Chondrosarcoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Rohan A. Bhimani, M.B.B.S., D.N.B., M.Ch.[2]

Chondrosarcoma is the second most common malignant primary tumor of bone. it is most frequently diagnosed in patients in their 4th and 5th decades of life.Men are slightly more affected with chondrosarcoma than women. There is no racial predilection to chondrosarcoma. Jaffe and Lichtenstein first described chondrosarcoma in 1948. Chondrosarcoma may be classified based on histological findings and location. The exact pathogenesis of chondrosarcoama is not fully understood. Multiple genes have been implicated in pathogenesis of chondrosarcoma. Cytogenetic analysis of chondrosarcomas revealed that structural abnormalities of chromosomes 1, 6, 9, 12 and 15 and numerical abnormalities of chromosomes 5, 7, 8 and 18 are most frequent associated. Anomalies associated with chromosome 9(9p12-22) are more commonly seen in central chondrosarcomas. Germline mutations in the exostosin (EXT1 or EXT2) genes, TP53 or pRb pathway, isocitrate dehydrogenase-1 and isocitrate dehydrogenase 2 genes and gene encoding the receptor for parathyroid have been implicated. On gross pathology, greyish-white lobulated mass, necrosis, calcification, and mucoid degeneration are characteristic findings of chondrosarcoma. On microscopic histopathological analysis abnormal cartilage, increased cellularity, and nuclear atypia are characteristic findings of chondrosarcoma. Chondrosarcoma may be divided into three grades based on cancer cells morphology under microscope and growth rate of tumor. There are no established causes for chondrosarcoma. Common risk factors in the development of chondrosarcoma are benign cartilage tumors such as enchondromas, osteochondromas, multiple exostoses, Ollier’s disease, and Maffucci’s syndrome. Chondrosarcoma must be differentiated from other diseases such as chondroma, enchondroma, osteochondroma, and osteosarcoma. Complications that can develop as a result of chondrosarcoma are metastasis and recurrence. The prognosis of chondrosarcoma correlates with the grade and stage of the lesion at the time of diagnosis. Chondrosarcoma is associated with a 5 year survival rate of 70%. The presence of grade 3 lesions are associated with a particularly poor prognosis. Biopsy is the gold standard test for the diagnosis of chondrosarcoma. Open biopsy is carried out for chondrosarcoma. The tumor is then staged based on Enneking system for chondrosarcoma. The most common symptoms of chondrosarcoma include pain and swelling in the area of tumor. Patients with chondrosarcoma usually appear lethargic and emaciated. Physical examination of patients with chondrosarcoma is usually remarkable for palpable mass, tenderness and decreased range of motion. On x-ray, chondrosarcoma is characterized by lytic lesion, intralesional calcification, endosteal scalloping, and cortical remodeling. On CT scan chondrosarcoma is characterized by matrix calcification, endosteal calcification, cortical breach, and heterogenous contrast enhancement. On MRI, chondrosarcoma is characterized by low to intermediate signal on T1, very high intensity in calcified portions on T2, and moderate to intense contrast enhancement on T1 contrast. Bone scan shows very hot uptake in all grades of chondrosarcoma. Chemotherapy and radiotherapy are indicated for chondrosarcoma as adjuvant therapy or palliative treatment in surgically inaccessible areas. Surgery is the mainstay of treatment for chondrosarcoma. Adjunctive chemotherapy and radiation may be required. Recurrence rate depends on the grade of chondrosarcoma.

In 1948, Jaffe and Lichtenstein described chondrosarcoma for the first time.

Chondrosarcoma may be classified based on histological findings and location.

