Chondrosarcoma is an uncommon, malignant, primary neoplasm of bone. It occurs in adults and older individuals, and it is different from most malignant bone tumors in terms of symptomatology, age distribution, anatomic locale, and natural history. Chondrosarcoma is a tumor generally arising in the medullary space and proliferating centrifugally. It is composed of malignant cells resembling chondrocytes of varying grades. Depending on the grade, these cells may produce hyaline cartilage, myxoid cartilage, or a fibromyxoid matrix. Chondrosarcoma of the highest grade may produce very little matrix and may be difficult to distinguish from other high-grade malignancies.

Perhaps the most important concept in chondrosarcoma is the variability in this disease from indolent to extremely fulminant. Clinical symptoms, radiographic findings, and histology will vary along a continuum, and accurate diagnosis can rarely be made with only one of these components. In fact, the most used study for diagnosis in musculoskeletal oncology, needle biopsy, is notoriously inaccurate in determining tumor grade for these diseases. Although diagnosis in musculoskeletal oncology frequently requires a clinical-radiographic-pathologic correlation, this diagnostic acumen is mandatory in chondrosarcoma because of the wide variations involved. Chondrosarcoma is resistant to most chemotherapy modalities and has very low radiosensitivity. Treatment is therefore almost exclusively surgical, the details of which will be discussed in the next paragraphs.

Although most sarcomas of bone present with a rapidly progressive, fulminant course, this is uncommon in chondrosarcoma. The reason for this is the paucity (or absence) of low-grade or intermediate-grade bone sarcomas for most tissue types, such as osteosarcoma or Ewing sarcoma, and their prevalence in chondrosarcoma. In general, high-grade bone sarcomas present with severe, unremitting pain, rapidly growing soft-tissue masses, and frequent pathologic fractures. Chondrosarcoma, unless of high grade, tends to present with a long-standing
history of pain, mild swelling, and progressive inability to perform sporting or daily activities.¹ Chondrosarcoma is more prevalent in adults in the third through seventh decades of life and is rare in children and adolescents.²

The anatomic distribution of chondrosarcoma strongly favors the axial and proximal appendicular skeleton. Chondrosarcoma in the distal extremities is extremely rare, and chondrosarcoma of the hand or foot, although reported, is exceedingly uncommon. Likewise, great care must be taken in diagnosing benign chondroid lesions of the axial skeleton, because most central or axial cartilage neoplasms behave in a more aggressive manner than their appendicular counterparts.

The natural history of chondrosarcoma varies depending on grade and subtype. Grade 1 chondrosarcomas are generally slow growing and will present with an insidious onset of pain with activity that will progress, sometimes over the course of years, to pain at night. Patients will often assume that the pain is caused by a more common, benign condition, such as sciatica, low back pain, rotator cuff disorders, or arthritis. The presence of a palpable soft-tissue mass is rare, but bony deformity may be palpable if remodeling has occurred. Pathologic fracture can occur but is unusual in the absence of a traumatic event unless the patient has lived with pain for months to years.

Grade 1 chondrosarcoma of the extremities has limited to no capacity for metastasis. Because of this distinction and the social or financial stigmata of a sarcoma diagnosis, it is more appropriate to classify these tumors as low-grade cartilage neoplasms, omitting the sarcoma diagnosis. Axial grade 1 chondrosarcomas do have the capacity for distant metastasis, however, and are generally considered to be true cancers.² For appendicular low-grade cartilage neoplasms, the risk of metastasis is less than 1%, with a recent meta-analysis reporting only five such occurrences worldwide.³ When axial tumors are included, the metastatic rate does increase, reflecting the fact that low-grade axial tumors are sarcomas and are true cancers. A metastatic rate as high as 8% has been recorded in this instance.⁴

Low-grade cartilage neoplasms (termed low-grade chondrosarcomas in axial lesions) have the ability to dedifferentiate. Dedifferentiation is the capacity for a low-grade neoplasm to undergo conversion to a high-grade neoplasm. This may occur after a substantial lag period, where the initial tumor remains fairly indolent for months or years, then rapidly changes into a high-grade tumor. This is accompanied by a significant increase in tumor size with corresponding symptom severity. This dedifferentiation phenomenon is thought to be a characteristic of low-grade neoplasms and is absent in benign chondromas. However, given the protean nature of chondroid neoplasms and the difficulty in determining grade based on histologic sampling, there should be a strong clinical suspicion for making this diagnosis.

