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Chondrosarcoma

Chondrosarcoma
Literature review current through: May 2024.
This topic last updated: Apr 27, 2023.

INTRODUCTION — Chondrosarcomas are a heterogeneous group of malignant bone tumors that all produce chondroid (cartilaginous) matrix [1]. Chondrosarcomas are the third most common primary malignancy of bone after myeloma and osteosarcoma [2]. They account for 20 to 27 percent of primary malignant osseous neoplasms [3].

Conventional chondrosarcomas, comprise a majority (90 percent) of all chondrosarcomas [1,4,5]. Atypical cartilaginous tumor/chondrosarcoma grade 1 (ACT/CS1) are also relatively common among patients with incidentally diagnosed cartilaginous tumors [6]. By contrast, high-grade chondrosarcomas are rare. These high-grade chondrosarcomas, along with other ultrarare variants, comprise approximately 5 to 10 percent of all chondrosarcomas [4]. Clinical behavior varies based on the subtype and the histologic grade.

This clinical presentation, diagnosis, and management of chondrosarcoma is presented here. Chondrosarcomas involving the head and neck and skull base, as well as diagnosis and biopsy techniques for general bone tumors, are discussed separately. (See "Chordoma and chondrosarcoma of the skull base" and "Head and neck sarcomas" and "Bone tumors: Diagnosis and biopsy techniques".)

HISTOLOGIC GRADING AND PROGNOSIS — Histologic grade is one of the most important indicators of clinical behavior and prognosis [7-10]. Conventional chondrosarcomas are graded on a scale from 1 to 3, based upon nuclear size, staining pattern (hyperchromasia), mitotic activity, and degree of cellularity (picture 1 and table 1).

The term "atypical cartilaginous tumor" (ACT) was introduced in the World Health Organization (WHO) 2013 classification system to define more accurately the clinical behavior of well-differentiated/low-grade lesions, previously termed "chondrosarcoma grade 1" (CS1) that, especially in the long bones, behave in a locally aggressive manner and do not metastasize [1]. Hence, they should not be classified as having full malignant potential.

In the subsequent WHO 2020 classification system (table 1), this category is now further defined to account for differences in biologic behavior depending on localization (analogous with the concept of atypical lipomatous tumor [which involve the extremities] and well-differentiated liposarcoma [which involve the retroperitoneum]) [1]. The term ACT is used to describe tumors involving the appendicular skeleton (long and short tubular bones), whereas "chondrosarcoma grade 1" can be used for tumors of the axial skeleton, including the pelvis, scapula, and skull base (flat bones). These tumors are moderately cellular, with an abundant hyaline cartilage matrix. The chondrocytes have small, round nuclei and are occasionally binucleate. Mitoses are absent. ACT/CS1 almost never metastasize (1 percent risk in one series of patients [4]). Ten-year survival is 83 to 95 percent [4,7,11].

Grade 2 chondrosarcomas are more cellular with less chondroid matrix than ACT/CS1 tumors. Mitoses are present, but widely scattered. The chondrocyte nuclei are enlarged and can be either vesicular or hyperchromatic. The metastatic potential is intermediate between low-grade and high-grade chondrosarcomas (approximately 10 to 15 percent). Ten-year survival is approximately 64 to 86 percent [4,7,11].

The vast majority of conventional (primary and secondary) chondrosarcomas are ACT/CS1 or chondrosarcoma grade 2 [4,11,12].

Grade 3 chondrosarcomas are highly cellular, with nuclear pleomorphism and easily detected mitoses, as well as characteristic spindle cell changes at the periphery of the tumor nodules. Chondroid matrix is sparse or absent. High-grade chondrosarcomas have a high metastatic potential (approximately 32 to 70 percent) and a poor prognosis with surgical resection alone [4,7]. The 10-year survival rate is approximately 29 to 55 percent [4,11].

In most cases, the histologic grade of differentiation of a recurrent chondrosarcoma is the same as the primary lesion; however, up to 13 percent of recurrences exhibit a higher grade of malignancy when compared with the original neoplasm [7,11,13]. This suggests that chondrosarcomas can progress biologically. Additionally, chondrosarcomas located in the axial skeleton have a worse outcome and are treated more aggressively [14-16].

Histologic grading is subject to interobserver variability [17,18], which can be problematic since surgical therapy for ACT/CS1 and grade 2 chondrosarcomas is often different. Because of this, there is a need for molecular markers that can predict clinical behavior, guide therapeutic decision-making, and provide novel targets for molecularly targeted therapy [19]. (See 'Investigational agents' below.)

CLASSIFICATION, HISTOLOGY, AND CLINICAL FEATURES

Precursor lesions — Two benign cartilaginous lesions that can precede chondrosarcoma are described below:

Osteochondroma — An osteochondroma (osteocartilaginous exostosis) is a cartilage-capped bony projection arising on the external surface of a bone (picture 2 and image 1); it contains a marrow cavity that is continuous with that of the underlying bone. The majority are located in the long bones, predominantly around the knee.

The inherited condition multiple osteochondromas (hereditary multiple exostoses) is characterized by the development of two or more osteochondromas in the appendicular and axial skeleton. This syndrome is inherited in an autosomal dominant fashion. The prevalence in the general population is 1:50,000, and males are affected slightly more often than females. (See "Nonmalignant bone lesions in children and adolescents", section on 'Osteochondroma and hereditary multiple osteochondromas'.)

Almost 90 percent of cases of multiple osteochondromas are caused by inheritance of a germline mutation in one of the tumor suppressor genes EXT1 or EXT2. (See 'Molecular pathogenesis' below.)

Although most are asymptomatic, osteochondromas can cause pain, functional problems, and deformity; they also carry a risk for fracture. Malignant transformation is estimated to occur in 5 percent of patients with a solitary or multiple osteochondromas [20-25]. In one series, the average time between initial diagnosis and malignant transformation was 9.8 years [24]. All chondrosarcomas arising in the setting of an osteochondroma are secondary peripheral tumors.

A change in the size of an osteochondroma or new onset of symptoms warrants investigation, as each may herald progression to malignancy [26,27]. Osteochondromas located at the pelvis, hips and shoulder girdle are reported to be particularly prone to malignant transformation [26,27]. Among patients with multiple osteochondromas, malignant transformation appears to be unrelated to the presence or absence of an EXT mutation, sex, severity of disease, or the number of lesions [25].

Enchondroma — Enchondromas are common benign cartilaginous tumors that develop in the medulla (marrow cavity) of bone (image 2). When multiple enchondromas are present that cause deformity, the condition is called enchondromatosis (image 3), of which the most common form is Ollier disease (estimated prevalence 1 in 100,000) [28]. When multiple enchondromas are associated with soft tissue hemangiomas, especially spindle cell hemangioma, the designation is Maffucci syndrome (image 4). Both are congenital but not inherited. (See "Nonmalignant bone lesions in children and adolescents", section on 'Enchondroma'.)

Ollier disease as well as Maffucci syndrome are caused by somatic mosaic mutations in the IDH1 or IDH2 genes [29,30]. (See 'Molecular pathogenesis' below.)

Although the vast majority are asymptomatic, clinical problems caused by enchondromas include skeletal deformity, limb-length discrepancy, and a risk for malignant transformation. Malignant transformation in a solitary enchondroma is presumed to be extremely rare (<1 percent) but it has been described (image 5) [24]. The risk of chondrosarcoma in Ollier disease or Maffucci syndrome is as high as 50 percent [28,31-35]. The risk is highest with enchondromas located in the pelvis [34]. Malignant transformation usually presents after skeletal maturity and may be heralded by the development of pain [24].

The histologic and radiographic distinction between an enchondroma and atypical cartilaginous tumor/chondrosarcoma grade 1 (ACT/CS1) may be difficult, even in experienced hands. (See 'Histologic appearance' below.)

Conventional chondrosarcomas

Central chondrosarcoma — Central chondrosarcomas of bone arise within the medullary cavity and constitute approximately 75 percent of all chondrosarcomas (table 2). The majority are thought to arise primarily (ie, without a benign precursor lesion). However, the finding of remnants of a preexisting enchondroma in approximately 40 percent of central chondrosarcomas and the fact that most enchondromas remain asymptomatic and clinically silent have led some to hypothesize that most central chondrosarcomas could be secondary to a preexisting enchondroma [36].

