Primary Bone Cancer

Article Author:
Jack Pullan
Article Editor:
Deepa Budh
Updated:
7/21/2020 5:56:50 PM
For CME on this topic:
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Primary Bone Cancer

Introduction

Primary bone cancer (PBC) is a rare malignant tumor of the bone, originating from primitive mesenchymal cells. It accounts for around 0.2% of all malignancies worldwide and is idiopathic in most cases. There are multiple subtypes, with osteosarcoma, chondrosarcoma, and Ewing sarcoma, the most common. Each varies in demographics, imaging appearance, and biological behavior. They are frequently aggressive and require early diagnosis, utilizing imaging and tissue biopsy. Surgical excision remains the mainstay of curative treatment, with chemotherapy and radiotherapy often used in conjunction.

Etiology

While primary bone cancer is most often idiopathic, risk factors also play a role in the development of this cancer.

  • Genetic factors are linked. Germline abnormalities in hereditary cancer predisposition syndromes have an increased risk of later developing bone cancer, through downregulation of tumor suppressor genes or upregulation of oncogenes. TP53 tumor suppressor gene is often altered in Li-Fraumeni syndrome, with patients at an increased risk of developing osteosarcoma. Similarly, a mutation in the Rb1 gene leading to hereditary retinoblastoma is linked to osteosarcoma. Werner and Rothmund-Thomson syndromes are also linked to an increased risk of developing osteosarcoma.[1]
  • Previous treatment for cancer with radiotherapy is linked to an increased risk of developing PBC in later life, particularly when exposed to ionizing radiation in childhood.[2]
  • Several benign conditions show the potential to progress to PBC. Paget disease of the bone is a condition characterized by a disorder of bone metabolism, particularly osteoclastic function. These patients are at an increased risk of developing osteosarcoma; however, it is a rare complication. Enchondromas and osteochondromas are benign cartilaginous neoplasms that can later develop into malignant chondrosarcoma.[3][4]

Epidemiology

primary bone cancer remains uncommon, accounting for 0.2% of all malignancies and 5% of childhood malignancies. In the United States, an estimated 3,600 new cases of PBC will be diagnosed in 2020, with 1,720 deaths, making up 0.3% of all cancer deaths. The National Cancer Institute data shows in adults, chondrosarcoma (40%) is most prevalent, followed by osteosarcoma (28%). In children and adolescents, osteosarcoma (56%) is most common, with Ewing sarcoma (34%) second. Chordoma, undifferentiated pleomorphic sarcoma, adamantinoma, fibrosarcoma, and giant cell tumor of the bone are also types of PBC; however, they are fewer in number. PBC has a male predominance, with worldwide osteosarcoma male-to-female ratio of 1.43 to 1.[5][6]

Pathophysiology

Primary bone cancer is a malignant tumor of the connective tissue with mesenchymal origin. The World Health Organisation (WHO) determined six categories: chondrogenic, osteogenic, notochordal, vascular, other malignant mesenchymal, and miscellaneous (including Ewing sarcoma). The pathophysiology varies considerably between groups, and in some cases, is poorly understood.[5]

Osteosarcoma is a highly malignant osteogenic tumor that can develop in any bone. It has a propensity to develop near the metaphysis of long bones in young patients. The most common sites are the distal femur, proximal tibia, and proximal humerus, where there is high bone turnover. In adults, the axial skeleton is more common, where previous irradiation or metabolic disease of the bone is often associated. Common genetic changes are not present to explain the growth of this tumor type; however, 70% of cases demonstrate some level of chromosomal abnormality. Alterations in p53, Rb1, and DNA repair/surveillance genes are present in patients with Li-Fraumeni, Bloom, and Rothmund-Thomson syndrome, all linked to increased rates of osteosarcoma.[7][8][9]

Chondrosarcoma is primarily a disease of adults, most frequently diagnosed between the ages of 30 to 60 years. They are generally slow-growing chondrogenic tumors of intermediate malignancy, rarely metastasizing. Chondrosarcoma arising de novo are classified as primary (>85% of cases), with those arising from pre-existing benign osteochondromas or enchondromas as secondary. The most common site for diagnosis is in the long bones of the appendicular skeleton. Flat bones can also be affected, including the pelvis, ribs, and scapula. The exact pathogenesis of chondrosarcoma is not known, though multiple genes are implicated. Cytogenic studies have identified structural and numerical chromosomal abnormalities. Gene mutations in EXT1/2, TP53, Rb1, and IDH1/2 have also been linked to malignant transformation in benign lesions.[5][4][10]

