Childhood bone tumours

• Osteosarcoma and Ewing sarcoma are the two malignant bone tumours you will meet most often in children and teenagers. They are different diseases that present the same way, so knowing the pattern matters.
• Osteosarcoma is a cancer of bone-forming cells that produces osteoid. On an X-ray it often gives a "sunburst" or Codman triangle periosteal reaction, and it usually sits in the metaphysis around the knee.
• Ewing sarcoma is a small round blue cell tumour driven by a translocation, most often t(11;22). On an X-ray it shows a layered "onion skin" periosteal reaction, and it favours the diaphysis, pelvis and ribs.
• Both present with progressive bone pain (often worse at night), a palpable mass or swelling, a limp, and occasionally a pathological fracture. Systemic symptoms such as fever, weight loss and anaemia point more to Ewing sarcoma or advanced disease.
• Neither is cured by surgery alone. The standard plan is multi-agent chemotherapy first to shrink the tumour, then wide surgical excision (limb-sparing where possible), then more chemotherapy; radiotherapy is added when the tumour cannot be resected cleanly or is unresectable.

By the end of this page you should be able to:

1. Separate osteosarcoma from Ewing sarcoma by age, site, histology and genetics, and name the X-ray sign that points to each.
2. Work out why a child with bone pain at night needs the right imaging and, when necessary, a biopsy, and avoid starting cancer treatment on a cytology result alone.
3. Recognise the hereditary risk factors (germline RB1 mutation, Li-Fraumeni syndrome) and explain how they change follow-up.
4. Choose the correct staging investigations and explain what "90% necrosis after neoadjuvant chemotherapy" means for prognosis.
5. Describe the neoadjuvant chemotherapy and surgery sequence for both tumours, including limb-sparing options and when radiotherapy is used.
6. Give the main prognostic numbers and know which site and pattern of disease carries the worst outlook.

Osteosarcoma is the most common primary malignant bone tumour of childhood and adolescence. It is a cancer in which the malignant cell produces osteoid or bone directly. Ewing sarcoma, the second most common malignant bone tumour in children, belongs to the family of small round cell sarcomas caused by a fusion of the FET family of genes with a member of the ETS family; the most common fusion is EWSR1::FLI1, which occurs in about 85%, followed by EWSR1::ERG in about 10%.^[6] Older names such as "peripheral primitive neuroectodermal tumour", "Askin tumour" (chest wall Ewing) and "extraosseous Ewing sarcoma" refer to the same tumour group.^[3]

Neither tumour has a dominant hereditary form in the usual sense, but each arises in characteristic genetic settings. That distinction, together with age, site and radiographic appearance, is what lets you tell them apart.

Osteosarcoma has an estimated incidence of 5.4 cases per 1 million people aged 0 to 19 years each year, from the National Cancer Institute National Childhood Cancer Registry; broader registry and review series report lower overall rates depending on the age and sex range examined, so the figure is best read with that definition in mind. In the United States that translates to roughly 440 cases per year in people under 20, and the tumour accounts for about 5% of childhood tumours, although reported shares vary by whether the denominator is childhood tumours or all childhood cancers. Over half of cases occur in the long bones around the knee.^[1] It is rare before the age of 5 and peaks during the adolescent growth spurt, which fits with its preference for sites of rapid bone growth.

Ewing sarcoma is reported at 3.0 cases per 1 million in children and adolescents under 20 years in the United States, from the National Childhood Cancer Registry for 2016 to 2020, with older SEER cohorts reporting 2.93 per million, so the difference reflects rounding and reclassification of related sarcomas of bone rather than a change in true incidence. Across the whole world the incidence is closer to 1 case per 1.5 million. In the United States counts range from about 200 children and teens (American Cancer Society) to about 400 children and adolescents (NCI and Matcuk review) a year, reflecting different age cut-offs. About 3% of paediatric primary malignant cancers are Ewing sarcoma by registry definitions; the American Cancer Society, using all childhood cancers as the denominator, quotes about 1%. Nearly 80% of patients are diagnosed before the age of 20, with a peak in the second decade of life.^[3][6]

