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Surgical resection of primary soft tissue sarcoma of the extremities

Surgical resection of primary soft tissue sarcoma of the extremities
Literature review current through: May 2024.
This topic last updated: Feb 08, 2024.

INTRODUCTION — Sarcomas are uncommon malignant tumors that arise from skeletal and extraskeletal connective tissues, including the peripheral nervous system. They can arise from mesenchymal tissue at any anatomic site.

Because of their rarity and the frequent need for multimodality treatment, surgical management of soft tissue sarcoma (STS) should ideally be carried out in a center with expertise in the treatment of sarcomas. The surgical expertise of dedicated subspecialists improves clinical outcomes.

The surgical management of primary STSs of the extremities is reviewed. The clinical features, diagnosis, classification, and staging of primary STS of the extremity and radiation-associated sarcomas, as well as an overview of multimodality therapy as used for STS of the extremities and chest wall, are discussed separately. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma".)

TREATMENT OVERVIEW — The goals of treating extremity soft tissue sarcomas (STSs) are to minimize local recurrence, perioperative morbidity, and mortality and to maximize function and long-term survival. While the mainstay of treatment of a localized soft tissue sarcoma is surgical resection, to achieve these goals, radiation therapy combined with wide surgical resection is recommended for most patients with high-grade primary extremity STS, with some exceptions [1]. The role of chemotherapy continues to be studied and debated.

Adjuvant radiation is often used to aid with local control when it is predicted that adequate margins will be difficult to achieve, usually around major nerves and blood vessels. Whether adjunctive therapy includes chemotherapy with radiation therapy is based upon the size and grade of the tumor (eg, chemotherapy if used, is primarily high-grade sarcomas >5 to 8 cm), but also upon institutional expertise, experience, and preferences. (See 'Adjuvant medical therapies' below.)

Wide local excision of STS involves excision of the sarcoma with an adequate margin of normal (uninvolved) tissue, leaving the tumor pseudocapsule (if one exists) intact and as part of the en bloc resection specimen. Following resection of small tumors, primary closure of the wound may be possible, but, for larger defects, rotation flaps or free flap reconstruction may be necessary. Many surgical teams at major centers now include dedicated reconstructive surgeons. (See 'Sarcoma resection and reconstruction' below and 'Soft tissue reconstruction' below.)

Although it is rarely needed, primary amputation may be indicated for patients with locally advanced or recurrent STS not amenable to resection or in those with severe medical comorbidities. A review from one large cancer center reported that 1.8 percent (29 out of 1628) of patients underwent a primary amputation due to multifocal disease, ulcerated tumor, pain, eroded bone, involved major nerves, advanced age, or comorbidities [2]. Amputations were equally distributed between the upper and lower extremity. Another 1 percent (16 out of 1599) underwent a secondary amputation for intralesional surgery performed elsewhere or local recurrence. If amputation is not accepted, radiation therapy alone is an alternative treatment for STS [3]. This is also considered when there is widespread metastatic disease and long-term survival is unlikely. Although some early data suggested that STSs were relatively radioresistant [3,4], cell lines derived from sarcomas are no less radiosensitive compared with epithelial cell lines [5]. Myxoid liposarcomas are a particularly radiosensitive subtype [6]. However, tumor size matters. Although local control can be readily obtained in small tumors, high radiation therapy doses may be needed for local control rates to exceed 90 percent for tumors of estimated volume that is 15 to 65 mL (approximately a sphere of 3 to 5 cm in diameter), which require high radiation therapy doses (>75 Gy) [7]. As most treatment volumes are relatively large, the late normal tissue changes resulting from these dose levels are clinically important in nearly all patients and must be considered. (See 'Primary amputation' below.)

Where available, techniques such as systemic chemotherapy with regional hyperthermia or regional chemotherapy (isolated limb perfusion, isolated limb infusion) may also be considered as a means of sparing the limb. (See 'Adjuvant medical therapies' below.)

PREOPERATIVE EVALUATION AND PREPARATION

Preoperative imaging — Magnetic resonance imaging is the most useful imaging test for the initial local assessment of a soft tissue sarcoma (STS). The main site of distant metastatic disease is within the chest for most histologic tumor types, and assessment for distant disease is carried out with chest computed tomography (CT).

The added value of fluorodeoxyglucose-positron emission tomography (FDG-PET) or integrated PET-CT over routine cross-sectional imaging is unclear, but these are being used more in most tumor centers for staging. PET scans are not routinely recommended as a component of the initial staging workup of STS in consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) [8] and the European Society for Medical Oncology (ESMO) [1]. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Is there a role for PET/CT?'.)

If neoadjuvant therapy is used for the primary tumor, such as preoperative radiation with or without chemotherapy, magnetic resonance imaging is usually repeated after the radiation treatment and before the resection to look for response or other changes, including progression, and to help with planning of the surgical procedure. (See 'Adjuvant medical therapies' below.)

Adjuvant medical therapies — Therapies used in conjunction with surgery for the treatment of STS include radiation therapy (most commonly) and chemotherapy, which can be administered preoperatively (neoadjuvant radiation therapy, neoadjuvant chemoradiotherapy) or postoperatively (adjuvant radiation therapy, adjuvant chemotherapy): (See "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Extremity sarcomas'.)

Radiation therapy – The combination of radiation therapy plus wide resection achieves better local control than either modality alone for the majority of STSs for which adjuvant therapy is indicated [9]. The use of adjuvant radiation lessens the necessity for primary amputation or radical resection, and if performed in a center with experienced radiotherapists and surgeons, this approach results in reasonable functional outcomes and acceptable cancer outcomes. (See "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Radiation therapy'.)