The exact pathogenesis of chondrosarcoama is not fully understood. Multiple genes have been implicated in pathogenesis of chondrosarcoma. Cytogenetic analysis of chondrosarcomas revealed that structural abnormalities of chromosomes 1, 6, 9, 12 and 15 and numerical abnormalities of chromosomes 5, 7, 8 and 18 are most frequent associated. Anomalies associated with chromosome 9(9p12-22) are more commonly seen in central chondrosarcomas. Germline mutations in the exostosin (EXT1 or EXT2) genes, TP53 or pRb pathway, isocitrate dehydrogenase-1 and isocitrate dehydrogenase- 2 genes and gene encoding the receptor for parathyroid have been implicated. On gross pathology, greyish-white lobulated mass, necrosis, calcification, and mucoid degeneration are characteristic findings of chondrosarcoma. On microscopic histopathological analysis abnormal cartilage, increased cellularity, and nuclear atypia are characteristic findings of chondrosarcoma. Chondrosarcoma may be divided into three grades based on cancer cells morphology under microscope and growth rate of tumor.

The cause of chondrosarcoma has not been identified.

Chondrosarcoma must be differentiated from other diseases such as chondroma, enchondroma, osteochondroma, and osteosarcoma.

Chondrosarcoma is the second most common malignant primary tumor of bone. It is most frequently diagnosed in patients in their 4th and 5th decades of life. Men are slightly more affected by chondrosarcoma than women. There is no racial predilection to chondrosarcoma.

Common risk factors in the development of chondrosarcoma are benign cartilage tumors such as enchondromas, osteochondromas, multiple exostoses, Ollier’s disease, and Maffucci’s syndrome.

Complications that can develop as a result of chondrosarcoma are metastasis and recurrence. The prognosis of chondrosarcoma correlates with the grade and stage of the lesion at the time of diagnosis. Chondrosarcoma is associated with a 5 year survival rate of 70%. The presence of grade 3 lesions are associated with a particularly poor prognosis.

Biopsy is the gold standard test for the diagnosis of chondrosarcoma. Open biopsy is carried out for chondrosarcoma. The tumor is then staged based on Enneking system for chondrosarcoma.

The most common symptoms of chondrosarcoma include pain and swelling in the area of tumor.

Patients with chondrosarcoma usually appear lethargic and emaciated. Physical examination of patients with chondrosarcoma is usually remarkable for palpable mass, tenderness and decreased range of motion.

There are no specific laboratory tests for the diagnosis of chondrosarcoma.

There are no ECG findings associated with chondrosarcoma.

On x-ray, chondrosarcoma is characterized by lytic lesion, intralesional calcification, endosteal scalloping, and cortical remodeling.

There are no echocardiography/ultrasound findings associated with Chondrosarcoma.

On CT scan chondrosarcoma is characterized by matrix calcification, endosteal calcification, cortical breach, and heterogenous contrast enhancement.

On MRI, chondrosarcoma is characterized by low to intermediate signal on T1, very high intensity in calcified portions on T2, and moderate to intense contrast enhancement on T1 contrast.

Bone scan shows very hot uptake in all grades of chondrosarcoma.

There are no other diagnostic studies associated with chondrosarcoma.

Chemotherapy and radiotherapy are indicated for chondrosarcoma as adjuvant therapy or palliative treatment in surgically inaccessible areas. Surgery is the mainstay of treatment for chondrosarcoma.

Surgery is the mainstay of treatment for chondrosarcoma. Adjunctive chemotherapy and radiation may be required. Recurrence rate depends on the grade of chondrosarcoma.

There are no established measures for the primary prevention of chondrosarcoma.

There are no established measures for the secondary prevention of chondrosarcoma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rohan A. Bhimani, M.B.B.S., D.N.B., M.Ch.[2]

Jaffe and Lichtenstein first described chondrosarcoma in 1948.

• In 1948, Jaffe and Lichtenstein described chondrosarcoma for the first time.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rohan A. Bhimani, M.B.B.S., D.N.B., M.Ch.[2]

Chondrosarcoma may be classified based on histological findings and location.

• Chondrosarcoma be classified based on histological findings and location.