Grade 2 chondrosarcomas may present in a manner similar to their grade 1 counterparts, especially if the tumor does not contain a substantial myxoid component. Those that are more myxoid may present with more rapid growth and a soft-tissue mass. Pain and disability are more rapidly progressive, with few patients maintaining these tumors for years before diagnosis.

Grade 3 chondrosarcoma, along with dedifferentiated chondrosarcoma, usually presents with a more fulminant course. Symptoms can rapidly progress from vague night pain to severe pain with functional difficulty, and this process can occur over a course of weeks to months. In the case of dedifferentiated chondrosarcoma, vague, indolent symptoms may have been present for months to years before the more severe symptoms occur. A soft-tissue mass is often evident and can grow to a very large extent, especially in pelvic cases. Instead of respecting surrounding anatomic boundaries, these tumors will invade surrounding structures, causing skin changes and enveloping neural or vascular structures.

Multiple chondrosarcoma variants are known to exist. These include juxtacortical chondrosarcoma, mesenchymal chondrosarcoma, clear cell chondrosarcoma, dedifferentiated chondrosarcoma, secondary chondrosarcoma, and extraskeletal myxoid chondrosarcoma. All of these entities are rarer than conventional chondrosarcoma, with small case series in the literature.

Juxtacortical chondrosarcoma is a chondrosarcoma arising from the periosteal surface of the bone. This is in contradistinction to conventional chondrosarcoma, which is a medullary or central process. Juxtacortical chondrosarcomas comprise fewer than 5% of chondrosarcomas as a whole. These tumors arise from bone and are not generally parosteal processes, because they do not surround and entrap the subjacent periosteum. This is a useful distinction, because the differential diagnosis of a juxtacortical chondrosarcoma often includes parosteal osteosarcoma. Because of their juxtacortical location, these tumors will much more readily present with a palpable mass or functional limitation, even as low-grade lesions (Figure 1).

Mesenchymal chondrosarcoma is an extremely rare, high-grade chondrosarcoma with a round cell component comprising less than 1% of all chondrosarcomas. The disease course is fulminant, with rapidly progressive pain, dysfunction, and soft-tissue mass formation. Mesenchymal chondrosarcoma has the uncommon ability to form skip metastases or to metastasize to other bones. Skeletal surveillance is necessary to screen for recurrence of this disorder. Management is difficult, and a 40% mortality rate has been reported.^5,6

Clear cell chondrosarcoma is an extremely rare variant. It is one of very few epiphyseal tumors and has therefore been dubiously associated with chondroblastoma. This lesion presents as a slow-growing, painful joint process. Progressive pain occasionally coupled with a joint effusion is a hallmark of this disease.

Secondary chondrosarcoma is a chondrosarcoma arising from a previously benign lesion. Originally described as a malignant transformation from a previous osteochondroma, this lesion has also been described as occurring from chondromas including enchondromas, periosteal chondromas, and synovial chondromatosis.² This transformation produces a low-grade cartilage neoplasm, with slow growth and an insidious increase in symptoms from a previous baseline.⁷ It is not yet known whether all low-grade cartilage neoplasms are in fact secondary to benign chondromas, or if they can arise de novo.

Dedifferentiated chondrosarcoma is the development of a high-grade chondrosarcoma from a low-grade cartilage neoplasm (including conventional grade 1 chondrosarcoma and secondary chondrosarcoma). These tumors present with a rapid change in clinical course from indolent to fulminant symptoms.

Extraskeletal myxoid chondrosarcoma is a high-grade, soft-tissue sarcoma. It differs from chondrosarcoma of the bone in nearly all aspects and is more properly discussed with soft-tissue sarcomas.