The majority of patients are over the age of 50. There is a slight male predominance.

The most commonly involved skeletal sites are the proximal femur, bones of the pelvis (particularly the ilium), and proximal humerus (together accounting for approximately 75 percent of cases), followed by distal femur, ribs, tibia, and metacarpal and metatarsal bones [3,4,37,38]. Other less frequently involved sites include the spine, the skull base, and the craniofacial bones. (See "Chordoma and chondrosarcoma of the skull base" and "Head and neck sarcomas".)

Chondrosarcomas of the pelvis often present with high-risk features that suggest worse overall survival compared with other locations [39]. Such clinical features include larger tumor size, extracompartmental extension, and metastatic disease.

Local swelling and pain are the most common presenting symptoms. Pain is typically insidious, progressive, worse at night, and often present for months to years before presentation. A pathologic fracture is present at diagnosis in 3 to 17 percent of patients [3]. Primary spinal chondrosarcomas are rare but can cause compression of the spinal cord.

Secondary peripheral chondrosarcoma — By definition, all peripheral chondrosarcomas arise within the cartilage cap of a preexisting osteochondroma (table 2). Patients with a secondary peripheral chondrosarcoma are generally younger than those with a central chondrosarcoma (table 2) [26]. The median age is 38 years and such patients are predominantly male (66 percent) [40].

The clinical presentation is like that of central chondrosarcoma, which is usually pain and local swelling. The most commonly involved bones are the pelvis and bones of the shoulder girdle, although in some series, the long bones predominate [24]. The distinction between osteochondroma and secondary peripheral atypical cartilaginous tumor/chondrosarcoma grade I (ACT/CS1) arising in osteochondroma can be difficult and should be made by a multidisciplinary team. The size of the cartilaginous cap is the most important parameter and should be measured perpendicularly [41]. A cartilage cap >2 cm in adults is suggestive of progression [42].

Periosteal chondrosarcoma — Less than 1 percent of chondrosarcomas arise on the surface of a bone and are designated periosteal (previously termed juxtacortical) chondrosarcomas. They most frequently affect adults in their 20s and 30s and have a slight male predilection. The metaphyses of long bones are most frequently involved, especially of the distal femur (figure 1). Patients typically present with a palpable, painless, slowly growing mass [3,43,44].

Periosteal chondrosarcomas usually have a good prognosis after adequate local surgery despite histologic features of a high-grade lesion [9,45-49]. Histologic grading is therefore not used at this location [44,49].

Histologic appearance — At low magnification, there is abundant cartilage matrix production, and the irregularly shaped lobules of cartilage, often separated by fibrous bands, may permeate the bony trabeculae in central tumors (picture 1) [1]. Necrosis or mitoses may be seen in high-grade lesions. The histology of periosteal chondrosarcomas is similar.

The histologic (and radiographic) distinction between a benign cartilage lesion and an ACT/CS1 can be extremely difficult [17,50,51]. ACT/CS1 is hypercellular when compared with benign cartilage lesions. The chondrocytes appear mildly to moderately atypical and contain enlarged hyperchromatic nucleoli. Permeation of preexisting host bone and mucomyxoid matrix changes are important characteristics that can be used to separate ACT/CS1 from an enchondroma [18]. Periosteal chondrosarcoma is distinguished from periosteal chondroma based upon size (≥5 cm) and/or the presence of cortical invasion. For phalangeal enchondromas, more worrisome histologic features are tolerated, and the diagnosis of chondrosarcoma at this site is based upon the presence of cortical destruction, soft tissue invasion, and mitoses [52].

Fortunately, the distinction between enchondroma and ACT/CS1 is not always essential for clinical decision-making since treatment (curettage and adjuvant phenol application or cryosurgery) is often similar for enchondromas as well as central ACT in the long or short tubular bones. (See 'Surgical treatment' below.)

Rare chondrosarcoma subtypes — In addition to conventional central, peripheral, and periosteal chondrosarcomas, several rare subtypes are described, together constituting less than 10 percent of all chondrosarcomas.

Dedifferentiated chondrosarcoma — Dedifferentiated chondrosarcomas are considered ultrarare bone sarcomas [53]. Dedifferentiated chondrosarcoma contains two juxtaposed components: a well-differentiated cartilage tumor (which can be either an enchondroma or a low-grade chondrosarcoma) and a high-grade noncartilaginous sarcoma, which most frequently is an osteosarcoma, fibrosarcoma, or an undifferentiated high-grade pleomorphic sarcoma (previously termed malignant fibrous histiocytoma) (picture 3) [1].

Both components appear to share some genetic aberrations [54,55] with additional genetic changes in the high-grade component [54-57]. This suggests a common precursor cell with early divergence of the two components. More than 50 percent of dedifferentiated chondrosarcomas harbor mutations in IDH1 or IDH2, frequently combined with a mutation in the TERT promoter [58], TP53, CDKN2A/B, or others. The IDH mutations are found in both components, confirming a common origin of both components [59].

The average age at presentation is older (between 50 and 60 years) than in other chondrosarcoma subtypes (table 2). The majority occur centrally in medullary bone; the most common sites of involvement are the pelvis, femur, and humerus. The typical presentation is with pain, although swelling, paresthesias, and pathologic fractures are also common [60]. The majority of patients have an associated soft tissue mass [61].

Dedifferentiated chondrosarcomas are biologically aggressive and they have a poor prognosis [13,61-63]. In a multicenter review of 337 patients, 71 (21 percent) had metastases at the time of diagnosis; they had a 10 percent chance of survival at two years [13]. Even for patients without metastases at diagnosis, survival was only 28 percent at 10 years. Poor prognostic factors include pathologic fracture, pelvic location, and older age. Outcomes are also not correlated to the extent of the dedifferentiated component; these tumors are aggressive even when the dedifferentiated component is small, emphasizing the need for thorough diagnostic sampling [64].

Mesenchymal chondrosarcoma — Mesenchymal chondrosarcomas are ultrarare [53], highly malignant tumors that are characterized by differentiated cartilage admixed with solid highly cellular areas that are composed of undifferentiated small round cells (picture 3) [1].

The average age is 25 to 30 years [65,66], younger than that of other types of chondrosarcoma (table 2). There is a high proportion of extraskeletal primary tumors, which is not seen with other chondrosarcoma subtypes [67]. Of the approximately one-third of cases that affect the extraskeletal soft tissues, the meninges are one of the most common sites [68]. Also, in contrast with conventional chondrosarcomas, mesenchymal tumors most commonly involve the axial skeleton, including the craniofacial bones (especially the jaw) [69], ribs, ilium, and vertebra, and there may be involvement of multiple bones. Approximately 20 percent have metastatic disease at diagnosis [70]. (See "Head and neck sarcomas", section on 'Chondrosarcoma' and "Chordoma and chondrosarcoma of the skull base".)

The main symptoms are pain and swelling, and it is not uncommon for symptoms to have been present for many months.

Mesenchymal chondrosarcomas have a tendency toward both local and distant recurrences, which may arise as long as 20 years following the initial diagnosis [71]. The prognosis is markedly worse than for conventional primary chondrosarcomas. Reported 10-year survival rates range from 10 to 54 percent [65,67,70-73].

Clear cell chondrosarcoma — Clear cell chondrosarcoma is an ultrarare low-grade variant of chondrosarcoma, which is characterized by the presence of lobulated groups of bland-appearing tumor cells with large, centrally-located nuclei and clear, empty cytoplasm in addition to hyaline cartilage (picture 3). Mitotic figures are rare. Many tumors contain zones of conventional chondrosarcoma with hyaline cartilage and minimally atypical nuclei.

Although these tumors can arise at any age, most patients are between the ages of 25 and 50 (table 2). Men are three times more likely as women to develop this particular subtype [1]. Approximately two-thirds of tumors arise in the epiphyseal ends of the humerus or femur (figure 1). Pain, which may have been present for longer than one year, is the most common complaint.

Serum alkaline phosphatase levels are often elevated at diagnosis and may provide a useful tumor marker [74].

