Chondrosarcoma are malignant cartilaginous neoplasms with diverse morphological features and clinical behavior. They account for about 20% of all primary malignant tumors of the bone . They usually arise in the pelvis or long bones . Primary or conventional chondrosarcoma arises in preexisting normal bone and is distinguished from the rarer secondary tumors, which occur in a preexisting enchondroma or osteochondroma . Conventional chondrosarcoma, which accounts for 85%–90% of chondrosarcomas is subdivided into the central, periosteal, and peripheral subgroups . Non-conventional chondrosarcoma variants include clear cell chondrosarcoma, mesenchymal chondrosarcoma, and dedifferentiated chondrosarcoma . The radiographic features of chondrosarcoma are often very characteristic, and a definitive diagnosis can usually be made by imaging examination alone.

Types of Chondrosarcoma

There are several types of chondrosarcoma that are named based on the way that they appear under the microscope. These include:

  • Conventional chondrosarcoma
  • Clear cell chondrosarcoma
  • Myxoid chondrosarcoma
  • Mesenchymal chondrosarcoma
  • Dedifferentiated chondrosarcoma

The 2013 World Health Organization (WHO) Classification of Tumors of Soft Tissue and Bone now separates chondrosarcoma into two International Classification of Diseases codes. This is reflective of the different prognosis of chondrosarcoma based on grade, with

  • Grade I distinguished from
  • Grade II and
  • Grade III chondrosarcoma. It has also introduced the synonym ‘atypical cartilaginous tumor’ for ‘Grade I chondrosarcoma’, classifying it as an intermediate type of tumor, not a malignancy. This may be a better reflection of its clinical behavior which demonstrates a locally aggressive nature with little risk of metastasis.

Grading of chondrosarcomas is essential and is useful in predicting histological behavior. Chondrosarcomas are divided into three grades based upon their histopathology

  • Grade I – considered to be low-grade (locally aggressive), also called atypical cartilaginous tumor . Grade I lesions will often closely resemble normal cartilage or the benign enchondroma. In this instance, the distinction between benign and malignant often depends on the demonstration of a “chondrosarcoma permeation pattern” where the tumor infiltrates through the marrow cavity instead of being confined by the native architecture. Grade I chondrosarcoma is moderately cellular and contain hyperchromatic, plump nuclei of uniform size.
  • Grade II – tumors contain a greater degree of nuclear atypia hyperchromasia, and nuclear size and are more cellular. Mitoses can be found.
  • Grade III – tumors are more pleomorphic and atypical than grade II chondrosarcomas. Mitoses are more easily detected. The cells at the periphery of the lobules are less differentiated and become spindled.
The fourth group of chondrosarcomas, considered as grade IV; is called dedifferentiated chondrosarcoma and makes up 10% of all chondrosarcomas . Dedifferentiation occurs in a small subset of patients and is defined histologically by the presence of a high-grade, often spindled or pleomorphic tumor without significant cartilaginous matrix. Dedifferentiated chondrosarcoma is, by definition, a high-grade neoplasm with an inferior prognosis.

Other less common types of chondrosarcomas are mesenchymal and clear cell chondrosarcomas .

Immunophenotype – Only a small percentage of the IDH1 mutations (20%) can be identified using a specific IDH1 R132H antibody.

Causes of Chondrosarcoma

The majority of chondrosarcomas are sporadic, but they may develop from the malignant transformation of osteochondromas and enchondromas . Malignant transformation occurs in 5% of osteochondromas either multiple or solitary forms .

Chromosomal anomalies detected in some types of chondrosarcomas include 9p21, 10, 13q14, and 17p13. Chromosomal structural abnormalities and genetic instability are reported in well-differentiated chondrosarcomas analyzed by cytogenetics. Moreover, the amplification of MYC and AP-1transcription factors plays a vital role in the pathogenesis of chondrosarcoma .

