The management of soft tissue sarcomas

Article Outline

• Abstract
• Introduction
• Aetiology
• Specialist sarcoma surgery in the UK
• Delays in referral
• The cardinal signs of malignancy
• The anatomy of a soft tissue tumour
• Investigations
  • Plain X-ray
  • MRI
  • Chest X-ray
  • Biopsy
• Histology and grading
• Surgery
  • Excision margins
• Soft tissue tumours in specific locations
  • Soft tissue sarcomas in the extremities
  • Pelvic tumours
  • Hand tumours
  • Retroperitoneal tumours
  • Metastatic disease in sarcoma
• Plastic surgery
• Adjuvant therapy
• Radiotherapy
• Chemotherapy
• Prognosis
• Local recurrence44,45
• Bony spread
• Lung metastases
• The future
• Funding sources
• Conflict of interest
• References
• Copyright

Abstract 

Background

Soft tissue sarcomas are a rare and heterogeneous group of malignancies that are derived from the mesenchymal cell lines. In the last few decades, the management of these lesions has been improved by the introduction of dedicated Multi Disciplinary Teams (MDTs) where most bone and soft tissue tumours are now treated.¹

Following the recent changes to management outlined by the NICE/IOGs, we believe it is pertinent to review the current thinking on soft tissue tumour management.² We also discuss the principles of diagnosis and treatment and the role of adjuvant therapy.

Methods

This is a retrospective review. In the preparation of this paper, we have referred to recent NICE guidelines in this field and have performed a Medline search of the existing literature.

Results

The key to success is early and appropriate patient referral. Whilst the responsibility for performing surgery has shifted away from the generalist and towards the super-specialist, improvements in survivability can be achieved by promoting basic knowledge within the medical profession as a whole.

Conclusions

Both excision and biopsy of a soft tissue sarcoma by a non-specialist surgeon have been shown to increase the risk of tumour recurrence and all invasive procedures should now be performed within the MDT setting.

Keywords: Soft tissue sarcoma, Diagnosis, Management, Tertiary referral centre

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Introduction 

Like many rare conditions, the management of soft tissue tumours is often misjudged. The incidence of soft tissue sarcomas has been estimated at around 1000 cases per year in the UK with the more solid, bone tumour-style sarcomas accounting for an additional 400 cases. Bone and soft tissue sarcomas combined represent less than 1% of all malignant tumours.³, ⁴ Soft tissue sarcomas can occur at any age but the incidence peak is in late adult life.⁵ Even in specialist units, the scale of the case load is often so low that many published papers lack real statistical power. Since many cases may be misdiagnosed, it is likely that the true incidence is higher than the figures quoted here.¹

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Aetiology 

The aetiology of soft tissue sarcoma is not understood. Some subtypes are known to be associated with single gene defects;⁶, ⁷, ⁸ for example, in neurofibromatosis,⁶ the lifetime risk of developing a malignant peripheral nerve sheath tumour is 10%. However, most forms of soft tissue sarcoma have no obvious cause or association. Claims that soft tissue sarcomas are more common adjacent to metal and plastic implants are largely unfounded.⁹, ¹⁰

Histologically, sarcomas are a heterogeneous group of tumours occurring in multiple locations. To date, 50 subtypes have now been identified.¹ They may be derived from almost any other tissue of mesodermal origin.

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Specialist sarcoma surgery in the UK 

In this paper, we concentrate mostly on soft tissue tumours in the limbs and the wall of the trunk. Since the introduction of the NICE Improving Outcomes Guidelines in 2006 the surgical treatment of these tumors has been concentrated into specialist units treating greater then 100 new cases per year.² This permits the concentration of surgical expertise within a specialist multidisciplinary team involving oncologists, pathologists, radiologists and specialist nurses. These specialist centres often have to work with peripheral diagnostic teams and oncology teams to allow investigation and prolonged oncological treatments to be undertaken locally to the patient's home when the specialist centre is many miles away.

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Delays in referral 

Although the management of soft tissue tumours is improving, a significant number of patients continue to suffer unnecessary morbidity and mortality.

One recent study showed that the average delay to presentation in a specialist centre was 110 weeks. In contrast, the average delay between experiencing symptoms and consulting a doctor was 24 weeks. This means that around ¾ of the delay in arrival in the specialist centre occurred after the patient first consulted their doctor.¹¹ The stumbling block here is in our ability to identify something that is exotic amidst the mundane and the ordinary.

It is, however, unrealistic for all soft tissue lesions to be dealt with by a tertiary referral unit as only about 1 in 200 soft tissue lumps represent a primary malignancy. Given that the non-specialist is unlikely to see more than one soft tissue sarcoma in their career, it is important to have a clear idea as to what constitutes a sinister lump (See Box 1 and Box 2).