Despite their low-grade nature, marginal excision or curettage is associated with a 70 percent or higher recurrence rate and should be avoided [74,75]. In incompletely excised cases, metastases may develop, usually to the lungs and other skeletal sites, and the overall mortality rate is up to 15 percent [1]. By contrast, en bloc wide local excision is usually curative.

Disease recurrence may occur up to 24 years after initial diagnosis [74,75]. Long-term follow-up is mandatory.

Myxoid chondrosarcoma — It is now generally accepted that myxoid chondrosarcoma of bone represents a high-grade conventional chondrosarcoma with prominent myxoid change and is unrelated to extraskeletal myxoid chondrosarcoma (EMC), a soft tissue sarcoma that most commonly arises in the lower extremities [76,77]. Further information on the clinical presentation and treatment of extraskeletal myxoid chondrosarcoma is discussed separately. (See "Uncommon sarcoma subtypes", section on 'Extraskeletal myxoid chondrosarcoma'.)

The term "chondrosarcoma" to describe EMC is a misnomer. Well-formed hyaline cartilage is found only in a minority of EMCs [78,79], while S100 expression (which is present in all or most chondrosarcomas) is often very focal or absent. Expression of collagen II and aggrecan (two other markers of cartilaginous differentiation) are absent in 86 percent of EMCs [79].

Furthermore, NR4A3 fusions that are specific for EMC are generally absent in so-called myxoid chondrosarcoma of bone, and its ultrastructure is different [78,80]. The reported cases of myxoid chondrosarcoma of bone that contain a proven translocation of t(9:22) have a large soft tissue component that makes distinction from EMC with secondary bone destruction extremely difficult [81], although some convincing cases have been reported [82]. (See "Pathogenetic factors in soft tissue and bone sarcomas", section on 'Extraskeletal myxoid chondrosarcoma'.)

Thus, EMC and so-called myxoid chondrosarcoma of bone appear to represent two different entities. The 2020 WHO classification classifies the entity EMC in the "tumors of uncertain differentiation" category [1]. Myxoid chondrosarcomas of bone are not designated as a unique entity, and these tumors should be regarded as a myxoid variant of intermediate- or high-grade conventional chondrosarcoma.

Molecular pathogenesis — Cartilaginous tumors are nearly always found in bones that arise from enchondral ossification. There are some parallels between chondrocyte growth and differentiation in the normal growth plate for both benign and malignant cartilaginous tumors [83].

Within the normal growth plate, resting zone chondrocytes proliferate and differentiate, becoming hypertrophic. These cells undergo apoptosis, allowing the invasion of vessels and osteoblasts that start to form bone and lead to longitudinal bone growth. This physiologic process is tightly regulated by components of the Indian hedgehog (IHH)/parathyroid hormone related (PTHRP) protein signaling pathway.

Patients with multiple osteochondromas (previously called hereditary multiple exostoses) have germline mutations in the exostosin (EXT1 or EXT2) genes [84-86], with loss of the remaining wild type allele in the cartilage cap of the osteochondroma [87]. The end result is decreased EXT expression. Loss of expression of the EXT genes through homozygous deletion of EXT1 is also seen in solitary osteochondromas that are unassociated with the hereditary syndrome [88,89]. The EXT gene products are involved in the biosynthesis of heparan sulfate proteoglycans (HSPGs), which are essential for cell signaling through IHH/PTHLH and other pathways [90].

In osteochondromas where EXT is inactivated, the HSPGs seem to accumulate in the cytoplasm and Golgi apparatus instead of being transported to the cell surface [89]. This hampers multiple growth signaling pathways (including the IHH/PTHRP protein pathways), which, as noted above, are important for normal chondrocyte proliferation and differentiation within the normal human growth plate.

In secondary peripheral chondrosarcomas arising in osteochondromas, EXT is usually wild type, suggesting that the wild type cells in osteochondroma are prone to malignant transformation through EXT independent mechanisms [91]. Using a mouse model, it was shown that additional genetic alterations involving the TP53 or pRb pathway are involved in the progression from osteochondroma to secondary peripheral chondrosarcoma [92]. In addition, a role for IHH signaling has been suggested, although the data are not entirely consistent [93-97]:

PTHRP signaling, which is downstream of IHH and is involved in chondrocyte proliferation, is absent in osteochondromas, but upregulated with malignant transformation towards secondary peripheral chondrosarcoma, especially in high-grade lesions [94,95,98-101].

There is decreased expression of downstream targets in the IHH signaling cascade during tumor progression in peripheral chondrosarcomas, while they are still active in central chondrosarcomas [102].

Data from in vitro and in vivo models show that treatment of central chondrosarcoma cells with recombinant hedgehog increases proliferation, whereas treatment with hedgehog signaling inhibitors inhibits tumor proliferation and growth in a small subset of tumors and chondrosarcoma cell cultures [97,102,103]. In addition, defective hedgehog signaling also affects bone morphogenetic protein signaling [104].

Molecular mutations — Next-generation sequencing has also defined various molecular alterations, some of which are associated with some chondrosarcoma subtypes.

Among enchondromas and primary (central) chondrosarcomas, point mutations in isocitrate dehydrogenase-1 and isocitrate dehydrogenase 2 genes IDH1 and IDH2 have been identified in 40 to 56 percent of cases, and seem to be an early event [29,105]. Also, Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations in IDH1 and IDH2 [29,30]. Isocitrate dehydrogenase is an enzyme that converts isocitrate to alpha-ketoglutarate in the TCA (tricarboxylic acid) cycle. Mutations in IDH1 and IDH2 cause elevated levels of the oncometabolite D-2-hydroxyglutarate (D-2-HG), which competitively inhibits alpha-ketoglutarate dependent enzymes, such as TET2, thereby inducing epigenetic changes, including DNA hypermethylation and histone modification, probably affecting differentiation [106]. Increased levels of D-2-HG promote chondrogenic and inhibit osteogenic differentiation of mesenchymal stem cells. Thus, mutations in IDH1 or -2 lead to a local block in osteogenic differentiation during skeletogenesis, causing the development of benign cartilaginous tumors [107,108]. Indeed, also in mice, mutant IDH or D-2-HG causes persistence of chondrocytes, giving rise to rests of growth-plate cells that persist in the bone as enchondromas [109]. These data confirm that mutations in IDH are an early event involved in the development of benign enchondromas. In chondrosarcoma cell lines, inhibition of mutant IDH1 seems not to affect tumorigenic properties [110], or only at a very high dose [111] or after prolonged treatment [112]. Data are conflicting for the association between the IDH mutation and survival outcomes [113-115].

IDH2-mutant tumors occur in older patients and are more frequent in patients with high-grade or dedifferentiated chondrosarcoma [58]. TERT mutations occur most frequently in IDH2-mutant tumors, although they do not affect survival in this group. In contrast, TERT mutations are rarer in IDH1-mutant tumors, yet they are associated with a less favorable outcome in this group [58].

TERT mutations are infrequent in the IDH wild-type tumors which tend to be diagnosed in a younger population than IDH-mutant chondrosarcomas [58]. Genomically, this molecular subgroup is characterized by haploidization and subsequent genome doubling. These tumors evolve less frequently to dedifferentiated disease and therefore constitute a lower-risk group.

At the transcriptome level, two subtypes of chondrosarcomas are defined by a balance in tumor differentiation and cell cycle activation [116]. Loss of the microRNA expression of the 14q32 locus was shown to have additional prognostic value in addition to IDH/methylation status.

In addition, although EXT is not involved, involvement of the IHH/PTHLH signaling pathway is suggested by the observations that PTHRP signaling is active in enchondromas [98,101], and hedgehog signaling is active in central chondrosarcomas [102]. Moreover, a mutation in the gene encoding the receptor for PTHRP (PTH-1 receptor or PTH1R) has been identified in very few patients with enchondromatosis [96,117]. Mutations in PTH1R have not been found in sporadic chondrosarcomas, nor in Maffucci syndrome [1,29,30]; this gene may contribute to pathogenesis in only a very small subset (<5 percent) of patients with Ollier disease. Moreover, using whole exome sequencing, mutations were found in different genes involved in hedgehog signaling [118].

