Diagnosis and management of soft tissue sarcoma

Ultrasound

A prospective cohort study of 358 patients with soft tissue masses showed that ultrasound can rapidly triage benign and more suspicious lesions.14 If clinical suspicion of malignancy exists but referral criteria are not met, an urgent ultrasound can help decide how fast to refer. But for lesions with a high degree of clinical suspicion, do not delay immediate referral to a specialist centre by imaging requests. Ultrasound guided biopsy of the lesion within a specialist centre helps avoid specific anatomical structures and ensures biopsy of viable rather than necrotic tumour tissue.

Plain radiography

For lumps that arise in extremities plain radiography can rule out a mass that arises from bone. Certain soft tissue sarcomas, and synovial sarcoma, may show characteristic calcification.

Computed tomography and magnetic resonance imaging

Magnetic resonance imaging is the preferred method of initial imaging for soft tissue sarcoma of the extremities, trunk, and head and neck in most specialist centres. Computed tomography is the gold standard for preoperative staging and is commonly used to assess intra-abdominal masses. Debate about which of the two modalities is superior continues. A multicentre trial, which included 133 evaluable soft tissue sarcomas and correlated radiological findings with histological and intraoperative findings found no statistically significant difference between the two modalities for efficacy of local staging of soft tissue sarcomas of the extremities.15 Small comparative studies have suggested that magnetic resonance imaging may be slightly better than computed tomography because it provides multiplanar images with better spatial orientation.^{w21 w22}. UK consensus guidelines state that high resolution computed tomography has a role in the identification of bony involvement and preoperative assessment to exclude pulmonary metastases.12 The role of routine positron emission computed tomography scanning for diagnosis and monitoring of soft tissue sarcoma is currently unknown.^w23

Biopsy

A histological diagnosis is needed to guide treatment planning. Core needle biopsy is the standard approach to diagnosing suspicious lesions, and open incision biopsy, with its high complication rate (12-17%) and association with a more radical resection, is no longer recommended.16 Several cores are needed to improve diagnostic accuracy. Single centre prospective and retrospective studies have shown that core needle biopsy has a diagnostic sensitivity of 90-95%; it is quicker than open biopsy, cheaper, and morbidity is lower.^w24-w26 A single centre study of 530 patients found a sensitivity of 96.3% in differentiating soft tissue sarcomas from benign tumours, with a complication rate of 0.4%.^w27 Ultrasound and computed tomography guided biopsies are used when the tumour is difficult to palpate or necrotic. In the rare instance that open biopsy is needed it should be undertaken in a specialist centre.

Fine needle aspiration is not recommended in the initial diagnostic evaluation of a suspicious mass. A review of five studies found that this technique had a lower diagnostic accuracy than core biopsy. It may have a role in confirming disease recurrence.17

NICE guidelines recommend that biopsy results should be interpreted by a specialist sarcoma pathologist in close conjunction with a surgeon and radiologist.2 Although histological diagnosis is the gold standard, newer methods such as cytogenetics and immunocytochemistry can aid diagnosis by identifying tumour lineage.^w28

Stage and grade of tumour

Information on tumour stage can help estimate prognosis and survival and plan management. Several systems are used to stage soft tissue sarcoma. The most widely accepted are those from the American Joint Committee on Cancer (AJCC) (table 2⇓) and International Union against Cancer (IUCC) (table 3⇓), which include information on both tumour grade and stage. The Musculoskeletal Tumour Society staging system (table 4⇓) also takes into account whether the tumour is intracompartmental or extracompartmental and presence of regional and distant metastases.

Tumour grade is related to prognosis. A commonly adopted system in the UK is the Trojani system, which incorporates information on degree of cellular differentiation, tumour necrosis, and mitotic count.^w29 High grade tumours are poorly differentiated or undifferentiated; they carry a high likelihood of metastasis and poor patient survival. A study of 1240 patients from a national database found that tumour grade was the most important prognostic factor in metastatic recurrence.18

A recent systematic review found an overall five year survival for patients with soft tissue sarcoma of 60-80%.19 A study of 2136 prospectively followed patients estimated sarcoma specific death to be 36% after 12 years.20 In the largest population based study assessing survival in patients with soft tissue sarcoma of the extremities, advanced age, large tumour size, and high grade all contributed to adverse prognosis and increased 10 year sarcoma specific mortality.^w30 This agrees with other population based studies^w31 and a large single centre study,21 both of which found metastatic disease at presentation and tumour depth to be adverse prognostic indicators.