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The cardinal signs of malignancy 

There are 4 cardinal signs that should make us suspicious of malignant change in a soft tissue lump.¹²

If a lump displays all 4 of the cardinal signs listed above then there is an 86% chance of malignancy.¹² In addition, an irregular soft tissue lesion that recurs after initial excision should be regarded as malignant until proven otherwise.

Lumps that are superficial, less than 5 cm in diameter and exhibiting static growth are highly unlikely to be malignant.

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The anatomy of a soft tissue tumour 

Soft tissue tumours exhibit centripetal growth and gradually surround themselves with a pseudo capsule and a still more peripheral reactive zone. Although the bulk of the tumour is contained within the pseudo capsule there are usually some viable tumour cells in the reactive zone and ideally these should be removed at the time of initial resection. Local spread of the tumour is along anatomical planes and within the compartment. In the extremities, the deep fascia is an effective barrier to tumour spread.

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Investigations 

Radiological investigations of the tumour site are best performed before biopsy and surgery since post-operative oedema and bleeding will distort the images.

Plain X-ray 

Plain X-ray is useful as an initial screening test to exclude solid bone tumour and to look for calcification within the soft tissue tumour.

MRI 

MRI has emerged as the preferred technique for evaluating soft tissue tumours (Fig. 3).¹³ It is however, unable to distinguish calcified from non-calcified tumours. MRI angiography reveals better detail in vascular tumours.

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• Fig.3. 

  MRI. Soft tissue sarcoma in the anteriorfascial compartment of the thigh. This is one of the most common locations for STS and the extensive surrounding muscle allows wide excision without compromising neurovascular structures.

Datir et al. reviewed MRI scans on soft tissue lumps and confirmed the previous findings.¹⁴ In this study, a lesion that was deep to the deep fascia was of limited prognostic importance. The mean age for benign lesions was 40 years, with the mean age for malignant lesions being 54 years.

Soler et al. also reported good results for MRI distinguishing between benign and malignant soft tissue tumours.¹⁵

CT is useful for distinguishing calcified lesions. It is also useful for patients who are unable to use an MRI scanner.

PET is useful for metabolic imaging. However, PET provides information on a tumour based on its metabolic rate. It is sensitive to secondaries but has a poor pick up on stromal tumours.

Ultrasound is generally regarded as a non-invasive investigation. It is useful for distinguishing cystic from non-cystic lesions and is relatively low cost. It is also used for ultrasound guided biopsies. It is not, however, a first line investigation.¹

Chest X-ray 

Soft tissue sarcoma patients are usually screened in follow up clinic with a plain chest X-ray. Chest X-ray alone will pick up 2/3 of lung metastases. About 10% of soft tissue sarcoma patients have metastases at the time of presentation to a tertiary referral unit and 8 out of 10 of these are in the lung.¹⁶

Biopsy 

After referral to a specialist centre, the lesion may be biopsied to confirm diagnosis.¹, ² It is common for sarcoma cells to be seeded along the biopsy tract causing local spread at the time of biopsy. For this reason, the biopsy tract should not transgress adjacent fascial compartments. The specialist surgeon performs the biopsy where he intends to perform later, definitive incision. Should the histology report show evidence of malignancy the biopsy tract itself, including an area of skin is then excised en bloc along with the primary tumour (Fig. 1).

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• Fig.1. 

  A malignant liposarcoma. Large, recurrent (there is a scar of previous excision) and nodular.

The tumour is then labelled with sutures (Medial, Superior), thus enabling the pathologist to orientate on the specimen (Fig. 2).

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• Fig.2. 

  An excised malignant rhabdomyosarcoma from a child’s anterior thigh. This is by far the most common malignant soft tissue tumour in children. Medial and Superior sutures label the specimen for orientation and the skin surrounding the earlier biopsy site has been excised en bloc with the main tumour.

If microscopy shows evidence of tumour in the margins of the specimen then the surgeon can be advised to re-explore the region to excise more tissue at the appropriate site.

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Histology and grading 

Histology on the biopsy specimens confirms the diagnosis and enables us to grade the tumour. Grading is useful for research purposes, for planning the definitive surgical procedures and for making informed judgements about prognosis.

The tumour cells can be assigned to one of three grades: high, medium or low. Histological grade is the single most important determinate of metastatic risk and disease-free survival. Tumour grade is also a good prognostic indicator for local recurrence. The most commonly used system in the UK is Trojani.¹⁷

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Surgery 

Excision margins 

The basis of good treatment is to surgically excise the tumour with a surrounding cuff of tissue that is histologically free of tumour cells. Such a specimen is said to have negative margins.

