Soft tissue sarcomas are a rare and heterogeneous group of tumors representing less than 1% of all adult malignancies. The extremities are the commonest site with about 60% of soft-tissue sarcomas arising in the extremities. Other localisations are the trunk (19%), the retroperitoneum (15%), or the head and neck (9%).1 Due to their uncommon nature most clinicians and pathologists have limited experience with the extensive variability in clinical and histopathological presentation of these tumors and their complex multimodality treatment.2
Musculoskeletal oncology is one of the newer developing subspecialties in the country. The developments in the last few years have greatly improved not only the local management of these lesions with limb salvage being the norm rather than the exception but have also seen increased patient survival. In spite of these exciting advances the paucity of exposure to these tumors results in most surgeons approaching them with trepidation and uncertainty.
Approximately half of all patients with intermediate or high-grade soft-tissue sarcomas develop metastatic disease and the overall survival is approximately 50% at 5 years.3 Multidisciplinary management of these tumors is the key to providing the optimal therapeutic approach.2 This article outlines the current concepts and principles of multimodality management of these challenging lesions.
Principles of management:
Though in most patients, no specific etiology can be identified, the risk factors for soft-tissue sarcomas include previous radiation therapy, exposure to chemicals (e.g., vinyl chloride, arsenic), immunodeficiency, prior injury (scars, burns), chronic tissue irritation (foreign-body implants, lymphedema), neurofibromatosis and certain germ line mutations like Li-Fraumeni syndrome (p53 mutations). 1
The presenting symptoms and signs of soft-tissue sarcomas are nonspecific. They commonly present as a painless, slow-growing mass. While sarcomas in the extremities may present earlier, diagnosis of sarcomas involving the pelvic cavity may be delayed. Their location deep within the body precludes palpation of the tumor mass early in the course of the disease. Consequently, these tumors often reach tremendous size prior to diagnosis without causing overt symptoms. Any soft tissue lump exhibiting any of the following four clinical features should be considered to be malignant until proved otherwise : (i) increasing in size, (ii) size >5 cm, (iii) deep to the deep fascia, (iv) painful. The more of these clinical features present, the greater the risk of malignancy with increasing size being the best individual indicator.3
It is best to complete all local imaging preceding a biopsy (contrast-enhanced magnetic resonance imaging is the preferred method for limb lesions). This helps the surgeon plan the direction of biopsy so as to minimize contamination while targeting the most representative areas of the lesion (avoiding cystic or necrotic areas). Though the material obtained by an open biopsy is generally adequate in quantity and less challenging to the skills of the pathologist, it is a more traumatic procedure. It involves greater tissue trauma, more blood loss and higher risk of complications such as hematoma and infection. If a tourniquet is used there is always a fear that the oozing from tumor vessels after the tourniquet is released may contaminate large areas of the limb. An open biopsy requires general anaesthesia. It is less forgiving and a correct technique is of utmost importance if limb salvage is considered. The skin removed at final procedure is more and can compromise closure during salvage surgery. Hence core needle biopsies which are usually accomplished as an outpatient procedure under local anaesthesia are preferred. Image guided biopsies are preferred in deep seated tumors which are difficult to palpate 4, 5. Several cores should be taken to maximise diagnostic yield. The material obtained from a core biopsy is superior (in amount and viability) compared to that obtained by FNAC and permits ancillary studies for more accurate diagnosis. The discovery of monoclonal antibodies and the application of this knowledge to histopathology by way of immunohistochemistry has given a tremendous boost to the diagnostic skills of the pathologist. For those diagnoses characterised by a chromosomal translocation the use of molecular pathology [fluorescent in-situ hybridisation (FISH) or reverse transcription polymerase chain reaction (RT-PCR)] can be of assistance if the histological diagnosis is doubtful. The additional material obtained from a biopsy can be used for tissue banking and research. Though excision biopsies are not routinely recommended, an excisional biopsy may be the most practical option for < 5 cm superficial lesions. An open biopsy may be an option in selected cases where repeated core biopsies have failed to achieve a diagnosis. All biopsies should be performed by a trained surgeon, or discussed between the surgeon and the radiologist. It should be planned in such a way that the biopsy pathway and the scar can be safely removed on definitive surgery. Though it does not demand great technical skills the decision related to the performance of a biopsy requires considerable thought and experience. It is important that a clinician knows how to obtain adequate material in the least traumatic way without jeopardising subsequent local control of the tumor. A poorly placed biopsy incision, a poorly performed biopsy, or the complications of a biopsy may make it difficult to salvage an extremity and in some instances may even affect the survival of the patient.6
Soft tissue sarcomas are classified histologically according to the soft tissue cell of origin, though the cell type is not part of the prognostic staging system. Additional studies, including electron microscopy, histochemistry, flow cytometry, cytogenetics and tissue culture studies may allow identification of particular subtypes within the major histologic categories. Malignant fibrous histiocytoma is the most common histologic type (28%). Others are leiomyosarcoma (12%), liposarcoma (15%),synovial sarcoma (10%), and malignant peripheral nerve sheath tumours (6%). 1 Pathologists assign grade based on number of mitoses per high-powered field, presence of necrosis, cellular and nuclear morphology and the degree of cellularity. 7 The metastatic potential of soft tissue tumors is better reflected by their histologic grade rather than the cellular classification.