Ewing sarcoma is an aggressive tumor of childhood and adolescence, most commonly occurring in the bone, but also seen in soft tissues. The peak incidence is at 15 years, and the male to female ratio is 1.5:1. Anatomically the most frequent sites involved are long bones in the lower limb, pelvic bones, and the axial skeleton (ribs and vertebral column). Ewing sarcoma characteristically develops at the diaphysis, in contrast to the pattern seen in osteosarcoma. Ewing sarcoma is genetically well described, with characteristic chromosomal translocations identified. The translocation leads to the fusion of a FET protein to an ETS transcription factor, most commonly FLI1 (>85% of cases). The result is the formation of fusion proteins that act to deregulate downstream genes, altering cell behavior.[11][12][13]

Histopathology

Diagnosis of primary bone cancer requires a tissue biopsy to allow histopathological assessment, with significant heterogeneity seen.

Osteosarcoma

The formation of bone or osteoid characterizes osteosarcoma, and identification of this is key to diagnosis. Several histological subtypes have been identified, determined by the location of the tumor in bone, and the tumor grade.[14][7]

Intramedullary:[14][7]

  1. Conventional ("classic"): The most prevalent subtype, comprising 80% of all osteosarcomas. Classically high-grade, arising from the intramedullary canal. Spindle to polyhedral cell shape malignant mesenchymal cells is seen. Cell nuclei are pleomorphic with occasional mitotic figures. Extracellular matrix production can be osteoblastic, osteoclastic, or fibroblastic; however, a combination is common.
  2. Telangiectatic: <4% of osteosarcomas. Dilated hemorrhagic sinusoids are seen with small amounts of osteoid. These cavities mimic the appearance of an aneurysmal bone cyst, with the presence of high-grade sarcoma cells distinguishing the tumor.
  3. Low-grade: <2% of osteosarcomas. Well-differentiated cells are seen embedded in the osseous matrix and fibrous stroma, with small amounts of osteoid.
  4. Small cell: 1.5% of osteosarcomas. Numerous small round malignant cells are seen within an osteoid matrix. Small cell sarcoma can resemble Ewing sarcoma; however, the production of osteoid and sporadic spindling of cells are distinguishing features.

Surface:[14][7]

  1. Parosteal: 1-6% of osteosarcomas. Slow growing, arising from the outer surface of the metaphysis. Low-grade, with a well-differentiated, mostly cartilaginous matrix with minimal osteoid.
  2. Periosteal: 1-2% of osteosarcomas. More aggressive than parosteal osteosarcoma, with intermediate-grade tumors showing increased cell atypia. Mostly cartilaginous matrix with minimal osteoid.
  3. High-grade: <1% of osteosarcomas. Histologically like conventional osteosarcoma, showing high-grade spindle shape cells with nuclear pleomorphism.

Chondrosarcoma

Chondrosarcomas are characterized by the production of hyaline cartilage to form a cartilaginous matrix. Lobules of cartilage are seen with significant variation in dimension. Cell nuclei show pleomorphism with chondrocytes varying in size and shape. Conventional chondrosarcoma accounts for over 85% of all chondrosarcomas. It can be further subcategorized into primary central (developing within the medullary canal), or secondary peripheral (developing from the surface of the bone secondary to pre-existing enchondroma or osteochondroma). Histologically both primary central and secondary peripheral are alike. Grading is an essential process to allow the prediction of clinical behavior.[4][15][16]

  • Grade I: Low-grade lesions, lowly cellular, with a predominantly cartilaginous matrix and small dense nuclei. Distinguishing grade I chondrosarcoma and benign enchondroma can be difficult, both radiologically and histologically.
  • Grade II: Reduced cartilaginous matrix and moderately cellular. Nuclei are enlarged and hyperchromatic, with increased atypia. Mitoses may be seen.
  • Grade III: High-grade lesions, highly cellular, with increased cellular atypia showing vesicular and enlarged nuclei. Cartilaginous matrix is rare or absent, with myxoid material evident. Mitoses are more readily identified.