The importance of obtaining negative margins was described by Simon and Enneking.¹⁸ In a landmark paper in 1976 2% local recurrence occured with adequate tissue margins and 100% local recurrence with positive resection margins.

Specialists recognise 4 levels of excision.¹, ², ¹⁸

In cases where the nature of the pathology has not been recognised, most patients have in effect, received an intra-lesional excision and the recurrence rate here approaches 100%. At the opposite extreme, radical excision may be associated with considerable loss of function in the limb. However, the most important predictive factor for local recurrence of a soft tissue sarcoma remains the existence of positive surgical margins.¹⁹

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Soft tissue tumours in specific locations 

Soft tissue sarcomas can occur at almost any site (see Box 3).

The extremities are the most common location for a soft tissue sarcoma, accounting for 59% of cases. The trunk accounts for 19% of cases, the retro-peritoneum 15% and the head and neck 9%. In the extremities, the lower limbs are more commonly affected than the upper with the anterior thigh being a particularly common site.¹, ²⁰

Soft tissue sarcomas in the extremities 

Given the importance of radical excision, amputation would appear to be an attractive treatment for a tumour of the extremities. However, the transition to limb salvage has been achieved through a better understanding of the natural history of the disease and improved plastic surgical techniques. If we compare the results of amputation with limb salvage surgery we see that there is no longer any difference in distant metastasis or in the duration of disease-free survival. Limb salvage continues to be associated with a slightly higher risk of local recurrence.²¹, ²²

Amputations are, however, still performed. The surgeon must discuss with the patient the relative benefits of limb salvage versus amputation. It must be remembered that below-knee amputation in a motivated and otherwise fit young adult is associated with a remarkably good functional result. Similarly, a procedure that requires the excision of the sciatic nerve is no longer regarded as an automatic indication for amputation since limb function without this nerve is often acceptable.²³

Working in New York, Gadd²⁴ noted that soft tissue sarcomas occurring in the lower limb have a worse prognosis than those occurring in the upper limb. In this study, the median survival after an adequate margins resection was 19 months; inadequate resection, 10 months; and no operation, 8 months (p = 0.005). The 3-year survival rate after adequate resection was 23%, compared with a 2% rate (1 of 57) in those treated non-surgically (p < 0.001). These sobering statistics remind us that the best results are achieved by early excision through adequate margins.

Pelvic tumours 

As in other regions, inadequate margins following excisions are associated with poor prognosis and it can be difficult to achieve clear margins in this part of the body. Tumours deep to the pelvic brim do very badly (35% survival at 5 years).²⁵

Hand tumours 

The hand is an unusual location for soft tissue sarcomas with only 2% of cases occurring here.

The most common soft tissue lump of any kind in the hand and wrist is a ganglion and these are characterised by fluctuation in size and their ability to trans-illuminate. If a soft tissue lump in the hand does not trans-illuminate then the chances of that lump being sinister increase dramatically. Unfortunately, soft tissue sarcomas in the hand tend to have a worse prognosis than other soft tissue sarcomas. Tumour cells spread between compartments very easily. Clear tissue margins are essential to a good prognosis. Amputation gives better soft tissue margins and a better prognosis than limb salvage. Radiotherapy does little to improve prognosis.²⁶

Retroperitoneal tumours 

Retroperitoneal sarcomas have a particularly bleak prognosis. The anatomy of the abdomen provides ample room for expansion and by the time of presentation, these tumours are often large and in direct contact with critical structures. Local recurrence is common with a disappointing response to adjuvant therapy.²⁷

Metastatic disease in sarcoma 

Medical schools have long emphasised the importance of checking regional lymph nodes in the assessment of malignancy. It is unusual for the lymph nodes to be involved in sarcoma. When lymph nodes are enlarged they are usually reactive. However, tumour spread to the lymph nodes has been reported as 3.6% (between 1.6 and 8.2%) and when present the prognosis is comparable to a high grade sarcoma with no metastases.²⁸

Sarcomatous tumours usually metastasise by haematogenous spread with the lungs being the most common destination for secondaries.

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Plastic surgery 

Wound closure can be difficult in sarcoma surgery, especially where adjuvant radiotherapy has been used and wounds have been closed under tension. The early involvement of a plastic surgeon reduces wound complications and improves outcome, including wound complication rates.²⁹

The modern surgical techniques in plastic surgery and microsurgery (i.e. pedicled flaps and free microsurgical flaps), allow a resecting surgeon to perform wide and radical resections whilst still covering deep structures (nerves, vessels, bones and tendons), thus preserving overall acceptable functionality of the limb.

Another useful tool, in selected cases, is the VAC (Vacuum Assisted Closure) Therapy. It can facilitate the wound healing, providing that the histology had confirmed the absence of involved margins.