While enchondromas and low-grade chondrosarcomas are near-diploid and carry few karyotypic abnormalities, high grade chondrosarcomas are aneuploid and have complex karyotypes [52,119]. Some of the few consistent genetic aberrations include 12q13-15 and 9p21 rearrangements [52,119-122].

Chondrosarcoma progression has been linked to the CDKN2A (p16) tumor suppressor gene, located at 9p21 [123,124] and by alterations in p53 [58,113,125].

Mutations in COL2A1 and YEATS2 are found in a subset of chondrosarcomas, the meaning of which is unknown [118,126]. Other genes reported to be recurrently mutated include ATRX and the TERT promoter [113]. Mutations in the TERT promotor are associated with disease progression [127].

Among conventional primary chondrosarcomas, activation and/or overexpression of platelet-derived growth factor receptor-alpha (PDGFRA) and beta (PDGFRB) has been described, although activating mutations have not been found [128,129]. The therapeutic implications of this finding are discussed below. (See 'Investigational agents' below.)

Dedifferentiated chondrosarcomas also contain IDH1 or IDH2 mutations in approximately 50 percent of cases [29,59,105], as well as COL2A1 and TERT promoter mutations [58,130].

Most mesenchymal chondrosarcomas was shown to harbor a specific HEY1-NCOA2 fusion product caused by an intrachromosomal rearrangement of chromosome arm 8q [131]. Alternatively, a IRF2BP2-CDX1 fusion gene brought about by translocation t(1;5)(q42;q32) was described [132]. The HEY1-NCOA2 fusion protein preferentially binds to promoter regions of canonical HEY1 targets, resulting in transactivation of HEY1 targets and enhancing cell proliferation [133]. Moreover, PDGFRB and PDGFRA were directly targeted by the fusion and increased the level of phospho-AKT (Ser473 [133]). In one study, imatinib decreased tumor growth in vitro as well as in a patient-derived xenograft [134].

Among clear cell chondrosarcoma, no specific recurrent alterations have been identified [59].

Mismatch repair deficiency and high tumor mutational burden is uncommon in chondrosarcomas, similar to other sarcomas [135]. (See "Second and later lines of therapy for metastatic soft tissue sarcoma", section on 'Tumors with dMMR, MSI-H, or high levels of TMB'.)

Preclinical models have shown that the immune microenvironment in chondrosarcoma, predominantly consisting of lymphocytes and macrophages in the peritumoral area, contribute to chondrosarcoma progression [136]. More specifically, three groups were defined using in-depth analysis on a relatively small series of chondrosarcomas (n = 22) [137]:

Subtype I, the "granulocytic-myeloid-derived suppressor cell (G-MDSC) dominant" cluster, with high number of HLA-DR negative CD14 negative myeloid cells; these tumors were IDH mutant and displayed myxoid morphology.

Subtype II, the "immune exhausted" cluster, with high exhausted T-cell and dendritic-cell infiltration; these tumors are often IDH mutant and of high histological grade.

Subtype III, the "immune desert" cluster, with few immune cells. These tumors are most often low grade and more often IDH wildtype.

DIAGNOSTIC AND STAGING WORK-UP — The goals of the preoperative evaluation are to establish the tissue diagnosis and evaluate disease extent, in order to select the appropriate therapeutic approach. One fundamental principle applying to diagnosis of both tumors of bone and cartilage is that both the histology and radiography of bone tumors are not specific. Integration of the clinical history, radiography, and pathology is necessary to render a specific diagnosis.

Radiographic imaging

Plain radiographs, CT, and MRI — The initial imaging study in a patient with a painful musculoskeletal swelling is typically a plain radiograph. The location and radiographic appearance of the different chondrosarcoma subtypes are often characteristic [1]. Although plain radiographs can provide a clue as to the probable histology of a potentially malignant bone lesion, evaluation of tumor size and local extent is most accurately achieved by magnetic resonance imaging (MRI) and/or computed tomography (CT) [138].

CT is optimal to detect matrix mineralization, particularly when it is subtle or the lesions are located in an anatomically complex area. Because of their high water content, most chondrosarcomas are of low attenuation on CT.

MRI is better for delineating the extent of marrow and soft tissue involvement. The high water content of chondrosarcomas is manifest as very high signal intensity on T2-weighted images [3].

In the long bones, central chondrosarcomas produce a fusiform expansion in the metaphysis or diaphysis (figure 2). The tumor has a mixed radiolucent and sclerotic appearance with the mineralized chondroid matrix appearing as a punctate or ring-and-arc pattern of calcifications that may coalesce to form a more radiopaque flocculent pattern of calcification (the so-called chondroid type of calcification (image 6)). Higher grade chondrosarcomas often contain relatively less extensive areas of mineralization (image 7).

The cortex is often thickened but a periosteal reaction is scant or absent. There may be features of endosteal scalloping and soft tissue extension. Evidence of a large soft tissue mass, particularly if unmineralized, that is associated with a lesion whose radiologic features otherwise suggest a chondrosarcoma should raise the level of suspicion for a high-grade tumor (image 7 and image 8).

Conventional radiographs are not reliable to distinguish between an enchondroma and central atypical cartilaginous tumor/chondrosarcoma grade 1 (ACT/CS1) [17,50,139,140], although localization in the axial as opposed to the appendicular skeleton and size greater than 5 cm favor chondrosarcoma [50,141]. The presence of a soft tissue mass excludes the diagnosis of an enchondroma.

Osteochondromas appear as a sessile or broadly-based smoothly calcified lesion at the surface of bone, with the cortex of the bone typically extending into the stalk of the osteochondroma and normal trabeculation centrally. The cartilaginous cap is best assessed on T2-weighted MRI and should not exceed 2 cm [42]. A thickened cap and irregular distribution of vague calcifications as well as size >2 cm suggest the development of a secondary chondrosarcoma. (See 'Osteochondroma' above and 'Secondary peripheral chondrosarcoma' above.)

Periosteal chondrosarcomas appear as a round to oval soft tissue mass on the surface of bone, containing typical chondroid matrix mineralization. They cause variable amounts of cortical bone erosion and appear to be covered by an elevated periosteum (Codman triangles). The medullary canal is typically not involved. The radiographic differentiation between a periosteal chondrosarcoma, periosteal osteosarcoma, and parosteal osteosarcoma can be difficult. (See 'Periosteal chondrosarcoma' above.)

Clear cell chondrosarcomas have a predilection for the epiphyseal ends of the femur and humerus (figure 1). Radiographs reveal a well-defined, predominantly lytic lesion, sometimes with a sclerotic rim. Matrix mineralization is not as frequently apparent as with conventional chondrosarcoma. (See 'Clear cell chondrosarcoma' above.)

As noted above, aggressive chondrosarcomas, such as the mesenchymal and dedifferentiated subtypes, often contain areas of matrix mineralization that suggest a low-grade chondroid neoplasm; however, these areas are relatively less extensive compared with conventional chondrosarcoma and are usually ill-defined. On CT and MRI, dedifferentiated chondrosarcomas may be seen to contain two distinct areas with differing radiographic characteristics: the low-grade conventional chondrosarcomatous component has low attenuation on CT and high signal intensity on T2-weighted MRI images, while the high-grade noncartilaginous component may have soft tissue attenuation on CT (isointense to muscle) and variable signal intensity on MRI T2-weighted images. There may be intraosseous lytic areas and an aggressive pattern of bone destruction with a moth-eaten or permeative pattern. These aggressive tumors are often associated with perforation of the cortex and a large soft tissue mass. (See 'Rare chondrosarcoma subtypes' above.)

Role of positron emission tomography — The imaging methods described above provide limited information as to the biologic activity of a suspected chondrosarcoma. Positron emission tomography (PET) scanning with fluorodeoxyglucose (FDG) has been proposed as a noninvasive method to assess tumor grade, to distinguish benign from malignant chondroid lesions, to identify otherwise occult metastatic disease, and to differentiate recurrent tumor from postoperative change [142-145]. However, the overall place of PET in the diagnostic and staging evaluation remains uncertain:

Although grade 2 and 3 chondrosarcomas have a higher glucose metabolism (and therefore a higher standardized uptake value [SUV]), PET cannot differentiate between benign cartilage tumors and ACT/CS1 [145].

The value of PET scanning to screen for metastatic or recurrent disease is also uncertain.