As with many cancers, the cause of chondrosarcoma is not clear. However, people with certain medical conditions have an increased risk for developing chondrosarcoma. These conditions include:

  • Ollier’s Disease
  • Maffucci Syndrome
  • Multiple Hereditary Exostoses (MHE, a.k.a., osteochondromatoses)
  • Wilms’ Tumor
  • Paget’s disease
  • Diseases in children that required previous treatment with chemotherapy or radiation therapy

Symptoms of Chondrosarcoma

  • Pain in the affected area that may worsen at night or during physical activity
  • Swelling in the painful area
  • A lump or mass
  • Enlargement of an existing growth
  • Limping
  • Difficulty moving the affected limb
  • Changes in urination (for pelvic tumors).
  • Back or thigh pain
  • Sciatica
  • Bladder Symptoms
  • Unilateral edema

Diagnosis of Chondrosarcoma

 History and Physical

Local swelling and pain are the most common presenting symptoms. The symptoms are usually of long duration (months to years). Tumors located in the skull base can cause neurological symptoms.

  • Macroscopic findings – Chondrosarcomas are large tumors, usually greater than 4 cm in size . They have a translucent lobular, blue-grey, or white cut surface corresponding to the presence of hyaline cartilage. There may be areas containing myxoid or mucoid material and cystic changes. Yellow-white chalky areas of calcium deposits are commonly present (mineralization). Erosion and destruction into soft tissue may be seen.
  • Microscopic findings – Chondrosarcomas show abundant blue-grey cartilage matrix-production. Irregularly shaped lobules of cartilage varying in size and shape are present. Fibrous bands separate these lobules or permeate bony trabeculae. Calcified areas suggesting the presence of a pre-existing enchondroma can often be found. The chondrocytes are atypical, with variable size and shape, and contain enlarged hyperchromatic nuclei. Binucleation is frequently seen. Chondroid matrix liquefaction or myxoid changes are a common feature of chondrosarcomas. Necrosis and mitoses can be seen. There is often permeation into the cortical bone and the marrow space with entrapment of bony trabeculae .
  • Twenty-four-hour urine test – A test in which urine is collected for 24 hours to measure the amounts of catecholamines in the urine. Substances caused by the breakdown of these catecholamines are also measured. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that makes it. Higher-than-normal amounts of certain catecholamines may be a sign of pheochromocytoma.
  • Blood catecholamine studies – A procedure in which a blood sample is checked to measure the amount of certain catecholamines released into the blood. Substances caused by the breakdown of these catecholamines are also measured. An unusual (higher than or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that makes it. Higher-than-normal amounts of certain catecholamines may be a sign of pheochromocytoma.
Plain radiography

Plain radiography is used for initial evaluation. Plain x-rays allow the identification of the cartilaginous nature and the aggressiveness of the lesion . Plain x-rays may reveal the following findings:

  • Lytic lesions in 50% of the cases
  • Intralesional calcifications: in about 70% of the cases (popcorn calcification or rings and arcs calcification)
  • Endosteal scalloping
  • The permeative appearance or moth-eaten appearance in high-grade chondrosarcomas
  • Cortical remodeling, thickening, and periosteal reaction
Computed tomography scan

Computed tomography scan can reveal the following findings :

  • Matrix calcification in 94% of the cases
  • Endosteal scalloping
  • A cortical breach in about 90% of long bone chondrosarcoma
  • Heterogenous contrast enhancement
Magnetic resonance imaging

In typical forms, MRI demonstrates a lobulated lesion with a high-signal intensity on T2 and a low or intermediate signal on T1-weighted images  .

Tissue biopsy

Tissue biopsy is essential to diagnose chondrosarcoma and differentiate it from other malignant or benign bone tumors. Biopsy should be taken from the most aggressive portion of cancer as determined by imaging.

  • Computed tomography scan (also called a CT or CAT scan) – This is an imaging test that uses X-rays and a computer to make detailed images of the body. A CT scan shows details of the bones, muscles, fat, and organs.
  • Magnetic resonance imaging (MRI) – A diagnostic procedure that uses a combination of large magnets, radiofrequencies, and a computer to make detailed images of organs and structures within the body.
  • Positron emission tomography (PET) scan – An imaging test in which radioactive-tagged glucose (sugar) is injected into the bloodstream. Tissues that use glucose more than normal tissues (such as tumors) can be detected by a scanning machine.
  • Bone scans – use a scanner and low-level radioactive material. They detect cancer cells in bones.
  • CT scan (CAT scan) – A procedure that makes a series of detailed pictures of areas inside the body, such as the neck, chest, abdomen, and pelvis, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
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Treatment of Chondrosarcoma

Treatment depends on the location of the disease and the aggressiveness of the tumors.[rx] Because chondrosarcomas are rare, they are treated at specialist hospitals with Sarcoma Centers.

