Cancers of the musculoskeletal system

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15 Cancers of the musculoskeletal system

HM. Hatcher, TV. Ajithkumar

Overview

Cancers of the musculoskeletal system or sarcomas can be divided into primary tumours of bone and soft tissue sarcomas. Each of these can be subdivided into specific subgroups. This results in a large number of tumours which are often grouped together, but which have different responses to treatment. Due to their rarity, sarcomas should be treated in a centre with appropriate expertise.

Primary bone tumours

Epidemiology and incidence

Primary malignant tumours of bone are rare. The most common subtypes are osteosarcoma, the Ewing’s family of tumours and chondrosarcoma.

In the UK, osteosarcoma accounts for up to 35% of all primary bone tumours. There are two peaks of incidence: in those aged 15–19 and a smaller second peak occurs over the age of 65 associated with Paget’s disease.

Ewing’s sarcomas and their soft tissue counterpart, primitive neuroectodermal tumour (PNET), are the second most common bone malignancy. The median age at diagnosis is 14 although they can occur at any age. There is a male predominance with a 1.5 : 1 male:female ratio.

Chondrosarcomas comprise less than 12% bone tumours and are the third most common malignant bone tumour. It is common over the age of 40 with the peak incidence in those over the age of 70.

Aetiology

Most primary bone tumours arise spontaneously without a predisposing risk factor. However for each subgroup there are recognized risk factors.

For osteosarcoma the most important risk factor is prior radiotherapy which accounts for only 3% of cases, with a time interval of 14 years (range 4–40 years). It is the most common secondary malignancy following treatment for childhood cancer. Other factors include chemotherapy with alkylating agents, Paget’s disease, chronic osteomyelitis, and hereditary conditions such as hereditary retinoblastoma and Li–Fraumeni syndrome (p. 53, 55). In hereditary retinoblastoma, the relative risk (RR) of osteosarcoma is 500 for limb osteosarcomas and 2000 for skull osteosarcomas following irradiation for retinoblastoma. Li–Fraumeni syndrome patients have a RR of 15 for osteosarcoma at all sites.

There are few risk factors for Ewing’s sarcoma but treatment for a primary cancer in childhood is a known association.

For chondrosarcoma, there is an increased risk is those with hereditary multiple exostosis or enchondromatosis syndromes, in whom it tends to present at an earlier age.

Pathogenesis

Ewing’s tumours consistently have reciprocal chromosomal translocations, usually between the EWS gene on chromosome 22 and FLI-1 on chromosome 11. In 85% of cases this is t(11;22)(q24;q12). Other variants place EWS with other genes such as t(21;22)(q22;q12) EWS-ERG translocation which occurs in up to 10%.

Unlike Ewing’s sarcomas there are no characteristic chromosomal translocations in osteosarcomas, although loss of heterozygosity in the regions of both the retinoblastoma gene and p53 have been described. A significant number of osteosarcomas express insulin-like growth factor receptor-1 (IGFR-1) which is being explored as a therapeutic target.

Clinical features

There are some features which are common to many types of bone tumour (Box 15.1).

Box 15.1
Clinical features seen in many types of bone tumour

• Localized bone pain, usually present for several months
• Pain at night or at rest
• In some cases localized swelling and overlying erythema
• Often a previous injury to the region has been noted and can result in delay in diagnosis

In advanced disease systemic symptoms may be present. These include

• fever
• weight loss and
• lethargy

Systemic symptoms occur more often in Ewing’s sarcoma than any other bone sarcoma. Ewing’s sarcomas which can have a significant soft tissue component may be mistaken for infection and can also occur in areas of long standing infection. These factors can also lead to significant delays which can impact on the prognosis and psychological impact for the patient.

Diagnosis

An X-ray of the affected area may be suggestive of a diagnosis but a diagnostic biopsy is required to make an accurate diagnosis and direct further treatment. A biopsy should only be performed by a specialist sarcoma surgeon who will take into account possible future surgery and will minimize the risks of tumour spread to the skin or adjacent structures. Fine needle biopsies are not suitable for primary diagnosis but can be used to confirm metastatic disease. The biopsy tract is often marked by clips to ensure it is removed at the time of definitive surgery.