• Chondrosarcoma may be classified based on histological findings into following groups:^[1][2]

Primary Chondrosarcoma

• Chondrosarcoma that arises denovo and comprises of following subtypes:
  • Conventional chondrosarcoma – Low-grade, high-grade, and dedifferentiated chondrosarcoma (90% of all chondrosarcomas)
  • Clear cell chondrosarcoma (1% of all chondrosarcomas)
  • Mesenchymal chondrosarcoma (2% of all chondrosarcomas)

Secondary Chondrosarcoma

• Chondrosarcoma that arises from benign cartilage lesions includes (7% of all chondrosarcomas):
  • Osteochondroma (<1% risk of malignant transfomation)
  • Multiple hereditary exostosis (1-10% risk of malignant transformation)
  • Enchondromas (1% risk of malignant transformation)
  • Ollier’s disease (25-40% risk of malignant transformation)
  • Maffucci’s disease(100% risk of malignant transformation)

• Chondrosarcoma may be classified based on location into following groups:^[3][4]
  • Centrally located within the medullary cavity. (central chondrosarcoma) (70% of all chondrosarcomas)
  • Peripherally located on the surface of bone as a result of malignant transformation within the cartilaginous cap. (Peripheral chondrosarcoma) (15% of all chondrosarcomas)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rohan A. Bhimani, M.B.B.S., D.N.B., M.Ch.[2]

The exact pathogenesis of chondrosarcoama is not fully understood. Multiple genes have been implicated in pathogenesis of chondrosarcoma. Cytogenetic analysis of chondrosarcomas revealed that structural abnormalities of chromosomes 1, 6, 9, 12 and 15 and numerical abnormalities of chromosomes 5, 7, 8 and 18 are most frequent associated. Anomalies associated with chromosome 9(9p12-22) are more commonly seen in central chondrosarcomas. Germline mutations in the exostosin (EXT1 or EXT2) genes, TP53 or pRb pathway, isocitrate dehydrogenase-1 and isocitrate dehydrogenase- 2 genes and gene encoding the receptor for parathyroid have been implicated. On gross pathology, greyish-white lobulated mass, necrosis, calcification, and mucoid degeneration are characteristic findings of chondrosarcoma. On microscopic histopathological analysis abnormal cartilage, increased cellularity, and nuclear atypia are characteristic findings of chondrosarcoma. Chondrosarcoma may be divided into three grades based on cancer cells morphology under microscope and growth rate of tumor.

• Cartilaginous tumors are seen in bones that arise from enchondral ossification.^[1]
• There is hypertrophy of the resting zone of chondrocytes due to proliferation and differentiation within the normal growth plate.^[1]
• These cells the undergo apoptosis resulting in invasion of vessels and osteoblasts that start to form bone and lead to longitudinal bone growth.
• This physiologic process is regulated by components of the Indian hedgehog (IHH)/parathyroid hormone related (PTHRP) protein signaling pathway.

• The exact pathogenesis of chondrosarcoma is not full understood.^[2]
• Multiple genes have been implicated in pathogenesis of chondrosarcoma.

• Cytogenetic analysis of chondrosarcomas revealed that structural abnormalities of chromosomes 1, 6, 9, 12 and 15.^[3]
• Also, numerical abnormalities of chromosomes 5, 7, 8 and 18 were most frequent associated with chondrosarcoma.^[4]
• Anomalies associated with chromosome 9(9p12-22) are more commonly seen in central chondrosarcomas.^[5]
• Patients with multiple osteochondromas seem to have germline mutations in the exostosin (EXT1 or EXT2) genes.^[6]
• This result is decreased EXT expression and decreased biosynthesis and release of heparan sulfate proteoglycans (HSPGs), which are essential for cell signaling through IHH/PTHLH pathways.^[7][8][9]
• This in turn decreases normal chondrocyte proliferation and differentiation within the normal human growth plate.
• Furthermore, the genetic mutations in the TP53 or pRb pathway are implied in the malignant transformation from osteochondroma to secondary peripheral chondrosarcoma.
• In enchondromas and central chondrosarcomas, point mutations in isocitrate dehydrogenase-1 and isocitrate dehydrogenase – 2 genes (IDH1 and IDH2) have been suggested.
• In addition, the Ollier disease and Maffucci syndrome are also result of somatic mosaic mutations in IDH1 and IDH2. ^[10]
• Isocitrate dehydrogenase is the necessary enzyme required for conversion of isocitrate to alpha-ketoglutarate in the tricarboxylic acid cycle.
• Mutations in IDH1 and IDH2 cause elevated levels of the oncometabolite D-2-hydroxyglutarate (D-2-HG) which promotes chondrogenesis and inhibit osteogenic differentiation of mesenchymal stem cells as well as causes DNA hypermethylation and histone modification, all resulting in decreased differentiation.^[11]
• A missense mutation (R150C) in the gene encoding the receptor for PTHRP (PTH-1 receptor or PTH1R) has been associated to enchondromatosis in patients with Ollier disease, and decreased receptor function.^[12][13][14]
• Low-grade chondrosarcomas are near-diploid and have very few karyotypic abnormalities.^[15]
• On the other hand, high grade chondrosarcomas are aneuploid and have complex karyotypes.^[15]
• The progression of chondrosarcoma has been linked to the CDKN2A (p16) tumor suppressor gene present at 9p21 and by mutation in p53.^[16][17]
• Mutations in COL2A1 have also been hypothesized in pathogenesis of chondrosarcomas.^[18]
• In addition, amplification of the c-myc and fos/jun protien has also been implicated in the pathogenesis of chondrosarcoma.^[19][20]
• A specific HEY1-NCOA2 fusion product due to an intra-chromosomal rearrangement of chromosome arm 8q result in mesenchymal chondrosarcoma.
• With extraskeletal myxoid chondrosarcomas, the t(9;22)(q22;q12) translocation is common.^[21]