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Adjuvant therapy 

Malignant neoplasms are usually treated by surgical resection. Controversy exists regarding the use of adjuvant therapy.

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Radiotherapy 

Radiotherapy can be delivered by external beam (DXT) or by brachytherapy. In brachytherapy, a radioactive source is implanted in the centre of the tumour in order to deliver the ionising radiation from within. However, brachytherapy is largely confined to very specific cases and for the most part, radiotherapy in sarcoma is delivered by external beam.

There is controversy surrounding the timing of external beam radiotherapy. Essentially, radiotherapy can be delivered before, during or after surgery.

In the UK, most soft tissue sarcomas are treated with post-operative radiotherapy although this does require a slightly higher radiation dose, typically 66 Gy with post-operative treatment versus 50 Gy with pre-operative radiotherapy.¹

There is some evidence that pre-operative radiation should be used for very large tumours where full surgical resection may be difficult to achieve.³⁰, ³¹

The principal side effect of DXT in sarcoma surgery is wound complication. When external beam radiation is applied to soft tissue sarcomas in the limbs, the lower limb is associated with a significantly higher wound complication rate. Data from the Canadian sarcoma group appears to support the use of pre-operative radiation for the treatment of soft tissue sarcoma although overall patient survival is little affected by timing of the DXT.³², ³³ These authors also recognised that large tumour size was a risk factor for wound complication. It would appear that pre-operative radiation causes more early (but reversible) wound complications and that post-operative radiation causes more late (persisting) wound complications, in part perhaps because of the increased radiation dose and field size required in post-op DXT.

Given the additional cost and morbidity of adjuvant therapy, it would be advantageous to be able to identify a subset of patients for whom surgical resection alone would give equal results and it is likely that such a subset does exist.

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Chemotherapy 

The benefits of chemotherapy in sarcoma management remain uncertain. There is some evidence that it can reduce rates of local recurrence and metastasis in STS patients³⁵, ³⁶, ³⁷, ³⁸ although this remains controversial.

As with radiotherapy, surgeons have looked for cohorts of patients who might be viably treated by surgery alone, thus avoiding the cost and side effects of chemo- and radiotherapy. Similarly grade, tumour depth, and tumour size could be used to select patients with a high metastatic risk, for which adjuvant chemotherapy could be beneficial.³⁹

More recent trials of chemotherapy have used drugs to stimulate bone marrow to overcome bone marrow suppression and allow higher doses of the chemotherapeutic agent.⁴⁰

In a large scale review of 508 patients with mixed soft tissue tumours, Gufstason observed that tumour size as well as tumour necrosis and vascular invasion were strong and reliable factors to predict metastases. This observation varied with the nature of the tumour. For example, in liposarcoma, only tumour necrosis and in synovial sarcoma, only tumour size had any bearing on the risk of metastases. The crude local recurrence rate in this series was 30%.⁴¹

Chemotherapy is controversial but probably contributes to patient survival and reduces local recurrence.⁴²

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Prognosis 

Soft tissue sarcomas are a heterogeneous group of tumours (Box 4) and the prognosis varies considerably between different histological types.

Overall survival in soft tissue sarcoma is 50–60% at 5 years. Five key prognostic factors appear to determine outcome.

Of these factors, histological grade is the single most important for determining the risk of metastases and the chances of disease free survival.⁴³

The clinician can do little to influence tumour depth, patient age or grade of histology. However, earlier and more appropriate referral ought to reduce tumour size at time of presentation.

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Local recurrence⁴⁴, ⁴⁵ 

About 30% of soft tissue sarcomas recur after excision, most of them early although late recurrence has been recognised, especially in the extremities. When recurrence is treated by surgical excision, the risk of subsequent recurrence is about the same as in the primary procedure. Local recurrence in itself appears to be a separate outcome variable from survival with the link – if any – between the two phenomena being high histological grade of a more aggressive tumour.

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Bony spread 

Osseous invasion by soft tissue sarcoma is rare.⁴⁶

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Lung metastases 

Low grade STS develops metastases in 15% or more of cases with this figure rising to 40% for high grade tumours. Median survival with metastases is 16 months.

The risk of metastases is highest in the first 2 years. Most secondaries occur in the lung and it is routine to perform an erect chest X-ray on STS patients at follow up. Attempts have been made to surgically resect lung metastases with mixed results.⁴⁷

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The future 

Progress in the field of soft tissue sarcoma management awaits a fundamental breakthrough in adjuvant therapy. Until that time, we could significantly reduce the morbidity and mortality causes by soft tissue sarcomas by early and appropriate referral.

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Funding sources 

None.

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Conflict of interest 

This is an academic review article. No payments of any kind or sponsorship to any of the authors.

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