Due to the consistency of chromosomal translocations in Ewing’s tumours these are used in diagnosis, either with cytogenetics, FISH or PCR.

Staging

Adequate staging includes optimal imaging of the primary site (MRI) and the entire bone to exclude intra-medullary skip metastases, which occur in osteosarcomas and Ewing’s tumours. A CT scan of the chest should be done to assess for possible pulmonary metastases. For PNETs arising in the lower half of the body a CT of the pelvis and abdomen can be considered as there may be lymph node involvement. A bone scintigram, or in some centres a CT-PET, will assess for bone metastases. A whole body MRI on STIR sequence has shown to be effective in detection of bone metastases which may not be visible with other forms of imaging, particularly in Ewing’s tumours. A bone marrow aspirate should be performed in patients with a Ewing’s tumour to exclude bone marrow involvement. Staging is according to the AJCC bone tumour staging (Table 15.1).

Table 15.1 AJCC 2002 TNM staging for primary bone tumours

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Patients should also undergo investigations which will be relevant to the further management of their individual sarcoma. LDH has prognostic value in Ewing’s tumours and ALP in osteosarcomas.

Principles of surgical management in bone tumours

Complete surgical resection of the tumour by specialist sarcoma orthopaedic surgeons is required for the best outcome. Surgery is the major component of management in chondrosarcomas but is also essential for local control in Ewing’s and osteosarcomas. Limb sparing surgery has evolved significantly in the past 30 years such that amputation is used less often and should be avoided if possible. Extending endoprostheses have also been developed to minimize the number of surgeries a growing child or young adult may require.

Osteosarcoma

Several subtypes of osteosarcoma exist. Over 90% are high-grade intramedullary tumours, half of which are osteoblastic and the other half are split equally between fibroblastic and chondroblastic osteosarcomas. The remaining 10% are made up of small subgroups including telangiectatic osteosarcoma, extraosseous osteosarcoma, juxtacortical osteosarcoma and malignant fibrous histiocytoma of bone which is treated in the same way as intramedullary osteosarcoma.

Figures 15.1 and 15.2 show imaging features of osteosarcoma. Box 15.2 shows prognostic factors in osteosarcoma. An overview of management is shown in Figure 15.3.

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Figure 15.1 Coronal MRI of pelvis and thighs showing osteosarcoma of the left acetabulum (arrow). Note the change in bone texture compared with the normal side.

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Figure 15.2 X-ray of left knee showing characteristic features of an osteosarcoma of the medial proximal tibia with bone destruction due to an expansile lesion (arrows) and periosteal elevation (arrow head).

(Courtesy of Mr Rob Grimer, Royal National Orthopaedic Hospital, Birmingham.)

Box 15.2
Factors predicting a poor prognosis

• Age <14 years or >40 years
• Poor response (<90% necrosis) to neoadjuvant chemotherapy
• Pathological fracture
• Large tumour volume, which is also associated with lung metastases
• Metastases at presentation with bone metastases having a worse prognosis than lung metastases
• Primary tumours which are axial or extraosseous. Secondary osteosarcoma
• Raised ALP or LDH
• Increased cadherin 11 expression

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Figure 15.3 Management of osteosarcoma.

Localized osteosarcoma

Localized osteosarcoma is treated with neoadjuvant chemotherapy followed by surgery (Figure 15.4) and adjuvant chemotherapy.

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Figure 15.4 X-ray of knee showing endoprosthetic replacement for osteosarcoma of the right tibia.

Chemotherapy

Prior to the 1980s all patients with apparently localized disease had surgery (usually amputation) but only 20–30% survived over 5 years. Most died of disseminated disease suggesting the presence of micrometastases in apparently early disease. A pivotal study showed that giving adjuvant chemotherapy improved survival from 17% to 66%, and neoadjuvant chemotherapy was subsequently implemented. The most frequently used drugs are cisplatin and doxorubicin. Methotrexate at doses up to 12 g/m2 is used in addition to cisplatin and doxorubicin in younger patients and has been found to increase tumour necrosis. The degree of tumour necrosis after neoadjuvant chemotherapy is of prognostic value. Less than 90% necrosis is associated with a poorer prognosis. Whether prognosis can be improved by changing chemotherapy after surgery is one of the roles of the international EURAMOS trial.