Preoperative radiation therapy is generally preferred over postoperative radiation therapy for most patients, although this is surgeon and center dependent, because of lower rates of late treatment-related toxicity since a lower dose and smaller field is used. A retrospective review compared neoadjuvant with adjuvant radiotherapy and reported that both radiotherapy groups had better local control than no radiation but it was not associated with improved metastasis-free or overall survival [10]. Neoadjuvant radiation provided better local control than postoperative adjuvant therapy. However, a meta-analysis found no difference in local control between the two delivery methods [11].

Another potential benefit of preoperative radiotherapy is better adherence; patients are to be more likely to receive the treatment compared with postoperative radiation. In a review of 2145 patients from the American College of Surgeons National Cancer Database (ACS NCDB), a significantly greater proportion of patients treated with preoperative compared with postoperative radiation therapy received the recommended dose (77.2 versus 64.9 percent) [12].

The disadvantage of preoperative compared with postoperative radiation therapy is the potential for more wound complications. Because of this, some centers prefer to use adjuvant radiation therapy after the resection because surgical resections are more challenging in a previously irradiated field, and wound healing is challenging in this setting. Most centers are now comfortable with operating after preoperative radiation therapy, and when performed at a cancer center with a multidisciplinary team that includes surgical oncologists, orthopedic oncologists, and plastic surgeons, wound complications can be minimized. However, a study showed that major wound complications (defined as having surgical intervention) occurred in 19 percent (24 out of 126) of patients. Risk factors for wound complications were age, tumor size, and proximal lower extremity sites [13]. Preoperative radiation, proximal tumor location, especially the medial thigh, and simple wound closure compared with pedicled or free flaps were identified as risk factors for wound complications in a study of 302 patients, 80 percent of whom received preoperative radiation [14].

Although it has been difficult to identify the appropriate subset, some patients with low-grade extremity STS do not appear to require adjunctive radiation therapy [15-20]. We reserve surgical excision without radiation therapy for patients with superficial low-grade tumors that are 5 cm or less in diameter, as well as for carefully selected patients with small, purely intramuscular or subcutaneous tumors, even if higher-grade, provided that adequate surgical margins can be obtained [21,22]. Some patients with larger, low-grade lesions that can be resected with wide margins may be considered for surgery alone [21]. For all other patients, including those with low-grade histology, we advise radiation therapy in addition to surgery.

Chemotherapy – Neoadjuvant chemotherapy is most often considered in the setting of a large or recurrent high-grade tumor, particularly if limb salvage is an issue. In these situations, radiation therapy is most commonly selected with or without chemotherapy. The optimal neoadjuvant regimen and how best to integrate radiation therapy, chemotherapy, and surgery are unknown. (See "Treatment of locally recurrent and unresectable, locally advanced soft tissue sarcoma of the extremities", section on 'Unresectable locally advanced disease'.)

The benefit of adjuvant chemotherapy for common adult STS of the extremities continues to be debated, and there is little consensus as to the indications or specific benefit. A review of the ACS NCDB reported that patients with stage II to III trunk/extremity STS who received neoadjuvant chemotherapy had improved overall five-year survival compared with patients treated with neoadjuvant radiation therapy alone. On multivariate analysis and propensity matching, the survival benefit (70 versus 65 percent) persisted [23]. Mostly younger patients with certain histologies such as synovial sarcoma received chemotherapy, but this study adds to others that suggest chemotherapy improves survival in selected patients.

The appropriateness of adjuvant chemotherapy should be addressed on a case-by-case basis, taking into consideration the patient's performance status, comorbid factors (including age), disease location, tumor size, and histologic subtype. The potential for benefit must be discussed in the context of expected treatment-related toxicities, including sterility in younger individuals, cardiomyopathy, renal damage, second cancers, and overall impairment of quality of life.  

In addition, for patients with large, locally advanced, or recurrent extremity STS, neoadjuvant chemotherapy can be administered systemically in conjunction with regional hyperthermia or regionally (intra-arterially) using procedures such as isolated limb infusion and isolated limb perfusion. These treatments are only available in a few centers in the United States, but, where available, they represent potentially limb-preserving options.

SARCOMA RESECTION AND RECONSTRUCTION

Wide local excision — Wide surgical excision of the primary tumor (total en bloc excision of the primary tumor without cutting into tumor tissue and pseudocapsule and having an adequate margin of normal tissue completely surrounding the tumor while preserving the major neurovascular structures, if possible) is the essential component of treatment for virtually all patients with soft tissue sarcoma (STS). The resection should take place through tissues outside of the tumor pseudocapsule, if one exists, through apparently normal uninvolved tissue. Violation of the tumor (ie, intralesional surgery or a resection that results in gross or microscopic residual tumor) is associated with a higher local failure rate even if radiation therapy is used. In one report, for example, the local control rate in 95 patients with extremity STS treated with preoperative radiation therapy followed by resection was 47 versus 87 percent in patients with and without tumor violation, respectively [24].

Lower versus upper extremity — The general principles of resection of STS are similar in the upper and lower extremities. The main difference is that amputation is avoided whenever possible in the upper extremity, particularly for proximal tumors. No prosthesis comes close to replicating the function of a normal hand, whereas for the lower extremity, modern prosthesis can offer reasonably good ambulatory function and, in younger patients, can support vigorous sport activities. Target muscle reinnervation can improve functional outcomes in upper extremity amputees. (See "Upper extremity amputation", section on 'Target muscle reinnervation'.)