Staging has an important role in determining the treatment and prognosis of soft tissue sarcomas. The major staging system used is the one formed by the International Union against Cancer (UICC) and American Joint Committee on Cancer (AJCC). This TNM system incorporates histologic grade, tumor size, depth, regional lymph node involvement and distant metastasis.
The lungs are the most common site for metastasis of soft tissue sarcomas. Approximately 10% of patients have pulmonary metastasis at presentation.8 Additional imaging to complete staging can include an X ray or a computed tomographic (CT) scan of the chest and an ultrasound or CT scan of the pelvis to identify involved lymph nodes if present. CT scan of the chest is recommended for sarcomas larger than 5 cm or with moderate to poor differentiation.9 Nodal involvement is rare, occurring in less than 3% of patients with sarcoma.10 It is more likely in epitheloid sarcomas, clear cell sarcomas, rhabdomyosarcomas, angiosarcomas and synovial sarcomas.
For complete staging, a thorough physical examination, imaging, laboratory studies, and careful review of all biopsy specimens (including those from the primary tumor, lymph nodes or other suspicious lesions) are essential.
Positron emission tomography (PET) is a recent imaging modality which assesses the metabolic activity (FDG uptake) of the disease and is helpful in detection of both loco regional and distant extent of the disease simultaneously.11 Based on standard uptake value (SUV), it may help in differentiating benign lesions from malignant ones. It can also help identify the most metabolic active area in a heterogeneous lesion for a targeted biopsy. PET is still not considered as a part of routine work up of soft tissue tumors and its exact role remains to be defined.
The prognosis for patients with adult soft tissue sarcomas depends on several factors, including the patient�s age and the size, histologic grade, and stage of the tumor. Factors associated with a poorer prognosis include age older than 60 years, tumors larger than 5 cm, or high-grade histology.12 It has also been shown that prior intervention at a non oncology centre could eventually compromise both, their local treatment and overall survival.13, 14
Soft tissue sarcomas are ubiquitous in their site of origin, and are best treated with multimodality treatment. Multidisciplinary treatment planning is therefore mandatory in all cases (involving pathologists, radiologists, surgeons, radiation therapists and medical oncologists). This should be carried out in referral centres for sarcomas as it has been shown that patients managed at specialty centres fare better.13
When feasible, function-sparing surgical excision with wide margins is the cornerstone of effective treatment, with the goal of preservation of a functional extremity.15 This may be facilitated by soft tissue reconstructive surgery including the use of local or free flaps and occasionally vascular and nerve resection with suitable graft reconstruction. Surgery for these lesions is best performed by a surgeon specifically trained in the treatment of this disease.14 The standard surgical procedure is a wide excision. This implies removing the tumor with a rim of normal tissue around. In high grade tumors, micronodules and extensions of the tumor into, and through, the reactive zone around the tumor pseudocapsule can lead to satellite and skip lesions.16 To avoid local recurrence the resection should be performed outside this reactive zone if possible. Generally 1 cm beyond the tumor is used as a cut-off to ensure adequate clearance, but it is important to realize that the margin can be minimal in the case of resistant anatomic barriers, such as muscular fasciae, periosteum and perineurium.3 However, on occasion, anatomical constraints mean that a true wide resection is not possible without the sacrifice of critical anatomical structures (such as major nerves or blood vessels) and in this situation a marginal excision may be acceptable as an individualized option in highly selected cases, having considered the risks of recurrence and morbidity of more radical surgery and having discussed these fully with the patient.3 In the case of inadequately excised tumors, re-operation should be considered if adequate margins can be achieved without major morbidity.17