Several rare subtypes of chondrosarcoma are also identified. Dedifferentiated chondrosarcoma is characterized by low-grade chondrosarcoma next to a dedifferentiated high-grade lesion, with a sharp transition between the two. The tumor is extremely aggressive. Mesenchymal chondrosarcoma is a high-grade tumor occurring in either bone or soft tissue. Undifferentiated small round cells are seen, with varying amounts of a cartilaginous matrix. Clear cell chondrosarcoma is a low-grade tumor, with cells showing clear, vacuolated cytoplasm. Areas of hemorrhage and cyst formation are seen.[4]

Ewing Sarcoma

Ewing sarcoma is a high-grade aggressive sarcoma and belongs to the group of small round cell tumors. Monomorphic small cells are seen in sheets, with round nuclei and finely dispersed chromatin, with nucleoli usually not identifiable. Frequently necrosis is seen, with remaining viable cells arranged perivascularly. Cell membranes express the glycoprotein CD99, with immunohistochemistry showing that >95% of Ewing sarcomas have extensive membranous expression. CD99 expression is not specific to Ewing sarcoma, and other markers are also used for diagnosis.[17][13]

Other Types of PBC

Chordoma, adamantinoma, and giant cell tumors of bone are typically low-grade locally invasive tumors. Undifferentiated pleomorphic sarcoma and fibrosarcoma are aggressive malignant tumors, with generally poor prognosis.[18][19]

History and Physical

Primary bone cancer is a rare diagnosis, with primary care practitioners unlikely to encounter a single case in their working life. Early diagnosis improves overall survival; however, delays remain common. History and examination form the first step in diagnosing PBC, and an urgent referral to a specialist center is needed for all patients with a possible diagnosis.[11][20][5]

Pain is the most common symptom, described as deep-seated dull pain progressing over time, often becoming refractory to simple analgesia. Pain can be troublesome at night, and this is always a red flag. A mass may be palpable with localized tenderness. Patients may exhibit signs of systemic disease including lethargy, malaise, and fever; however, even in high-grade tumors, these are often not present and may suggest metastatic disease. A pathological fracture can be the first sign, and any abnormal fracture requires further investigation. History of predisposing genetic conditions (Li-Fraumeni syndrome, hereditary retinoblastoma, Werner syndrome, and Rothmund-Thomson syndrome) or diseases (Paget's disease) is crucial information.[5]

Physical examination should focus on the area of pain, tenderness, or mass. The area should be inspected and palpated, with size, consistency, mobility, location of the mass, and overlying skin changes noted. Lymph nodes should be palpated.[20]

Evaluation

Diagnostic modalities used in primary bone cancer include imaging, laboratory blood tests, and tissue biopsy.

Plain film radiograph:[21][20]

All patients should have orthogonal plain film radiographs when a potential PBC is identified. Plain x-rays may show the following findings:

  • Osteolytic, osteoblastic, or mixed changes.
  • A moth-eaten appearance, suggesting bone destruction secondary to a rapidly expanding tumor within a bone, commonly seen in Ewing sarcoma and telangiectatic osteosarcoma
  • A permeative appearance, suggesting tumor progressing through bone, with an ill-defined zone between tumor and healthy bone, often seen in small cell tumors, including Ewing sarcoma
  • "Onion skinning," with the tumor lifting partially-formed periosteal bone, classically seen in Ewing sarcoma.
  • "Codman triangle," with periosteum lifted off bone and osteoid laid down.
  • "Sunburst" appearance, with vertical osteoid calcification due to significant periostitis.

Magnetic resonance imaging (MRI):

MRI scan remains the gold standard for assessment of local tumor extent. The whole anatomical compartment should be imaged, with MRI sensitive for bone and soft tissue lesions. Biopsy planning is crucial, and MRI allows the definition of neurovascular structures. Modern techniques, including dynamic MRI, allow for better characterization of high-grade areas of tumor and have been used to assess tumor response to chemotherapy.[20][5][22]

Computed tomography (CT):

CT scan is used when the diagnosis remains unclear following MRI, or MRI is contraindicated. It remains the modality of choice in pelvic PBC and for planning reconstructive surgery. Patients with confirmed PBC require staging, and although many centers still perform chest radiographs, a CT chest is the gold standard for assessing metastatic pulmonary disease.[20][5]

Whole-body bone scintigraphy (bone scan):

Whole-body bone scintigraphy is a nuclear medicine study that utilizes Technetium-99m as an active agent, highlighting areas of osteoblastic activity. It allows the detection of malignancy and is useful in diagnosing metastatic disease.[20]

Positron emission tomography (PET):