To this end, when a major nerve requires resection, tendon transfers and (at times) nerve grafts are used in the upper extremity. While this is also possible in the lower extremity, in general, the functional results are not as favorable. (See "Surgical reconstruction of the upper extremity" and "Surgical reconstruction of the lower extremity".)

Resection margins — The status of the surgical margins is the most important surgical variable that influences local control [7,15,24-38]. Although a positive margin by itself is not associated with a survival detriment, a positive surgical margin increases the risk of a local recurrence, which in turn is a risk factor for distant metastasis and inferior long-term survival [27,37]. Even in patients treated with combined surgery and radiation therapy, the status of the surgical margins influences the rate of local recurrence [27-32,35,38-41].

However, the exact width (thickness) of the negative margin that is optimal for local control is not known. The postoperative assessment of the margin width is difficult once the specimen is removed due to the retraction of the tissues, especially skeletal muscle, when the specimen is passed off the surgical field. It is essential that the surgeon and pathologist work closely together to assess the true margin. Inking of the specimen may help, but the surgeon's assessment of how to orient and mark the specimen adds to the ability of the pathologist to determine a correct statement regarding margin. What may seem like a very wide margin through muscle to the surgeon may look very different to the pathologist when the muscle retracts. There is no perfect way to definitively assess margins, but the optimal result happens when there is direct communication between the surgeon and the pathologist.

Most clinicians recommend that if surgery is used as the sole modality of treatment, the margin should be at least 1 cm in all directions or include a fascial barrier [42]. One-centimeter margins seldom occur in reality, especially around neurovascular structures, and it is generally accepted that the type of tissue is important: thinner (1- to 2-mm) margins of fascia are likely adequate, whereas wider margins that consist of fat or muscle are suggested [43].

If surgery is combined with radiation therapy, the thickness of the surgical margin can be safely reduced without compromising local control [35]. In one study of patients treated with preoperative radiation therapy followed by surgery for an extremity STS, local control rates were similar among patients with a negative margin of ≤1 or >1 mm (96 versus 97 percent) [35]. In a later study, no local failures were seen among 56 patients treated with preoperative computed tomography-planned radiation therapy if the surgical margins were ≥1 mm [44].

Strategies to reduce wound complications — The following strategies may help to reduce wound morbidity in patients being treated with preoperative radiation therapy or perioperative brachytherapy for STS, although high-level evidence to support these recommendations is lacking:

Gentle handling of tissue during surgery.

The use of contemporary prospectively planned reconstructive efforts with vascularized tissue flaps, which have reduced the incidence of serious wound healing issues to 3 to 5 percent in most (but not all [45,46]) series.

Meticulous attention to achieving hemostasis before wound closure.

Avoidance of closure under tension.

Minimizing wound dead space, using rotational or free tissue muscle transfers if necessary.

Wound drainage with tubes remaining in place until drainage is decreasing is usually advised, although there are few studies that document benefit [47,48].

Use of bulky, cotton compression dressings may be helpful.

Immobilization of the affected extremity until it is clear that there are no significant wound healing issues.

Use of image-guided preoperative intensity-modulated radiation therapy may spare the proposed surgical flap and reduce acute wound healing complications [49]. (See 'Adjuvant medical therapies' above.)

Handling the bone — Since the majority of STSs do not invade bone, it is seldom necessary to resect adjacent bone to achieve a negative margin [50,51]. In the absence of frank bone invasion, resection up to and possibly including the periosteum is believed to be an adequate surgical margin for STSs that are treated with wide excision and radiation. Resection of the periosteum should be limited to those cases where the tumor is abutting the periosteum. Periosteal stripping should be avoided unless necessary to achieve a negative margin because it may increase the risk of a later radiation-related pathologic fracture, particularly of the femur, although the evidence to relate fractures to periosteal stripping is weak [52-54]. A fracture through irradiated bone does not heal normally and may be quite prolonged.

Large, deep tumors often do require periosteal stripping to obtain a margin. If radiation will be part of the treatment, some surgeons advocate prophylactic stabilization with a rod or a plate at the time of the resection, particularly when the femur is involved [55]. However, the evidence to support prophylactic fixation is weak [52,53]. The incidence of these fractures is fortunately low, but it is highest in the femur and directly related to radiation dose [56]. Because of poor fracture healing in irradiated bone, treatment may sometimes be augmented with the use of a vascularized fibular graft to assist in bony union [57].

Nerve resection — It is rarely necessary to resect a major nerve unless the sarcoma actually invades the nerve. Surgical resection of the tumor can be accomplished in most patients without sacrificing a major nerve.

Major nerves can often be preserved if they are carefully resected from the tumor, leaving the nerve sheath as a margin, as it is rare that a nerve is actually invaded by a tumor. But if this is the case, such as with neurogenic tumors arising in the nerve itself, it is necessary to resect the nerve in continuity with the tumor. Ambulatory function is still possible with complete resection of the sciatic nerve [58]. The patient will need to use an ankle-foot orthosis and extreme care in protecting the plantar skin to avoid pressure ulcers since protective sensation will be lost.

In the upper extremity, one tends to try to preserve the major nerves if at all possible, but if one of the nerves (median, ulnar, or radial) requires resection, at times, nerve grafts may be useful, and tendon transfers can be used to restore some function. Nerve grafts are seldom useful in the lower extremity in adults, particularly in a radiated field, but may be successful in children or, at times, in the upper extremity.

