continuing research of the genes and how the proteins encode for them will offer tremendous insight into the growth of these cancerous cells. This information is important since chondrosarcoma is a problem with the growth of cells. An understanding of the involved gene and the function of its protein may eventually lead to better treatment. It is feasible that, in the future, genetic manipulations may aid in the detection, treatment and/or prevention of chondrosarcoma.

Where in the body are chondrosarcomas usually found?

Chondrosarcomas may develop in any part of the body, but most are commonly found in the pelvis, rib cage, arms (humerus), shoulder blades (scapula) and legs (proximal femur, tibia). Although any bone can be affected, the long bones (legs, arms, fingers, toes,) pelvis and shoulder blades are most commonly involved. Occasionally chondrosarcoma has been found in the spine or skull bones. It is extremely rare to find chondrosarcoma in any internal organs, but this has been described. If chondrosarcoma spreads from its primary site (i.e., metastasizes), it usually spreads to the lungs. Metastasis is rare with low-grade tumors, but has been seen, even up to 10 years after diagnosis (Lee et al., 1999). About half of grade III and nearly all de-differentiated chondrosarcomas will metastasize; see Table 2.

How does someone with chondrosarcoma feel?

People with benign cartilage tumors (i.e., enchondroma or osteochondroma) rarely have pain that is caused by the tumor (Marco et al., 2000b). Most patients with a chondrosarcoma will have pain (Bjornsson et al., 1998; Marco et al., 2000a; Mirra et al., 1985; Murphey et al., 1996) and many will have swelling. It has been reported that in patients with grade I chondrosarcoma, 60% have night pain or rest pain, 21% have vague regional pain, and only 19% have painless tumors (Marco et al., 2000a). People with higher grade tumors (grade II or III chondrosarcoma) have pain up to 80% of the time (Pritchard et al., 1980). Rarely, people will discover they have a chondrosarcoma when they develop a fracture through the tumor (Bjornsson et al., 1998).

Pain associated with chondrosarcoma is usually in the location of the lesion or adjacent joints, muscles, tendons, nerves, blood vessels, or other soft tissues. In addition to pain, patients with chondrosarcoma may notice an enlargement of a bone or limb, changes in their ability to walk normally, or decreased range of motion in joints near the affected bone. Sometimes patients with benign cartilage tumors can have pain caused by something other than the tumor. For example, a rotator cuff injury can be painful at night and an x-ray might show a cartilage tumor in the shoulder. It is very important to determine whether pain is being caused by the tumor or by another process. This difference is vital in the diagnosis and treatment of chondrosarcomas.

Distinguishing between low-grade chondrosarcoma and benign enchondroma is perhaps one of the most challenging endeavors in the field of musculoskeletal oncology because they are difficult to differentiate. Even with diligent clinical practice and advanced radiographic and histologic technologies, the diagnosis may still prove elusive.

What tests are needed to determine if someone has chondrosarcoma?

After a doctor asks questions (a history) and performs a physical examination, he/she may order plain x-rays to evaluate the area of concern. It can be very difficult for doctors to tell the difference between benign cartilaginous lesions and low-grade chondrosarcomas on x-rays. Both can demonstrate the classic stippled calcified appearance of cartilaginous bony lesions (Figure 2). If the hard outside covering of the bone (cortex) appears to be getting chewed away (endosteal scalloping) there is an increased likelihood that the tumor has malignant potential, but is not necessarily confirmatory. One helpful analysis of chondrosarcoma had endosteal scalloping of more than 2/3rd of the cortical thickness, whereas only 9% of enchondromas had similar findings (Murphey et al., 1996).

More aggressive (malignant) tumors may show more telling signs of malignancy on x-ray. This includes adaptive changes such as expansion and/or thickening of the cortex and expansion of the surrounding soft tissues (Murphey et al., 1996; Unni, 1996). Features typical of lower grade lesions include dense calcifications appearing in rings or spicules, uniformly distributed calcifications and eccentric lobular growth of a soft tissue mass. Findings suggestive of higher grade include faint amorphous calcifications, large areas lacking calcifications and a concentrically growing soft tissue mass.

Perhaps the most reliable radiographic finding when differentiating between benign and malignant lesions is the recognition of change in radiographic appearance over time. In particular, there may be more endosteal scalloping and destruction of the cortex or a decrease in the calcifications with more malignant tumors. If there is no change in the appearance of a benign cartilage tumor on radiographs over time, it is appropriate for the doctor to continue to recommend watchful waiting and repeat x-rays at a later visit.

A bone scan of the entire body can also be helpful in differentiating between benign and malignant tumors, and in identifying whether more than one bone is involved (although multiple bone involvement is rare with chondrosarcomas). This test works by injecting a small amount of radioactive material into the blood stream and taking images using a gamma camera to detect uptake of radioactive material. Lesions demonstrated on bone scan can be compared to internal controls (Murphey et al., 1996). Those lesions demonstrating a higher degree of uptake are more likely to be of higher histologic grade. However, most enchondromas exhibit some radioisotope uptake, and some will erroneously appear as malignancy. Great caution should therefore be used in drawing conclusions from bone scan results, but these results can add to the overall picture, and better inform the decision making process.