Histological subtype

Several single centre studies have shown that histological subtype may help predict prognosis.^w32-w34 A recent retrospective analysis of 17 364 patients from a population based study showed that within a tumour grade, survival differed according to histological type, but small numbers in some histological groups limited interpretation of the findings.^w34 Advances in genetic diagnosis and in the ability to predict the behaviour of certain histological subtypes of tumour may affect treatment planning and staging in the future.

Surgery

Surgery is the mainstay of treatment in patients with localised disease. It aims to excise the soft tissue sarcoma completely, along with a biological barrier of normal tissue. Table 5⇓ summarises the four categories of surgical margin that have been described histologically.22 No international consensus exists on what constitutes an acceptable resection margin. Limb salvage surgery, which aims to retain a functional limb (to maintain a good postoperative quality of life) while providing an acceptable resection margin (to ensure a low risk of recurrence), is the standard of care for most patients with soft tissue sarcoma of the extremities. UK consensus guidelines state that 1 cm of normal soft tissue or equivalent (for example, fascia) is an acceptable margin.12 Single centre retrospective case series have shown that positive margins carry an increased risk of disease recurrence and reduced disease specific survival.21 In a retrospective study of 248 patients, those with wide surgical margins or margins greater than 2 mm had a five year survival of around 70% compared with 47% in those with positive margins or margins less than 2 mm.^w35 A tumour’s proximity to important anatomical structures such as nerves and blood vessels can make it difficult to achieve an acceptable tumour-free margin.

Improved adjuvant radiotherapy and reconstructive surgery have enabled more limited surgery to be performed and function to be preserved. The surgical objective of maintaining a functional limb may require a planned microscopic positive margin and adjuvant radiotherapy. A seminal prospective study showed that less radical surgery had no detrimental effect on overall survival but was associated with a higher rate of local recurrence compared with amputation.23 When considering more limited surgery make patients aware of the risks of tumour recurrence and the possibility of further surgery, including potential amputation.

Advances in reconstructive techniques have enabled limb preservation in complex cases in the form of pedicled and free tissue transfers (figure⇓). Several single centre studies have shown that surgical flaps can successfully achieve wound closure, minimise surgical dead space, shorten the duration of wound healing, and protect vital structures (blood vessels, nerves, tendons, and joints).^w36-w38 A recent review showed that reconstructive techniques are cost effective.^w39

(A) Defect after excision of buttock soft tissue sarcoma. (B) Raising of a pedicled flap. (C) Reconstruction of sarcoma excision with flap

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Early complications of surgery may include haemorrhage, wound infection, and deep venous thrombosis. Although, microvascular free flap reconstructions have a success rate of greater than 95%, they can fail or experience wound breakdown, which can delay subsequent planned adjuvant treatment. The patient must be told about the risks of these complications before surgery.

European Society of Medical Oncology guidance states that treatment by wide excision surgery is sufficient for low grade tumours that are superficial or deep and less than 5 cm, in addition to high grade superficial tumours.11 Single centre retrospective case series have shown that surgery alone is suitable for selected patients with soft tissue sarcoma, with one series reporting 10 year outcomes of 93% for local control and 73% for overall survival.^{w40 w41} In one prospective trial of patients with T1 tumours and negative surgical margins treated by surgery alone the five and 10 year estimated recurrence rates were 14% (standard deviation 4%) and 16.2% (4.45%), respectively, with an estimated sarcoma specific death rate of 3.2% (2.2%) at 10 years.24

In advanced disease, surgery may be an appropriate palliative procedure. A single centre study found amputation rates of 9-14% in patients with recurrent soft tissue sarcoma of the extremities and less than 5% in those with primary disease. ^{w42 w43} Amputation may be recommended when limb salvage surgery is not possible, after careful discussion with the patient regarding surgical morbidity compared with the pros and cons of other palliative treatment options. Typically such patients have high grade, large, recurrent tumours that often affect anatomically important sites. They are likely to have poor long term survival, and the need to relieve local symptoms such as pain or fungation may outweigh negative factors associated with amputation.

A surgical and reconstructive procedure can take up to 12 hours. A small single centre study assessing the cost effectiveness of limb reconstruction found that the mean length of stay was eight days and 6.6 days for procedures involving upper and lower extremities, respectively.^w39 The duration of postoperative rehabilitation will vary from patient to patient and according to the type of surgery. This will require intensive specialist nursing, physiotherapy, and occupational therapy.