Vascular resection — Major arteries such as the superficial femoral artery can be excised if necessary to achieve negative margins and reconstructed with reverse saphenous vein grafts or prosthetic graft material [59]. (See "Lower extremity surgical bypass techniques".)

Reconstructing the vein does not appear to be essential but has been accomplished successfully and may reduce the severity of postoperative edema and late sequelae of chronic venous insufficiency [60]. (See 'Extremity edema' below.)

Handling the specimen — At the completion of the surgical resection, the specimen should be oriented for the pathologist with sutures denoting proximal-distal, deep-superficial, and medial-lateral orientations. With the specimen removed, we usually place vascular clips in the wound to mark the tumor bed for the radiation therapist to guide any potential postoperative radiation therapy.

Ideally, the specimen will be reviewed by the pathologist and surgeon either in the operating room or the cutting room. The surgeon should point out areas of the resected specimen where the margin is concerning and discuss retraction of muscle from the specimen with the pathologist. If there is a question of a positive margin, additional tissue can be taken at the time of resection for frozen section study (and, later, permanent pathology) to look for residual tumor. Orientation of the additional tissue for the pathologist may be difficult in these situations, but communication with the pathologist regarding the "new" margin is critical.

If a positive margin is recognized at the time of the resection, further resection should be attempted to obtain final negative margins. Preoperative radiation therapy may make close margins more acceptable but can also make intraoperative assessment of margins more difficult because of radiation changes in the surrounding normal but irradiated tissues.

If a positive margin is detected postoperatively on the final specimen, then the treatment team needs to weigh the pros and cons of re-resection compared with adding more radiation. (see 'Inadequate initial resection' below). Sometimes, it is possible to resect more tissue if it is known where the area of concern is, and at other times, this may add too much morbidity. It may not be possible to determine exactly where the positive margin is, or it might be near a vital structure, in which case another operation will not be helpful.

Where the margins are questionable and the defect is deemed appropriate for flap closure, some surgeons have preferred to use negative pressure wound therapy in the interim. Formal wound closure is delayed until the surgical margins are certain, and if they are positive, more tissue can be resected before definitive flap closure. (See 'Soft tissue reconstruction' below and 'Use of negative pressure wound therapy' below.)

Lymphadenectomy — Most adult-type STSs have a ≤5 percent risk of lymph node metastases. Exceptions are synovial sarcoma, the vascular sarcomas, rhabdomyosarcoma (RMS), and the epithelioid and clear cell subtypes, which have a higher risk of nodal metastases (9 to 44 percent). (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Pattern of spread'.)

In most cases, regardless of the histologic tumor type, regional lymph node dissection is recommended only if there is clinical or radiologic evidence of regional nodal disease. In most (but not all [61]) series, isolated nodal metastases do not carry the same dire prognosis as distant metastases [62-64]. Some series report four- to five-year survival rates of 46 to 71 percent following lymphadenectomy [63-65]. In the 8th edition (2017) of the TNM staging system, regional nodal metastases have been reclassified as stage IV disease (table 1) [66]. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Staging'.)

Sentinel lymph node biopsy — Sentinel lymph node biopsy (SLNB) has emerged as a reliable method of detecting occult nodal metastases in a variety of malignancies (eg, melanoma, breast, penile cancer). For these cancers, the status of the sentinel lymph node (SLN) reflects the status of the nodal basin with 95 to 97 percent accuracy.

For STSs, particularly those types with a higher frequency of nodal involvement, it is unknown if earlier identification and treatment of occult nodal metastases using SLNB (followed by completion lymphadenectomy if the SLN is positive) would result in improved survival compared with lymphadenectomy only for clinically evident nodal metastases found by physical examination or radiologic imaging. The role of SLNB in patients with high-risk STS subtypes has been addressed in a few retrospective reports [67-73]. The two largest are described in detail:

In a series of 62 consecutive patients with clear cell sarcoma, synovial sarcoma, epithelioid sarcoma, or RMS who underwent SLNB, positive sentinel nodes were identified in 2 of 42 patients with synovial sarcoma and in 6 of 12 with clear cell sarcoma [73]. Only two patients with clear cell sarcoma had additional metastatic nodes after regional dissection, both of whom developed later distant metastases and died of disease. The other four were without evidence of disease on follow-up. One patient with synovial sarcoma and another with epithelioid sarcoma developed regional nodal disease following a negative SLNB, while a further patient with RMS developed distant, local, and regional metastases following a negative SLNB.

In another report, 29 patients with a nonmetastatic extremity STS associated with a high rate of nodal metastases (synovial, clear cell, angiosarcoma, RMS, epithelioid sarcoma) underwent SLNB along with resection of the primary tumor [67]. Among the 20 who had it, the preoperative staging positron emission tomography (PET) scan was interpreted as negative in 16, indeterminate in 3, and suspicious in 1. At least one SLN was found in 28 patients (97 percent). Only one patient (who had a suspicious PET scan) had a positive SLN with micrometastatic disease on pathologic evaluation. He refused completion lymphadenectomy and, despite regional nodal irradiation, developed lung metastases. Two other patients had only immunohistochemical evidence of SLN involvement, and neither relapsed despite not having a completion lymphadenectomy. An additional patient with a negative SLNB later developed a nodal metastasis, and five other patients with a negative SLNB developed distant metastatic disease.

