summary Chondrosarcoma is the second most common malignant primary bone tumor. These cancers are composed of malignant chondrocytes. There are various subtypes of chondrosarcoma, each with unique characteristics. "Conventional" chondrosarcoma accounts for >90% of chondrosarcomas and typically presents in adults over 40 with progressive pain Diagnosis is made by correlating clinical and imaging (x-ray, CT, MRI) findings with lesional biopsy showing malignant cartilage that permeates and entraps pre-existing bone trabeculae Treatment is usually wide surgical resection; conventional chondrosarcomas do not respond to chemotherapy or radiation Epidemiology Demographics (conventional chondrosarcoma) occurs in older adults (40 to 75 years) most >50 years slight male predominance specific subtypes of chondrosarcoma may present at younger ages (see below) Anatomic location (conventional chondrosarcoma) most common locations include the pelvis (25% of all cases), proximal femur, distal femur, proximal humerus, distal tibia, and scapula. Rarely involves the spine or craniofacial bones typically metaphyseal or diaphyseal, rarely epiphyseal (except clear cell chondrosarcoma) tumor location is important for diagnosis: cartilage tumors of the small bones of the hands and feet are mostly benign, whereas those of the flat bones (pelvis, scapula, ribs, sternum) are malignant until proven otherwise specific subtypes of chondrosarcoma have specific anatomic predilections (see below) Etiology Majority of chondrosarcomas are sporadic (primary chondrosarcomas), but they may develop from the malignant transformation of osteochondromas or enchondromas (secondary chondrosarcomas) Primary chondrosarcoma conventional type account for >90% of all chondrosarcomas can be central intramedullary (99%) or juxtacortical / periosteal (~1%) non-conventional dedifferentiated chondrosarcoma (<10%) clear cell chondrosarcoma (<5%) mesenchymal chondrosarcoma (<1%) Secondary chondrosarcoma arise from a pre-existing benign cartilage lesion osteochondroma account for the majority (>80%) of secondary chondrosarcomas solitary osteochondromas have <1% risk of malignant transformation multiple hereditary exostosis (5-10% risk of malignant transformation) enchondromas (1% to 9% risk of malignant transformation) Ollier's disease (25-30% risk of malignant transformation) Maffucci's (>50% risk of malignant transformation) histologically indistinguishable from conventional chondrosarcoma Genetics mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) identified in primary and secondary conventional chondrosarcomas and enchondromas mesenchymal chondrosarcomas are characterized by HEY1-NCOA2 fusion protein Chondrosarcoma subtypes Conventional chondrosarcoma account for >90% of all chondrosarcomas graded 1 through 3 Grade 1 (60%) grow slowly and almost never metastasizes histologic features similar to enchondroma, requiring clinical and radiographic features to support diagnosis Grade 2 (25%) more locally aggressive and metastasis in 10-15% Grade 3 (5%) locally aggressive and >50% metastasize imaging features, histology, and treatment see sections below De-differentiated chondrosarcoma pathology a secondary, high-grade spindle-cell sarcoma (typically undifferentiated pleomorphic sarcoma, osteosarcoma, or fibrosarcoma) arises adjacent to a (typically low-grade) conventional chondrosarcoma ~10% of chondrosarcomas may dedifferentiate may be considered "grade 4" chondrosarcoma demographics typically arise in older patients (~60 years) anatomic location similar to conventional chondrosarcoma presentation similar to conventional chondrosarcoma pathologic fracture is common imaging and histology see below sections treatment wide surgical resection spindle-cell component may respond to chemotherapy prognosis malignant, aggressive neoplasm with poor prognosis poor prognosis, <20% 5-year survival Clear cell chondrosarcoma pathology low-grade malignant chondrogenic neoplasm characterized by lobules of clear cells demographics occurs in younger patients (20 to 40 years) than conventional chondrosarcomas rare (~5% of chondrosarcomas) anatomic location strong predilection for the epiphysis of long bones 2/3 of cases present in the humeral or femoral head may be mistaken for a benign chondroblastoma presentation commonly presents with pain, which can be severe locally destructive and may present with pathologic fracture imaging and histology see below sections treatment wide resection prognosis 10-year survival is nearly 80% metastasis in ~15% Mesenchymal chondrosarcoma pathology high-grade biphasic chondrosarcoma characterized by poorly differentiated small round blue cells and islands of hyaline cartilage may be difficult to distinguish from other round blue cell tumors like Ewing's and rhabdomyosarcoma demographics occurs in younger patients (20 to 40 years) than conventional chondrosarcoma rare (<1%) anatomic location widespread anatomical distribution 30% of cases are isolated to the soft tissue most common in the flat bones (ilium, ribs, skull) presentation painful mass imaging and histology see below sections treatment wide resection may respond to chemotherapy and radiation prognosis poor, <50% 5-year survival metastasis common Periosteal (juxtacortical) chondrosarcoma pathology low-grade sub-periosteal cartilaginous tumor that develops on the surface of bone erosion of the underlying bone helps to differentiate from a benign periosteal chondroma demographics occurs in younger patients (2nd to fourth decade of life) than conventional chondrosarcoma rare (~1%) anatomic location metaphysis of long bones, especially the femur and humerus presentation painless or painful mass imaging and histology see below sections treatment wide resection prognosis slow, indolent course, and metastasis are rare Secondary chondrosarcoma pathology chondrosarcoma (usually low grade) that arises from an enchondroma or osteochondroma demographics usually found in significantly younger patients (3rd and 4th decades) than primary conventional chondrosarcoma anatomic location ~40% of secondary chondrosarcomas in HME arise from the ilium presentation osteochondromas account for >80% of secondary chondrosarcomas new pain or enlargement of previously non-growing osteochondroma after skeletal maturation enchondroma new onset pain at site of known enchondroma that is attributable to the lesion imaging and histology see below sections treatment same as for primary chondrosarcoma prognosis most are low grade with similar prognosis to low-grade primary chondrosarcoma Presentation Signs and Symptoms pain is the most common symptom pain attributable to the lesion as opposed to other causes (e.g. rotator cuff tear) is important to differentiate low grade chondrosarcoma from enchodroma variable rapidity of presentation dependent on tumor grade and location may present with slowly growing mass or symptoms of bowel/bladder obstruction due to mass effect in the pelvis new pain or increasing size of a known osteochondroma (secondary chondrosarcoma) 50% of de-differentiated chondrosarcomas present with a pathologic fracture Imaging Radiographs views orthogonal views of the region are mandatory findings findings vary somewhat with different subtypes malignant cartilage has characteristic imaging features best exemplified by conventional chondrosarcoma chondrosarcomas are typically large (>4cm) at the time of diagnosis subtypes conventional chondrosarcoma lytic lesion with intralesional calcifications (matrix mineralization) lobules of malignant cartilage undergo dystrophic calcification, forming characteristic "rings and arcs" or "popcorn calcification" periosteal reaction may be present low-grade tumors may lack signs of aggressive behavior and are difficult to distinguish from enchondromas see "Differential" section below higher-grade chondrosarcomas often show less matrix mineralization and appear more lytic with extensive endosteal scalloping, have permeative borders, and may break through the cortex with soft-tissue extension de-differentiated chondrosarcoma bi-morphic appearance with aggressive appearing unmineralized mass (spindle component) adjacent to the mineralized chondroid tumor is characteristic there may be no radiographic evidence of an underlying chondroid tumor soft-tissue mass is common clear cell chondrosarcoma well-defined osteolytic lesion in the epi-metaphyseal region 2/3 of cases involve the humeral or femoral head often a thin sclerotic border and may show matrix mineralization may simulate a benign lesion, especially chondroblastoma may present as a secondary aneurysmal bone cyst and pathologic fracture usually no periosteal reaction mesenchymal chondrosarcomas moth-eaten or permeative lytic lesion with variable matrix calcification cortical destruction and extraosseous extension is common periosteal chondrosarcoma juxtacortical soft-tissue mass with sharply defined borders often contains ring-and-arc calcifications or popcorn calcification underlying cortex is usually eroded, thickened, or saucerized secondary chondrosarcoma osteochondroma cartilage cap >2cm on MRI or CT highly concerning for secondary chondrosarcoma intralesional lysis of calcifications cortical destruction enchondroma see "differential" below MRI indications MRI helpful in determining size of tumor soft-tissue involvement findings lobulated mass with low to intermediate signal on T1 and high T2 signal (due to the high water content of cartilage), separated by low-intensity septa. Calcifications are dark on T1 and T2 gadolinium: heterogeneous and moderate uptake enhancement of septa is common, corresponding to the fibrovascular septations between cartilage lobules - "rings and arcs enhancement" mesenchymal and dedifferentiated chondrosarcomas may have a biphasic appearance: separated calcified (cartilaginous) and non-calcified (cellular) areas CT indications CT most useful study for low-grade cartilage neoplasms to determine cortical involvement findings matrix calcifications more easily identified on CT compared to radiographs deep endosteal scalloping suggests chondrosarcoma instead of enchondroma 90% have cortical breach Bone scan indications can help distinguish (not definitively) chondrosarcoma and enchondroma can determine location of metastastic disease findings usually very hot in all grades of chondrosarcoma greater uptake than the anterior superior iliac spine is characteristic Histology percutaneous core needle biopsy or open biopsy (gold standard) are necessary large chondrosarcomas