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Bone Tumor, Primary Malignant

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Bone Tumor, Primary Malignant

BASICS

DESCRIPTION

Initial Tests (lab, imaging)

11 Eyre пїЅR, Feltbower пїЅRG, Mubwandarikwa пїЅE, et al. Epidemiology of bone tumours in children and young adults. Pediatr Blood Cancer. 2009;53(6):941-952.22 Krych пїЅA, Odland пїЅA, Rose пїЅP, et al. Oncologic conditions that simulate common sports injuries. J Am Acad Orthop Surg. 2014;22(4):223-234.33 Schwab пїЅJH, Springfield пїЅDS, Raskin пїЅKA, et al. What's new in primary bone tumors. J Bone Joint Surg Am. 2012;94(20):1913-1919.44 Biermann пїЅJS, Chow пїЅW, Adkins пїЅDR, et al. Bone Cancer. National Comprehensive Cancer Network, Inc. (NCCN) Guidelines version 2.2016. 2015:1-84.55 Nishisho пїЅT, Hanaoka пїЅN, Miyagi пїЅR, et al. Local administration of zoledronic acid for giant cell tumor of bone. Orthopedics. 2015;38(1):e25-e30.

  • 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 cellsChondrosarcoma: cellular cartilaginous tumor with abundant binucleate cells, myxoid areas, pushing borders; lacks osteoidFibrosarcoma: 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
  • 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

EPIDEMIOLOGY

  • 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 ageOsteosarcoma: bimodal: ages 13 to 16 years and >65 yearsChondrosarcoma: 3rd to 7th decadesFibrosarcoma: 2nd to 6th decadesEwing sarcoma: children and teen aged 10 to 15 years (70% of Ewing patients <20 years of age)MFH: adults and elderlyGCTB: skeletally mature young adult in 2nd to 4th decadesChordoma: >40 years
  • Predominant genderFor most, male = femaleOsteosarcoma, male > female (1.5:1); Ewing, male > female; chondrosarcoma, male > female (2:1); chordoma males > females
  • RaceEwing sarcoma is more common in Caucasian than in African American children.Osteosarcoma is slightly more common in African American than in Caucasian children.
  • 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
  • For most, male = female
  • Osteosarcoma, male > female (1.5:1); Ewing, male > female; chondrosarcoma, male > female (2:1); chordoma males > females
  • 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.
  • Genetic risk factors include:Paget disease: osteosarcomaMultiple hereditary exostosis: chondrosarcomaMultiple enchondromatosis (Ollier disease): chondrosarcomaEnchondromatosis and hemangiomatosis (Maffucci syndrome): chondrosarcomaGermline retinoblastoma, especially after radiation: osteosarcomaLi-Fraumeni syndrome (germline p53 or CHEK2 mutation): osteosarcomaRothmund-Thomson syndrome (autosomal recessive): osteocarcomaRAPADILINO syndrome: osteosarcomaDiamond-Blackfan anemia (disorder of bone marrow): osteosarcoma
  • Tumor geneticsEwing 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.
  • Paget disease: osteosarcoma
  • Multiple hereditary exostosis: chondrosarcoma
  • Multiple enchondromatosis (Ollier disease): chondrosarcoma
  • Enchondromatosis and hemangiomatosis (Maffucci syndrome): chondrosarcomaGermline retinoblastoma, especially after radiation: osteosarcomaLi-Fraumeni syndrome (germline p53 or CHEK2 mutation): osteosarcomaRothmund-Thomson syndrome (autosomal recessive): osteocarcomaRAPADILINO syndrome: osteosarcomaDiamond-Blackfan anemia (disorder of bone marrow): osteosarcoma
  • 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
  • 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 malignancyMyeloma, especially in patients >40 yearsLymphoma 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)
  • Myeloma, especially in patients >40 years
  • Lymphoma at any age

DIAGNOSTIC TESTS & INTERPRETATION

  • 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"пїЅ for Ewing sarcoma and Codman triangle formation and soft-tissue "sunburst"пїЅ 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
  • Open or needle biopsyFrozen section problematic if calcifiedTouch prep; permanent section; snap freezingElectron microscopyCytogenetic and molecular studiesDNA indicesImmunoperoxidase stainingImmunophenotyping to rule out lymphoma
  • Biopsy tract should be excised in continuity with the tumor at the time of resection.
  • 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
  • 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.)
  • OsteosarcomaPatients 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].
  • PrecautionsLeft 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 effectsMyelosuppressionRenal tubular dysfunction with ifosfamideRenal and hepatic dysfunction and GI mucositis with MTXNephrotoxicity and ototoxicity with cisplatin
  • 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
  • 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
  • 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.
  • 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 resectableDespite irradiation, local recurrence common in up to 25% with pelvic lesions.After neoadjuvant chemotherapy, reassess resectability of lesion; either surgery or irradiationAdjuvant therapy with chemotherapy, пїЅ 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
  • 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, пїЅ radiotherapy, after surgical excision
  • Primary goal is eradication of disease.
  • Secondary goal is preservation of function.
  • 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

  • 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

ADDITIONAL READING

  • Arndt пїЅCA, Rose пїЅPS, Folpe пїЅAL, et al. Common musculoskeletal tumors of childhood and adolescence. Mayo Clin Proc. 2012;87(5):475-487.
  • Gorlick пїЅR, Janeway пїЅK, Lessnick пїЅS, et al. Children's Oncology Group's 2013 blueprint for research: bone tumors. Pediatr Blood Cancer. 2013;60(6):1009-1015.
  • Siegel пїЅR, Naishadham пїЅD, Jemal пїЅA. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11-30.
  • Wesolowski пїЅR, Budd пїЅGT. Use of chemotherapy for patients with bone and soft-tissue sarcomas. Cleve Clin J Med. 2010;77(Suppl 1):S23-S26.
  • Wu пїЅX, Cheng пїЅB, Cai пїЅZD, 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

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.