The results of other smaller series and single-case reports are mixed [68-72]. In many but not all cases, patients with positive SLNB have developed distant metastases despite therapeutic lymphadenectomy, and several SLN-negative patients have developed later metastatic disease.

Taken together, these sparse data suggest that a positive SLNB does not necessarily imply future metastatic disease, nor does the removal of involved nodes by completion lymphadenectomy prevent later distant metastatic spread. Furthermore, a negative SLNB does not imply the absence of disease spread. The rarity of lymph node positivity makes the role of SLNB a difficult question to answer prospectively; this would require proof that patients with a positive SLN have inferior outcomes compared with those with a negative sentinel node in a population of patients, all of whom have had SLNB. Thus, the role of SLNB in this disease, even for histologies with a high rate of nodal spread, remains unclear.

Inadequate initial resection — If a positive margin is detected postoperatively on the final specimen, the treatment team needs to weigh the pros and cons of re-resection compared with additional radiation. Sometimes, it is possible to resect more tissue if it is known where the area of concern is, and at other times, this may add too much morbidity. It may not be possible to determine exactly where the positive margin is, or it might be near a vital structure, in which case another operation will not be helpful. If the resection has been performed elsewhere prior to referral to the tumor center, it may not be possible to know whether the margins were adequate from the pathology reports or even from the histologic slides since this requires careful analysis. Many times, these are "shell-out" or "oops procedures" where the surgeon thought they were excising a benign neoplasm.

Because local control is still worse with positive as compared with negative margins, it is generally considered prudent to re-resect the tumor bed, but this can be challenging with regard to knowing what to resect and in achieving wound healing. However, it is important to note that only a minority of margin-positive (R1) resections ever result in a local recurrence (approximately 30 percent in most series), whereas not all complete (R0) resections avoid recurrence (5 to 10 percent in most series) [74-78]. Re-resection to negative margins is performed in conjunction with radiation therapy given either before or after re-resection. Approximately 37 to 68 percent of such patients will have residual tumor in the re-resection specimen.

Re-excision must take into account the size of the re-excised field and the potential for damage or exposure of critical neurovascular structures necessitating reconstructive surgical procedures. In major sarcoma centers, positive margins in patients with extremity lesions usually reflect tumor on the neurovascular bundle, and further surgery to achieve negative margins would usually entail an amputation; most patients in this setting are treated with higher doses of adjuvant radiation therapy (in the range of 66 to 68 Gy), with amputation reserved for salvage.

Partial excision of the tumor before referral to a tertiary center also does not appear to compromise limb preservation, local control, or, in most series, survival [74,78-81]. However, a higher incidence of distant metastatic disease has been reported in such patients [82], and re-resection may entail a larger procedure than a de novo procedure and impact upon the functional result. These data underscore the importance of transferring patients with soft tissue masses of uncertain diagnosis to centers that specialize in treating sarcomas so that they can undergo adequate initial resection.

Some patients are not candidates for re-resection because of either a medical contraindication or the desire to preserve extremity function. The use of radiation therapy as an alternative to re-resection can help secure local control in a substantial proportion of these patients, although there may be dose limitations because of prior radiation to the site.

Brachytherapy — Brachytherapy is a well-established modality for treatment, but it may extend hospitalization and may not be covered by insurance. Because of these issues and the increasing use of outpatient intensity-modulated radiation therapy, brachytherapy is less often chosen.

For patients who are selected to undergo brachytherapy, afterloading catheters are placed in a target area of the tumor operative bed, defined by the surgeon, and spaced at 1-cm intervals to cover the entire area of risk. Brachytherapy minimizes the radiation dose to surrounding normal tissues, maximizes the dose delivered to the tumor, and shortens treatment times [83]. In the usual schedule, treatment is completed within six days and requires only one hospitalization. (See "Radiation therapy techniques in cancer treatment", section on 'Brachytherapy'.)

There are no randomized comparisons of the relative efficacy or morbidity of external beam radiation therapy (EBRT) compared with brachytherapy. Although it is unclear if brachytherapy is associated with a higher risk of wound complications, the rate of wound reoperation may be higher [84].

Brachytherapy has been combined with free flap construction as a means of enhancing primary healing in difficult anatomic situations without an increase in the incidence of wound breakdown [85].

Soft tissue reconstruction — Rotational flaps or free tissue transfers may be necessary to achieve wound closure [86]. (See "Overview of flaps for soft tissue reconstruction" and "Surgical reconstruction of the lower extremity".)

The determination of the need for free or rotational flaps is beyond the scope of this review, but it emphasizes the team approach to treatment of these patients. A plastic surgeon is an essential part of this team. Discussion preoperatively about the resection plan, including how much skin and other soft tissue will be removed, and an estimation of the resulting "dead space" and the quality of the remaining soft tissues, especially in older adult patients who have had radiation, will affect the decision for the use or not of rotational or free flaps. More proximal sarcomas around the thigh and pelvic area are more likely to develop soft tissue healing problems and require special attention from the surgical team.

PRIMARY AMPUTATION — At times, primary amputation may be the only reasonable alternative or may be necessary if there is a major complication. It should not be considered a "defeat" when it is indicated. Sometimes this is as difficult for the surgeon as it is for the patient, but when indicated, amputation may be a good option. The indications for primary amputation for soft tissue sarcoma (STS) include distal disease where the limit of resection encompasses an entire digit or significant portion of the hand/foot; for massive disease such that a functional limb following resection is not achievable; the need for resection of certain major nerves (eg, brachial plexus); or severely compromised tissue perfusion due to age, peripheral artery disease, or other comorbidities.

