Benign and Malignant Soft Tissue Tumors Treatment & Management

High-grade soft tissue sarcomas often are treated with ifosfamide- and doxorubicin-based chemotherapy. This is controversial, as no definitive studies exist proving that adjuvant chemotherapy contributes to prolonged overall survival.^{[21, 22, 23]}

Localized tumors

Complete local excision is adequate treatment for benign soft tissue tumors. However, a variety of treatment options, including surgery alone or combined with radiation therapy or chemotherapy, may be considered for treatment of localized primary and recurrent sarcomas.

Extremity sarcoma

Extremity sarcomas may be treated surgically, with or without radiation therapy and adjuvant chemotherapy.

Surgery is the most important component of any treatment plan for a clinically localized primary or recurrent soft tissue sarcoma. On the basis of the achievable margin, 4 types of excisions may be performed.

• Intracapsular excisions and amputation - The excision or amputation passes within the tumor itself. The tumor inside the pseudocapsule is removed (often piecemeal). Incidence of local recurrence with these types of excisions is virtually 100%; these procedures are performed only in unusual circumstances.
• Marginal excisions and amputation - The excision is performed through the pseudocapsule surrounding the tumor. Shelling-out procedures and most excisional biopsies belong to this category. The chance of local recurrence is 20-75%, depending on the nature of the tumor and whether or not radiotherapy is used.
• Wide excisions and amputation - The tumor is excised with a wide margin of surrounding normal tissue but within the muscular compartment. Without adjuvant therapy, the incidence of local recurrence following wide excision varies but may reach 30%; the rate of recurrence depends on the selection criteria used and the adequacy of the histologically assessed surgical margin. A wide amputation is performed through the normal tissue proximal to the reactive zone around the tumor but remains within the involved compartment. Limb-sparing procedures belong to this category.
• Radical excisions and amputation - These are en bloc excisions of the tumor along with the entire muscle compartment. Amputation with disarticulation of the joint proximal to the involved compartment is called radical amputation. The risk of local recurrence is lowest with this procedure.

Small, superficial, or low-grade tumors treated with only a wide, local excision have a very low risk of local recurrence.^[13] For better local control, many patients undergoing surgical excision receive radiation therapy. In patients who refuse or cannot tolerate surgery, radiation alone can be an effective treatment for certain extremity sarcomas.

• Postoperative radiation therapy - Following wide surgical excision, radiation therapy enhances local control for primary extremity sarcomas. The concept of limb-sparing surgery with postoperative radiation has been validated by randomized trials of amputation versus wide local excision.^[24] Usually, a total dose of about 60 grays (Gy) is adequate.
• Brachytherapy - Postoperative radiation can also be delivered to the tumor bed by means of brachytherapy (in which radioactive sources are implanted in the patient). The advantage of this approach is that it requires a much shorter time for initiation and completion of therapy than does external radiation. External beam radiation is used for 6 weeks beginning a month or more following surgery; brachytherapy usually is started within a week of surgery and completed in 4 or 5 days. Because of its technical complexity, brachytherapy requires an experienced radiation oncologist during the operating procedure. Brachytherapy and external beam radiation appear to be equally effective when properly administered.
• Preoperative radiation therapy - The employment of preoperative radiation therapy may allow less radical forms of surgery to be used, specifically on large tumors that otherwise may compromise limb-sparing procedures. Radiation-induced tumor shrinkage decreases the magnitude of resection needed and reduces the risk of seeding by viable tumor cells. Local fibrosis may make the resection more challenging.
• Intensity-modulated radiotherapy - Findings from one study showed that intensity-modulated radiotherapy (IMRT) had better local control of high-grade soft tissue sarcoma at 5 years compared with brachytherapy, though higher rates of adverse features occurred in the group receiving IMRT.^[25]

Even after achieving local control in patients with intermediate- and high-grade soft tissue sarcomas, the risk of metastatic disease following multimodality treatments without amputation is as high as 50%. The risk is even greater if stage IIIB tumors are included. Thus, effective systemic, adjuvant chemotherapy is desirable following definitive treatment of local disease. However, conclusive evidence that adjuvant chemotherapy for extremity sarcomas increases overall survival rates is lacking. Randomized trials have not demonstrated that higher overall survival rates occur with surgery and adjuvant doxorubicin therapy than with surgery alone.

In randomized clinical trials, multiagent chemotherapy with doxorubicin, cyclophosphamide, and methotrexate following surgery improved disease-free survival rates for patients with high-grade extremity sarcomas (except when the lesions were associated with the trunk or retroperitoneum).^[26] However, the toxicity associated with this regimen was substantial.^[27]

Preoperative chemotherapy, also called neoadjuvant chemotherapy, is an option for most patients with osteosarcomas of the extremity. However, it has not been established that this treatment is superior to conventional chemotherapy for soft tissue tumors. Preoperative chemotherapy may be used alone or with preoperative or postoperative radiation therapy.

A significant hypothetical advantage of neoadjuvant chemotherapy is that it allows treatment effectiveness to be monitored through evaluation of the degree of necrosis in the resected primary tumor. However, no evidence exists that this results in improved clinical prognosis.

Nonextremity sarcoma

As with sarcomas of extremities, options for therapeutic management of nonextremity sarcomas include surgery, radiation, and chemotherapy. Sarcomas arising in the head and neck, thoracic or abdominal wall, mediastinum, or retroperitoneum are difficult to treat. Most of these tumors develop in areas where surrounding normal tissue limits the maximum dosage of radiation that can safely be delivered to the tumor bed. In general, the risk of local recurrence is high. For retroperitoneal tumors, the patient usually succumbs as a result of local complications, before metastases are evident.