Surgery is the main form of treatment for chondrosarcoma. Musculoskeletal tumor specialists or orthopedic oncologists are usually chosen to treat chondrosarcoma, unless it is located in the skull, spine, or chest cavity, in which case, a neurosurgeon or thoracic surgeon experienced with sarcomas is chosen. Often, a limb-sparing operation can be performed, but in some cases amputation is unavoidable. Amputation of the arm, leg, jaw, or half of the pelvis (called a hemipelvectomy) may be necessary in some cases.

There are two kinds of hemipelvectomy – internal and external.

  • External hemipelvectomy – is removal of that half of the pelvis with the amputation of the leg. It is also called the hindquarter amputation.
  • Internal hemipelvectomy – is removal of that half of the pelvis, but the leg is left intact.

Surgery – Location and histologic grade determine the treatment approaches of chondrosarcoma. The primary treatment modality of chondrosarcoma is surgical excision. Low-grade central chondrosarcoma can be treated with intralesional curettage, burring, and surgical adjuvant applications such as hydrogen peroxide .  Tumors with intraarticular or soft tissue involvement, larger tumors, axial or pelvic tumors must be treated with wide excision. For the intermediate or high-grade chondrosarcoma, wide en bloc excision is the surgical approach of choice .

Chemotherapy – Chemotherapy is generally not efficient in conventional chondrosarcoma. However, it may have a role in dedifferentiated chondrosarcomas containing a high-grade spindle cell component .

Radiation therapy – After incomplete resection of high-risk chondrosarcomas, radiation therapy is indicated to improve the high local failure rates. These indications include locally recurrent tumors intermediate to high-grade tumors, and tumors in locations where surgical resection is challenging or limited. Definitive radiation can also be indicated for unresectable tumors .

Cryosurgery – To lower the odds that cancer returns, your doctor might also put liquid nitrogen in the area where the tumor was. It freezes and kills any cancer cells that might have been missed.

Limb-sparing surgery – It involves taking out the affected bone and replacing it with a bone graft (bone taken from another part of the body). Unfortunately, it’s not always possible to use limb-sparing surgery. Sometimes the cancer may spread from the bone to the nerves and blood vessels around it. If this happens the only way to treat the cancer may be to remove part of the limb known as a partial amputation.

After treatment

After treatment for sarcoma you may benefit from rehabilitation services. They can offer specialist advice and treatment that aids your recovery and helps you to deal with the effects of cancer and its treatment.

Rehabilitation services include:

Occupational therapy

Occupational therapists assess your ability to carry out daily living activities such as washing, dressing and meal preparation. They can also help you return to normal daily activities such as work, parenting, and leisure activities.

Physiotherapy

Physiotherapists help you return to as active a lifestyle as possible. They will help you strengthen your muscles and ensure your joints regain as much mobility as they can.
This may involve designing a special exercise program, providing advice about managing tiredness or teaching you to use equipment to help you walk or to support your joints.

Dietary services

Dieticians assess whether you need any special diet and can advise on the most appropriate nutritional support to help you before, during and after treatment.

Orthotics and prosthetics

After surgery for bone sarcoma you may need aids to help you. For example, an orthotist can help by providing you with supports or splints. If you have had an amputation, a prosthetist can assess and fit an artificial limb.

Rehabilitation usually starts after treatment. However, with bone sarcoma you may find that it helps to start rehabilitation earlier. Ask your sarcoma clinical nurse specialist or doctor to refer you to the rehabilitation team.