Axial computed tomography (CT) can assist in determining the extent of bony destruction, and in better delineating bony architecture. CT will also help in better understanding intralesional calcifications. As with plain radiographs, disappearance or change in the nature of calcifications with repeat scanning can be suggestive of malignancy.

Magnetic Resonance Imaging (MRI) can be helpful in differentiating between benign and malignant lesions in several ways. First, the degree to which the tumor fills the medullary canal can be helpful (Figure 4). Greater than 90% medullary involvement can be suggestive of chondrosarcoma, while the absence of 90% medullary involvement of non-contiguous areas of cartilage within the bone can suggest the presence of an enchondroma (Colyer et al., 1993). In addition, the timing and progression of gadolinium contrast enhancement patterns may help direct a clinician toward or away from a diagnosis of malignancy (Geirnaerdt et al., 2000). Early enhancement (within 10 seconds of arterial enhancement) may be seen in chondrosarcoma but not in enchondroma. Many surgeons consider MRI critical for surgical planning because it can illustrate the extent of tumor involvement in bone and soft tissues.

Recently, there has been some research into the use of a specialized radiographic test called fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET) for grading of tumors in patients with chondrosarcoma (Aoki et al., 1999; Brenner et al., 2004). This test is not yet available at all centers, but may become a useful tool for tumor grading and prediction of outcome in chondrosarcoma patients. This may hence allow for identification of patients at high risk for local relapse or metastatic disease.

What if a chondrosarcoma is suspected?

If chondrosarcoma is suspected, two additional (staging) tests will usually be done to determine whether the tumor has spread. These include: 1) a computerized tomography (CT) scan of the lungs; and, 2) a total body bone scan. The results of these staging studies help physicians determine treatments and outcomes (prognosis). Blood tests are generally not helpful in making the diagnosis, although they can be used to make sure that there is not another process going on, such as infection or a different malignant process. After all of these tests are performed, a sample of the tumor (biopsy) is necessary to figure out if the problem is truly chondrosarcoma. Most biopsies for chondrosarcoma are achieved by surgical excision (i.e., complete removal of the tumor) of the lesion rather than through incisional biopsy (i.e., surgery to remove only part of the tumor for diagnostic evaluation).

What will biopsy tell the patient and the doctor?

When fresh tissue from a chondrosarcomas is viewed under a microscope after a biopsy, it is generally not difficult to identify a clear distinction between normal host tissue and the malignant tissue. However, with higher-grade tumors, more aggressive margins may have more malignant tissue, and have infiltrating satellite components. They will exhibit heterogeneous gross properties including lobulated areas of chalky calcific admixture, regions of firm translucent unmineralized gray cartilage and relatively low vascularity. Higher-grade tumors tend to have areas of necrosis and degenerative material as well (Enneking, 1983).

As both benign and malignant cartilage lesions can share certain clinical and histological characteristics, pathologists will often consider the patient’s history when interpreting specimens. Permeation of cortical and/or medullary bone is an important characteristic of conventional chondrosarcoma that the pathologist can use to separate it from enchondroma. The decision by the orthopaedic oncologist for definitive treatment is based upon the areas of highest concern for malignancy. Lesions appearing more aggressive clinically and radiographically must be widely resected without biopsy to avoid contamination of healthy tissue, which would likely necessitate an additional surgery. However, this remains controversial.

What is known about the genetics of chondrosarcoma?

As evolving molecular techniques are available, several genotypic and phenotypic markers for chondrosarcoma have been tested to see if they assist in determining tumor grade prognosis. There is considerable complexity and heterogeneity in the pathologic and clinical behavior of chondrosarcomas. This is reflected in the diversity of cytogenetic and molecular genetic characteristics that have been described in these tumors. Please see Sandberg and Bridge (2003), Sandberg (2004), and Bovee et al. (2005) for a thorough review.

The genetic changes specific to chondrosarcoma continue to be investigated extensively. Although studies have not yet established a specific or recurrent karyotypic feature for any of these tumors, different chondrosarcomas have demonstrated anomalies in several tumor suppressor genes, oncogenes, and transcription factors, including TP53, RAS, EXT1, EXT2, and Sox9. Available cytogenetic and comparative genomic hybridization (CGH) studies reveal changes in some chondrosarcomas, but fail to do so in others. These studies are thus far difficult to interpret.

Based on the available studies, it is likely that chondrosarcomas are generated by a coordinated, multi-step process involving primarily tumor suppressor genes. In fact, the complexity and variety of genetic changes seen in chondrosarcomas may indicate several distinct genetic pathways. Some of the same genes may be involved in each, but the order and manner in which they are affected may differ among chondrosarcomas. Establishing the genes that initiate the neoplastic processes, and that are subsequently involved along the pathways leading to chondrosarcoma may lead to therapies addressing these molecular changes, as has been accomplished for several other sarcomas.

What are the current treatments for chondrosarcoma?