A single centre prospective study found that the preoperative expectations of patients influenced functional outcome—uncertain expectations were associated with worse functional outcomes.^w44 This finding stresses the importance of clear preoperative communication with patients regarding the often long and difficult rehabilitative process and functional limitations that they may experience.

Radiotherapy

Prospective and retrospective studies have shown that radiotherapy improves local control in surgically resectable disease.25 ^{w45 w46} Most intermediate or high grade soft tissue sarcomas, large deep low grade sarcomas, and incompletely resected tumours that are close to important structures (such as nerves and blood vessels) are candidates for radiotherapy.11 12 The optimum timing of radiotherapy for soft tissue sarcoma of the extremities is unclear. In the UK and other countries, postoperative radiotherapy is the standard approach. Preoperative radiotherapy can reduce the size of some radiosensitive tumours, such as myxoid liposarcoma. A recent systematic review and meta-analysis of five studies that compared preoperative and postoperative radiotherapy in localised resectable soft tissue sarcoma found a lower risk of recurrence in the preoperative radiotherapy group (odds ratio 0.61, 0.42 to 0.89). However, no overall survival benefit was seen.26 A multicentre, prospective randomised study of 190 patients found an increased incidence of wound complications in those receiving preoperative radiotherapy (35% v 17%), but this risk was negated when reconstruction involved imported vascularised tissue.25 A randomised phase III trial showed that the timing of radiotherapy had little effect on postoperative function.27 Further prospective randomised controlled trials are needed to evaluate the role of preoperative radiotherapy. Single centre studies have shown that the complications associated with postoperative radiotherapy include joint stiffness, oedema, and pathological fractures. Five to 10 year local control rates for postoperative radiotherapy range from 82% to 87%.^{w45 w47}

The results of the VORTEX randomised controlled trial comparing a single phase of radiotherapy with the standard two phase technique in patients with soft tissue sarcoma of the extremities with the aim of improving postoperative function are awaited.^w48 Other technological advances, including brachytherapy, where radioactive seeds or wires are placed into the tumour bed after tumour resection, and intensity modulated radiotherapy (a method of delivering radiotherapy to protect the soft tissues needed to achieve wound closure) do not yet have a convincing evidence base.^w49

Chemotherapy

The role of adjuvant chemotherapy in the management of soft tissue sarcoma of the extremities is controversial because the evidence for its use is conflicting. Different histological subtypes vary greatly in chemosensitivity—for example, myxoid liposarcomas are more chemosensitive than some other types. UK consensus guidelines do not advocate chemotherapy as standard management.12 The use of adjuvant chemotherapy may be considered in specific cases of advanced disease with palliative intent.

Doxorubicin based regimens are the first line drug for most histological subtypes. A large meta-analysis including data from 14 randomised phase III controlled trials showed that adjuvant doxorubicin chemotherapy improved 10 year survival by 7% (P=0.029) compared with no chemotherapy in high risk patients with localised disease.28 A more recent meta-analysis that included data from the Italian sarcoma group trial supported these findings.^w50 It found a significant increase in overall survival with adjuvant chemotherapy and that the addition of ifosfamide significantly improved survival.29 Interestingly, the EORTC trial, which is the largest trial of adjuvant chemotherapy for soft tissue sarcoma, found no improvement in overall survival.30 Future trials should include homogeneous groups of tumours (of specific histological and molecular subtypes) and patients. There is no recognised second line chemotherapy after failure of doxorubicin and ifosfamide. Most data on newer agents include phase II trials, and as knowledge about the molecular profile of tumours increases, tailored novel agents may emerge.

Several single centre studies and a multicentre phase II trial have suggested that neoadjuvant chemotherapy may be appropriate for patients who have large and high grade tumours (typically synovial sarcoma and liposarcoma) to shrink the tumour before palliative surgery.31 ^{w51 w52} A randomised phase III trial has shown that regional hyperthermia (heat kills cells by direct thermal toxicity and increases drug efficacy) reduces local progression and death in high risk patients.^w53 Studies in lower risk patients are needed.

Isolated limb perfusion

Isolated limb perfusion is used to treat melanoma. It is widely used in Europe to treat soft tissue sarcoma of the extremities, but it is available in only a few centres in the UK. High concentrations of tumour necrosis factor and melphalan (a chemotherapeutic agent) are delivered under hyperthermic conditions via arterial and venous cannula to a limb isolated by tourniquet compression. This treatment can be used to reduce tumour size to enable limb salvage procedures, or for palliative treatment. Single and multicentre studies of this technique have shown limb salvage rates of 74-87% in selected patients with intermediate or high grade disease.^{w54 w55}