If required, standard amputations are used:

Upper extremity – For upper extremity lesions, a ray amputation of the index, middle, ring, or little finger can be performed with relatively little loss of function and acceptable cosmesis. A thumb amputation is more devastating from a functional point of view, but a pollicization of the index finger or a toe-to-thumb free tissue transfer can be used depending on the location of the tumor. Other amputation levels, depending on the location of the tumor and prior treatments such as radiation therapy, include below- and above-elbow amputation, shoulder disarticulation, and, on rare occasions, forequarter amputation. Prosthetics that mimic hand function are lacking, but this is an area of active research. Prototypes of myoelectric hand prostheses have been developed, and this field continues to evolve. (See "Upper extremity amputation".)

Lower extremity – For lower extremity lesions, standard amputations include below-knee for foot lesions, above-knee for large calf lesions, and hip disarticulation for large proximal thigh lesions. For major amputations, many patients can usually function quite well with modern prosthetics, depending on the level of the amputation, their age, and comorbidities, and it should not always be considered a "defeat." (See "Lower extremity amputation" and "Techniques for lower extremity amputation".)

POSTOPERATIVE CARE AND FOLLOW-UP — Patients who have received preoperative radiation, or those who present with large tumors and have significant dead space in the aftermath of major surgical resection, are those who need particular attention in the postoperative setting. It is important to get patients up and moving early after surgery, but if they have delicate wounds, rotational or free flaps, and/or skin grafts, more prolonged bed rest is advised.

For the lower extremity, most patients are able to get out of bed and are ambulating with supports as needed within one or two days unless the wound is tenuous. For both upper and lower extremity resections, the wound is monitored until wound healing is progressing, and then physical therapy can be initiated to work on range of motion of the joint and muscle strengthening. Patients who received radiation therapy (especially preoperative radiation therapy) usually progress more slowly because of the delayed wound healing, but it is important to work on range of motion early so that mobility is not permanently lost, assuming the wound will tolerate it.

After discharge from the hospital, the wound is checked within two weeks and the patient is followed at intervals thereafter for local recurrence and metastatic surveillance. (See 'Posttreatment surveillance' below.)

Adjunctive radiation therapy — Adjuvant radiation therapy is recommended for most patients who did not receive preoperative radiation therapy. Radiation therapy at higher doses can improve the outcome in patients with positive margins for whom re-resection of the tumor bed is not feasible [40,87]. (See "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Radiation therapy'.)

As noted above, some patients with low-grade extremity soft tissue sarcoma (STS) do not appear to require adjunctive radiation therapy. We reserve surgical excision without radiation therapy for the following groups (see 'Adjuvant medical therapies' above):

Patients with superficial, low-grade tumors that are 5 cm or less in diameter.

Carefully selected patients with small, purely intramuscular or subcutaneous tumors, even if higher-grade, provided that adequate surgical margins can be obtained.

Carefully selected patients with larger, low-grade lesions that can be resected with wide margins.

For all other patients, including those with low-grade histology, we advise radiation therapy in addition to surgery.

Posttreatment surveillance — Posttreatment cancer surveillance guidelines have not been established through rigorous clinical investigation [88,89]. Frequent follow-up is recommended, particularly in the first two years after treatment, since more than 80 percent of recurrences will be detected during this period [89]. (See 'Recurrence' below.)

Long-term follow-up and resection site surveillance include periodic physical examination, imaging the primary site, and chest imaging to rule out metastatic disease.

Following treatment, for patients with stage II or III disease (table 1), we suggest history, physical examination, and chest imaging every three to six months for two to three years, then every six months for the next two years, then annually.

Following treatment of stage I disease, we suggest a history and physical examination at three- to six-month intervals for the first two years and yearly thereafter.

Periodic imaging of the primary site is also indicated in high-risk patients. For patients at higher risk of local recurrence, such as those with positive margins or whose primary tumor site is not easily examined, a computed tomography scan is preferred for imaging the lungs and abdomen, and magnetic resonance is preferred for the extremity.

These recommendations are consistent with consensus-based surveillance guidelines from the National Comprehensive Cancer Network (NCCN) [8]; alternative guidelines are available from the European Society for Medical Oncology (ESMO) [1]. (See "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Posttreatment sarcoma surveillance'.)

PERIOPERATIVE MORBIDITY AND MORTALITY — The most common perioperative complications are wound healing delays, wound dehiscence, and infection [86]. (See 'Wound-related complications' below and 'Strategies to reduce wound complications' above.)

Venous thromboembolism (VTE) prophylaxis protocols used for lower extremity operations are appropriate to lessen the likelihood of thrombophlebitis, and this may need to be prolonged if the patient has prolonged bed rest for wound problems. (See 'Venous thromboembolism' below.)

For extremity sarcomas, perioperative mortality is low unless the patient has severe comorbidities preoperatively. In those patients, serious discussion with all members of the team and consultations with appropriate medical subspecialties may make it possible to optimize the patient for surgery or lead to a decision to avoid operative intervention.

Wound-related complications — Wound healing is affected by the extent of the surgical resection and variability in the amount and type of tissue removed at resection, the type and timing of radiation therapy, and chemotherapy. The incidence of postoperative wound infection in one study was 6 percent, but the relative risk was increased in patients who received radiation therapy, had hip and pelvic lesions, or had other factors such as diabetes and increased body mass index (BMI) [90]. The duration of the surgery, the amount of blood loss, and the addition of artificial devices such as joint implants also affect the likelihood of surgical site infection (SSI). One study that compared infections associated with bone versus soft tissue sarcoma (STS) noted that soft tissue tumors were more commonly polymicrobial [91].