For benign-appearing, asymptomatic cartilage tumors (i.e., enchondroma), patients are usually followed with clinical evaluation and sequential x-rays 3, 6 and then 12 months apart. This is continued unless there is a change in clinical examination findings or the radiographic appearance of the lesion at different points in time. Symptomatic enchondromas (i.e., those that cause pain, discomfort, or are disfiguring but do not show indications of malignancy) can be treated with a relatively non-invasive procedure, involving curettage of the lesion within the bone with placement of a bone graft. Fractures through the tumor (called a pathologic fracture) can be treated with either concurrent or staged treatment of both the fracture and the lesion if there is concern over the risk of recurrent pathologic fracture.

Surgical resection remains the primary and most successful means of treating chondrosarcomas. The decision regarding the extent of surgical resection and adjuvant therapy is dependent upon the clinical and histologic characteristics of the lesion. Optimal treatment for low-grade chondrosarcoma remains a dilemma for surgical oncologists, but no chemotherapy or radiation is indicated. For higher-grade tumors, with a worse prognosis for recurrence and metastasis, adjuvant therapies may be considered. Unfortunately, to date, studies have not shown adjuvant treatments such as chemotherapy or radiation to have any significant impact on patient morbidity or mortality in the majority of isolated primary lesions. Proton beam radiation is generally reserved for refractory tumors in high risk anatomic areas such as the skull base and axial skeleton. As these adjunctive modalities are of no proven benefit, the burden of a cure still falls upon adequate initial surgical resection.

In the past, wide resection was considered the method of choice for all chondrosarcomas. Unfortunately, these tumors are frequently found in regions such as the pelvis or proximal long bones, where aggressive surgical management may endanger adjacent vital organs and structures or compromise limb function. Thus, less aggressive approaches such as marginal excision and extended intralesional excision with margin expansion using adjuncts such as phenol or cryotherapy have received increasing attention with a national study underway to investigate efficacy. Most surgical oncologists prefer limb salvage techniques with bone graft and prosthetics, preserving the function of the limb. Amputation is still used in advanced disease or as a last option.

While rigorous evidence-based criteria are presently lacking, individual centers may have their own criteria and algorithms for surgical decision-making. In general, benign lesions should be treated conservatively, while high-grade malignancies should be treated aggressively with complete resection. If surgical margins are not clear on histologic evaluation of the tissue after resection of an intermediate- or high-grade lesion, wider surgical resection and possibly bone and/or joint prosthesis may be necessary.

Are there any emerging therapies in the treatment of chondrosarcoma?

During the past several years, substantial new insights have been gained about molecular cell biology, molecular cytogenetics, and immunopathology (Terek, 2006). These have led to a better understanding of chondrosarcoma development at the molecular level and will ultimately lead to the development of targeted treatments. Though they are at present highly experimental, researchers are investigating several new treatments for chondrosarcoma. Examples include agents targeting estrogen receptors (Cleton-Jansen et al., 2005), new chemotherapeutic agents, such as ET-743 (Marchini et al., 2005), and agents effecting cytogenetic pathways (Bovee et al., 2005).

Where is the best place to go to receive appropriate treatment?

Patients with chondrosarcoma are best treated at major Sarcoma Centers with specialized diagnostic and treatment facilities and the availability of musculoskeletal tumor specialists or orthopedic oncologists. Because this disease, like all bone sarcomas, are not common, it is often a good idea to seek an opinion from a major cancer center that has a wide experience in treating bone cancers. A Sarcoma Center will offer an organized group of doctors and other health care professionals who work together to provide the best treatment options and recovery. If your primary care physician suspects chondrosarcoma, a simple referral to an orthopedic doctor may not be adequate. Be sure that you are referred to an orthopaedic oncologist or "bone cancer specialist."

What are the chances for cure and survival from chondrosarcoma?

In general, the prognosis for chondrosarcoma depends on the grade of the tumor and the attainment of complete excision of the tumor and other conditions the patient has such as diabetes, lupus, and clotting and coagulation problems (Table 2). For lower grade chondrosarcomas, prognosis is very good after adequate excision. There is a low incidence of pulmonary metastasis if the primary lesion is widely resected. Metastasis to other bones can occur, but is much less common. Dedifferentiated chondrosarcoma have a uniformly poor prognosis.

Summary

Cartilaginous lesions of the human skeleton exist on a continuum spanning from the completely benign embryonic inclusion, to the dangerously aggressive neoplastic process. In order to determine the appropriate treatment for each individual lesion, musculoskeletal oncologists must take into account the clinical, radiographic, histologic and soon the microbiologic characteristics of the tumor. It is important for patients to seek treatment for these tumors at a Sarcoma center with availability of specialists possessing a sound understanding of these lesions and a firm grasp of the evolving treatment options. The health care team at these centers will keep patients informed about the details of the treatment course in both the short and long term. Understanding and recognizing the spectrum of appearances of the various types of chondrosarcoma allow improved patient assessment and are vital for optimal clinical management including diagnosis, biopsy, staging, treatment and prognosis. As more advanced molecular tools for predicting tumor behavior are developed, more sophisticated means of diagnosing and treating these tumors will be developed and put into use.