Recurrent and metastatic disease

As many as 35% of patients develop local recurrence or distant metastases following a combination of surgical resection and adjuvant therapy.^[28] Eighty percent of local recurrences and disseminated metastases were observed within 5 years.^[5]

Although removal of normal lymph nodes generally has no role in the treatment of soft tissue sarcomas, dissection of biopsy-proven tumor-positive lymph nodes is recommended in the absence of metastatic disease elsewhere. Radical lymphadenectomy in patients who have nodal involvement without pulmonary metastases may yield better 5-year survival rates.^[29]

Whenever it is technically amenable, surgical removal of pulmonary metastases is recommended following thorough evaluation for extrapulmonary tumor. In 1 study, resection of isolated pulmonary metastases achieved an actuarial 3-year survival rate of 38%.^[5] The presence of fewer than 3 or 4 metastatic nodules, as observed with preoperative CT scanning, is a favorable prognostic factor.

Because some clinical response has been achieved with neoadjuvant chemotherapy in soft tissue sarcomas, studies to evaluate the use of high-dose therapy with autologous stem cell transplantation have been conducted. These studies have been pursued for patients with a high risk of metastatic disease at the time of diagnosis and as salvage therapy at the time of disease relapse. Most of this research has been conducted in children with small blue cell tumors (Ewing sarcomas, PNETs).^[30] The results of these studies have been mixed. Randomized trials have not been reported. Some studies showed better survival rates for patients treated with the newer technique than for control patients treated with conventional therapy. Other research has failed to show any improvement in outcomes. Thus, the use of high-dose therapy in sarcomas remains controversial. This approach should be investigated further in well-designed, randomized clinical trials.

Compressive bandages and suction drains should be used to minimize seroma formation that can delay administration of chemotherapy or radiation therapy. Physical therapy and rehabilitation support may be required.

General follow-up care includes surveillance studies to evaluate local recurrence and distant metastasis of malignant and intermediate tumors. The precise interval between and the duration of various follow-up studies are not well defined. In general, vigorous surveillance continues for 3-5 years after treatment. Benign tumors generally do not require such surveillance.^[31]

Complications can be divided into those that occur before therapy is completed and those that develop after its completion.

Before completion of therapy

• Related to the tumor: Depending on histopathologic category and anatomic site, the tumor may cause complications such as skin ulceration, thrombocytopenia, hemorrhage, and fracture.
• Related to operative procedures: Infection and wound dehiscence are possible.

After completion of therapy

• Related to the tumor: Complications include local recurrence and distant metastasis.
• Related to chemotherapy and radiation therapy: Infections may result from immunosuppression. Postirradiation sarcomas can occur, usually 10 years or longer after radiation therapy.

Outcome and prognosis depend on several, often interrelated factors.

• Tumor size - As with tumors of other tissues, a direct relationship exists between the size of soft tissue sarcomas and outcome. The larger tumors confer a worse prognosis.^[32]
• Depth of tumor - Superficially located tumors (dermis and subcutaneous tissue) have a relatively better prognosis than do deep-seated lesions (intermuscular/intramuscular, retroperitoneal) of similar histologic type.^{[33, 34]} This difference probably results from the fact that superficial lesions are considerably smaller at the time of excision.
• Histologic type - With few exceptions, most sarcomas of the same stage and grade behave the same regardless of histologic subtype. Some soft tissue tumors (eg, atypical lipomatous tumors) are low-grade, without any ability to metastasize. Others, such as pleomorphic liposarcoma, are highly aggressive, with a tendency for distant metastases.
• Surgical margins - Adequacy of surgical margins is directly related to local relapse.^{[35, 36, 34, 37, 32]} However, development of distant metastases may not be related to the development of local recurrence.^[38]
• Histologic grade - A relationship exists between various microscopic grading systems and outcome.^{[33, 32]}
• Clinical stage - Clinical stage is the most important predictor of clinical outcome. The GTNM staging system, which incorporates microscopic grading, is described in Table 2.
• DNA ploidy - DNA ploidy can be evaluated by flow-cytometric studies performed on formalin-fixed, paraffin-embedded tissue sections or by image analysis using cytology smears. Aneuploidy is observed in tumors that have a higher microscopic grade and a greater rate of cell proliferation. However, its role as an independent prognostic factor has not been established.^[39]
• Cell proliferation - The number of mitotic figures stratifies the tumors into benign, intermediate, and malignant categories and is incorporated into most grading systems. Proliferation markers, including Ki-67 and p105, are useful for evaluation of proliferative activity and its relationship to prognosis.^{[40, 41, 42]} However, similar to ploidy, proliferation markers remain to be established as independent prognostic factors.
• Oncogene mutations - Mutations of TP53, overexpression of MDM2, and altered expression of the retinoblastoma gene have reportedly been associated with a worse prognosis.^{[43, 44, 45]}

Management of soft tissue tumors may evolve as a result of the advent of molecular diagnostics and antitumor therapies. It is problematic, however, that despite the existence of many histologic subtypes of soft tissue tumors, only a small number of them are seen at any one institution. More multi-institutional studies are necessary.

Soft tissue sarcomas are challenging lesions that demand a multidisciplinary and multimodality approach for proper clinical evaluation and treatment. Although, in the past, high-grade extremity sarcomas were treated with amputation, limb-sparing therapies for these tumors are well established today. The successful management of such lesions requires a multidisciplinary team of surgeons, radiologists, pathologists, medical oncologists, radiation oncologists, oncology nurses, rehabilitation therapists, and social workers.

Because of the comparative rarity of soft tissue sarcomas and a general lack of related medical expertise, patients with these tumors should be considered for referral, preferably during the initial evaluation phase, to medical centers experienced in sarcoma management.^[46]