Nuclear Chondrosarcoma Treatment

State of the Art

The risk of local recurrence and metastasis of conventional chondrosarcomas largely increases with histological grade []. For low grade tumors, intralesional excision may be sufficient [], whereas surgery with wide margins has become the primary care for malignant cartilage lesions []. Yet, depending on the location in the skeleton, wide resection may not be possible [,] and adjuvant therapies may be needed. Unfortunately, conventional chondrosarcomas are highly resistant both to radiation and chemotherapy [,,]. Chemoresistance of chondrosarcoma may be due to slow proliferation, multidrug resistance protein 1 (MDR1) overexpression [,], poor vascularity [,] and dense hyaline ECM [] when compared to other cancers. Notably, under moderately hypoxic conditions (5% O2) radiation resistance of chondrosarcoma cell lines was significantly higher compared to standard cell culture conditions (21% O2) [], indicating that prevalent hypoxia may also interfere with radiation response in chondrosarcoma. Yet, there are publications indicating sustained stable disease after chemotherapy in palliative care for some patients with dedifferentiated chondrosarcoma [,,,]. Also, proton beam radiation therapy resulted in sustained local control of some chondrosarcomas of the skull base []. Besides, carbon ion radiation may be useful for inoperable pelvic chondrosarcomas [].

In addition, chondrosarcomas tend to be genetically unstable with loss of heterozygosity at many loci [,], which exacerbates the identification of relevant targets and raises the question whether single agent approaches may be applicable at all. Moreover, many older studies investigating genetic aberrations and potential target proteins in chondrosarcoma did not distinguish between different subtypes and gradings.

In summary, there is an urgent need for new targeted therapies in chondrosarcoma which are discussed in the following paragraphs.

Targetting the Hh Pathway

The Hh pathway is involved in stem cell proliferation and differentiation during development and tissue regeneration []. In addition, Hh signaling is also implicated in the formation and progression of several kinds of cancer, including basal cell carcinoma, medulloblastoma, osteosarcoma, Ewing sarcoma and rhabdomyosarcoma [,,,,]. The Hh pathway is activated by binding of one of the three human ligands (IHH, DHH, SHH) to the patched 1 (PTCH1) receptor. Subsequently, smoothened (SMO) initiates downstream signaling via the glioma associated oncogene family (GLI) transcription factors []. Depending on the tumor, aberrant Hh pathway activation may be mediated by ligand overexpression or PTCH loss-of-function mutations. But also ligand-independent activation via SMO gain-of-function mutations, respectively constitutive overexpression and activation of GLIs is possible []. Yan et al., 2008 detected a single SMO mutation in a selection of dedifferentiated chondrosarcomas. All SNPs detected in the PTCH1 gene of chondrosarcomas resulted in silent alterations []. Therefore, mutations in the Hh pathway seem to be infrequent in chondrosarcomas. However, Tiet et al., 2006 reported a constitutive active Hh pathway in human chondrosarcoma explant cultures similar to growth plate chondrocytes, although in high-grade chondrosarcomas IHH, PTCH1, and GLI1 mRNA expression declined when compared to low-grade lesions [,]. Also in peripheral chondrosarcomas, PTCH1, GLI1 and GLI2 mRNA expression was reduced compared to benign osteochondromas [].

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Indeed, in animal models, ligand-dependent Hh signaling required primary cilia []. Therefore, drug efficacy of SMO inhibitors like vismodegib (GDC-0449) or saridegib (IPI-926) is probably dependent on the presence of primary cilia, where Hh pathway components have been shown to be concentrated in murine chondrocytes []. Yet, Ho et al. observed that most chondrosarcoma and enchondroma cells (70–100%) lack primary cilia, whereas 65% of human AC chondrocytes had primary cilia []. Notably, ablation of primary cilia in chondrosarcoma explants enhanced Hh pathway regulated transcription, probably via the prevention of GLI3 processing in its repressor form, whereas the SMO inhibitor cyclopamine was ineffective in these cells [].

With this in mind, it is not surprising that GDC-0449 did not meet the primary endpoint in a phase II clinical trial with chondrosarcoma patients, although some patients with grade I or II chondrosarcomas seemed to benefit from the treatment []. Also the results of a phase II trial using IPI-926 for treatment of chondrosarcoma patients were discouraging [].