PET scan is a nuclear medicine study that utilizes the high metabolic rate of tumor cells, measuring the uptake of injected radiolabeled F-18 fluoro-deoxy-glucose (FDG). PET scan is in some centers for initial staging of PBC, and studies have suggested it as a modality for follow up when used in combination with CT scan.[20][23]

Laboratory blood tests:

Specific laboratory blood tests are not used in the diagnosis of PBC; however, they form part of the patient workup. In patients undergoing chemotherapy, baseline urea, creatinine, and liver function tests allow baseline assessment of renal and hepatic function. Biochemical markers alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) offer some prognostic value, and levels can be monitored in follow up to assess for disease recurrence.[20][21]

Tissue biopsy:

Biopsy of the lesion is needed for definitive diagnosis, allowing for histopathological assessment and tumor grading. Biopsy should be performed in conjunction with the operating surgical team, ideally in a specialist bone cancer center. It requires meticulous planning, with suboptimal biopsy impacting on definitive surgical treatment options. Imaging should be performed before a biopsy, aiding in approach planning and preventing tissue disruption that could make radiological assessment more difficult. Percutaneous, incisional, or excisional techniques are used. Ultrasound, x-ray, and CT scans allow precise guidance. The tract should be well marked, allowing for excision at the time of surgery, and a specialist bone cancer pathologist should assess samples.[20]

Treatment / Management

The management of primary bone cancer requires a multidisciplinary approach by a specialist bone cancer center, including staff trained in providing age-appropriate care to children or adolescents. Management is dependent on several factors, including tumor type, stage and grade, and patient preference. Surgical excision remains the cornerstone of PBC treatment. Neoadjuvant and adjuvant chemotherapy are also commonplace in the management, with radiotherapy used in specific cases.

Surgery:

Surgical resection aims to remove all tumor tissue with adequate margins while preserving as much limb function as possible. A decision for either limb salvage surgery or amputation is made using imaging, histopathology, response to adjuvant treatment, and patient wishes. Surgery often leads to significant tissue loss, and open discussion with the patient is vital. Potential risks, benefits, and expected long term functional impact of the surgery must be highlighted. Low-grade tumors amenable to surgical excision typically require wide excision (removing the involved part of the bone with a cuff of healthy tissue), with high-grade tumors requiring radical excision (removing the affected bone and associated soft tissues within the anatomical compartment).[5][24]

Chemotherapy:

Multiple chemotherapy agents and regimens are used in the management of PBC. Often this consists of induction (neoadjuvant) and postoperative combination therapy (adjuvant), with improvements in rates of limb salvage surgery and overall survival since their introduction. Chemotherapy forms part of the standard treatment protocol for osteosarcoma and Ewing sarcoma. Chondrosarcoma is still primarily managed surgically, except in cases of mesenchymal chondrosarcoma, where chemotherapy and radiotherapy are often used.[25][26]

Neoadjuvant chemotherapy is primarily used to reduce the rate of future metastatic spread; however, studies have suggested it can also contribute to primary tumor control. A good response to neoadjuvant therapy is determined by a histological necrosis rate of >90%, with a poor response often initiating a change in postoperative adjuvant chemotherapy agents and showing poorer outcomes.[27][28][29]

Radiotherapy:

Radiotherapy is often used as adjunctive therapy in PBC. Ewing sarcoma is a radiosensitive tumor, with radiotherapy commonly used as part of the definitive treatment plan. Preoperative radiotherapy is used if the response to neoadjuvant chemotherapy is poor or the tumor positioned in a problematic anatomical location, where reduction of tumor volume will aid surgical resection. If sufficient tumor volume cannot be removed surgically or it would be unacceptably disabling, radiotherapy is used for local treatment. Where adequate margins have not been resected, postoperative radiotherapy is utilized. Chondrosarcomas are relatively radioresistant, with radiotherapy only utilized for surgically unresectable or incompletely resected tumors.[30][31][5]

Radiotherapy has a palliative role in all PBC, used to slow tumor growth locally and relieve pain.

Differential Diagnosis

Other types of tumor (malignant):

  • Metastases
  • Lymphoma
  • Multiple myeloma

Other types of tumor (benign):

  • Giant cell tumor
  • Osteoblastoma
  • Enchondroma
  • Chondromyxoid fibroma
  • Cortical desmoid

Infection:

  • Osteomyelitis

Trauma:

  • Fracture callus

Other:

  • Aneurysmal bone cyst
  • Fibrous dysplasia

Staging

Two staging systems are used in primary bone cancer, the TNM, and Enneking systems.