Biopsy — For suspicious lesions, a diagnostic biopsy can be undertaken to establish the diagnosis and plan the surgical approach. The initial percutaneous biopsy may not accurately reflect the true histologic grade of the lesion, because of lesion heterogeneity and the possibility of sampling error [146]. If it is undertaken, biopsy should always be performed in collaboration with the surgeon that will perform the final surgery in case of malignancy, and should be directed at the more aggressive-appearing areas as seen on the radiographic studies (ie, the soft tissue components, or the more diffusely enhancing regions with limited or no matrix mineralization). In difficult cases, mutation analysis for IDH1 and -2 can help to distinguish chondrosarcoma from (chondroblastic) osteosarcoma [147].

Specific issues surrounding the diagnostic biopsy for suspected primary bone tumors are discussed separately. (See "Bone tumors: Diagnosis and biopsy techniques".)

Staging system — The staging system used for bone sarcomas was developed by Enneking et al at the University of Florida and based upon a retrospective review of cases of primary malignant tumors of bone treated by primary surgical resection (table 3) [148,149]. This system characterizes nonmetastatic malignant bone tumors by grade (low grade [stage I] versus high grade [stage II]) and further subdivides these stages according to the local anatomic extent. The compartmental status is determined by whether the tumor extends through the cortex of the involved bone. Patients with distant metastases are categorized as stage III.

The American Joint Committee on Cancer (AJCC) developed a tumor, node, metastasis (TNM) staging system in its 1997 fifth edition [150], which despite several modifications, has not been widely adopted for clinical use. The latest 2017 revision (eighth edition, 2017) has separate and distinct TNM classifications for primary bone tumors (including chondrosarcomas) arising in the appendicular skeleton/trunk/skull/facial bones and those arising in the pelvis and spine (table 4) [151]. It remains to be seen whether this version will be used in clinical practice.

Completing the staging work-up — As with other sarcomas, the lungs are the main site of metastatic disease; much less commonly, the regional nodes and liver are involved. Given the extremely low rate of metastases in patients with ACT/CS1, imaging of the lungs is generally not necessary. However, patients with intermediate and high-grade chondrosarcomas have a higher rate of metastatic disease (10 to 50 percent for grade 2 lesions and 50 to 70 percent for grade 3 lesions) [3,7]. In these patients, the staging evaluation should at least include a thoracic CT to rule out the presence of pulmonary metastases.

As noted above, the place of PET scanning (which in other oncologic settings is generally more sensitive but less specific than CT for detection of metastatic disease) is uncertain. Although the use of PET can reveal sites of metastatic disease among patients with grade 2 or 3 chondrosarcomas, it is clear that sensitivity is lower than that of conventional CT for small lung metastases [145]. The utility of integrated PET/CT has not been addressed.

SURGICAL TREATMENT — For all grades and subtypes of nonmetastatic chondrosarcoma, surgical treatment offers the only chance for cure. The optimal type of surgical management depends upon histologic grade, location, and tumor extent. Treating chondrosarcoma patients in high-volume centers is associated with improved overall survival [152,153].

Intermediate- and high-grade chondrosarcomas — Wide en bloc local excision is the preferred surgical treatment for all nonmetastatic intermediate- and high-grade chondrosarcomas [10]. Depending on the location of the primary, wide excision can lead to considerable morbidity and may require a demanding reconstruction.

For patients with grade 2 or 3 chondrosarcoma with intraarticular or soft tissue involvement, and the periosteal, clear cell, mesenchymal, and dedifferentiated subtypes [48], intralesional excision represents an inadequate form of local treatment, with high rates of local recurrence [3,154]. Wide local resection is preferred [154].

Atypical cartilaginous tumor/chondrosarcoma grade 1 — For patients where clinical features and radiologic imaging suggest atypical cartilaginous tumor (ACT), based on nonaggressive features and thereby excludes chondrosarcoma of higher histologic grade, ACT (involving the long and short tubular bones) can be observed using magnetic resonance imaging (MRI). There is no consensus about the frequency and duration of such MRI, which is typically institution dependent.

For patients with disease progression while on observation, we suggest intralesional curettage, followed by local adjuvant chemical treatment (phenolization or cryotherapy) and cementation or bone grafting of the cavity rather than wide local excision. This produces satisfactory, long-term local control while minimizing the need for extensive reconstruction [155-160]. However, wide local excision is also a reasonable option. For large tumors, curettage can be technically difficult, and sampling error may result in a focus of higher-grade disease being missed. The tumor size cutoff beyond which a wide resection is preferred has not been studied and is highly dependent on location.

Most authors also consider wide local excision to be the preferred treatment for a low-grade chondrosarcoma involving the axial skeleton and pelvis. Several (but not all [10,74,161]) reports note higher local recurrence rates with curettage or marginal excision of tumors at these sites, with a higher tendency to metastasize [154,161-164].

A thorough review of radiology and histology results in a multidisciplinary tumor board is crucial before treatment planning. The decision to perform a curettage rather than wide local excision on the basis of a diagnostic biopsy is complicated by tumor heterogeneity and variation in histopathologic interpretation. A failure to recognize higher grade areas in a predominantly low-grade chondrosarcoma is possible when a needle or limited open biopsy has been performed without adequate previous correlation between radiology and histology. A presumed ACT treated by curettage and local adjuvant treatment that is found to contain foci of intermediate- or high-grade areas on the final histologic sections might require additional surgery. In order to minimize this risk, the diagnostic biopsy should always be directed at the more aggressive-appearing areas on the radiographic studies (ie, the soft tissue components or the more diffusely enhancing regions with limited or no matrix mineralization). (See 'Histologic grading and prognosis' above and 'Biopsy' above.)

Peripheral chondrosarcomas — For patients with a preexisting osteochondroma, complete surgical removal of the cartilage cap with the pseudocapsule provides excellent long-term clinical and local results. In one observational series of 107 patients with a tumor arising in solitary or multiple osteochondromas, 5- and 10-year local recurrence rates after surgery were 16 and 18 percent, and the 10-year mortality rate was only 5 percent [26]. In a separate observational series of 214 secondary peripheral chondrosarcomas arising in solitary osteochondroma, 17.3 percent of the patients developed local recurrence, and 5.1 percent developed metastases [40]. Besides age, a high histologic grade was the only factor associated with worse five- and 10-year overall survival. Surgical debulking instead of complete removal was associated with significantly worse disease-free survival [40].

When these tumors arise in the pelvis, the large cartilage cap can be difficult to excise, but outcomes are better if the excision is complete [154,165]. As an example, in a series of 61 patients with grade 1 or 2 secondary peripheral chondrosarcoma of the pelvis, local recurrence rates after wide local or incomplete excision were 3 versus 23 percent, respectively [165].

Management of recurrent disease — Local recurrence of an ACT in the long bones may compromise survival [166]. If the local recurrence is solitary, without progression in grade and located in the long bones, repeat intralesional resection with local adjuvant therapy is reasonable.

Local recurrence of an intermediate- or high-grade chondrosarcoma located in the long bones or recurrence of any grade histology in the flat bones is an indication for a wide excision [161], although it is often challenging to reach adequate wide resection margins in these patients. Long-term survival is achievable in a substantial number of patients. In a series of 28 patients treated surgically for a recurrence of a chondrosarcoma of the extremities or pelvis (grade 1, 2, and 3 in 4, 61, and 33 percent, respectively), the post-local recurrence survival rate was 59 percent at both five and 10 years [167]. In multivariate analysis, the most important factors predicting favorable long-term outcomes were age under 50 years and a local recurrence-free interval of one year or more.

RADIOTHERAPY

Patient selection — Although chondrosarcomas are relatively radioresistant tumors, radiation therapy (RT) may still be of benefit to the following populations:

Patients with an incomplete resection of a high-grade conventional, dedifferentiated, or mesenchymal chondrosarcoma to maximize the likelihood of local control (potentially curative intent)

Patients where resection is not feasible or would cause unacceptable morbidity (palliative intent)

As most chondrosarcomas are slow growing, with a relatively low fraction of dividing cells and radiation-related cytotoxicity is dependent upon cell division, chondrogenic tumors are considered relatively (but not absolutely [168,169]) radioresistant. This intrinsic relative radiation therapy (RT) resistance has been confirmed via in vitro studies, which suggest that response correlates with alterations in cell cycle-related genes [170]. Nevertheless, RT may still be of benefit in the two clinical situations noted below.