What is Chondrosarcoma?

Chondrosarcoma is a malignant cancer whose tumor cells produce a pure hyaline cartilage that results in abnormal bone and/or cartilage growth. The term chondrosarcoma is used to define a heterogeneous group of lesions with diverse morphologic features and clinical behavior.

Who gets chondrosarcoma? Is it common?

Chondrosarcoma is a rare disease, with an estimated incidence of 1 in 200,000 per year.¹ Classically, chondrosarcomas have been described with a slight preference for male patients.⁴ However in a recent analysis of the SEER Database (Surveillance, Epidemiology and End Results) a higher proportion of appendicular chondrosarcomas was found in women (60.9%) than in men (46.7%) and a lower proportion of axial chondrosarcomas was found in women (30.3%) than in men (40.4%). The age distribution of patients with chondrosarcoma shows a gradual age-related increase, with the peak incidence occurring during the sixth and seventh decades of life. In an analysis of the National Cancer Data Base (NCDB) of the American College of Surgeons over 70% of reported cases were in patients aged 40 years and older.

Chondrosarcoma is not contagious. It cannot be passed on to another person by exposure to a chondrosarcoma patient. Although specialists are not yet certain what causes chondrosarcoma, there are several factors that put people at a higher risk.

Certain hereditary conditions may make people more susceptible to chondrosarcomas. These include Ollier's Disease, Maffucci Syndrome, and Multiple Hereditary Exostoses (MHE, a.k.a., osteochondromatoses), People affected by these conditions are at a higher risk because they usually develop several benign bone tumors (sometimes called bone spurs in the case of MHE), which have a higher chance of becoming malignant. People with these hereditary conditions who experience sudden growth spurts or increases in hormone production, such as pregnancy, have a slight increased risk of a benign bone tumor changing into a chondrosarcoma. These patients should be followed by a bone tumor specialist for all of their lives. However, most patients with chondrosarcoma do not have any of these genetic conditions. Adults with Paget's disease, a non-cancerous condition characterized by abnormal development of new bone cells, may be at increased risk for chondrosarcoma. When chondrosarcoma occurs in children and young adults, it is often in patients who have had radiation or chemotherapy treatments for other conditions.

What are the different types of chondrosarcoma?

Chondrosarcomas are actually a heterogeneous group of tumors. They are classified as primary (or conventional chondrosarcoma) if they are unassociated with a pre-existing lesion and secondary if they develop from a pre-existing chondroid lesion, such as enchondroma or osteochondroma. More than 90% are designated conventional chondrosarcomas. They can be further sub classified as central when they arise from within the medullary cavity and peripheral when they arise from the surface of the bone. Conventional chondrosarcoma are nearly always central; secondary chondrosarcomas can be central but usually they are peripheral. They can also be classified by their location within the body (i.e., axial skeleton versus appendicular skeleton), whether it fits into a specific histological variant (i.e., clear cell, myxoid, mesenchymal, dedifferentiated).

The single most important factor to consider when evaluating the malignant potential of a chondrosarcoma is its cytologic and histologic grade, determined by the appearance of tumor material under the microscope combined with the clinical and radiologic presentation (Table 1).^5-10

While grading is very important in the management of chondrosarcoma, it can be contentious. Although several grading systems have been described, usually they are graded on a scale of 1-3. The grading is based primarily on nuclear size of tumor cells, nuclear staining (hyperchromasia, or darker staining of nuclear material) and cellularity.¹¹ Approximately 90% are low grade to intermediate-grade tumors (grade 1 or 2) and only 5–10% of conventional chondrosarcomas are grade 3 lesions.

• Grade I (low grade) tumors are moderately cellular and contain hyperchhromatic plump nuclei of uniform size and the cytology is very similar to enchondroma (a benign cartilage tumor). Occasionally binucleated cells may be seen.
• Grade II (intermediate grade) are more cellular with a greater degree of nuclear atypia, hyperchromasia and nuclear size.
• Grade III (high grade) tumors have significant areas of marked pleomorphism, large cells with more hyperchromatic nuclei than grade II, occasional giant cells and abundant necrosis. Mitoses are frequently detected.

Chondrosarcomas variants are rare and include the following:

• Mesenchymal chondrosarcoma is a highly malignant tumor characterized by the presence of solid, highly cellular areas composed of round or slightly spindled primitive mesenchymal cells and is histologically similar to Ewing's sarcoma with foci of cartilaginous differentiation. This is a very aggressive type of chondrosarcoma with a high risk of local recurrence and distant metastasis.
• Dedifferentiated chondrosarcoma contains two clearly defined components, a well differentiated cartilage tumor, either an enchondroma or a low grade chondrosarcoma, juxtaposed to a high grade noncartilaginous sarcoma. It is typically thought of as a tumor in which a low grade chondrosarcoma or benign cartilage tumor transforms into a high grade sarcoma with features of osteosarcoma, fibrosarcoma, or malignant fibrous histiocytoma. Radiographically the tumor produces an ill defined, lytic, interosseous lesion associated with cortical disruption and extension into the soft tissues. They are aggressive neoplasms and have a dismal prognosis.
• Clear cell chondrosarcomas are low-grade tumors with significant amounts of glycogen. They typically involve the epiphyseal end of a long bone. Histologically, cells have abundant clear cytoplasm embedded in a loose hyaline cartilaginous matrix and an infiltrative growth pattern. Radiographs show a lytic defect at epiphyseal end of long bones that is sharply demarcated with sclerotic margins. They carry a low recurrence rate and a good prognosis with wide resection.
• Myxoid chondrosarcoma is a slow-growing tumor characterized by prominent myxoid degeneration histologically and prolonged course, despite a high incidence of local recurrence and metastasis clinically.

What is known about the genetics of chondrosarcoma?

As evolving molecular techniques are available, several genotypic and phenotypic markers for chondrosarcoma have been tested to see if they assist in determining tumor grade prognosis. There is considerable complexity and heterogeneity in the pathologic and clinical behavior of chondrosarcomas. This is reflected in the diversity of cytogenetic and molecular genetic characteristics that have been described in these tumors. Please see Sandberg and Bridge (2003),¹² Sandberg (2004), and Bovee et al. (2005)¹³ for a thorough review.

The genetic changes specific to chondrosarcoma continue to be investigated extensively. Although studies have not yet established a specific or recurrent karyotypic feature for any of these tumors, different chondrosarcomas have demonstrated anomalies in several tumor suppressor genes, oncogenes, and transcription factors, including TP53, RAS, EXT1, EXT2, and Sox9. Available cytogenetic and comparative genomic hybridization (CGH) studies reveal changes in some chondrosarcomas, but fail to do so in others. These studies are thus far difficult to interpret.

Based on the available studies, it is likely that chondrosarcomas are generated by a coordinated, multi-step process involving primarily tumor suppressor genes. In fact, the complexity and variety of genetic changes seen in chondrosarcomas may indicate several distinct genetic pathways. Some of the same genes may be involved in each, but the order and manner in which they are affected may differ among chondrosarcomas. Establishing the genes that initiate the neoplastic processes, and that are subsequently involved along the pathways leading to chondrosarcoma may lead to therapies addressing these molecular changes, as has been accomplished for several other sarcomas.

How can one differentiate a low grade chondrosarcoma from a benign cartilage tumor?

It is important to understand the difference between a benign and malignant cartilage tumor. Chondrosarcoma is a sarcoma, or malignant tumor of connective tissue. An enchondroma is a benign bone tumor. Benign bone tumors are not sarcomas. Benign bone tumors do not spread to other tissues and organs, and are not life threatening. They are generally left alone or cured by surgical removal if they cause symptoms such as tenderness via pressure on surrounding muscles, tendons or nerves. Low grade chondrosarcoma also has relatively little potential to spread but can recur locally if not treated appropriately. If these tumors due recur they can start to behave more aggressively.

Distinguishing chondrosarcoma from its benign counterpart, enchondroma, is crucial to the patient treatment and prognosis but can be difficult at times. The diagnosis of cartilage lesions requires expert evaluation. First, clinical and radiographic features such as the age of the patient, symptoms, localization in the skeleton, and the pattern of bone destruction or mineralization should be scrutinized. The role of biopsy in low grade lesions is quite contentious as sampling errors are a distinct possibility. A wait and see approach is generally recommended at first. If symptoms worsen or there is a progression on radiographic examination then consideration for intralesional surgical treatment may be indicated. Because of the possibility that the tumor is a low grade chondrosarcoma, it should be removed by an experienced musculoskeletal oncologist at a designated sarcoma center with expert pathology and radiology support. The removed specimen must be thoroughly evaluated for features concerning for malignancy.^14,15 Distinguishing between enchondroma and chondrosarcoma is one of the most frequent diagnostic dilemmas facing orthopaedic oncologists and their colleagues in diagnostic radiology and pathology.¹⁶

Clinical Presentation

Patients with chondrosarcoma experience a wide range of clinical courses, from slow insidious tumor growth over years in low grade lesions to rapid neoplastic progression, metastasis, and death in higher grade lesions. The vast majority of chondrosarcomas is low grade and accordingly is very slow to progress. Clinical symptoms may be helpful in the initial evaluation of a cartilaginous tumor. Pain is more common with chondrosarcoma than with the benign enchondroma. In a review from Murphey et al 95% of patients with chondrosarcoma experienced pain.¹⁷ Eefting et al reported that 35% of patients with enchondromas and 62% of the patients with central grade I chondrosarcoma presented with spontaneous pain. It has been reported that in patients with grade I chondrosarcoma, 60% have night pain or rest pain, 21% have vague regional pain, and only 19% have painless tumors.¹⁸ This difference is significant, although presentation without pain does not exclude malignancy and should not delay additional analysis.¹⁹ Pathologic fractures occur in 3% to 8% of patients with chondrosarcoma.¹⁸

Imaging

Radiographs - Enchondromas and low grade intramedullary chondrosarcomas of long bones can have similar radiologic appearances. Both types of tumors demonstrate stippled calcifications, and both may display endosteal scalloping on plain radiographs.²⁰ Calcification is manifested by punctuate mineralization or popcorn like calcification (Figure 1).