Radiotherapy complements adequate surgery as standard treatment of intermediate and high grade, deep tumors with a diameter of > 5 cm. It can consist of preoperative or postoperative radiation depending on institution protocols.18 Preoperative radiotherapy can occasionally permit limb conservation of extremity sarcomas which otherwise would be inoperable or require amputation.19 Reports suggest that preoperative radiotherapy is associated with a greater risk of wound complications than postoperative radiotherapy.18 Intra operative brachytherapy either exclusively or in combination with post operative radiation is an option that is also often employed. Radical brachytherapy alone, when used judiciously has demonstrated good local control and functional outcomes with reduced treatment-related morbidity.20 Intensity-modulated radiation therapy (IMRT) has the potential to better target the delivered radiation dose with decreased morbidity, and is under investigation.21
The role of chemotherapy in soft tissue sarcomas is still debatable. A quantitative meta-analysis of updated data from 1,568 individual patients from 14 trials of doxorubicin-based adjuvant therapy showed an absolute benefit from adjuvant therapy of 6% for local relapse-free interval, 10% for distant relapse-free interval and 10% for recurrence-free survival; however, there was no overall survival benefit at 10 years.22 The histological type may play a role in the decision making to offer chemotherapy, since some types are felt to be more chemosensitive, whereas others are less so. Patients with high-grade tumors larger than 5 cm in diameter have the greatest tendency for disease to metastasize and are likely candidates for prospective clinical trials of adjuvant chemotherapy.
Patients with localized tumors that, despite multimodality treatments, cannot be resected completely should be considered for amputation to minimize the risk of distant site relapse. In addition, patients with multiple relapses, untreatable pain, bleeding or fungation may also benefit from an amputation of a limb.
Post treatment surveillance forms an important part of the overall treatment plan of these patients. There are no published data supporting specific policies for follow-up of surgically treated patients with localized disease. Relapses most often occur to the lungs. The risk assessment based on tumor grade, tumor size and tumor site may help in choosing the routine follow-up policy.23 High risk patients generally relapse within 2�3 years, while low-risk patients may relapse later, although it is less likely. The best method of follow-up has not been established. Although the use of MRI to detect local relapse and CT to scan for lung metastases is likely to pick up recurrence earlier, it is yet to be demonstrated that this is beneficial or cost effective compared with clinical assessment of the primary site and regular chest X-rays.
Soft tissue sarcomas have a predilection for developing pulmonary metastases at some point in their natural history. Studies have shown that a select subset of these patients will benefit from complete excision of these metastases provided the primary disease is controlled. The primary selection criteria for considering a patient for pulmonary metastetectomy have largely remained unchanged over the years.24
1. Complete resection should be technically possible
2. Primary disease should be controlled or controllable
3. Absence of extrapulmonary metastatic disease
4. Patient should have the physiological reserve to withstand the procedure
Palliative chemotherapy may be beneficial in some patients with advanced metastatic soft-tissue sarcoma. It has been established that good performance status, young age, and absence of liver metastasis may improve survival time.25
Conclusion:
The presence of a soft-tissue sarcoma in the extremity is no longer an indication for amputation.26 The last few decades have seen rapid strides in surgery with function preserving alternatives for local control in these lesions becoming the norm without compromising on overall disease survival. The advent of better imaging modalities, more effective adjuvant modalities, a better understanding of anatomy with continuous refinement in surgical techniques have all played a part in achieving this goal. Good functional and oncological results can be achieved with a combination of excision of the tumor, and where required, suitable adjuvant therapies (fig:1). These lesions are best managed at specialty centres where the requisite multidisciplinary care can be offered to the patient to optimise results in these challenging tumors.
