BASICS
DESCRIPTION
- Primary malignant bone tumors are rare (<1% of all tumors). In >40, rule out more common metastatic disease (breast, lung, prostate, thyroid, kidney)
- Osteogenic sarcomas arise from mesenchymal cells capable of differentiating into bone, cartilage, or fibrous tissue. The three histologic types are:
- Osteosarcoma: characterized by the production of osteoid or immature bone by malignant cells
- Chondrosarcoma: cellular cartilaginous tumor with abundant binucleate cells, myxoid areas, pushing borders; lacks osteoid
- Fibrosarcoma: spindle cells and collagen; no osteoid
- Ewing sarcoma: small, round blue-cell neoplasm of unknown histologic origin
- Malignant fibrous histiocytoma (MFH): pleomorphic sarcoma; 10-year survival 20% for high-grade, 90% for low-grade
- Giant cell tumor of bone (GCTB) has both benign (90%) and malignant forms; prefers epiphyseal long bone, often recurs; 5-10% of primary bone tumors; very destructive
- Chordoma develops from remnants of primitive notochord at base of skull or sacrum; rare; slowly progressive; recurrent; cure possible
EPIDEMIOLOGY
Incidence
- Rare: Estimated 2,970 primary bone tumors will be diagnosed in the United States in 2015; 1,490 deaths
- In adults: most common osteosarcoma (35%), chondrosarcoma (30%), Ewing sarcoma (16%)
- In resource-rich populations: malignant bone tumors represent 3-5 % of cancers diagnosed in children ages 0 to 14 years of age and 7-8% of cancers in adolescents 15 to 19 years of age (1)[A]. Third most common childhood cancer (after leukemia and brain tumor)
- In children: most common is osteosarcoma (52%); Ewing sarcoma (34%) 2nd; and chondrosarcoma 3rd.
- Predominant age
- Osteosarcoma: bimodal: ages 13 to 16 years and >65 years
- Chondrosarcoma: 3rd to 7th decades
- Fibrosarcoma: 2nd to 6th decades
- Ewing sarcoma: children and teen aged 10 to 15 years (70% of Ewing patients <20 years of age)
- MFH: adults and elderly
- GCTB: skeletally mature young adult in 2nd to 4th decades
- Chordoma: >40 years
- Predominant gender
- For most, male = female
- Osteosarcoma, male > female (1.5:1); Ewing, male > female; chondrosarcoma, male > female (2:1); chordoma males > females
- Race
- Ewing sarcoma is more common in Caucasian than in African American children.
- Osteosarcoma is slightly more common in African American than in Caucasian children.
ETIOLOGY AND PATHOPHYSIOLOGY
- Generally unknown, but likely multifactorial
- Chondrosarcoma may arise in preexisting enchondroma or exostosis.
- MFH often follows irradiation or arises in old bone infarct.
- GCTB RANKL-RANK-OPG signal pathway involved.
Genetics
- Genetic risk factors include:
- Paget disease: osteosarcoma
- Multiple hereditary exostosis: chondrosarcoma
- Multiple enchondromatosis (Ollier disease): chondrosarcoma
- Enchondromatosis and hemangiomatosis (Maffucci syndrome): chondrosarcoma
- Germline retinoblastoma, especially after radiation: osteosarcoma
- Li-Fraumeni syndrome (germline p53 or CHEK2 mutation): osteosarcoma
- Rothmund-Thomson syndrome (autosomal recessive): osteocarcoma
- RAPADILINO syndrome: osteosarcoma
- Diamond-Blackfan anemia (disorder of bone marrow): osteosarcoma
- Tumor genetics
- Ewing sarcoma has chromosomal translocation t(11;22) (q24;q12) in 90% of tumors and resulting EW5-FLI1 fusion protein. Mutation in theEWSR1 causes Ewing sarcoma (somatic mutation)
- Osteosarcoma shows loss of retinoblastoma 1 gene (RB1) and p53 suppressor genes and amplification of the genes c-myc, mdm-2, SAS, and cyclin-dependent kinase.
RISK FACTORS
- High fluoride exposure, residing on farmland (1)[A]
- Previous irradiation is a risk factor for osteosarcoma and MFH.
- Rapid bone growth, teenage growth spurt
- Fibrous dysplasia, uncommon genetic disorder
COMMONLY ASSOCIATED CONDITIONS
- Genetic conditions listed previously
- Patients with enchondromatosis more often die of GI malignancies than of metastatic chondrosarcoma.
DIAGNOSIS
HISTORY
- Pain with weightbearing, at rest and at night; often dull or aching; swelling, tenderness; systemic symptoms of weight loss and fever; failure of symptoms to resolve after a 2 to 3 weeks
- Clinical course without expected recovery for common sports injury (2)[A]
- Fracture with minor trauma (pathologic fracture present in 10-15% of cases)
- Minor injury may bring attention to lesion.