Sex and ancestry differ between the two. For Ewing sarcoma, pooled European data found 59% male and 41% female patients, and the incidence is about nine times higher in White people than in Black people, with an intermediate rate in Asian people. Females have a better prognosis than males in Ewing sarcoma.^[3] Osteosarcoma shows no large, consistent sex difference in incidence, but male sex is associated with a worse outcome once the disease is diagnosed.^[1]

Osteosarcoma. The exact cause is not known. Tumour formation tracks sites of rapid bone growth, presumably because proliferating osteoblastic cells acquire mutations that lead to transformation. Defects in the RB1 (retinoblastoma) and TP53 (Li-Fraumeni) pathways are the best established genetic drivers: germline mutations in RB increase the risk of osteosarcoma roughly 1,000-fold in the most quoted studies, although published estimates range from about 69-fold to 400-fold or more after radiation exposure, so the magnitude depends heavily on treatment history, and patients with Li-Fraumeni syndrome also have a greatly elevated incidence. Younger Children with hereditary retinoblastoma, Bloom syndrome, Rothmund-Thomson syndrome, Werner syndrome and Diamond-Blackfan anaemia are also at increased risk. Ionising radiation has a dose-dependent causal role, and prior chemotherapy (alkylating agents) raises risk. Paget disease of bone and infarcted or otherwise damaged bone underlie secondary osteosarcoma in adults.^[2][5][1]

Ewing sarcoma. This is a translocation-driven tumour. The EWSR1::FLI1 (and related) fusion produces an aberrant transcription factor that drives oncogenesis from a primordial bone marrow-derived mesenchymal stem cell. Conventionally patients are not considered to have an inherited predisposition, because the translocation is somatic, but recent genome-wide studies have identified susceptibility loci and germline variants in cancer predisposition genes such as FANCC. Fanconi anaemia has been reported to increase risk. Ewing sarcoma is far commoner in White populations than other ethnic groups.^[3][6]

Osteosarcoma. The diagnosis requires demonstration of osteoid produced directly by malignant cells. Most tumours are conventional (high-grade) osteosarcoma, subclassified histologically as osteoblastic, chondroblastic or fibroblastic. Other variants include telangiectatic (lytic and expansile with blood-filled spaces), low-grade central and surface forms (parosteal, periosteal). Macroscopically the tumour is grey-white, gritty and extends beyond the cortex with a soft tissue mass.^[1][5]

Ewing sarcoma. Under the microscope it is a sheet of small round blue cells with scant cytoplasm. The cells are positive for CD99 by immunohistochemistry, and molecular confirmation of EWSR1 rearrangement is now standard. Before genetic testing, Ewing sarcoma was diagnosed by morphology and CD99 staining alone.^[3][4]

The presentation of both tumours is remarkably similar, which is why imaging and biopsy, not the history, make the diagnosis.

• Pain is the first symptom in most patients. It is progressive, localised and often worse at night. In osteosarcoma it is usually metaphyseal and constant; in Ewing sarcoma it may be diaphyseal and can persist for weeks to months. A median interval of 2 to 5 months between first symptom and diagnosis has been reported for Ewing sarcoma, longer in older patients and pelvic primary sites.^{[3] [5]}
• Swelling or a mass follows, often warm and tender. Size matters: larger tumours carry a worse prognosis.^[3][6]
• A limp or refusal to use a limb, stiffness of a joint, and limited range of movement are common in children who will not verbalise pain clearly.
• Pathological fracture occurs when tumour replaces enough cortex. In osteosarcoma this is reported in about 11% of patients before treatment in one large series.^[1]
• Systemic symptoms are much commoner in Ewing sarcoma: fever, weight loss, fatigue, anaemia and raised lactate dehydrogenase (LDH) or C-reactive protein (CRP). In Ewing sarcoma such symptoms often imply metastatic disease and an elevated LDH is an adverse prognostic marker.^[3][6]
• Neurological findings occur if a vertebral or sacral primary compresses the cord or nerves.^[3]