In general, the addition of radiation therapy to surgery increases the frequency of wound complications [52,92-95]. Preoperative radiation is associated with a higher incidence of acute wound complications compared with surgery alone or postoperative radiation therapy, particularly for lower extremity lesions [45,92]. However, compared with postoperative radiation therapy, lower preoperative doses (50 versus 60 to 66 Gy) and smaller field sizes can be used [92]. With preoperative radiation therapy, the higher rate of generally reversible acute wound healing complications in preoperatively treated patients is offset by a lower rate of generally irreversible late complications. Acute wound complications can usually be managed and heal in the long run, while late-treatment effects are generally irreversible.

Complications of graft or flap-based reconstruction include vascular compromise, hematoma, seroma, SSI, and complications specific to the donor site. (See "Overview of flaps for soft tissue reconstruction" and "Surgical reconstruction of the lower extremity".)

Use of negative pressure wound therapy — For patients who develop a perioperative wound complication, especially partial or total wound dehiscence, negative pressure wound therapy (NPWT) can facilitate wound healing and primary wound closure, or wound bed preparation for wound coverage with a graft or flap [96-98]. By using controlled negative pressure, NPWT evacuates fluid, stimulates the formation of granulation tissue, and decreases bacterial colonization. There are potential risks associated with the use of these devices. The general management of acute and chronic wounds, and specifically the indications and contraindications and use of NPWT devices, is discussed separately. (See "Basic principles of wound management" and "Overview of treatment of chronic wounds" and "Negative pressure wound therapy".)

Venous thromboembolism — The rate of venous thrombosis and thromboembolism appears to be similar to that of other orthopaedic procedures. In one study of bone and soft tissue neoplasms, the detected incidence of deep vein thrombosis (DVT) was 4 percent and of pulmonary embolism was 1.2 percent [99]. Fatal pulmonary embolism occurred in 0.4 percent in this study of 94 bone sarcomas and 158 STSs. It should be noted that not all patients (70 percent) received DVT prophylaxis. Unless the risk of hematoma or bleeding is high, it is reasonable to use thromboprophylaxis postoperatively, especially in lower-extremity STS resections. (See "Risk and prevention of venous thromboembolism in adults with cancer", section on 'Surgical patients'.)

Extremity edema — Following resection of STS in the extremities, edema can be related to obstruction of the lymphatics or venous obstruction [60]. Following radiation and resection for lower-extremity sarcomas, patients often require physical therapy and compressive stockings postoperatively to help control edema, particularly if there was extensive dissection involving lymphatics or veins. This is permanent in some patients but can often be controlled with stockings and other lymphedema treatment techniques. Many centers have specialized clinics to deal with these issues. (See "Clinical features and diagnosis of peripheral lymphedema" and "Overview of lower extremity chronic venous disease" and "Clinical staging and conservative management of peripheral lymphedema".)

RECURRENCE — More than 80 percent of recurrences (local, distant) will be detected in the first two years after resection [89].

Risk factors — In a review of prognostic factors in 1041 patients with extremity soft tissue sarcomas (STSs), tumor size and grade were the main predictors of distant recurrence, while age over 50 years and the presence of positive resection margins predicted local recurrence [15]. Specific histopathologic subtypes were associated with higher rates of local failure (fibrosarcoma and malignant peripheral nerve sheath tumor [MPNST]) and worse tumor-related survival (leiomyosarcoma [LMS] and MPNST).

Local — Local recurrence rates following wide excision are between 8 and 30 percent (table 2). Following simple excision alone (ie, removal of the gross lesion with only a narrow margin of normal tissue), recurrence rates are 60 to 90 percent. Following intracompartmental resection, local failure rates are between 10 and 20 percent.

While it is well documented that the risk of a local recurrence is higher for high-grade tumors, it is not uniformly low for low-grade tumors. In one of the randomized trials, the improvement in local control in irradiated patients appeared to be limited to patients with high-grade histopathology [83], but, in the other, there was a significant reduction in risk for low-grade tumors as well (5 versus 30 percent local recurrence rate for patients treated with surgery alone) [100].

A postoperative nomogram, which was based upon data from 684 patients with an extremity sarcoma treated with limb-sparing surgery alone at Memorial Sloan Kettering Cancer Center over a 24-year period, was proposed for predicting local recurrence rates at three and five years after limb-sparing surgery without radiation therapy [101]. The nomogram includes five independent predictors of recurrence: age, size, margin status, grade, and histology. While this nomogram may be a useful tool to estimate the risk of a local recurrence in an individual patient, the appropriate cutoff point for deciding that the risk justifies the addition of radiation therapy is unclear. Furthermore, the nomogram has not been independently validated.

Distant — Isolated limited metastatic tumor to the lung is frequently asymptomatic and can be resected. Isolated hepatic metastases may also be amenable to potentially curative resection, although there are fewer available data than with pulmonary metastasectomy. (See "Surgical treatment and other localized therapy for metastatic soft tissue sarcoma".)

LONG-TERM OUTCOMES

Functional — Functional outcomes for patients undergoing limb salvage procedures are reasonable, with similar outcomes for those who do versus do not require soft tissue reconstruction [7,102-106]. Compared with limb salvage procedures, functional outcome in patients requiring primary amputation is generally considered to be not as good, although studies to document this are lacking.