Potentially, the use of Hh pathway inhibitors acting downstream of SMO like HPI-4 may be more successful in chondrosarcoma treatment by means of targeting cancer stem cells and early grade chondrosarcoma cells [], but maybe also later stages as its mechanism of action is not necessarily dependent on the presence of primary cilia. In the SW1353 chondrosarcoma cell line the use of arsenic trioxide (ATO) induced G2/M cell cycle arrest and apoptosis as well as autophagy. In addition to the GLI transcription factors ATO has several other targets and indeed, autophagy induction in SW1353 cells was reported to depend on mTOR inhibition []. Thus, using ATO alone or in combination with other substances may aid to develop novel treatment strategies for chondrosarcomas.

Targetting IDH1, IDH2 and HDACs

The isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) catalyze the conversion of isocitrate to to α-ketoglutarate (α-KG) in the Krebs cycle and concomitantly produce nicotinamide adenine dinucleotide phosphate (NADPH) from NADP+ []. Missense mutations at arginine 132 in IDH1 or the homologous arginine 172 in IDH2 occur in 80–90% of enchondromas [,] and 50–60% of central chondrosarcomas with IDH1 mutations dominating []. Also, dedifferentiated chondrosarcomas predominantly contain IDH1 mutations []. Indeed, IDH mutations seem to be an early event in chondrosarcoma genesis []. The mutant enzymes have a modified enzymatic activity reducing α-KG under consumption of NADPH to the oncometabolite R(−)-2-hydroyglutarate (2-HG) []. IDH mutations are always restricted to one allele and it seems that the presence of the wild type protein in a homodimer increases the capacity of 2-HG generation []. Many cellular enzymes are dependent on the presence of α-KG including the Ten-Eleven-Translocation (TET) protein family reducing DNA methylation, the JumonjiC domain-containing (JmjC) histone demethylases altering histone methylation, prolyl and lysyl hydroxylases implicated in collagen folding and maturation, and prolyl hydroxylases (PHD) regulating hypoxia-inducible factor (HIF) protein degradation []. Thus, mutant IDH is capable of altering the epigenetic state of cells leading to DNA and histone hypermethylation which affects differentiation [] and impairs collagen maturation as well as oxygen homeostasis []. Indeed, the generation of 2-HG not only reduces α-KG abundance but 2-HG directly inhibits enzymes dependent on α-KG by occupying the binding site [].

In human MSPC, the expression of the IDH1 R132C mutant also upregulated global histone methylation, but repressed osteogenic differentiation and induced chondrogenic differentiation indicated by SOX9 and collagen type II α 1 chain (COL2A1) expression, whereas no functional cartilage matrix was deposited []. This effect might contribute to the incomplete chondrogenic differentiation of chondrosarcomas.

Inhibition of the mutant IDH1 in the human chondrosarcoma cell line JJ012 (IDH1 R132G) by AGI-5198 significantly reduced 2-HG production, colony formation and migration and induced apoptosis [], illustrating that IDH1 inhibition may have therapeutic value.

Indeed, different clinical studies targeting IDH mutant chondrosarcomas and other tumors are currently ongoing. The phase I/II, a multicenter study has been actually completed. In this study, AG-221, an oral IDH2 inhibitor, has been tested in patients with advanced solid tumors, including gliomas, angioimmunoblastic T-cell lymphomas and chondrosarcomas with an IDH2 mutation. In two other ongoing phase I studies (NCT02481154/NCT02073994), the IDH inhibitors AG-881 and AG-120 are under clinical evaluation for advanced solid tumors that harbor an IDH1 and/or IDH2 mutation, including gliomas, cholangiocarcinomas and chondrosarcomas. In addition, there is a phase Ib, open-label, single-center, nonrandomized study recruiting patients that evaluates the toxicity and efficacy of the antidiabetic drug metformin in combination with the antimalarial drug chloroquine in IDH1/2 mutated patients with a glioma, intrahepatic cholangiocarcinoma or chondrosarcoma (NCT02496741) [].

In addition to methylation, acetylation of histones regulates gene expression and differentiation. Since many tumors exhibit aberrant histone modifications, HDAC inhibitors have emerged as new class of anticancer drugs []. Indeed, the HDAC inhibitor depsipeptide (romidepsin) induced growth arrest, apoptosis and differentiation in human chondrosarcoma cell lines in vitro []. A phase II study (NCT00112463) including extra-skeletal chondrosarcoma patients treated with romidepsin has been actually completed. Whether IDH inhibition or HDAC inhibition is indeed a beneficial therapy in chondrosarcoma remains to be demonstrated.