Osteosarcoma patient-derived symptom lists include swelling over a bone or bony part of the body, pain in a bone or joint, pain in the arm when lifting, joint stiffness, a limp or difficulty walking, and a bone that breaks for no known reason.^[2] Ewing sarcoma patients may have a lump (often soft and warm) in the arms, legs, chest or pelvis, pain and swelling near the lump, unexplained fever, pathological fracture, limp, fatigue, weight loss, anaemia and shortness of breath.^[4]

Red-flag distribution of primaries:

• Ewing sarcoma: 45% in the lower extremities (diaphysis or diaphyseal-metaphyseal region), 20% pelvic and 10% upper extremities; flat bones (pelvis, scapula, ribs) are also common. Other series report pelvis 18%, femur 11%, tibia/fibula/foot 14%, ribs 11% (NCI Table 2); imaging reviews quote somewhat different fractions (femur around 18-21%, tibia/fibula 8-11%, ribs around 8%).^[3][6]
• Osteosarcoma: lower end of the femur, upper end of the tibia and upper end of the humerus in descending order; about half occur around the knee. Involvement of non-long bones (jaw, pelvis, spine, scapula, skull) increases with age.^[1][5]

The possibilities split into two questions. First, can the presentation be explained by something other than a tumour? Second, once a mass is present, which tumour or mimic is it?

Figure 1Ewing sarcoma tibia child

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Long description

Lateral radiograph of Ewing sarcoma of the tibia in a child (white arrow).

Figure 2Osteosarcoma1

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Long description

Radiograph of osteosarcoma of the distal femur.

The sequence in paediatric bone sarcoma is usually plain X-ray first, then cross-sectional imaging of the whole bone and the chest, then biopsy.

• Plain X-ray of the whole bone (with the joint above and below) is the best first test. For osteosarcoma it shows sun-burst or spiculated new bone, Codman triangle from lifted periosteum, permeative bone destruction and soft tissue mineralisation. For Ewing sarcoma it shows a permeative, purely lytic lesion with a layered "onion skin" (lamellated) periosteal reaction, present in almost 60% of cases, and an associated soft tissue mass. Codman triangle or sun-burst changes can occasionally be seen in Ewing sarcoma as well.^[5][6]
• MRI of the whole bone determines the intramedullary extent, soft tissue mass, joint involvement, skip lesions, and the relation to neurovascular structures; it is the single most accurate tool for local extent. One joint above and below is scanned so skip lesions are not missed.^[5]
• CT of the chest detects lung metastases, which appear as cannon ball nodules. It picks up nodule smaller than a plain chest X-ray can. Up to 20% of osteosarcoma patients have radiographically detectable metastases at diagnosis, most often in the lung. About 20% to 25% of Ewing patients have metastatic disease at diagnosis, with lung, bone and bone marrow the common sites.^[1][3][6]
• Bone scan or whole-body MRI/PET looks for skeletal metastases and skip lesions. In Ewing sarcoma a bone marrow biopsy is used for staging, although omission may be considered when PET imaging is negative in otherwise localised disease. Pooled bone marrow involvement is 4.8% in all newly diagnosed Ewing sarcoma and 17.5% in metastatic disease.^[3]
• Labs include LDH and alkaline phosphatase (the latter raised in osteosarcoma from increased osteoblastic activity and linked to tumour burden), full blood count and renal function.^[5]
• X-ray of the primary after neoadjuvant chemotherapy often shows the tumour becoming better mineralised and more sharply defined, which is one clue that treatment is working.^[5]

Classically 50% of osteosarcomas occur around the knee and 91% arise in metaphyses of extremity long bones. That pattern, combined with an aggressive periosteal reaction in a teenager during a growth spurt, should make you think of osteosarcoma.^[5]

The diagnosis must be confirmed histologically before treatment. Biopsy is performed only after the full clinical examination and imaging are complete, because the approach changes the surgery that follows.