Adjuvant RT following incomplete resection – When RT is given with curative intent, doses in excess of 60 Gy are required to achieve local control. However, application of this dose with conventional high energy photons is often impossible in the vicinity of critical structures, especially in chondrosarcomas arising in the skull base and axial skeleton. Unfortunately, it is in this exact situation that postoperative RT is often indicated, as these tumors are less accessible for radical resection compared with lesions in the appendicular skeleton. The treatment approach to these tumors is discussed separately. (See "Chordoma and chondrosarcoma of the skull base" and "Chordoma and chondrosarcoma of the skull base", section on 'Radiation therapy'.)

The potential benefits of RT in this scenario are illustrated in an observational study of 21 patients with primary chondrosarcoma of the spine who underwent 28 surgical procedures that included 7 complete and 21 subtotal resections [171]. The median survival for the entire group was six years, and the addition of RT to resection prolonged the median disease-free interval from 16 to 44 months. Similarly, in other observational studies, RT has been associated with an overall survival benefit in patients with locally advanced, unresectable disease [169], and trended towards improved overall survival in patients with positive surgical margins [172].

Other studies have shown a high rate of local control (90 percent) with the addition of neoadjuvant or adjuvant RT to surgical resection in a group of 60 patients with high-risk extracranial chondrosarcoma, of whom 50 percent had either an R1 (microscopically positive) or R2 (grossly positive margins) resection [173].

Palliative RT for patients ineligible for resection – Palliative RT is also a reasonable option for local treatment of a primary or locally recurrent chondrosarcoma if resection is not feasible or would cause unacceptable morbidity. This is particularly true for mesenchymal chondrosarcomas, which, in our experience, are more radiosensitive than are other subtypes.

The benefit of RT in this setting can be illustrated by a retrospective review of 15 patients with mesenchymal chondrosarcoma (all but one nonmetastatic, most extraosseous) treated in several protocols of the German Society of Pediatric Oncology and Hematology [67]. All patients had surgical resection, which was complete in eight; 13 received chemotherapy and six were irradiated. At a median follow-up of 9.6 years, four of seven incompletely resected patients were still alive, three of whom had been irradiated.

Conventional RT can sometimes provide local control and symptom relief for other histologies, as long as sufficient doses are administered [174,175]. In one study of 20 patients with chondrosarcoma who were treated for cure, 5 of 11 patients who received RT as monotherapy achieved local control with doses from 40 to 70 Gy [174].

Charged particle irradiation — Given the limitations of conventional photon irradiation, alternative radiation modalities have been tested. Unlike photons, which lack mass and charge, particle beams interact more densely with tissue, causing greater levels of ionization per unit length, and therefore, an increased radiobiologic effect (RBE). The most data are available for protons, but there is limited experience with carbon ions as well.

Proton beam irradiation – The theoretical advantage of charged particle irradiation using protons is in its dose distribution. The physical characteristics of the proton beam result in the majority of the energy being deposited at the end of a linear track, in what is called a Bragg peak. The radiation dose falls rapidly to zero beyond the Bragg peak. Proton beam therapy permits the delivery of high doses of RT to the target volume while limiting the "scatter" dose received by surrounding tissues.

Proton beam RT has been studied most for incompletely resected chondrogenic tumors of the skull base and axial skeleton [176-178]. Local control rates of 78 to 100 percent with mixed photon-proton or proton only protocols (doses up to 79 cobalt Gray equivalents [CGE], or 7900 cGy) are reported by several authors [179-183], with limited severe late effects (<10 percent RTOG grade 3 toxicity) [176].

While promising, whether higher dose photon irradiation using newer techniques (eg, image-guided intensity-modulated RT) will provide similar short-term and long-term outcomes as proton beam irradiation is not established [184,185]. (See "Chordoma and chondrosarcoma of the skull base".)

Carbon ions – Carbon ions represent another attractive radiation modality, which combines the physical advantages of protons with a higher radiobiologic activity. The available data are in patients treated for skull based chondrosarcomas, which are discussed separately. (See "Chordoma and chondrosarcoma of the skull base" and "Chordoma and chondrosarcoma of the skull base", section on 'Radiation therapy'.)

Although promising, these techniques are not widely available, in contrast with photon irradiation. Particle beam irradiation requires adaptation of particle accelerators designed for other purposes or specialized dedicated equipment. (See "Chordoma and chondrosarcoma of the skull base".)

SYSTEMIC TREATMENT — Chemotherapy has been generally considered ineffective in chondrosarcomas, especially for the most frequently observed conventional type and the rare (low grade) clear cell variant (table 2). Chemoresistance in these tumors may be attributable to several factors:

Most chondrosarcomas are slow-growing, with a relatively low fraction of dividing cells; most conventional chemotherapeutic agents act on actively dividing cells.

Chondrosarcoma cells may reduce intracellular access of chemotherapy agents by expression of the multidrug-resistance-1 gene, P-glycoprotein [186,187], poor vascularity, and the large amount of extracellular matrix. However, abundant extracellular matrix as well as multidrug resistance pump activity did not necessarily prevent doxorubicin from accumulating in the nuclei of tumor cells in one study [188].

High activity of anti-apoptotic and pro-survival pathways (eg, expression of Bcl-2 family members such as Bcl-XL) is probably the most important cause of chemoresistance [188-190], as demonstrated in multiple histologies, including dedifferentiated, clear cell, and mesenchymal chondrosarcoma [189,191].

The benefit of chemotherapy for higher-grade (grade 2 or 3) chondrosarcomas is difficult to assess. Due to the rarity of chondrosarcomas (especially of intermediate- and high-grade tumors), there are few prospective studies, and no randomized trials. Although data mainly comes from a few small, retrospective studies, some studies challenge the prevailing view that chondrosarcomas are entirely chemotherapy-resistant [169,192]. As with other cancers, the specific histology also dictates the degree of responsiveness of that sarcoma subtype. (See 'Resectable disease (adjuvant and neoadjuvant chemotherapy)' below and 'Advanced and metastatic disease' below.)

Regardless, outcomes remain generally poor overall with conventional cytotoxic chemotherapy, and there is a need for inclusion of these patients in clinical trials assessing novel therapeutics. (See 'Investigational agents' below.)

Resectable disease (adjuvant and neoadjuvant chemotherapy) — There is no role for adjuvant chemotherapy in patients who undergo surgical treatment for an atypical cartilaginous tumor/chondrosarcoma grade 1 (ACT/CS1) and clear cell chondrosarcoma. However, its benefit for dedifferentiated and mesenchymal chondrosarcomas is unclear.

Dedifferentiated chondrosarcoma — Data are conflicting for the efficacy of adjuvant chemotherapy in those with dedifferentiated chondrosarcoma. We offer eligible patients enrollment in clinical trials evaluating the effectiveness of adjuvant chemotherapy. For patients who are ineligible for such trials, we manage these patients on a case-by-case basis, discussing the risks and uncertain benefit of adjuvant chemotherapy.

At least two retrospective studies suggest that patients with dedifferentiated chondrosarcoma who are managed with surgery and chemotherapy may have a better outcome than those managed with surgery alone [193,194]. By contrast, other studies suggested limited benefit from chemotherapy in patients with nonmetastatic disease [13,61,62,195,196].

In one prospective nonrandomized clinical trial (EURO-B.O.S.S), 57 patients with dedifferentiated chondrosarcoma were treated with surgical resection and chemotherapy [197]. Chemotherapy consisted of cisplatin, doxorubicin, and ifosfamide, with methotrexate added in cases of poor histologic response. Although most patients received surgery and adjuvant chemotherapy, approximately one-third (21 patients) received neoadjuvant chemotherapy followed by surgical resection. In the entire study population, the median overall survival was 24 months and five-year overall survival was 39 percent. Chemotherapy toxicity was significant (grade ≥3 toxicity rate of 78 percent, mostly hematologic) but manageable, as most patients (70 percent) were able to complete six cycles or more of the planned nine cycles of chemotherapy.