TNM system - American Joint Committee on Cancer (AJCC):[32]

This refers to the extent of tumor (T), spread to local lymph nodes (N), metastatic spread (M), and histological grade (G).

Stage IA (T1 N0 M0 G1/GX):

  • ≤8cm in size, with no lymph node or metastatic spread. Low grade.

Stage IB (T2 N0 M0 G1/GX, or T3 N0 M0 G1/GX):

  • >8cm in size (T2), with no lymph node or metastatic spread. Low grade.
  • Cancer at more than one location in the same bone (T3), with no lymph node or metastatic spread. Low grade.

Stage IIA (T1 N0 M0 G2/G3):

  • ≤8cm in size, with no lymph node or metastatic spread. High grade.

Stage IIB (T2 N0 M0 G2/G3):

  • >8cm in size, with no lymph node or metastatic spread. High grade

Stage III (T3 N0 M0 G2/G3):

  • Cancer at more than one location in the same bone, with no lymph node or metastatic spread. High grade.

Stage IVA (Any T N0 M1a Any G):

  • Any size and maybe in more than one location in the same bone, with no lymph node involvement. Metastatic spread to the lungs (M1a). Any grade.

Stage IVB (Any T, N1, Any M, Any G, or Any T, Any N, M1b, Any G):

  • Any size and maybe in more than one location in the same bone. It has spread to local lymph nodes (N1). It may or may not have metastasized to distant organs. Any grade.
  • Any size and maybe in more than one location in the same bone. It may or may not have spread to local lymph nodes. Metastatic spread to distant sites like other bones, liver, or brain (M1b). Any grade.

Enneking system:[33]

Refers to the histological grade (G), the extent of the tumor in relation to the anatomical compartments of the body (T), and metastatic spread (M)

Stage IA (G1 T1 M0):

  • Low grade, intra-compartmental, no metastasis.

Stage IB (G1 T2 M0):

  • Low grade, extra-compartmental, no metastasis.

Stage IIA (G2 T1 M0):

  • High grade, intra-compartmental, no metastasis.

Stage IIB (G2 T2 M0):

  • High grade, extra-compartmental, no metastasis.

Stage III (Any G, Any T, M1):

  • Any grade, any location, regional, or distant metastatic spread.

Prognosis

The prognosis of primary bone cancer is dependent on multiple factors, and there has been no significant improvement in 5-year survival over the past 25 years. In the United States, the National Cancer Institute shows overall 5-year survival is 66%, with studies suggesting rates are lower in the UK.[11]

When the disease is localized, osteosarcoma has a 10-year survival of 60% to 78%. This number falls to 20% to 30% in patients with metastatic disease at presentation, with other negative prognostic factors including axial or proximal extremity tumor location, increased tumor size, raised ALP or LDH, increased age, pathological fracture, and poor response to neoadjuvant chemotherapy.[34][35][36]

The most potent prognostic factor in chondrosarcoma is histological grade. Other identified factors are metastatic disease at presentation, increased age, and pelvic tumor location. 5-year survival in grade I chondrosarcoma is 83%, with only 53% of patients surviving to 5 years with grade I and II disease.[37][4][38]

Ewing sarcoma has a 5-year survival of 70% to 80% when the disease is localized. This number falls to 50% in patients with isolated pulmonary metastases, and less than 30% in patients with any other metastatic disease at diagnosis. Other negative prognostic factors include pelvic tumor location, increased tumor size, and poor response to neoadjuvant or adjuvant chemotherapy treatment.[39][13]

Complications

Tumor-related complications:[40][26]

  • Pathological fracture
  • Tumor recurrence
  • Distant metastasis

Treatment-related complications:

  • Surgery[41]
    • Surgical site or periprosthetic infection
    • Implant failure
    • Non-union/fracture of biological implant
  • Chemotherapy[42]
    • Short-term side effects include malaise, anemia, nausea, vomiting, and alopecia.
    • Long-term side effects include cardiotoxicity, renal toxicity, hearing loss, and an increased risk of developing a secondary malignancy.
  • Radiotherapy[43]
    • Side effects following radiation therapy are site-dependent, affecting the skin, pelvic organs, gastrointestinal tract, and lungs.
    • Long-term, there is a small increased risk of developing a secondary malignancy.