In line with chondrosarcomas, accumulating evidence also shows epigenetic dysregulation in OA [,]. However, IDH mutations have not been detected in AC so far, but inflammatory cytokines suppressed IDH and TET activity in human primary chondrocytes in vitro [], a mechanism which might also apply in chondrosarcomas without IDH mutation.

Targeting the PI3K-AKT-mTOR and SRC Pathway

AKT kinases are highly active in human chondrosarcomas [,]. Indeed, PI3K-AKT signaling is activated by many growth factors including FGF2 and IGF1 as well as inflammatory cytokines like CCL5, which have been implicated in chondrosarcoma genesis and progression []. In addition, p70 S6 kinase (p70S6K) activation was increased with histological grade of conventional chondrosarcomas and has been also detected in dedifferentiated chondrosarcomas []. P70S6K is a downstream target of mTOR in the PI3K-AKT pathway phosphorylating the ribosomal S6 protein, which enhances protein synthesis []. However, activating mutations in the PI3K-AKT pathway are very rare in chondrosarcomas []. Although IGF1R positivity of human central chondrosarcomas increases with histological grade, IGF1R inhibition did not impair the proliferation or migration of chondrosarcoma cell lines in vitro []. Treatment with BEZ235, a PI3K/mTOR inhibitor, significantly reduced the growth of chondrosarcoma cell lines in vitro and in a murine xenograft model []. In a rat chondrosarcoma model, the use of the mTOR inhibitor everolimus suppressed tumor progression and delayed recurrence of microscopic residual disease []. Moreover, in a small retrospective study with patients with unresectable chondrosarcoma, a combination of sirolimus (rapamycin) inhibiting mTOR and the chemotherapeutic agent cyclophosphamide was successful in disease control in 70% of patients during a period of several months []. Yet, a phase II clinical trial (NCT02008019) utilizing everolimus in patients with primary or relapsed chondrosarcomas has been suspended in 2016 due to the unavailability of everolimus.

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Aberrant activation of SRC kinase signaling has been detected in human chondrosarcoma tissues [,]. SRC is a common mediator of growth factor and integrin signaling and may also act upstream of PI3K-AKT []. Together SRC and AKT activate survival pathways and HIF1α, which is upregulated in high-grade chondrosarcoma tissues [,].

Dasatinib (BMS354825), which targets SRC as well as Abelson tyrosine-protein kinase (ABL), KIT and platelet-derived growth factor receptor (PDGFR) decreased viability of chondrosarcoma cell lines in vitro [,]. Moreover, dasatinib especially sensitized p53 mutant chondrosarcoma cell lines to doxorubicin treatment, indicating a potential of dasatinib to overcome chemoresistance []. Nevertheless, in the SRC009 phase II trial, the use of dasatinib as a single agent in pretreated, high-grade sarcomas, including chondrosarcomas showed no benefit []. Therefore, inhibition of PI3K-AKT-mTOR and SRC might be advantageous in combination therapy of chondrosarcoma patients, although reliable clinical data are still missing.