The margins of the tumor should be examined for osteolysis and endosteal scalloping. Chondrosarcoma can demonstrate adaptive and aggressive radiologic signs. Cortical expansion and thickening are adaptive changes, and cortical disruption and soft-tissue masses are aggressive changes associated with chondrosarcoma. The extent and degree of endosteal scalloping correlate with the likelihood of the lesion being a chondrosarcoma. The imaging characteristics that should suggest chondrosarcoma are endosteal scalloping depth and extent (greater than two-thirds of cortical thickness and along more than two thirds of the lesion), extent of matrix mineralization (within less than two-thirds of the lesion as seen on radiographs), presence of cortical remodeling or destruction and thickening, periosteal reaction, pathologic fracture, and associated soft-tissue mass.¹⁷ There is an overlap in the radiographic size of both, however a lesion larger than 5-6 cm in diameter are much more likely to represent a chondrosarcoma.

Anatomic tumor localization is different but should not be considered of diagnostic value. Enchondromas are most common in the hands or feet while chondrosarcomas are common in the axial skeleton (spine and pelvis), typically with large associated soft-tissue masses. The ilium is the most frequently involved bone followed by the proximal femur, proximal humerus, distal femur and ribs.

Advanced Imaging

Computed Tomography (CT) – CT is helpful in detecting more details of the lesion. Enchondromas as a rule should not progress during adulthood and any change in size or radiographic appearance of an enchondroma should be considered as a red flag for the presence of a malignant tumor. CT is superior to radiography for detecting focal areas of scalloping and is considered the best modality to detect mineralization characteristic of a chondroid neoplasm. Murphey et al reported that all enchondromas showed evidence of calcification on CT scans but only 95% revealed these areas on radiographs.¹⁷

Magnetic Resonance Imaging (MRI) – MRI is particularly useful in determining the nonmineralized intramedullary extent of the tumor and soft-tissue extension (Figure 2).

The axial and coronal images accurately demonstrate marrow replacement by tumor, providing measurements that can guide the surgeon when either an intralesional or a wide excision is performed. Greater than 90% medullary involvement can be suggestive of chondrosarcoma, while the absence of 90% medullary involvement of non-contiguous areas of cartilage within the bone can suggest the presence of an enchondroma. The relationship of a soft-tissue mass to important paraosseous structures, such as the joint capsule and the neurovascular bundle, is accurately demonstrated on MR images. Fast contrast-enhanced MR imaging has the potential to help differentiation between enchondroma and chondrosarcoma. MR imaging results should be seen as an additive tool and may not be considered alone. The use of gadolinium-enhanced MR imaging adds substantially to the characterization of cartilaginous tumors. The timing and progression of gadolinium contrast enhancement patterns may help direct a clinician toward or away from a diagnosis of malignancy. Early enhancement (within 10 seconds of arterial enhancement) may be seen in chondrosarcoma but not in enchondroma. Differentiation of malignancy on the basis of early and exponential enhancement has been demonstrated to have a sensitivity of 61%, specificity of 95%, positive predictive value of 92% and negative predictive value of 72%.²¹ Gadolinium-enhanced MR imaging shows septal enhancement in low-grade chondrosarcomas, corresponding to fibrovascular septation between lobules of hyaline cartilage. This feature is usually absent in benign cartilaginous lesions.^22,23

Bone Scan - This test works by injecting a small amount of radioactive material into the blood stream and taking images using a gamma camera to detect uptake of radioactive material. Bone scintigraphy has limited application in the differential diagnosis of tumors with low biologic activity such as Grade-I chondrosarcoma. A whole-body bone scan with a high degree of radionuclide uptake within the lesion compared with an internal standard, such as the anterior superior iliac spine or acromioclavicular joint, has been considered as more consistent with chondrosarcoma than enchondroma¹⁷ (Figure 3). Great caution should therefore be used in drawing conclusions from bone scan results, but these results can add to the overall picture, and better inform the decision making process.

PET Scan - Recently, there has been some research into the use of a specialized radiographic test called fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET) for grading of tumors in patients with chondrosarcoma Preliminary studies showed that (FDG PET) could be an objective and quantitative adjunct in differentiating chondrosarcomas from enchondromas and osteochondromas and in assessing the grade of chondrosarcomas.²⁴ In a more recent study FDG PET imaging was found a useful parameter for tumor grading and prediction of outcome in chondrosarcoma patients.²⁵ However, the measurement of glucose metabolism by positron emission tomography alone cannot distinguish between benign and grade-I malignant cartilaginous tumors. It is important to understand the advantages and disadvantages of imaging modalities for accurate interpretation of results. Although positron emission tomography has limitations, it may be useful for predicting high-grade chondrosarcomas from benign chondroid lesions and grade-I chondrosarcoma.²⁶

What if a low grade chondrosarcoma is suspected?