Pearls and Other Issues

Here are some important points about primary bone cancer:

  • PBC is a rare form of malignancy derived from primitive mesenchymal cells.
  • All patients presenting with unresolved bone pain should be assessed, and orthogonal plain film radiographs organized.
  • MRI is the gold standard for assessment of local tumor extent.
  • PBC should be managed by a multidisciplinary team in a specialist bone cancer center.
  • Surgical excision remains the mainstay of treatment for PBC, with chemotherapy and radiotherapy often used as adjuncts.

Enhancing Healthcare Team Outcomes

Patients diagnosed with PBC should ideally be managed under the care of a bone cancer specializing multidisciplinary team. The team should consist of specialists from radiology, histopathology, oncology, orthopedics, and a clinical nurse specialist or key worker. Radiologists and pathologists interpret initial imaging and tissue samples, allowing for a definitive diagnosis to be reached and operative planning to begin.

Oncologists determine the most appropriate neoadjuvant and adjuvant chemotherapy protocols, as well as arranging future follow-up and surveillance. Orthopedics plan and perform surgical resection of the tumor, along with any initial or future reconstruction that is required. Clinical nurse specialists or key workers act to educate the patient and their family, as well as direct towards different services available. They are a point of contact throughout the patient journey and work to coordinate the various teams. Other team members include physiotherapists, occupational therapists, prosthetists, orthotists, dieticians, social workers, and counselors.[44][45]