Targeting Angiogenesis and Invasion

As already discussed in chapters 3 and 4, both VEGF and FGF2 signaling are activated in chondrosarcomas and apparently contribute to angiogenesis and invasion. Since enhanced activation of PDGFR has been shown in human chondrosarcoma cell lines in vitro [], PDGFR may be a therapeutic target as well. SU6668, an inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2), PDGFR-β and FGFR1 induced growth inhibition in chondrosarcoma animal models, which seems to be attributed to the antiangiogenic effects of SU6668 []. The ongoing NCT01330966 phase II study is investigating the efficacy and safety of the single agent pazopanib, inhibiting KIT, FGFR, PDGFR and VEGFR among other enzymes [], in patients with unresectable or metastatic chondrosarcoma. Another phase II trial (NCT02389244) currently recruiting patients utilizes regorafenib, an oral multikinase inhibitor, which targets VEGFR, tyrosine kinase with Ig and EGF homology domains-2 (TIE2), KIT, rearranged during transfection (RET), RAF-1, BRAF, BRAFV600E, PDGFR and FGFR, in patients with metastatic bone sarcomas including chondrosarcomas. Sorafenib, a multi-kinase inhibitor inhibiting several tyrosine kinases including VEGFR, PDGFR and RAF, mediated pMEK and pERK inhibition leading to growth arrest and apoptosis in the chondrosarcoma cell lines SW1353 and CRL7891, which was accompanied by downregulation of cyclin D1, retinoblastoma susceptibility protein (RB), B-cell lymphoma-extra large (BCL-XL) and myeloid cell leukemia sequence 1 (MCL-1) expression []. Two-phase II studies utilizing sorafenib in patients with different types of sarcomas indicated prolonged stable disease when evaluated in 3 chondrosarcoma patients [,]. Moreover, imatinib, another multi-kinase inhibitor, inhibiting ABL, KIT, and PDGFR, was tested in a phase II trial with patients having recurrent, non-resectable, PDGFR positive chondrosarcomas. However, in this trial, no benefit of imatinib treatment has been reported []. Another open-label study (NCT00928525) utilizing imatinib in chondrosarcoma patients is ongoing. Once data of the ongoing trials are available, it may be determined, whether the use of multikinase inhibitors is a therapeutic option for chondrosarcoma patients.

Additional Targets and Biomarker

In addition to the pathways mentioned in the previous chapters that are currently being investigated in clinical trials, there may be other signaling pathways involved in chondrosarcoma genesis and progression that could serve as potential novel targets.

Canonical WNT signaling is implicated in the β-catenin-dependent regulation of mitotic and cell fate-determining gene transcription of MSPC, whereas two non-canonical WNT pathways affect cell shape and motility in the planar cell polarity pathway and the Ca2+/WNT pathway []. Dickkopf WNT signaling pathway inhibitor 1 (DDK1), an antagonist of canonical WNT/β-catenin signaling as well as β-catenin were progressively overexpressed in chondrosarcoma tissues with increasing histological grade and correlated with poor prognosis []. In the chondrosarcoma cell line SW1353 WNT3A, WNT6, WNT7B and frizzled-3 (FZD3) mRNA expression was upregulated compared to MSPC and rWNT3A enhanced SW1353 proliferation []. Recombinant WNT inhibitory factor 1 (WIF1), which inhibits WNT signaling by binding of several WNT ligands including WNT3A and WNT5A, prevented WNT induced MSPC growth by neutralizing rWNT3A-mediated inhibition of chondrogenesis in micro mass cultures of embryonic chick limb bud cells []. WIF1 is epigenetically silenced via promoter methylation in human chondrosarcoma tissues and cell lines, and loss of WIF1 protein expression correlated with lower progression-free and overall survival rates []. Interestingly, aging reduced expression of β-catenin in bone marrow-derived MSPC, while β-catenin phosphorylation increased, indicating enhanced proteasomal degradation []. Therefore, targeting of WNT signaling might be of interest for chondrosarcoma treatment.

NOTCH signaling maintains the stem cell phenotype and prevents the differentiation of different types of MSPC. In 3D cultures of hMSPC NOTCH signaling was downregulated with increased chondrogenic differentiation. Indeed, jagged 1 (JAG1) overexpression prevented chondrogenesis in hMSPC []. In adults, AC NOTCH1 expression is restricted to MSPC in the SZ which proliferate during the onset of OA and form clusters []. In a human conventional chondrosarcoma of the maxilla strong NOTCH3 and JAG1 protein expression was detected at areas of tumor proliferation []. Increased NOTCH1, hairy and enhancer of split 1 (HES1), hairy/enhancer-of-split related with YRPW motif (HEY) 1, and HEY2 protein expression indicating active NOTCH signaling has been detected in human chondrosarcoma tissues []. In conclusion, inhibition of NOTCH signaling might impede proliferation and induce differentiation in chondrosarcomas.

Differential Diagnosis

  • Chondromyxoid fibroma
  • Enchondroma
  • Chondroblastic osteosarcoma
  • Fracture callus

Complications

Recurrence of the tumor

Distant metastases: the primary site of metastasis is the lung. The rate of metastasis varies according to the grade of chondrosarcoma .

  • Low-grade: less than 10%
  • Intermediate-grade: 10%–50%
  • High-grade : 50%–70% .

References

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