• Where and who: Ideally the biopsy is done at the centre that will deliver definitive treatment, by an experienced oncology surgeon, so the tract can be excised with the tumour. A badly placed biopsy has been shown to contribute to major diagnostic error in about 18.2% of cases and to change outcome in about 8.5% of cases.^[5]
• Which technique: Percutaneous core needle biopsy with a Jamshidi needle taking multiple cores from a representative part of the tumour is now preferred; it is safe, quick, image-guidable and less contaminating. Open (incisional) biopsy remains the fallback when needle cores are non-diagnostic or when more tissue is needed for molecular studies. Fine needle aspiration cytology is inadequate for most bone sarcomas: ideally treatment should never be started on a cytological diagnosis alone.^[5][1]
• Placement details: The skin incision is made longitudinally so it can be excised entirely with the tumour. Transverse incisions in a limb, biopsying through the buttock or through rectus femoris, and long incisions with widely placed sutures marks are all errors that compromise later function or coverage.^[5]
• Image guidance: Core needle biopsy under CT, MRI or ultrasound improves accuracy in difficult or deep sites such as the pelvis and spine.^[5]
• Molecular confirmation: Ewing sarcoma must have cytogenetic or RT-PCR (or equivalent molecular) confirmation of an EWSR1 fusion, in addition to morphology and CD99 staining. Molecular testing on the same specimen can also clarify variants of Ewing sarcoma and rule out lymphoma or infection.^[3][4]
• Tissue handling: Osteosarcoma needs enough material to show osteoid and to grade the tumour; samples are also taken for immunohistochemistry and genetic studies.^[5]

There is no single blood test or imaging that diagnoses either tumour; both need histology plus the right immunohistochemistry and molecular testing.

Osteosarcoma. The essential diagnostic criterion is osteoid produced by malignant cells. The tumour is then graded histologically and subtyped. Serum alkaline phosphatase and LDH are commonly raised and help track tumour burden, but they are not diagnostic.^[1][5]

Ewing sarcoma. The diagnosis rests on small round cells with CD99 positivity and demonstration of an EWSR1 rearrangement, usually with EWSR1::FLI1 (t(11;22)). Molecular confirmation separates Ewing sarcoma from CIC-rearranged or BCOR-altered round cell sarcomas, which used to be called translocation-negative Ewing sarcoma but are now recognised as different tumours.^[3][4]

Staging. Two systems are used in musculoskeletal oncology, most often the Enneking and the American Joint Committee on Cancer (AJCC) systems. Enneking stages by grade and local compartment: stage I (low grade), stage II (high grade, subdivided into intracompartmental A and extracompartmental B) and stage III (any grade with metastasis). AJCC stages I to III high-grade tumours by size (8 cm or less versus larger), skip lesions and metastasis, with stage IV-A (pulmonary metastases only) and IV-B (non-pulmonary metastases). The distinction between lung-only and other metastases matters because patients with bone or combined pulmonary disease fare worse.^[5][3]

A child with either tumour should be treated in a multidisciplinary sarcoma unit that includes paediatric oncology, orthopaedic oncology, radiology, radiotherapy and rehabilitation. Neither tumour is cured by local treatment alone: systemic therapy is always part of the plan.

Immediate steps. Control pain, splint or brace the affected limb, protect against pathological fracture, and arrange urgent imaging and referral. Look for an occult fracture or lung metastases on staging CT before biopsy. Avoid letting biopsy delay and avoid unwarranted admission for "infection" when imaging is aggressive.