PHYSICAL EXAM
- Bone tenderness
- Palpable bony or soft tissue mass
DIFFERENTIAL DIAGNOSIS
- Metastatic cancer: breast, prostate, thyroid, lung, kidney
- Hematologic malignancy
- Myeloma, especially in patients >40 years
- Lymphoma at any age
- Benign bone tumors: endochondroma, osteochondroma, nonossifying fibroma, chondroblastoma, osteoid osteoma, osteoblastoma, periosteal chondroma (benign), giant cell tumor, chondromyxoid fibroma
- Other space-occupying lesions: aneurysmal bone cyst, unicameral bone cyst, fibrous dysplasia, eosinophilic granuloma
- Infection (osteomyelitis)
- Metabolic bone disease (osteopenia, Paget, hyperparathyroidism)
- Synovial diseases (pigmented villonodular synovitis, synovial chondromatosis, degenerative or inflammatory synovitis)
- Myositis ossificans and repair reaction to trauma
- Avascular necrosis
- Gardner syndrome (familial adenomatous polyposis)
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Calcium, phosphate, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), blood count (CBC)
- 50% of osteosarcomas have an ↑ALP.
- Ewing sarcoma: ↑ESR and LDH
- Prostate-specific antigen to exclude prostate cancer
- Thyroid function tests to exclude thyroid carcinoma
- ↑ESR and WBCs in osteomyelitis
- Serum protein electrophoresis and urine electrophoresis to exclude myeloma
- Plain films guide further testing.
- Classic plain-film findings include "onion skin"� for Ewing sarcoma and Codman triangle formation and soft-tissue "sunburst"� for osteosarcoma.
- Bone scan prior to biopsy to look for other lesions
- NM Thallium-201 to differentiate malignant tumor (77% sensitivity, 74% specificity, 75% accuracy)
- CT scan for cortical destruction and internal calcification or ossification
- MRI determines the extent of marrow involvement and associated soft-tissue mass.
- Osteosarcoma: Location of lesion is important. Surface osteosarcomas often may be cured by surgery alone.
- Chest radiograph and CT scan for metastatic disease
- Abdominal CT scan, MRI, or renal ultrasound
- Mammogram to exclude breast carcinoma
Diagnostic Procedures/Other
- Open or needle biopsy
- Frozen section problematic if calcified
- Touch prep; permanent section; snap freezing
- Electron microscopy
- Cytogenetic and molecular studies
- DNA indices
- Immunoperoxidase staining
- Immunophenotyping to rule out lymphoma
- Biopsy tract should be excised in continuity with the tumor at the time of resection.
Test Interpretation
- Elevated apoptotic index correlates with gross tumor size and worsened 5-year survival.
- Histology with special studies and radiographic findings confirm the diagnosis.
- 90% of osteosarcomas are high-grade, intramedullary tumors.
- Osteosarcoma may express Her-2/neu; if present, it is more aggressive but may respond more favorably to trastuzumab (Herceptin).
- Ewing sarcoma expresses MIC-2 protein (CD99).
- Electron microscopy: glycogen granules in Ewing sarcoma
TREATMENT
MEDICATION
- Neoadjuvant chemotherapy treats micrometastatic disease, allows time for ordering replacement prosthesis and bone graft, and for in vivo assessment of response to chemotherapy. (Address fertility issues prior to initiation.)
- Osteosarcoma
- Patients with low-grade osteosarcoma do not require chemotherapy (3)[A].
- Standard agents: doxorubicin (Adriamycin) and cisplatin; high-dose methotrexate with doxorubicin and cisplatin (MAP) with or without ifosfamide; ifosfamide, cisplatin and epirubicin. (4)[C].
- One of the most important prognostic indicators is tumor response to neoadjuvant chemotherapy. Increased 5-year survival to 90% if 90% tumor necrosis after neoadjuvant chemotherapy
- Chondrosarcoma: Grades 1 to 3 no standard chemo options; high-grade cyclophosphamide and sirolimus (4)[C]
- Ewing sarcoma: Radiotherapy along with surgery and chemotherapy. Response to induction chemotherapy important prognostic factor:
- A dramatic decrease in size of Ewing sarcoma usually occurs after initial chemotherapy.
- Adjuvant chemotherapy improves cure rate dramatically; cure rate is 10-20% with surgery or radiation alone.
- Standard agents: vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide (VAC/IE); vincristine, doxorubicin, and ifosfamide (VAI) for patients with good histologic response or small tumors; vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) (4)[C]. MFH: less histologic response to chemotherapy than conventional osteosarcoma; survival similar
- GCTB: excision and curettage with cementation, perioperative bisphosphonates (for stage III), adjuvant local administration of zoledronic acid and artificial bone or denosumab for recurrent/unresectable/metastatic disease (5)[C]
- Chordoma: resistant to chemotherapy (imatinib with cisplatin or sirolimus); surgical resection with radiotherapy is first line (4)[C].