Mesenchymal chondrosarcoma — There is modest clinical evidence from nonrandomized trials that mesenchymal chondrosarcomas (especially those with a substantial round cell component) are sensitive to doxorubicin-based combination chemotherapy, similar to other bone tumors. Given these limited data, adjuvant chemotherapy is a reasonable option for those patients who are medically fit, willing, and able to tolerate such treatment. In patients with locally advanced disease, neoadjuvant chemotherapy is a reasonable option, as this approach both gauges the genuine chemotherapy sensitivity of a specific primary tumor and may increase the likelihood of subsequent complete resection or function-preserving surgery. Further randomized studies are needed to assess this approach.

The best regimen is not established. Based on data discussed below and guidelines from the National Comprehensive Cancer Network (NCCN) and European Society of Medical Oncology (ESMO), either an Ewing sarcoma-based multidrug regimen or an osteosarcoma-type doxorubicin plus cisplatin-based chemotherapy regimen may be used [195,198,199]. (See "Chemotherapy and radiation therapy in the management of osteosarcoma".)

Mesenchymal chondrosarcoma is modestly more sensitive to chemotherapy than other subtypes of chondrosarcoma, but data are limited. In particular, limited experience with adjuvant (or neoadjuvant) chemotherapy in patients with mesenchymal chondrosarcoma suggests a potential benefit for chemotherapy:

Experience with 15 cases of mesenchymal chondrosarcoma (all but one nonmetastatic, most extraosseous) was reported from the soft tissue and osteosarcoma study groups of the German Society of Pediatric Oncology and Hematology [67]. All patients had surgical resection, which was complete in eight; 13 received chemotherapy and six were irradiated. The treatment regimens consisted of a variety of chemotherapy drugs given in various combinations in several trials.

Response to induction chemotherapy could be assessed in seven patients, four of whom had a 50 percent reduction in tumor volume or ≥50 percent "histologic devitalization." At a median follow-up of 9.6 years, characteristic late recurrences were not observed and the actuarial event-free and overall survival rates at 10 years were 53 and 67 percent. The authors concluded that these outcomes were better than expected, and attributed the improved outcomes to combined modality treatment.

A retrospective series of 26 patients with mesenchymal chondrosarcoma included 24 surgically treated patients, 12 of whom received chemotherapy [70]. After a median follow-up of 48 months, 10 remained alive. The 10-year rates of disease-free survival were markedly higher among those who received chemotherapy (31 versus 19 percent) as was overall survival (76 versus 17 percent).

A benefit for chemotherapy was also suggested in a retrospective study of 113 patients with mesenchymal chondrosarcoma from the European Musculoskeletal Oncology Society (EMSOS), which included 95 patients with localized disease who were surgically treated, 54 of whom received chemotherapy (21 preoperatively, 30 postoperatively, and 3 both) [65]. Overall, the five- and 10-year survival rates were 79 and 60 percent, respectively. The five- and 10-year rates of overall survival were markedly higher among those who received chemotherapy (84 and 80 percent, respectively) compared with those who did not (73 and 46 percent, respectively).

Advanced and metastatic disease

Initial therapy — For patients with advanced, unresectable, or metastatic disease, we offer enrollment in clinical trials, where available, as the benefits of conventional chemotherapy are limited in these patients. For those who are ineligible for clinical trials, we offer a doxorubicin plus cisplatin combination as is used for other bone sarcomas. (See "Chemotherapy and radiation therapy in the management of osteosarcoma".)

High-grade chondrosarcomas seem to preferentially benefit from chemotherapy, but this is unpredictable. In one small prospective trial in high-grade spindle cell sarcomas of bone, two of six patients treated for an advanced dedifferentiated chondrosarcoma had a complete response to doxorubicin plus cisplatin, while the best response among five patients with metastatic mesenchymal chondrosarcoma was stable disease in two patients [195].

Although the majority of patients with recurrent or metastatic sarcoma do not respond to the usual chemotherapy regimens for advanced sarcoma, there have also been isolated reports of successful treatment with ifosfamide alone, doxorubicin-based chemotherapy, or single agent methotrexate [67,72,169,192,200-203].

Subsequent therapy — For patients with chemotherapy refractory disease who are ineligible for clinical trials, we offer the use of the antiangiogenic agent pazopanib as an off-label option for those with conventional chondrosarcomas. Patients with dedifferentiated chondrosarcomas may benefit from immunotherapy with PD-1 inhibitors; patients could be treated off-label with agents such as pembrolizumab or nivolumab.

Pazopanib — Pazopanib has some efficacy in conventional chondrosarcomas [204]. In a phase II trial of 47 patients with unresectable or metastatic conventional chondrosarcoma, the disease control rate at 16 weeks was 43 percent, with partial responses seen in one patient [205]. Median overall and progression-free survival was 18 and 8 months, respectively.

Pazopanib is approved by the US Food and Drug Administration for soft tissue sarcomas that are refractory to initial chemotherapy. We offer pazopanib as an off-label option to patients with advanced, unresectable or metastatic conventional chondrosarcoma, which is classified as a sarcoma of the bone. (See "Second and later lines of therapy for metastatic soft tissue sarcoma", section on 'Pazopanib'.)

Regorafenib — Regorafenib is an antiangiogenic agent with modest efficacy in conventional chondrosarcoma. Regorafenib was evaluated in a randomized placebo-controlled phase II trial of 46 patients with metastatic or locally advanced chondrosarcoma [206]. Of the 40 evaluable patients, no progression at 12 weeks was seen in 13 of 24 patients treated with regorafenib (54 percent) versus 5 of 16 patients treated with placebo (31 percent). However, the primary endpoint of the study was not met for the regorafenib arm (at least 16 patients with nonprogression at 12 weeks). Median progression-free survival on regorafenib and placebo was 20 and 8 weeks respectively.

Immunotherapy — Data for the efficacy of checkpoint inhibitor immunotherapy in patients with chondrosarcoma are limited, as the majority of available data are from clinical trials evaluating diverse sarcoma types. Patients should be encouraged to enroll in clinical trials evaluating immunotherapy, where available. (See "Overview of the initial treatment of metastatic soft tissue sarcoma".)

However, expression of programmed cell death ligand 1 (PD-L1) is observed in up to 41 percent of dedifferentiated chondrosarcomas, suggesting efficacy for agents that inhibit the PD-L1 pathway in this specific subtype [207]. In a phase II trial (SARC028) of 86 patients with unresectable or metastatic sarcoma of various histologies treated with pembrolizumab, objective responses were seen in one of five patients with chondrosarcoma (20 percent) [204]. Another observational study showed a partial response in one patient with dedifferentiated chondrosarcoma after six cycles of nivolumab [208].

Investigational agents — The discovery of novel signaling pathways in several histologic subtypes of chondrosarcoma has prompted interest in molecularly-targeted therapies, particularly for chemotherapy refractory nonoperable or metastatic chondrosarcomas [83,209]. Patients should be encouraged to enroll in clinical trials, where available. As examples:

IDH inhibitors – Mutations in isocitrate dehydrogenase-1 and isocitrate dehydrogenase 2 genes IDH1 and IDH2 have been identified in 40 to 56 percent of chondrosarcomas and seem to be an early event. In a phase I trial, ivosidenib, a selective inhibitor of the mutant IDH1 enzyme, has shown activity in patients with advanced IDH1 mutated chondrosarcoma [210]. (See 'Molecular pathogenesis' above.)

While preclinical studies did not show efficacy for inhibition of mutant IDH1 [110-112], other such studies have demonstrated some efficacy in agents targeting the downstream effects of the IDH mutation. Examples are drugs that inhibit NAMPT (eg, NAD synthesis pathway inhibition) [211]; enzyme poly ADP ribose polymerase (PARP) inhibitors [212]; and inhibitors of glutaminolysis (eg, metformin, phenformin, chloroquine, and glutaminase inhibitors) [213]. A phase Ib clinical trial with metformin and chloroquine in IDH mutant solid tumors, including chondrosarcoma, did not demonstrate a clinical response [214].

mTOR inhibitors – The mechanistic (previously called mammalian) target of rapamycin (mTOR) pathway is activated in the majority of chondrosarcoma cell lines [215,216]. Agents that inhibit the mTOR pathway (eg, sirolimus) have limited activity in chondrosarcoma, based on. observational data [217] and clinical trials of sirolimus plus cyclophosphamide [218].