Neoadjuvant chemotherapy for osteosarcoma. Chemotherapy is given for about three cycles before surgery to shrink the tumour, make surgery easier and treat micrometastases. Standard drugs include methotrexate, doxorubicin and cisplatin (often called the MAP backbone), with other active agents such as ifosfamide, etoposide, carboplatin, cyclophosphamide, gemcitabine and docetaxel used in the trial or relapse setting. Chemotherapy is continued after surgery.^[2][1]

Surgery for osteosarcoma. The aim is complete excision with clear margins. Options include wide local excision, limb-sparing surgery with biological or prosthetic reconstruction, amputation, and rotationplasty. Limb-sparing and amputation have equivalent survival when clear margins are achieved. If a pathological fracture was present at diagnosis, limb-sparing may still be possible in selected cases. Radiation therapy is reserved for positive or close margins, axial or unresectable disease, and palliation, because osteosarcoma is relatively radioresistant.^[2][5]

Neoadjuvant and adjuvant chemotherapy for Ewing sarcoma. Ewing sarcoma is strikingly chemosensitive. For children under 18, interval-compressed VDC-IE (vincristine, doxorubicin and cyclophosphamide alternating with ifosfamide and etoposide every two weeks) is more effective than a three-week schedule, and the Euro Ewing 2012 trial showed superiority of VDC-IE over a VIDE regimen. Induction lasts several months, and total chemotherapy spans roughly 6 to 12 months. Drugs used alone or in combination include vincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposide and others.^[4][6]

Local control in Ewing sarcoma. Surgery and radiotherapy are complementary. Limb-sparing wide excision or amputation is chosen when clear margins and good function can be achieved; definitive radiotherapy at 54-60 Gy is an effective alternative where function-preserving surgery is not possible, but local failure rates are higher after definitive radiotherapy (about 26%) than after surgery (about 7.5%) in older trial data. Pre- or post-operative (adjuvant) radiotherapy is used for poor responders, marginal margins or residual disease. Protons are increasingly used in young children to spare surrounding tissue. Metastatic sites are also treated locally when possible: whole-lung irradiation after systemic therapy, surgical excision of limited pulmonary nodules, and treatment of bone metastases. High-dose chemotherapy with stem cell transplant is not recommended outside clinical trials, as it has not improved prognosis.^[4][3][6]

Follow-up. Assess histological response at surgery (percentage tumour necrosis), then imaging of the primary and chest during and after treatment. Chemotherapy is resumed promptly after surgery; delays in restarting have an adverse prognostic signal.

• Metastatic disease, most often to the lung and bone, is the principal cause of death.
• Pathological fracture complicates local disease and may require resection.
• Post-operative complications after limb salvage include infection, non-union, prosthesis or graft failure and limb length discrepancy.
• Late effects of treatment include anthracycline cardiotoxicity, ifosfamide renal tubular toxicity, secondary malignancies (in osteosarcoma; acute myeloid leukaemia, myelodysplastic syndrome and sarcoma in previously irradiated field in Ewing sarcoma), infertility, and survivors often need revaccination and rehabilitation.^[2][4][6]

Osteosarcoma. Five-year survival has risen from about 40% to 72% in children under 15 and from about 56% to about 71% in adolescents aged 15 to 19. However, little has improved since the 1980s. The strongest prognostic factors are:^[1]

• Metastasis at diagnosis (as many as 20%) with lung the main site, and multifocal bone disease carrying an extremely poor prognosis.^[1]
• Histological response to neoadjuvant chemotherapy: at least 90% tumour necrosis is associated with significantly better event-free survival than less necrosis.^[1]
• Primary site: distal extremity better than proximal; axial and pelvic disease worst (pelvic survival 20-47% in cooperative series; newer population-based cohorts report worse outcomes for axial primaries). Craniofacial tumours in the mandible and maxilla do better than other head and neck sites.^[1]
• Resectability: complete excision with clear margins is essential; positive margins and early local recurrence predict failure.^[1]
• Age and sex: older adolescent and young adult age and male sex are adverse; higher body mass index and pathological fracture in adults are also adverse.^[1]