After all of the imaging modalities are obtained an experienced orthopaedic oncologist must decide whether to observe the patient or intervene. If a low grade chondrosarcoma is suspected, then an aggressive curettage is indicated. When a more aggressive lesion is suspected a sampling biopsy is indicated as surgical excision is more extensive and so the diagnosis of a high grade cancer should be established. When fresh tissue from a chondrosarcomas is viewed under a microscope after a biopsy, lower grade chondrosarcomas will exhibit increasing amounts of relatively acellular cartilage stroma as well as regions of modestly increased cellularity. By contrast, higher-grade lesions tend to harbor regions of densely packed hyperchromatic malignant looking cells.

Histologic features to distinguish benign from malignant cartilaginous tumors were advocated in the past although the diagnostic value of individual morphologic criteria or how they are handled in clinical practice is controversial.²⁷ Recent studies have tried to establish a more precise standard method for distinction of cartilage neoplasms in long bones. The American Skeletal Lesions Interobserver Correlation among Expert Diagnosticians (SLICED) Study Group showed that radiologic and pathologic interpretations of cartilaginous lesions in long bones are not optimally reliable, even among specialized experts.²⁸ Another recent study reported that distinction between a high grade chondrosarcoma seems to be less problematic, however differentiation of grade I chondrosarcoma from enchondroma remains a diagnostic challenge. In that study there was considerable interobserver variability, even among expert bone tumor pathologists, in the histologic diagnosis of enchondroma and low-grade chondrosarcoma. In an attempt to distinguish between low-grade chondrosarcoma and enchondroma the authors identified four most important histologic parameters, as following: host bone entrapment, high cellularity, marked nuclear pleomorphism, and irregular distribution of cells. The differential diagnosis could be assessed with a higher great degree of accuracy if the biopsy specimen contained a combination of: presence of host bone entrapment, open chromatin, mucoid matrix degeneration, and the patient’s age was above 45 years.¹⁹

What are the current options of treatment for low grade chondrosarcoma?

The management of low grade chondrosarcoma can be a challenge. Grade I chondrosarcomas may not all behave in the same way clinically or radiographically. In some cases a painful cartilaginous lesion in a long bone has the radiologic appearance of a low-grade chondrosarcoma (e.g., lytic areas or high-grade endosteal scalloping without adaptive or aggressive radiographic changes) and the histologic appearance of an enchondroma. This borderline type of lesion has been referred as grade 0.5 chondrosarcoma, atypical enchondroma, grade 0 chondrosarcoma and chondrosarcoma in situ by different authors.^9,13,18 The decision making process about the management of these lesions should involve the following considerations:

• Intralesional excision grossly removes the tumor but conceivably leaves microscopic and macroscopic tumor in the tumor bed. Intralesional excision with some sort of adjuvant therapy (e.g. liquid nitrogen, argon beam, hydrogen peroxide, phenol) has the potential benefits of adjacent bone and joint preservation and better functional outcome.
• Wide resection includes a cuff of normal tissue surrounding the tumor completely. Depending on the location, wide resection may cause increased morbidity and require complex reconstruction. Generally, this is reserved for higher grade lesions.

The key for long term successful treatment of these lesions is to adequately identify those patients who would benefit from less aggressive surgical resection without the risks of local recurrence and distant metastasis.

The local recurrence rate and potential for metastasis in low-grade chondrosarcoma are low, so limited surgery (intralesional resection) with adjuvant therapy has been advocated for less aggressive-appearing lesions.^5,7,8,14,18 Leerapun et al¹⁴ recently report that intralesional excision with adjuvant therapy only works well in confined bony defects. In their series, tumors that had no associated cortical perforation or soft tissue mass were successfully treated with intralesional curettage. Patients with more aggressive lesions (eg, cortical disruption, Stage IB) were selected for en bloc resection and had excellent local control. They excluded lesions of the central skeleton because these historically behave differently from long bone lesions. Marco et al described a subset of patients with low-grade chondrosarcoma that could be treated with intralesional excision with adjuvant therapy without compromise of the oncologic outcome: painful, intramedullary low-grade chondrosarcoma (stage IA) of the appendicular skeleton, which can demonstrate a high degree of endosteal scalloping without adaptive or aggressive radiologic signs. The only local recurrence in their series was in a patient with cortical disruption and expansion, as well as a soft tissue mass. Bauer⁵ reported on patients with low-grade intramedullary chondrosarcoma of a long bone treated by intralesional excision and followed for 2-25 years. The authors concluded that a central grade I chondrosarcoma of long bones can be treated with curettage and filling with either bone graft or bone cement (methylmethacrylate) but distal more radiographic aggressive lesions requires en bloc resection. Lesions of the pelvis and shoulder girdle should also be treated aggressively since they have a high risk of recurrence. In another recent study Van Der Geest et al²⁹ reported excellent oncological and functional results the use of cryosurgery as an adjuvant in the surgical treatment of active or aggressive enchondromas and chondrosarcomas grade I. Post-operative fracture was seen as the most common complication in their series.