Careful consideration of radiographic findings is critical in the diagnosis and appropriate management of cartilage neoplasms. As stated previously, these diseases exist on a continuum, and the radiographs will reflect this. Because of the microscopic heterogeneity inherent in these tumors, accurate interpretation of radiographs is much more beneficial in determining treatment option than a limited histologic sample via biopsy. Likewise,
anatomic locale matters in these diseases: central lesions behave much more aggressively than appendicular or distal lesions and should be managed in a more aggressive manner.

Diagnostic studies must be chosen carefully. Radiographic evaluation should begin with high-quality plain radiographs. Although other modalities can yield useful information and may alter the diagnostic and treatment plan, routine plain radiographs are the best test for determining the interaction between tumor biology and bone biology. This, when combined with the clinical picture, yields the most helpful information in determining tumor grade. Plain radiographs help determine whether the bone is keeping up with the growth of the tumor, or whether the tumor is growing at such a rapid rate that biology is unable to maintain the bone’s structure.^1,8

Beyond plain radiography, the choice of diagnostic study becomes more complex. MRI is the most frequent second-line study in orthopaedics and is often used as a follow-up when plain radiographs show abnormal findings. Unfortunately, because of both the high water content of cartilage tumors and the fact that bone appears black on all MRI sequences, MRI often obscures the fine changes at the endosteal surface and overcalls the aggressiveness of the lesion. It is, however, a superlative study in determining marrow extent of any tumor and is the best anatomic study for any bone tumor with a soft-tissue extension. CT yields the finest detail of cortical integrity and is therefore a superior study for lower-grade cartilage neoplasms. In determining endosteal scalloping or cortical penetration, CT yields the highest-quality images.

Other imaging modalities have little utility in chondrosarcoma, especially in low-grade lesions. Although necessary for skeletal or chest screening, other imaging techniques have little to add to the diagnosis and treatment of any local disease. CT of the chest is used to determine whether the patient has pulmonary metastasis. Radionuclide bone scanning can be used to determine whether the patient has a bony metastasis in chondrosarcomas possessing this pattern (ie, mesenchymal chondrosarcoma) or in the rare instance of multifocal disease. It has limited benefit in determining grade, because many enchondromas are positive on routine bone scanning. Some advocate comparing radiotracer uptake in the tumor with physiologic uptake such as that seen in the iliac crest as a determinant of aggressiveness. Although there is interest in positron emission tomography (PET) scanning throughout oncology, its utility in diagnosis of many sarcomas remains limited. PET-CT scanning has demonstrated some efficacy in the diagnosis of recurrent chondrosarcomas,⁹ but its utility in grading primary sites is unproven.

Because grade 1 chondrosarcoma comprises approximately 60% of all chondrosarcomas, distinguishing between a low-grade cartilage neoplasm and an enchondroma is of first importance. Generally, enchondromas cause little pain and are often found incidentally. Although they can grow and fill the medullary space, they cause little endosteal scalloping (<50% of cortical thickness) and do not cause substantial cortical expansion. Endosteal scalloping is the phenomenon where the medullary tumor pushes into the endosteum of the bone. The cortex often remodels around this tumor expansion, and a small pit is formed in the cortex. This is not true bony invasion, but rather application of the Wolfe law in demonstrating the interaction between the biology of the tumor and the biology of the bone. Tumors that grow more rapidly are able to push deeper into the bone, and the bone is not able to remodel quickly enough to respond to the tumor’s pressure. Deeper scallops are therefore a hallmark of more active tumors and help in the distinction between enchondromas and low-grade cartilage neoplasms (Figure 2). As the lesions age, they progressively calcify and demonstrate the typical radiographic characteristics of cartilage tumors (punctate calcifications, rings and arcs, and a popcorn appearance). Grade 1 chondrosarcoma in the axial skeleton and low-grade cartilage neoplasms in the appendicular skeleton will be of similar appearance, but will display increasing activity. These tumors will cause deeper and more aggressive-appearing endosteal scalloping, and the surrounding bone may be expanded by the tumor. The cortices will generally be intact circumferentially unless a fracture has occurred, but may be thinned. These active findings should be regarded with caution, and a careful search for extraosseous tumor should be undertaken, because this has diagnostic, treatment, and prognostic implications.¹⁰