References

[1] Hameed M,Mandelker D, Tumor Syndromes Predisposing to Osteosarcoma. Advances in anatomic pathology. 2018 Jul;     [PubMed PMID: 29668499]
[2] Berrington de Gonzalez A,Kutsenko A,Rajaraman P, Sarcoma risk after radiation exposure. Clinical sarcoma research. 2012 Oct 4;     [PubMed PMID: 23036235]
[3] Hansen MF,Seton M,Merchant A, Osteosarcoma in Paget's disease of bone. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2006 Dec;     [PubMed PMID: 17229010]
[4] Gelderblom H,Hogendoorn PC,Dijkstra SD,van Rijswijk CS,Krol AD,Taminiau AH,Bovée JV, The clinical approach towards chondrosarcoma. The oncologist. 2008 Mar;     [PubMed PMID: 18378543]
[5] Gerrand C,Athanasou N,Brennan B,Grimer R,Judson I,Morland B,Peake D,Seddon B,Whelan J, UK guidelines for the management of bone sarcomas. Clinical sarcoma research. 2016;     [PubMed PMID: 27148438]
[6] Mirabello L,Troisi RJ,Savage SA, International osteosarcoma incidence patterns in children and adolescents, middle ages and elderly persons. International journal of cancer. 2009 Jul 1;     [PubMed PMID: 19330840]
[7] Messerschmitt PJ,Garcia RM,Abdul-Karim FW,Greenfield EM,Getty PJ, Osteosarcoma. The Journal of the American Academy of Orthopaedic Surgeons. 2009 Aug;     [PubMed PMID: 19652033]
[8] Morrow JJ,Khanna C, Osteosarcoma Genetics and Epigenetics: Emerging Biology and Candidate Therapies. Critical reviews in oncogenesis. 2015;     [PubMed PMID: 26349415]
[9] Hayden JB,Hoang BH, Osteosarcoma: basic science and clinical implications. The Orthopedic clinics of North America. 2006 Jan;     [PubMed PMID: 16311106]
[10] Chow WA, Chondrosarcoma: biology, genetics, and epigenetics. F1000Research. 2018;     [PubMed PMID: 30519452]
[11] Whelan J,McTiernan A,Cooper N,Wong YK,Francis M,Vernon S,Strauss SJ, Incidence and survival of malignant bone sarcomas in England 1979-2007. International journal of cancer. 2012 Aug 15;     [PubMed PMID: 21913189]
[12] Bernstein M,Kovar H,Paulussen M,Randall RL,Schuck A,Teot LA,Juergens H, Ewing's sarcoma family of tumors: current management. The oncologist. 2006 May;     [PubMed PMID: 16720851]
[13] Grünewald TGP,Cidre-Aranaz F,Surdez D,Tomazou EM,de Álava E,Kovar H,Sorensen PH,Delattre O,Dirksen U, Ewing sarcoma. Nature reviews. Disease primers. 2018 Jul 5;     [PubMed PMID: 29977059]
[14] Klein MJ,Siegal GP, Osteosarcoma: anatomic and histologic variants. American journal of clinical pathology. 2006 Apr;     [PubMed PMID: 16627266]
[15] van Praag Veroniek VM,Rueten-Budde AJ,Ho V,Dijkstra PDS,Fiocco M,van de Sande MAJ, Incidence, outcomes and prognostic factors during 25 years of treatment of chondrosarcomas. Surgical oncology. 2018 Sep;     [PubMed PMID: 30217294]
[16] Murphey MD,Walker EA,Wilson AJ,Kransdorf MJ,Temple HT,Gannon FH, From the archives of the AFIP: imaging of primary chondrosarcoma: radiologic-pathologic correlation. Radiographics : a review publication of the Radiological Society of North America, Inc. 2003 Sep-Oct;     [PubMed PMID: 12975513]
[17] Desai SS,Jambhekar NA, Pathology of Ewing's sarcoma/PNET: Current opinion and emerging concepts. Indian journal of orthopaedics. 2010 Oct;     [PubMed PMID: 20924475]
[18] Giannoulis DK,Gantsos A,Giotis D,Paschos NK,Vagionas A,Arnaoutoglou CM,Pentheroudakis G,Xenakis TA, Multiple recurrences and late metastasis of adamantinoma in the tibia: a case report. Journal of orthopaedic surgery (Hong Kong). 2014 Dec;     [PubMed PMID: 25550030]
[19] Doyle LA, Sarcoma classification: an update based on the 2013 World Health Organization Classification of Tumors of Soft Tissue and Bone. Cancer. 2014 Jun 15;     [PubMed PMID: 24648013]
[20] Plant J,Cannon S, Diagnostic work up and recognition of primary bone tumours: a review. EFORT open reviews. 2016 Jun;     [PubMed PMID: 28461955]
[21] Kundu ZS, Classification, imaging, biopsy and staging of osteosarcoma. Indian journal of orthopaedics. 2014 May;     [PubMed PMID: 24932027]
[22] Amit P,Patro DK,Basu D,Elangovan S,Parathasarathy V, Role of dynamic MRI and clinical assessment in predicting histologic response to neoadjuvant chemotherapy in bone sarcomas. American journal of clinical oncology. 2014 Aug;     [PubMed PMID: 23388556]
[23] Quartuccio N,Fox J,Kuk D,Wexler LH,Baldari S,Cistaro A,Schöder H, Pediatric bone sarcoma: diagnostic performance of ¹⁸F-FDG PET/CT versus conventional imaging for initial staging and follow-up. AJR. American journal of roentgenology. 2015 Jan;     [PubMed PMID: 25539251]
[24] Endo M,Lin PP, Surgical margins in the management of extremity soft tissue sarcoma. Chinese clinical oncology. 2018 Aug;     [PubMed PMID: 30173528]
[25] Carrle D,Bielack SS, Current strategies of chemotherapy in osteosarcoma. International orthopaedics. 2006 Dec;     [PubMed PMID: 16896870]