- Precautions
- Left ventricular dysfunction with doxorubicin; cumulative dose >450 mg/m2 increases risk.
- High-dose MTX requires hydration, alkalinization of the urine, and monitoring of plasma levels.
- Significant adverse effects
- Myelosuppression
- Renal tubular dysfunction with ifosfamide
- Renal and hepatic dysfunction and GI mucositis with MTX
- Nephrotoxicity and ototoxicity with cisplatin
ADDITIONAL THERAPIES
- Radiation therapy, see NCCN Guidelines for details (4)[C].
- Adjuvant treatment for Ewing sarcoma with surgery and chemotherapy
- Palliative care in chondrosarcoma
SURGERY/OTHER PROCEDURES
- Complete surgical resection with adequate margins
- In osteosarcoma, surgical removal of all tumor (primary and metastatic) is required for cure.
- Chondrosarcoma in the extremities should be treated exclusively by surgery, unless mesenchymal or dedifferentiated high-grade.
- Ewing sarcoma is radiosensitive; however, surgery with limb salvage is increasingly accepted.
- Surgery preferred if lesion is resectable
- Despite irradiation, local recurrence common in up to 25% with pelvic lesions.
- After neoadjuvant chemotherapy, reassess resectability of lesion; either surgery or irradiation
- Adjuvant therapy with chemotherapy, � radiotherapy, after surgical excision
- Limb salvage is used whenever a safe margin can be obtained.
- Primary goal is eradication of disease.
- Secondary goal is preservation of function.
- In selected patients, limb salvage does not increase risk of death.
- Limb-sparing surgery may require endoprosthesis or bone graft (allograft or homograft).
- Rotationplasty is a procedure used when tumor dictates resection of the distal femur.
- Lower leg spared and rotated 180 degrees; tibia fused to femur.
- Reattached, reversed ankle serves as knee joint. Prosthesis fitted to reversed foot
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- CBC for myelosuppression
- Serial ECGs when doxorubicin is being used; granulocyte colony-stimulating factor (G-CSF) is often used to minimize neutropenia.
- Chest radiographs every 2 months for the first year, every 3 months for the second year, and every 4 months for the third year
- CT scans of the lungs every 6 months during the first 2 years
- Ewing sarcoma may recur >5 years after diagnosis.
PROGNOSIS
- With chemotherapy and surgery, the overall survival for nonmetastatic osteosarcoma is 75%; 65% for event-free survival
- In metastatic osteosarcoma, 5-year survival is 25-50%
- With amputation alone, 80% of patients with osteosarcoma had pulmonary metastatic disease by 2 years. With chemotherapy, the 5-year disease-free survival rate is 50-85%.
- Favorable prognostic factors for MFH and osteosarcoma include responsiveness to chemotherapy, distal portions of the extremities, small size, and age >10 years.
- Most chondrosarcomas are of lower grade and have a low risk of metastatic spread and a low incidence of local recurrence after adequate surgery.
- MFH, osteosarcoma, and Ewing sarcoma have an overall 50% survival with combined treatment.
- Patients with metastatic Ewing sarcoma have approximately 20-30%, 2 to 3 years event-free survival.
- Chordoma: overall 5-year survival rate 65%
COMPLICATIONS
- For limb salvage with any primary malignant bone tumor, potential complications include leg length discrepancy, infection, wound dehiscence, skin-coverage problems, and artery and nerve injury.
- Nonunion of bone grafts and mechanical loosening of prosthetic implants
- Local recurrence risk for osteosarcoma with limb salvage is <10%.
- Micrometastatic disease may have occurred by the time of presentation and can appear at any time during the course of treatment or follow-up.
- Thoracotomy and continued chemotherapy are often recommended for metastatic disease to the lung.
- Ewing sarcoma metastatic to the lung is often diffuse and not amenable to resection.
- Children after tumor treatment have decrease bone density with potential for decreased bone formation.
REFERENCES
11 Eyre �R, Feltbower �RG, Mubwandarikwa �E, et al. Epidemiology of bone tumours in children and young adults. Pediatr Blood Cancer. 2009;53(6):941-952.22 Krych �A, Odland �A, Rose �P, et al. Oncologic conditions that simulate common sports injuries. J Am Acad Orthop Surg. 2014;22(4):223-234.33 Schwab �JH, Springfield �DS, Raskin �KA, et al. What's new in primary bone tumors. J Bone Joint Surg Am. 2012;94(20):1913-1919.44 Biermann �JS, Chow �W, Adkins �DR, et al. Bone Cancer. National Comprehensive Cancer Network, Inc. (NCCN) Guidelines version 2.2016. 2015:1-84.55 Nishisho �T, Hanaoka �N, Miyagi �R, et al. Local administration of zoledronic acid for giant cell tumor of bone. Orthopedics. 2015;38(1):e25-e30.