Characteristic features of chondrosarcoma on gross pathology are:^[22][23]

• Greyish-white lobulated mass
• Necrosis
• Calcification
• Mucoid degeneration

In general chondrosarcomas are multi-lobulated (due to hyaline cartilage nodules) with central high water content and peripheral enchondral ossification. Characteristic features on microscopic analysis are variable depending on the chondrosarcoma subtype:

• Lobules of uniform to polymorphic densely-packed large cells.^[24][25][26]
• Well defined pushing borders.
• Clear to intensively acidophilic granular cytoplasm with vacuoles.
• Central nuclei with occasional prominent nucleoli.
• Low mitotic rate.
• Clear cell areas lack production of hyaline chondroid matrix.
• Areas with osteoclast-type giant cells mixed with small trabeculae of reactive bone.
• May contain conventional low-grade chondrosarcoma.
• May have secondary aneurysmal bone cyst changes.

Mesenchymal chondrosarcoma is a malignant tumor with a characteristic biphasic pattern:^[27][28][29]

• Poorly differentiated small round blue cells
• Islands of well-differentiated hyaline cartilage
  • Progressive maturation of cartilage towards the center
  • Central calcification or bone formation
• Can have a hemangiopericytomatous vascular pattern.

• It shows myxoid background.^[30]
• In addition, small cells with eosinophilic cytoplasm are seen.^[31]

• Poorly differentiated mesenchymal malignancy.^[32]
• Well-differentiated cartilaginous component

• Chondrosarcomas can be classified into the following three histologic grades, depending on findings of cellularity, atypia, and pleomorphism:^[33][34]

Grade 1

• Chondrosarcoma grows relatively slowly, has cells whose histological appearance is quite similar to cells of normal cartilage.
• Mostly chondroid matrix, little if any myxoid.
• Mild-to-moderate increase of cellularity +/- binucleated cells.
• Have much less aggressive invasive and metastatic properties.

Grade 2

• Intermediate grade chondrosarcoma
• Little chondroid matrix, necrosis and more common prominent myxoid.

Grade 3

• Grade 3 chondrosarcoma is increasingly faster-growing cancer, with more varied and abnormal-looking cells.
• Characterized by myxoid stroma, nuclear pleomorphism and mitoses.
• Absent chondroid matrix.
• These are much more likely to infiltrate surrounding tissues, lymph nodes, and organs.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Rohan A. Bhimani, M.B.B.S., D.N.B., M.Ch.[2]

There are no established causes for chondrosarcoma.

The cause of chondrosarcoma has not been identified.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Rohan A. Bhimani, M.B.B.S., D.N.B., M.Ch.[2]

Chondrosarcoma must be differentiated from other diseases such as chondroma, enchondroma, osteochondroma, and osteosarcoma.