[26] Ibrahim T,Mercatali L,Amadori D, Bone and cancer: the osteoncology. Clinical cases in mineral and bone metabolism : the official journal of the Italian Society of Osteoporosis, Mineral Metabolism, and Skeletal Diseases. 2013 May;     [PubMed PMID: 24133529]
[27] Burgert EO Jr,Nesbit ME,Garnsey LA,Gehan EA,Herrmann J,Vietti TJ,Cangir A,Tefft M,Evans R,Thomas P, Multimodal therapy for the management of nonpelvic, localized Ewing's sarcoma of bone: intergroup study IESS-II. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1990 Sep;     [PubMed PMID: 2099751]
[28] Anninga JK,Gelderblom H,Fiocco M,Kroep JR,Taminiau AH,Hogendoorn PC,Egeler RM, Chemotherapeutic adjuvant treatment for osteosarcoma: where do we stand? European journal of cancer (Oxford, England : 1990). 2011 Nov;     [PubMed PMID: 21703851]
[29] Ferrari S,Smeland S,Mercuri M,Bertoni F,Longhi A,Ruggieri P,Alvegard TA,Picci P,Capanna R,Bernini G,Müller C,Tienghi A,Wiebe T,Comandone A,Böhling T,Del Prever AB,Brosjö O,Bacci G,Saeter G, Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2005 Dec 1;     [PubMed PMID: 16246977]
[30] Bacci G,Palmerini E,Staals EL,Longhi A,Barbieri E,Alberghini M,Ferrari S, Ewing's sarcoma family tumors of the humerus: outcome of patients treated with radiotherapy, surgery or surgery and adjuvant radiotherapy. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2009 Nov;     [PubMed PMID: 19576648]
[31] Indelicato DJ,Keole SR,Shahlaee AH,Shi W,Morris CG,Marcus RB Jr, Definitive radiotherapy for ewing tumors of extremities and pelvis: long-term disease control, limb function, and treatment toxicity. International journal of radiation oncology, biology, physics. 2008 Nov 1;     [PubMed PMID: 18455323]
[32] Edge SB,Compton CC, The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Annals of surgical oncology. 2010 Jun;     [PubMed PMID: 20180029]
[33] Enneking WF,Spanier SS,Goodman MA, A system for the surgical staging of musculoskeletal sarcoma. Clinical orthopaedics and related research. 1980 Nov-Dec;     [PubMed PMID: 7449206]
[34] Wadhwa N, Osteosarcoma: Diagnostic dilemmas in histopathology and prognostic factors. Indian journal of orthopaedics. 2014 May;     [PubMed PMID: 24932029]
[35] Bacci G,Longhi A,Ferrari S,Briccoli A,Donati D,De Paolis M,Versari M, Prognostic significance of serum lactate dehydrogenase in osteosarcoma of the extremity: experience at Rizzoli on 1421 patients treated over the last 30 years. Tumori. 2004 Sep-Oct;     [PubMed PMID: 15656333]
[36] Scully SP,Ghert MA,Zurakowski D,Thompson RC,Gebhardt MC, Pathologic fracture in osteosarcoma : prognostic importance and treatment implications. The Journal of bone and joint surgery. American volume. 2002 Jan;     [PubMed PMID: 11792779]
[37] Fromm J,Klein A,Baur-Melnyk A,Knösel T,Lindner L,Birkenmaier C,Roeder F,Jansson V,Dürr HR, Survival and prognostic factors in conventional central chondrosarcoma. BMC cancer. 2018 Aug 24;     [PubMed PMID: 30143018]
[38] Stevenson JD,Laitinen MK,Parry MC,Sumathi V,Grimer RJ,Jeys LM, The role of surgical margins in chondrosarcoma. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2018 Sep;     [PubMed PMID: 29929901]
[39] Gaspar N,Hawkins DS,Dirksen U,Lewis IJ,Ferrari S,Le Deley MC,Kovar H,Grimer R,Whelan J,Claude L,Delattre O,Paulussen M,Picci P,Sundby Hall K,van den Berg H,Ladenstein R,Michon J,Hjorth L,Judson I,Luksch R,Bernstein ML,Marec-Bérard P,Brennan B,Craft AW,Womer RB,Juergens H,Oberlin O, Ewing Sarcoma: Current Management and Future Approaches Through Collaboration. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2015 Sep 20;     [PubMed PMID: 26304893]
[40] Salunke AA,Chen Y,Xi C,Puhaindran M, Does a pathological fracture affect the prognosis in patients with osteosarcoma of the extremities? Journal of cancer research and therapeutics. 2015 Oct-Dec;     [PubMed PMID: 26881673]
[41] Tiwari A, Current concepts in surgical treatment of osteosarcoma. Journal of clinical orthopaedics and trauma. 2012 Jun;     [PubMed PMID: 25983449]
[42] Zhang Y,Yang J,Zhao N,Wang C,Kamar S,Zhou Y,He Z,Yang J,Sun B,Shi X,Han L,Yang Z, Progress in the chemotherapeutic treatment of osteosarcoma. Oncology letters. 2018 Nov;     [PubMed PMID: 30405759]
[43] Longhi A,Ferrari S,Tamburini A,Luksch R,Fagioli F,Bacci G,Ferrari C, Late effects of chemotherapy and radiotherapy in osteosarcoma and Ewing sarcoma patients: the Italian Sarcoma Group Experience (1983-2006). Cancer. 2012 Oct 15;     [PubMed PMID: 22415578]
[44] Stitzlein RN,Wojcik J,Sebro RA,Balamuth NJ,Weber KL, Team Approach: Osteosarcoma of the Distal Part of the Femur in Adolescents. JBJS reviews. 2017 Dec;     [PubMed PMID: 29278618]
[45] Siegel GW,Biermann JS,Chugh R,Jacobson JA,Lucas D,Feng M,Chang AC,Smith SR,Wong SL,Hasen J, The multidisciplinary management of bone and soft tissue sarcoma: an essential organizational framework. Journal of multidisciplinary healthcare. 2015;     [PubMed PMID: 25733913]