ADDITIONAL READING
- Arndt �CA, Rose �PS, Folpe �AL, et al. Common musculoskeletal tumors of childhood and adolescence. Mayo Clin Proc. 2012;87(5):475-487.
- Gorlick �R, Janeway �K, Lessnick �S, et al. Children's Oncology Group's 2013 blueprint for research: bone tumors. Pediatr Blood Cancer. 2013;60(6):1009-1015.
- Siegel �R, Naishadham �D, Jemal �A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11-30.
- Wesolowski �R, Budd �GT. Use of chemotherapy for patients with bone and soft-tissue sarcomas. Cleve Clin J Med. 2010;77(Suppl 1):S23-S26.
- Wu �X, Cheng �B, Cai �ZD, et al. Determination of the apoptotic index in osteosarcoma tissue and its relationship with patients prognosis. Cancer Cell Int. 2013;13(1):56.
SEE ALSO
Ewing Sarcoma �
CODES
ICD10
- C41.9 Malignant neoplasm of bone and articular cartilage, unsp
- C40.90 Malig neoplasm of unsp bones and artic cartlg of unsp limb
- C41.0 Malignant neoplasm of bones of skull and face
- C41.2 Malignant neoplasm of vertebral column
- C40.00 Malig neoplasm of scapula and long bones of unsp upper limb
- C40.30 Malignant neoplasm of short bones of unspecified lower limb
- C40.22 Malignant neoplasm of long bones of left lower limb
- C40.21 Malignant neoplasm of long bones of right lower limb
- C40.20 Malignant neoplasm of long bones of unspecified lower limb
- C40.12 Malignant neoplasm of short bones of left upper limb
- C40.11 Malignant neoplasm of short bones of right upper limb
- C40.10 Malignant neoplasm of short bones of unspecified upper limb
- C40.82 Malig neoplm of ovrlp sites of bone/artic cartl of left limb
- C40.01 Malig neoplasm of scapula and long bones of right upper limb
- C41.4 Malignant neoplasm of pelvic bones, sacrum and coccyx
- C40.32 Malignant neoplasm of short bones of left lower limb
- C40.80 Malig neoplm of ovrlp sites of bone/artic cartl of unsp limb
- C40.31 Malignant neoplasm of short bones of right lower limb
- C40.81 Malig neoplm of ovrlp sites of bone/artic cartl of r limb
- C40.91 Malig neoplasm of unsp bones and artic cartlg of right limb
- C40.92 Malig neoplasm of unsp bones and artic cartlg of left limb
- C41.3 Malignant neoplasm of ribs, sternum and clavicle
- C40.02 Malig neoplasm of scapula and long bones of left upper limb
- C41.1 Malignant neoplasm of mandible
ICD9
- 170.9 Malignant neoplasm of bone and articular cartilage, site unspecified
- 170.7 Malignant neoplasm of long bones of lower limb
- 170.0 Malignant neoplasm of bones of skull and face, except mandible
- 170.2 Malignant neoplasm of vertebral column, excluding sacrum and coccyx
- 170.1 Malignant neoplasm of mandible
- 170.4 Malignant neoplasm of scapula and long bones of upper limb
- 170.5 Malignant neoplasm of short bones of upper limb
- 170.6 Malignant neoplasm of pelvic bones, sacrum, and coccyx
- 170.8 Malignant neoplasm of short bones of lower limb
- 170.3 Malignant neoplasm of ribs, sternum, and clavicle
SNOMED
- Primary malignant neoplasm of bone (disorder)
- Osteosarcoma of bone (disorder)
- Chondrosarcoma (disorder)
- Malignant fibromatous neoplasm (disorder)
- Primary malignant neoplasm of short bone of upper limb
- Primary malignant neoplasm of vertebral column
- Primary malignant neoplasm of ribs and/or sternum and/or clavicle
- Primary malignant neoplasm of bone of face
- Primary malignant neoplasm of bone of skull
- Primary malignant neoplasm of bone of upper limb
- Primary malignant neoplasm of long bone of lower limb
- Primary malignant neoplasm of mandible
- Primary malignant neoplasm of pelvic bone
- Primary malignant neoplasm of short bone of lower limb
CLINICAL PEARLS
- Literature consistently recommends bone tumor biopsies should ideally be performed at the same institution that can provide comprehensive definitive treatment using a multispecialty approach.
- Have a high index of suspicion when sports injury in an adolescent does not heal within a reasonable time. Start investigation with plain films. Osteosarcoma occurs most commonly in adolescents.
- The younger the patient, the more important it is to have a follow-up plan to surveil for late effects of the primary cancer as well as side effects of treatment.