Recently a study with the bacterial cell wall mimic muramyl tripeptide (MTP) when added to combination chemotherapy showed an improvement in 6-year survival to 78% in primary osteosarcomas.

Radiotherapy

Radiotherapy is markedly inferior to surgical resection of the primary tumour for osteosarcomas in terms of overall survival but has been used in patients who decline or who are unable to have surgery.

Metastatic osteosarcoma

In one study 11.4% osteosarcoma patients had metastases at the time of presentation. Metastases can occur in the lungs, bone and bone marrow. Lymph node and brain metastases are exceptionally rare. Isolated pulmonary metastases have the best prognosis and bone metastases the worst prognosis. Overall survival at 5 years ranges from 10–50%. Up to 30% of patients with lung metastases survive over 10 years with a combination of surgery, combination chemotherapy and occasionally radiotherapy. Although the chance of cure is small, patients particularly with limited and potentially resectable lung metastases should be treated aggressively with chemotherapy and surgery.

Chemotherapy

As in the adjuvant setting, the most effective agents are cisplatin, doxorubicin, methotrexate and ifosfamide (Box 15.3). Response rates are between 20–40% although some tumours and metastases may not reduce in size. Apparent calcification of lung metastases can occur (Figure 15.5). If the presentation is with metastases, combination chemotherapy should be the primary treatment.

Box 15.3
Chemotherapy for metastatic osteosarcoma

• In younger patients: cisplatin, doxorubicin and methotrexate (PAM)
• In older patients the methotrexate is often omitted due to increased toxicity
• If the patient has relapsed with metastases within 1–2 years of original treatment, ifosfamide with or without etoposide can be effective
• High-dose methotrexate with folinic acid rescue can be effective if previously treatment was with cisplatin and doxorubicin alone

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Figure 15.5 Axial CT of chest showing pleurally based and calcified metastases characteristic of osteosarcoma (arrow). These lung metastases can bleed giving rise to bloody pleural effusions.

High-dose treatment with stem cell rescue has shown no improvement in survival. Trials are underway to evaluate biological agents such as insulin like growth factor 1 receptor (IGF1-R) antagonists. Immunotherapy may have a role and the use of liposomal muramyl tripeptide-phosphatidyl-ethanolamine has been shown to produce a survival benefit in the adjuvant setting.

Surgery

Surgery in the metastatic setting should either be aimed at palliation of symptoms, e.g. resection of a large primary extremity tumour with low volume lung metastases, or with the intention of cure, e.g. resection of lung metastases.

Radiotherapy

Although osteosarcomas are relatively radio resistant tumours, radiotherapy has been successfully used in a number of clinical situations such as to control bone pain. It has also been used in addition to chemotherapy and surgery, e.g. following resection of lung metastases some groups advocate whole lung radiotherapy in addition to chemotherapy. It may provide local control for some patients with advanced metastatic disease for whom resection of the primary is inappropriate.

Recurrent osteosarcoma

Approximately 40% of patients treated with a primary osteosarcoma will recur either locally or with metastatic disease. Management of local recurrence can involve chemotherapy, surgery or radiotherapy. Chemotherapy drugs are the same as those used for metastatic disease. Surgery may be possible but limb sparing surgery is less likely for local recurrence of extremity tumours. Radiotherapy may be useful for local control but is less effective than surgery.

Ewing’s sarcoma

Presentation

Unlike osteosarcomas which present most often in the epiphyses of long bones, Ewing’s sarcomas occur within the diaphysis and are often associated with a soft tissue mass. The soft tissue reaction may be confused for infection and contribute to delay in diagnosis. The median delay from symptoms (Box 15.1) to diagnosis is 6–9 months. The most common sites are long bones (53%) or the axial skeleton (47%). 25% have a soft tissue primary. Systemic symptoms (fever, anorexia, weight loss, and lethargy) may be present and are associated with advanced disease. 25% patients have metastases at presentation. Subclinical metastases are present in 80–90% with apparently localized disease, necessitating multimodality treatment even in apparently small volume localized disease. Prognostic factors are listed in Box 15.4.