Most authors agree that adequate surgical margins lower the risk of local recurrence in patients with chondrosarcoma.^7,8,14,18,30 Wide resection should be implemented for the treatment of low grade chondrosarcoma in a long bone if it shows radiographic signs of adaptive changes (cortical expansion or thickening) or aggressive changes (cortical disruption, stage IB) and if its associated with a soft tissue mass. Wide resection is recommended for virtually all low grade chondrosarcomas of the pelvis and sacrum because in these locations there is a higher chance of local recurrence and metastasis.^14,31,32

Is there a need to further treatment of low grade chondrosarcoma by radiation or chemotherapy?

For higher-grade tumors, with a worse prognosis for recurrence and metastasis, adjuvant therapies may be considered. Adjuvant radiation and chemotherapy have been reserved for patients who have a mesenchymal chondrosarcoma or a dedifferentiated chondrosarcoma or for those who have had inadequate operative treatment. Unfortunately, to date, studies have not shown adjuvant treatments such as chemotherapy or radiation to have any significant impact on patient morbidity or mortality in the majority of isolated primary lesions. Proton beam radiation is generally reserved for refractory tumors in high risk anatomic areas such as the skull base and axial skeleton.³³

There is no indication for the use of chemotherapy or radiation in the management of low grade chondrosarcoma as adequate initial surgical resection can virtually be successful in all patients.

Clinical Trials and Emerging Therapies

Earlier this decade, a national clinical trial was opened in the United States. However, due to the National Cancer Institute’s budgetary constraints and the relative rarity of chondrosarcoma compared to other cancers, the trial had to be closed prematurely. Investigators hope that the trial can be reinitiated soon.

During the past several years, substantial new insights have been gained about molecular cell biology, molecular cytogenetics, and immunopathology.³⁴ These have led to a better understanding of chondrosarcoma development at the molecular level and will ultimately lead to the development of targeted treatments. Though they are at present highly experimental, researchers are investigating several new treatments for chondrosarcoma. Examples include agents targeting estrogen receptors,³⁵ new chemotherapeutic agents, such as ET-743,³⁶ and agents effecting cytogenetic pathways.¹³

Where is the best place to go to receive appropriate treatment?

Patients with chondrosarcoma are best treated at major Sarcoma centers with specialized diagnostic and treatment facilities and the availability of Musculoskeletal Tumor Specialists or Orthopedic Oncologists. Because this, like many other bone cancers, are not common, it is often a good idea to seek an opinion from a major cancer center that has a wide experience in treating bone cancers. A major sarcoma center will offer an organized group of doctors and other health care professionals who work together to provide the best treatment options and recovery. If your primary care physician suspects chondrosarcoma, a simple referral to an orthopedic doctor may not be adequate. Be sure that you are referred to an orthopaedic oncologist or "bone cancer specialist." Ideally, the center should be a member of The National Comprehensive Cancer Network.

What are the chances for cure and survival from low grade chondrosarcoma?

In general, the prognosis for chondrosarcoma depends on the grade of the tumor and the attainment of complete excision of the tumor and other conditions the patient has such as diabetes, lupus, and clotting and coagulation problems. Table 2 below shows a comparison between the prognosis based on the tumor grade. Pathological fracture, metastasis, local recurrence, and death are usually more common in patients with a high grade chondrosarcoma.

For low grade chondrosarcomas, prognosis is excellent after adequate excision, with very low rates of recurrence or spread when treated at an established sarcoma center. In a review of 70 patients with low grade chondrosarcoma of the appendicular skeleton only three presented with metastasis.¹⁴

Summary

Cartilaginous lesions of the human skeleton exist on a continuum, spanning from the completely benign embryonic inclusion, to the far less common but dangerously aggressive neoplastic process. Differentiating a benign enchondroma lesion from a low grade (grade I) chondrosarcoma is a challenging task even for the more experienced team of Sarcoma specialists. Based upon imaging characteristics, for less aggressive lesions, a wait and watch approach is the best initial management. At follow-up, if there appears to be progression, intervention should be considered.

The majority of patients with less radiographically aggressive low grade chondrosarcoma may be safely treated with a limited surgical interventional (intralesional resection). Patients with any signs of a radiographically aggressive lesion should be treated with a staged biopsy and a more extensive wide resection surgery to keep the local recurrence rate and potential for metastases low. In order to determine the appropriate treatment for each individual lesion, musculoskeletal oncologists must take into account the clinical, radiographic, histologic and soon the molecular biologic characteristics of the tumor.

It is important for patients to seek treatment for these tumors at a recognized sarcoma center with availability of specialists possessing a sound understanding of these lesions and a firm grasp of the evolving treatment options. The health care team at these centers will keep patients informed about the details of the treatment course in both the short and long term. Understanding and recognizing the spectrum of appearances of the various types of chondrosarcoma allow improved patient assessment and are vital for optimal clinical management including diagnosis, biopsy, staging, treatment and prognosis.