A few studies have assessed quality-of-life issues in amputees who had been treated for soft tissue sarcomas (STSs) with amputation and chemotherapy compared with patients who underwent limb salvage with radiation therapy and chemotherapy [107,108]. Contrary to expectations, there were no significant differences in measures of psychologic outcome. Thus, a psychologic advantage of limb-salvage surgery compared with amputation has yet to be demonstrated.

Limb salvage — In addition to improving local control, the increased use of adjuvant radiation therapy (along with improved imaging using magnetic resonance imaging) has had a significant impact on rates of limb salvage for extremity STS. In the 1970s, up to one-half of patients with extremity STS underwent primary amputation, whereas in contemporary series, the rate of amputation has been reduced to approximately 1 percent (without any measurable fall in overall survival) [7,33,34,74,109,110]. Certainly, adjuvant radiation therapy has played a major role in this improvement, but the ability to plan the operation better with techniques such as magnetic resonance imaging and greater experience and specialization of orthopedic and oncology surgeons have also contributed to improved local control since the 1970s.

Even when the minimum surgical margin is narrow (less than 2 mm), such as with resection of STS in the hand or foot, limb amputation can be avoided as primary therapy in most patients, and up to two-thirds of patients can retain a normal or fairly normal extremity.

Long-term survival — Long-term survival following surgical treatment of STS of the extremities depends on the histologic grade and presence of metastatic disease.

STSs of the hand and foot tend to have a slightly better prognosis than do more proximal extremity STSs. Five-year survival rates are approximately 80 percent, which is better than expected for proximal extremity disease [111-113].

Nomograms have been proposed to predict long-term outcomes following resections of sarcomas, some of which are available online. Their usefulness is still being studied. This subject is discussed in detail elsewhere. (See "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Prognosis'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Soft tissue sarcoma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Soft tissue sarcoma (The Basics)")

SUMMARY AND RECOMMENDATIONS

Soft tissue sarcoma – Soft tissue sarcomas (STSs) are uncommon malignant tumors that arise from skeletal and extraskeletal connective tissues, including the peripheral nervous system. They can arise from mesenchymal tissue at any body site. (See 'Introduction' above.)

Surgical resection – Surgical resection of the primary tumor is an essential component of treatment for virtually all patients.

The guiding principle is total resection of the primary tumor with a margin of normal tissue surrounding the tumor and avoidance of cutting into tumor tissue during the resection. (See 'Wide local excision' above.)

What constitutes an "adequate" margin is not well defined and probably depends on the type of tissue. (See 'Resection margins' above.)

Re-resection is preferred, if possible, for patients with an incompletely resected primary STS. For patients who are not candidates for re-resection, either because of a medical contraindication or the desire to preserve extremity function, adjuvant radiation therapy can secure local control in a substantial proportion. (See 'Inadequate initial resection' above.)

Lymphadenectomy – Regional lymph node dissection is recommended only if there is clinical or radiologic evidence of regional nodal disease, regardless of the histologic tumor type. In the absence of clinical or radiologic nodal disease, we do not perform lymphadenectomy even for certain histologies in adults that have a higher risk of nodal metastases than other types (11 to 44 percent versus 5 percent; eg, synovial sarcoma, the vascular sarcomas, rhabdomyosarcomas [RMSs], and the epithelioid and clear cell subtypes). The role of sentinel lymph node biopsy (SLNB), even in patients with high-risk subtypes, is unclear. (See 'Lymphadenectomy' above.)

Adjuvant therapy – Surgical excision is typically in conjunction with radiation therapy. (See 'Adjuvant medical therapies' above.)

Radiation therapy – The combination of radiation therapy plus surgery achieves better local control than either modality alone for most STSs in which adjuvant therapy is indicated. Adjuvant radiation provides reasonable functional outcomes and acceptable cancer outcomes and the lessens the need for primary amputation or radical surgery and the significant morbidity and cosmetic deformity associated with it. Radiation therapy is most often considered in the setting of a large or recurrent high-grade tumor, particularly if limb salvage is an issue. In these situations, radiation therapy is most selected with or without chemotherapy. Neoadjuvant radiation therapy is generally preferred by the author over postoperative radiation therapy because of significantly lower rates of late treatment-related toxicity. Surgical resections are also more challenging in a previously irradiated field, and wound healing is challenging in this setting.

Chemotherapy – For patients with large, locally advanced, or recurrent extremity STS, neoadjuvant chemotherapy can be administered systemically in conjunction with regional hyperthermia or regionally (intra-arterially) using procedures such as isolated limb infusion and isolated limb perfusion. These treatments are rarely used in the United States, but, where available, they represent potentially limb-preserving options.

Follow-up – Following treatment, for patients with stage II or III disease, we suggest history, physical examination, and chest imaging every three to six months for two to three years, then every six months for the next two years, then annually. Following treatment of stage I disease, we suggest a history and physical examination at three- to six-month intervals for the first two years, and yearly thereafter. Periodic imaging of the primary site is also indicated in high-risk patients. For patients at higher risk of local recurrence, such as those with positive margins or whose primary tumor site is not easily examined, magnetic resonance imaging is preferred over computed tomography scanning. (See 'Posttreatment surveillance' above and "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Posttreatment sarcoma surveillance'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David Harmon, MD, who contributed to an earlier version of this topic review.

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Topic 109748 Version 18.0

References

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