• Chondrosarcoma must be differentiated from following bone disorders:^[1][2][3][4]

Disease	Malignant lesion in patients > 40 years	chondrogenic Histology	Sacral lesions in elderly	Treatment is wide resection alone
Chondrosarcoma	+	+	+	+
Metastic disease	+	–	+	–
Lymphoma	+	–	+	–
Myeloma	+	–	+	–
Malignant Fibrous Histiocytoma	+	–	+	–
Secondary sarcoma	+	–	–	–
Enchondroma	–	+	–	–
Periosteal chondroma	–	+	–	–
Osteochondroma	–	+	–	–
Parosteal osteosarcoma	–	–	–	+
Adamantinoma	–	–	–	+
Chordoma	–	–	–	+
Squamous cell carcinoma	–	–	–	+

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Rohan A. Bhimani, M.B.B.S., D.N.B., M.Ch.[2]

Chondrosarcoma is the second most common malignant primary tumor of bone. It is most frequently diagnosed in patients in their 4th and 5th decades of life. Men are slightly more affected by chondrosarcoma than women. There is no racial predilection to chondrosarcoma.

• Chondrosarcoma is the second most common primary bone sarcoma.^[1]
• The incidence of chondrosarcoam is approximately 1 per 100,000 individuals worldwide.^[2]

• Chondrosarcoma is most frequently diagnosed in patients in their 4th and 5th decades of life.^[3]
• The average age at presentation is 51 years.

• There is no racial predilection to chondrosarcoma.^[2]

• Chondrosarcoma affects men and women almost equally with slight male predominance.^[4]
• Exception to this is the clear cell sub-type which has significant male preponderance.
• The male to female ratio is almost 1:1 except for clear cell chondrosarcoma it is 2.4:1.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Rohan A. Bhimani, M.B.B.S., D.N.B., M.Ch.[2]

Common risk factors in the development of chondrosarcoma are benign cartilage tumors such as enchondromas, osteochondromas, multiple exostoses, Ollier’s disease, and Maffucci’s syndrome.

Chondrosarcoma may arise from pervious benign cartilage tumors. Some of these tumors are:^[1][2][3][4]

• Enchondromas are type of benign bone tumor that often occurs in the hands, but can also occur in other sites of the body.
• Osteochondromas are benign tumors that arise near the growth plate of the bone.
• Multiple exostoses are multiple overgrowths of cartilage that occur at the end of the growth plate.
• Ollier’s disease is a disease causing multiple enchondromas.
• Maffucci’s syndrome is a disease with multiple enchondromas and angiomas.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rohan A. Bhimani, M.B.B.S., D.N.B., M.Ch.[2]

Complications that can develop as a result of chondrosarcoma are metastasis and recurrence. The prognosis of chondrosarcoma correlates with the grade and stage of the lesion at the time of diagnosis. Chondrosarcoma is associated with a 5 year survival rate of 70%. The presence of grade 3 lesions are associated with a particularly poor prognosis.

• Chondrosarcoma may metastatize to other organs.^[1]
• Lung is the most common location for metastatic disease.
• Chondrosarcoma can rarely metastatize to skin.^[1]
• Chondrosarcoma may recur and may need treatment with surgery, chemotherapy or radiation.
• Unlike other cancers, chondrosarcoma can return many years later.
• Follow up scans are extremely important for chondrosarcoma to make sure there has been no recurrence or metastasis.

• The prognosis of chondrosarcoma correlates with the grade and stage of the lesion at the time of diagnosis.^[2]
  • Prognosis varies with grade:^[3]
  • Grade I tumors – 90% survival at 5 years
  • Grade II tumors – 81% survival at 5 years
  • Grade III tumors – 29% survival at 5 years
• Depending upon the subtype, prognosis vary substantially:^[4]
  • Clear cell chondrosarcoma: 70% survival rate at 5 years.
  • Myxoid chondrosarcoma: 70% survival rate at 5 years.
  • Mesenchymal chondrosarcoma: < 50% survival rate at 5 years.
  • Dedifferentiated chondrosarcoma: 10% survival rate after 1 year.
• Prognosis varies with location:^[5]
  • Long bones have a better prognosis than axial skeleton.