Grade 2 chondrosarcoma demonstrates a more aggressive behavior pattern. These tumors will often breach the cortex¹¹ and will cause substantial bony destruction and potentially an extraosseous component. Changes may occur on the periosteal surface as the tumor invades through the cortex, and periosteal new bone formation may occur. Mineralization will be decreased or absent, but the lobular pattern of tumor growth is often preserved. Pathologic fracture or joint disruption may occur more frequently than in low-grade neoplasms.

Because treatments often differ between grade 1 chondrosarcoma or low-grade cartilage neoplasm and grade 2 chondrosarcoma, an accurate radiographic diagnosis is quite important. Although low-grade cartilage neoplasms are often active lesions, they do not produce any extraosseous tumor, do not permeate the cortex, and reflect a bone-tumor relationship that is compensated, meaning that the bone biology is able to remodel and respond to the tumor biology, maintaining the bone’s structural integrity. The appearance of grade 2 chondrosarcoma is often uncompensated, where the bone is not able to respond adequately in response to the tumor. Periosteal reactions, extraosseous tumor, and substantial cortical changes may occur. These should be regarded with extreme caution because limited surgical techniques are often not sufficient for treatment of this grade of disease.

Grade 3 chondrosarcoma looks like a high-grade tumor, with substantial bony destruction, cortical disruption, large soft-tissue masses, and substantial malignant periosteal changes. Differential diagnosis includes osteosarcoma, Ewing sarcoma, and fibrosarcoma of bone. Unless the remnants of a prededifferentiated lesion exist, calcification will rarely be present and will not be prominent. MRI will likely find extraosseous soft-tissue mass formation (sometimes massive), and the internal characteristics will lack resemblance to typical cartilage neoplasms.¹² Although PET scanning is increasingly used for certain carcinomas and hematologic malignancies, its utility in sarcoma is unclear. PET may, however, express differential uptake in low-grade and high-grade cartilage tumors and may therefore be of diagnostic benefit.¹³

Juxtacortical chondrosarcoma may appear similar to a large periosteal chondroma. If of lower grade, calcification may be present and may be prominent. The tumor’s lobular architecture is usually readily apparent because the tumor does not have the surrounding cortex to contain its growth. In contrast to periosteal chondroma, substantial saucerization and shouldering of the subjacent cortex is rarely present because the tumor invades that cortex rather than pushing on it. This, along with the size of the lesion, is the most important clue that a surface cartilage neoplasm is malignant.

Mesenchymal chondrosarcoma demonstrates imaging characteristics similar to those of Ewing sarcoma, befitting the small-cell nature of its histopathology. Lytic bone destruction with permeation and periosteal sunbursting may occur. Because of this disease’s propensity for skeletal metastasis and multifocal disease, skeletal scanning with either radionuclide bone scan or PET scanning is of benefit.

Fitting to its biphasic nature, dedifferentiated chondrosarcoma often combines the radiographic characteristics of a grade 1 and grade 3 chondrosarcoma. The diagnosis can be made when the radiographs show two distinct, apposed areas, one being heavily calcified and more benign appearing and the other having the radiographic characteristics of a high-grade sarcoma of bone.

Secondary chondrosarcoma’s imaging depends on the primary lesion. In a secondary tumor arising from a prior osteochondroma, the stalk of the initial lesion may be seen to be eroded or perforated, with a large (>10 mm) cartilage cap destroying either the stalk or the surrounding bony cortex. Care must be taken in interpreting the thickness of a cartilage cap: in children, adolescents, and young adults, the cap may be as thick as 20 mm without concern for secondary transformation. In older adults, the cartilage cap should be less than 10 mm and is often much thinner. Secondary transformation of an intraosseous tumor, such as enchondroma, will demonstrate imaging as described for grade 1 chondrosarcoma.⁷