Box 15.4
Poor prognostic factors in Ewing’s sarcoma

• Age over 14 years
• Metastases at presentation (especially non-pulmonary metastases)
• Pelvic or axial primary site
• Size greater than 8 cm
• Raised LDH

X-ray may show a characteristic destructive lesion within the bone with surrounding periosteal reaction known as an onion skin appearance (Figure 15.6). A soft tissue reaction may also be seen on X-ray and a pathological fracture is seen in 15%. Ewing’s sarcomas, like osteosarcomas, show intense tracer uptake in bone scan (Figure 15.7). Staging is given in Table 15.1 and Figure 15.8 shows an overview of management.

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Figure 15.6 X-ray of Ewing’s sarcoma of right proximal femur with destructive lesion and onion skin appearance of periosteal reaction.

Courtesy of Mr Rob Grimer.

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Figure 15.7 Bone scintigram of Ewing’s sarcoma of left proximal radius showing localized uptake at the site of the tumour.

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Figure 15.8 Management of Ewing’s sarcomas (VIDE – vincristine, ifosfamide, doxorubicin & etoposide; VAI – vincristine, actinomycin-D & ifosfamide; VAC – vincristine, actinomycin-D & cyclophosphamide).

Management of localized disease

Chemotherapy

Combination chemotherapy is usually given pre- and postoperatively. Alkylating agents have the highest response rate and have been combined with doxorubicin, vincristine, actinomycin D and etoposide. Trials such as IESS-III showed that alternating ifosfamide and etoposide with vincristine, doxorubicin and cyclophosphamide (VAC) improved survival from 54 to 69% in localized disease. High-dose treatment in localized low-risk disease has not been shown to improve survival. Response to chemotherapy at the time of surgery reflects prognosis.

Stratifying treatment according to risk is under investigation in the EUROEWING99 trial (Figure 15.9). Low-risk patients are randomized between standard treatment and less intense treatment. High-risk/metastatic patients are randomized between standard treatment and high-dose with stem cell rescue.

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Figure 15.9 Management of Ewing’s sarcoma Euro Ewing 99 Protocol.

Surgery

Surgery is performed if possible after neoadjuvant chemotherapy to assess response and reduce risk of relapse. Pelvic tumours are the most difficult to resect, especially if they involve the sacrum, due to the risk of sacral nerve involvement.

Radiotherapy

Unlike osteosarcomas, Ewing’s tumours are radiosensitive and, radiotherapy used to be the principle method of achieving disease control. Studies have shown radiotherapy without surgery has a worse outcome than surgery for local control but there may be some selection bias. However, radiotherapy still remains a primary method of local control in unresectable tumours when doses of 45–55 Gy have been used (Box 15.5).

Box 15.5
Radiotherapy in sarcomas

Indications

• Radical radiotherapy – inoperable Ewing’s sarcoma
• Postoperative adjuvant – deep, >5 cm or high-grade soft tissue sarcoma. Positive margins and further surgery is not contemplated. Local recurrence after a repeated resection
• Preoperative – soft tissue sarcoma and Ewing’s sarcoma progress during chemotherapy
• Palliative radiotherapy
• Whole lung radiotherapy – Ewing’s sarcoma with lung metastases and good response to chemotherapy
Position & immobilization – depends on site of tumour
Tumour localization – with CT scan or co-registered CT/MRI

Clinical target volume

• Ewing’s sarcoma:

• Long bones – pre-treatment tumour with 5 cm margin superoinferior and 2 cm axial for phase 1 and 2 cm margin for phase II. Whole bone if extensive intramedullary involvement with sparing of epiphyseal plate
• Flat bones and soft tissue – pre-treatment tumour with 2 cm circumferential
• Pelvis and chest wall – post-chemotherapy residual volume in areas of non-infiltrative tumour near critical organs with 2 cm margin

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