Tyrosine kinase inhibitors – Receptor tyrosine kinases (eg, Akt1/GSK3beta, the src pathway, and the platelet-derived growth factor receptor [PDGFR]) are commonly activated in chondrosarcomas [219]. While preclinical studies initially suggested activity of tyrosine kinase inhibitors in chondrosarcomas [184], subsequent clinical trials of imatinib and dasatinib failed to demonstrate meaningful clinical activity in patients with advanced or metastatic chondrosarcoma [220,221].

Estrogen receptors – Although estrogen receptors and aromatase activity have been identified in chondrosarcomas [222-224], aromatase inhibitors did not improve progression-free survival relative to untreated patients in one study [224].

PARP inhibitors – Chondrosarcoma cell lines are variably sensitive to inhibition of poly(ADP-ribose) polymerase (PARP) using talazoparib, irrespective of the presence or absence of an IDH mutation [212]. Moreover, PARP inhibition sensitizes chondrosarcoma cell lines to chemotherapy (ie, temozolomide) and/or radiation therapy [225]. In one phase II trial, three of five patients with IDH-mutant chondrosarcoma had clinical benefit with olaparib, including one patient with a partial response and two with stable disease lasting longer than 7 months [226].

HDAC inhibitors – Chondrosarcoma cells demonstrate high sensitivity to histone deacetylase (HDAC) inhibition in both 2D and 3D in vitro models [227]. Preclinical studies would also support combination of DNA methyltransferase (DNMT) inhibitors with HDAC inhibition [228].

Other agents – Other agents under active investigation include death receptor agonists, angiogenesis inhibitors [229,230], vascular endothelial growth factor antisense molecules [231], recombinant human Apo2L/TRAIL [232], and monoclonal antibodies that trigger apoptosis pathways [233].

POST-TREATMENT SURVEILLANCE — As with other bone sarcomas, there are no prospective data that address the appropriate schedule or selection of tests for surveillance after initial treatment for localized disease. Consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) recommend physical examination, complete blood count, and chest as well as local imaging every three months for years 1 and 2, every four months during year 3, every six months for years 4 and 5, then annually [234]. Routine post-treatment surveillance should be extended to 10 years, as late recurrences can occur [9].

Additionally, our practice is to perform magnetic resonance imaging of the primary tumor one, two, and five years after initial surgery.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bone sarcomas".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Chondrosarcoma (The Basics)" and "Patient education: Bone cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

Clinical variability of chondrosarcoma – Chondrosarcomas are a very heterogeneous group of malignant bone tumors that produce chondroid (cartilaginous) matrix. Clinical behavior varies based on the subtype and the histologic grade. While the majority are indolent tumors with a low metastatic potential, some are aggressive and have a poor prognosis following resection (eg, high-grade chondrosarcomas, dedifferentiated and mesenchymal subtypes) (table 1 and table 2). (See 'Classification, histology, and clinical features' above.)

Diagnostic evaluation – Treatment is guided by findings on radiographic imaging studies (eg, conventional radiographs, magnetic resonance imaging [MRI], and computed tomography [CT]) and diagnostic biopsy. (See 'Diagnostic and staging work-up' above.)

Treatment of localized nonmetastatic disease

Surgery – For all grades and subtypes of localized, nonmetastatic chondrosarcoma, surgical treatment offers the only chance for cure. The optimal type of surgical management depends upon histologic grade, location, and tumor extent. The goal of surgery is complete excision while minimizing functional disability. (See 'Surgical treatment' above.)

-For small, central atypical cartilaginous tumors (ACT) involving an extremity (appendicular skeleton; long and short tubular bones) that are confined to the bone, patients may be observed using MRI. For patients with disease progression on observation, we suggest intralesional curettage with local adjuvant therapy (phenol application or cryosurgery followed by cementation or bone graft of the cavity) rather than wide local excision (Grade 2C). However, wide local excision is also a reasonable option. For large tumors, curettage can be technically difficult, and sampling error may result in a focus of higher-grade disease being missed. A thorough review of radiology and histology results in a multidisciplinary tumor board is crucial before treatment planning. (See 'Atypical cartilaginous tumor/chondrosarcoma grade 1' above.)

-For all other patients, we recommend wide local resection rather than less invasive surgical procedures (Grade 1B). This includes those with grade 2 or 3 histology (including the mesenchymal and dedifferentiated subtypes); large tumor size; intraarticular or soft tissue involvement; periosteal or clear cell subtypes; a grade 1 central chondrosarcoma in the pelvis, scapula, or elsewhere in the axial skeleton; or a peripheral chondrosarcoma.

-Locally recurrent chondrosarcomas should be managed aggressively because they may be of higher histologic grade than the original tumor, increasing the risk of metastases and fatal outcome. For nonmetastatic recurrence of an ACT/chondrosarcoma grade 1 (CS1), we suggest repeat intralesional resection with local adjuvant therapy if the local recurrence is solitary, without progression in grade and located in the long bones (Grade 2C). Otherwise, wide local excision is preferred. (See 'Management of recurrent disease' above.)

Radiation therapy – While most low-grade chondrosarcomas are considered relatively radioresistant, radiation therapy (RT) may be of benefit in specific situations (see 'Radiotherapy' above):

-For most patients with incompletely excised high-grade conventional, dedifferentiated, or mesenchymal chondrosarcomas, we suggest adjuvant RT rather than observation (Grade 2C). Doses of more than 60 Gy are needed for maximal local control after incomplete resection. (See 'Patient selection' above.)

Depending on the tumor site, conventional photon beam RT may not be feasible. In such cases, referral for treatment using newer techniques (eg, proton beam RT) is appropriate, where available. (See 'Charged particle irradiation' above.)

-Palliative RT is a reasonable option for local treatment of patients with a primary or locally recurrent chondrosarcoma if resection is not feasible or would cause unacceptable morbidity, as well as for those with symptomatic metastatic disease.

Chemotherapy – The efficacy of chemotherapy in patients with resectable disease depends on the histology (see 'Systemic treatment' above):

-There is no established role for adjuvant chemotherapy in patients with complete resection of ACT/CS1 or clear cell chondrosarcoma, because these histologies are chemotherapy-resistant. (See 'Resectable disease (adjuvant and neoadjuvant chemotherapy)' above.)

-Doxorubicin-based chemotherapy has activity in mesenchymal chondrosarcoma, particularly those that contain a high percentage of round cells on histology. This may be incorporated as adjuvant chemotherapy for patients with completely resected disease or as neoadjuvant chemotherapy for those with locally advanced disease. In this latter group, neoadjuvant chemotherapy may increase the likelihood of complete resection or function-preserving surgery. (See 'Mesenchymal chondrosarcoma' above.)

-Data are conflicting for the efficacy of adjuvant chemotherapy in dedifferentiated chondrosarcoma, and its use is best evaluated in the context of a clinical trial. For those who are ineligible for such trials, we manage these patients on a case-by-case basis, discussing the risks and uncertain benefit of adjuvant chemotherapy. If the high-grade component is an osteosarcoma, we treat the patient as per osteosarcoma protocols. (See 'Dedifferentiated chondrosarcoma' above.)

Management of metastatic disease – For patients with advanced unresectable or metastatic disease, we offer enrollment in clinical trials, where available, as the benefits of conventional chemotherapy are limited in these patients. (See 'Advanced and metastatic disease' above and 'Investigational agents' above.)

For those who are ineligible for clinical trials, we offer initial therapy with the combination of doxorubicin plus cisplatin, as is used for other bone sarcomas. (See 'Initial therapy' above and "Chemotherapy and radiation therapy in the management of osteosarcoma".)

For patients with chemotherapy-refractory disease who are ineligible for clinical trials, we offer antiangiogenic agents (eg, pazopanib, regorafenib) to those with conventional chondrosarcomas and PD-1 inhibitors (eg pembrolizumab or nivolumab) to those with dedifferentiated chondrosarcoma. (See 'Subsequent therapy' above.)

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Topic 7724 Version 48.0

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