The histologic characteristics of chondrosarcoma are as varied as the clinicoradiographic findings detailed earlier. The overarching theme of chondrosarcoma histology is heterogeneity: lesions will demonstrate not only cellular
heterogeneity but also areas within the tumor of varying grades. This heterogeneity causes several problems. In terms of diagnosis, limited biopsy techniques (fine-needle aspiration, core needle, or even limited open biopsies) may not accurately reflect the final diagnosis. Furthermore, management (as detailed in the following section) will reflect not only the suspected grade of the tumor but also the amount of damage that has been done to the surrounding bone. Determination of the grade will depend on the anatomic locale: the same histology in the finger may be a benign enchondroma, whereas the identical lesion in the pelvis will be a grade 1 or 2 chondrosarcoma and will act accordingly. Accurately determining the final grade of any cartilage neoplasm therefore demands examination of the clinical, radiographic, and histologic characteristic by an experienced musculoskeletal pathologist, and ideally a multidisciplinary team.¹⁴

Grade 1 chondrosarcoma or low-grade cartilage neoplasm will often appear very similar to an enchondroma. The cartilage will be hyaline, with all of the cells residing within lacunae and minimal myxoid changes (Figure 3, A). As stated earlier, distinguishing between enchondromas and low-grade neoplasms will be strongly dependent on the anatomic locale, symptoms, and corresponding radiographic changes. Classic histologic changes in low-grade neoplasms include hypercellularity, disorganization, increased nuclear detail (often the presence of a nuclear membrane), and more than occasional binucleate cells.⁸ In certain circumstances, such as distal extremity lesions or synovial chondromas, all of these characteristics may be present without any concrete diagnosis of malignancy. Anatomic locale and integration of imaging characteristics are essential to render an accurate diagnosis.

Grade 2 chondrosarcoma generally becomes distinctive, as the typical characteristics of benign cartilage disappear. The overall architecture remains lobular, but hyaline matrix gives way to a myxoid background (Figure 3, B). The cells appear more disorganized, and the cytologic features of sarcoma, such as the presence of nucleoli and mildly pleomorphic forms, become more evident.

Grade 3 chondrosarcoma scarcely resembles cartilage (Figure 3, C). Unless a component of dedifferentiated chondrosarcoma, no hyaline cartilage is present. The architecture remains lobular, but substantial pleomorphism and near-complete anaplasia mark the tumor as high grade. Mitoses, which are generally not present in lower grades of chondrosarcoma, become more prominent and more abnormal. As high-grade chondrosarcoma is quite rare, this diagnosis requires a careful search for malignant osteoid because the features of grade 3 chondrosarcoma and chondroblastic osteosarcoma overlap substantially.

Chondrosarcoma variants have interesting histopathologic features. Mesenchymal chondrosarcoma is a biphasic tumor, where the features of a low-grade chondrosarcoma are juxtaposed (and sometimes superimposed) with those of a small round blue cell tumor. Lobules of hyaline cartilage-containing areas of disorganization and binucleate cells will be interspersed with areas of monotonous, small blue cells similar to Ewing sarcoma. At times these features will exist in the same field, with the small cell, high-grade component seen within the hyaline matrix.

Clear cell chondrosarcoma, the rare, epiphyseal bone sarcoma, maintains the lobular architecture characteristic of all cartilage neoplasms. As opposed to hyaline chondrocytes, the cells in this entity are large, vacuolated cells with clear cytoplasm. Highly malignant features, such as bizarre mitoses, marked nucleoli, and open chromatin, are generally absent, and the cellular grade is usually low. Giant cells, either individually or in clusters, are prominent and assist with the diagnosis.

Dedifferentiated chondrosarcoma is a biphasic tumor with a specialized pattern. One portion will be comprising a typical, low-grade or intermediate-grade chondrosarcoma, with all of the characteristics described previously. The other will be a high-grade sarcoma, with the tissue types being high-grade chondrosarcoma, chondroblastic osteosarcoma, or high-grade fibrosarcoma. An abrupt change from one tumor type to the other will occur, sometimes within one high-power field. This generates the appearance of two completely different tumors occurring together with no transition from one to the other (Figure 4).