Ewing sarcoma. Five-year survival has risen from 59% to 80-85% for children under 15 and from 20% to 69% for adolescents aged 15 to 19. Once metastases are present the outlook drops: about 20-25% have metastatic disease at diagnosis, and three-year cancer-specific survival is about 56%. Prognostic markers include:^[3][6]

• Metastatic status, the single most powerful predictor; metastases confined to lung fare better than bone or bone marrow involvement.^[3]
• Primary site: distal extremity most favourable, pelvic/axial least; larger tumours (greater than 8 or 10 cm, or volume over 100-200 mL) and elevated LDH are adverse.^[3][6]
• Age: younger children fare better than adolescents on North American analyses; infants have a similar overall survival.^[3]
• Histological response: good responders (little or no viable tumour after pre-surgical chemotherapy) have markedly better event-free survival.^[3]
• Molecular features such as co-occurrence of STAG2 and TP53 variants and complex karyotype may worsen outcome, though routine testing is still evolving.^[3]

Very young children. Both tumours are rare before school age; a bone sarcoma in an infant should prompt specialist review, and Ewing sarcoma in very young children often presents with soft tissue primaries. Hereditary cancer syndromes are more likely when the patient is very young, multiple or recurrent.^[1][3]

Treatment setting. In low-resource settings the affordable essentials are: a single plain X-ray, a focused clinical history and a plain-film chest X-ray; a Jamshidi core needle biopsy under local anaesthesia; staging imaging of the chest by CT where available; pain control, splinting and referral to a sarcoma centre. If cardiopulmonary-bypass or advanced limb reconstruction is unavailable, early referral for amputation rather than late, complicated surgery saves lives.

• Osteosarcoma is the commonest primary malignant bone tumour of childhood; Ewing sarcoma is the second.
• Osteosarcoma is a cancer of bone-forming cells producing osteoid, linked to RB1 and TP53 defects (retinoblastoma and Li-Fraumeni) and to ionising radiation; Ewing sarcoma is a small round cell tumour driven by EWSR1::FLI1 (t(11;22)).
• Peak ages are the adolescent growth spurt for osteosarcoma and the second decade for Ewing sarcoma.
• Osteosarcoma favours the metaphysis around the knee; Ewing sarcoma favours the diaphysis, pelvis and ribs.
• On X-ray, osteosarcoma is classically sun-burst/Codman triangle; Ewing sarcoma is permeative with an onion skin periosteal reaction.
• Both present with progressive pain often worse at night, swelling, mass, limp and pathological fracture; fever, weight loss and raised LDH/CRP are commoner in Ewing sarcoma.
• About 20% (osteosarcoma) and 20-25% (Ewing) of patients have metastases at diagnosis, usually to the lung.
• Differential diagnoses include osteomyelitis, Langerhans cell histiocytosis, benign bone tumours, stress fracture and other small round cell sarcomas.
• Biopsy comes only after imaging; core needle biopsy at the definitive centre, never a fine needle aspiration alone, and molecular testing for EWSR1 in Ewing.
• Need neoadjuvant chemotherapy, then wide excision with clear margins (limb-sparing often possible), then adjuvant chemotherapy; radiotherapy is essential for local control in some Ewing cases and adjuvant/palliative in osteosarcoma.
• Osteosarcoma responds to multi-agent chemotherapy (methotrexate, doxorubicin, cisplatin backbone); Ewing responds to interval-compressed VDC-IE.
• At least 90% tumour necrosis after neoadjuvant chemotherapy predicts a much better outcome in both.
• Children under 15 have 5-year survival 72% (osteosarcoma) and 80-85% (Ewing); pelvic and other axial primaries carry the worst outlook.
• Late effects of treatment are common; survivors need long-term follow-up, late surveillance and sometimes revaccination.

Plain text: osteomyelitis; osteochondroma and other benign bone tumours; retinoblastoma; Li-Fraumeni syndrome; Bloom, Rothmund-Thomson and Werner syndromes; cancer pain; late effects of childhood cancer treatment; amputation and limb reconstruction.