are heterogenous and often have low- and high-grade regions area of reduced T2 signal intensity may represent foci of dedifferentiation and should be the preferred biopsy site enchondromas of hand, Ollier's disease, Maffucci's disease, periosteal chondromas, and low-grade chondrosarcoma may all have similar histology Conventional chondrosarcoma graded 1 through 3 grade is based on histologic features of cellularity, cytological atypia (nuclear size and hyperchromasia), myxoid stroma, and mitotic activity grade 1 features similar to normal cartilage or benign enchondroma diagnosis requires correlation of histologic, radiographic, and clinical data bland hyaline cartilage appearance with low cellularity bi-nucleated chondrocytes invasion and "entrapment" of pre-existing bone trabeculae is diagnostic grade 2 plump cartilage cells that are bi- or tri-nucleated increased cellularity, nuclear atypia, and hyperchromasia myxoid change or necrosis may be prominent occasional mitotic figures grade 3 permeative hypercellular stroma with rare if any hyaline cartilage matrix myxoid stroma is common more disorganization, more pleomorphism, and more mitotic figures Dedifferentiated chondrosarcoma "grade 4" chondrosarcoma malignant, aggressive neoplasm with poor prognosis characterized by a bimorphic histology low grade (although sometimes high grade) chondrosarcoma component adjacent to a high grade spindle cell component (usually osteosarcoma, fibrosarcoma, MFH) there is an abrupt transition between the two components and they are not admixed Mesenchymal chondrosarcoma poorly differentiated "small round blue cells" with scant cytoplasm staghorn vascular pattern is characteristic interspersed islands of malignant hyaline cartilage HEY1-NCOA2 rearrangement Clear cell chondrosarcoma lobular architecture similar to other cartilage neoplasms, but cells are large and vacuolated with ample pale cytoplasm minimal chondroid matrix frequently (~50%) have areas resembling conventional low-grade chondrosarcoma t(12:22) S100+ and PAS positive (heavy glycogen accounts for clear cytoplasm) Differential Differentiating a low grade chondrosarcoma from enchondroma in a long bone is a common diagnostic challenge Enchondroma vs Low Grade Chondrosarcoma Enchondroma Chondrosarcoma Age younger (<50) older (>50) Tumor size small (ie. <5cm) larger (ie. >5cm) Location axial skeleton and pelvis rare hands and feet common axial skeleton and pelvis common hands and feet rare Pain no, or pain is due to other locoregional pathology (ie. subacromial impingement) yes, pain attributable to lesion soft tissue mass no yes cortical destruction no yes periosteal reaction no yes endosteal scalloping <2/3 cortex >2/3 cortex bone expansion no yes bone scan uptake less than ASIS uptake greater than ASIS Differential of Chondrosarcoma Malignant lesion in older patient May have similar chondrogenic histology Sacral lesions in older patients Treated with wide resection alone Chondrosarcoma o o o o Metastatic disease o o Lymphoma o o Myeloma o o MFH o o Secondary sarcoma o Enchondroma / Olliers / Maffuccis o Periosteal chondroma o Osteochondroma (MHE) o Parosteal osteosarcoma o Adamantinoma o Chordoma o o Squamous cell o o Treatment Nonoperative chemotherapy & radiation indications chondrosarcomas are resistant to chemotherapy and radiation Operative intra-lesional curettage indications Grade 1 lesions in the extremities (minimal rate of metastasis) treatment of grade 1 lesions located in the pelvis or axial skeleton is controversial (higher rate of local recurrence and metastasis) most authors recommend wide excision of all chondrosarcomas (even grade 1) if located in the pelvis technique curettage, high-speed burring, and adjuvant treatment with subsequent packing of the defect, with internal fixation as needed common adjuvants include cryotherapy, liquid nitrogen, argon beam, phenol, ethanol, and hydrogen peroxide wide surgical excision indications grade 2 or 3 lesions any lesion in the pelvis wide surgical excision combined with multi-agent chemotherapy indications mesenchymal chondrosarcoma may also respond to radiation possible role for chemotherapy in dedifferentiated chondrosarcoma Complications Local recurrence for high-grade lesions, local recurrence is associated with distant metastasis and decreased survival grade 1 chondrosarcoma: rare after wide resection with negative margins 5-15% after curettage with adjuvant treatment grade 2 chondrosarcoma: varies depending on resection margins grade 3 chondrosarcoma: 25% local recurrence rate and >30% rate of metastasis Prognosis Histologic grade and subtype correlates with survival Grade I 90% 5-year survival grade 1 chondrosarcomas are generally slow growing Grade II 60-70% 5-year survival Grade III 30-50% 5-year survival De-differentiated chondrosarcoma <20% 5-year survival Poor prognostic variables axial and proximal extremity lesions have a more aggressive course pelvic location advanced patient age inadequate surgical margins Increased telomerase activity as determined by reverse transcriptase-polymerase chain reaction (RT-PCR), increased telomerase activity has been shown to directly correlate with the rate of recurrence referral to orthopedic oncologist is necessary for best prognosis