Extremity and Trunk Soft Tissue Sarcoma
Introduction
Extremity and trunk soft tissue sarcomas (ETSTS) constitute a broad group of histologically diverse tumors which make clinical management challenging. There are more than 70 recognized subtypes of sarcoma, each with distinct biology and clinical course. Extremity and trunk locations make up nearly 80% of all soft tissue sarcomas[1].
The etiology of most sarcomas is unknown with 10% or fewer cases associated with known causative factors, such as environmental chemicals, radiation, viral infection, immunodeficient patient status, and genetic mechanisms (e.g. Li-Fraumeni, neurofibromatosis, familial adenomatous polyposis). Five-year overall survival for all patients with ETSTS is around 65%, ranging from 81% for those with localized disease to as low as 15% for those with metastatic disease[2].
The goal of the below article is to aid in the management of ETSTS, which can present the clinician with a diagnostic challenge differentiating these rare soft tissue tumors from common benign entities. General management and prevailing treatment principles will also be reviewed. Given the breadth of histologies and presentations, it is impossible to review every treatment scenario here, but the goal is rather to ensure that the initial work-up and treatment are conducted in a methodical, oncologically-sound manner that can be subsequently managed by a high-volume sarcoma center with multidisciplinary expertise as needed.
Symptoms
Most patients will present noting a history of a painless mass that has grown over the preceding months or years. In some cases, a previously stable mass will undergo sudden growth, which is worrisome for transformation to a malignant or more aggressive entity.
The size of the mass on presentation is variable and dependent upon the location. Masses in larger muscular compartments such as the thigh can go unnoticed until sizes of 10-15 cm are reached. Occasionally patients will note pain as the compartment becomes stretched or with nerve involvement. Neurovascular compromise is less common but can be seen in later stages of disease with larger, more invasive tumors.
On physical exam, one should make note of the size of the tumor, pain elicited on palpation, skin involvement by the tumor, any signs of neurovascular compromise such as numbness or extremity edema, and if the tumor is fixed to the underlying tissue or if it is freely mobile.
Diagnostic Workup
Adequate work-up prior to any treatment or surgical intervention is of the utmost importance. Magnetic resonance imaging (MRI) with and without contrast should be considered for all soft tissue masses that are enlarging or larger than 4 cm. If imaging obtained prior to referral is suboptimal, the clinician should not hesitate in repeating or obtaining additional imaging to adequately view the tumor. T1 phases on MRI are excellent at demonstrating benign, fatty tumors such as lipomas or low-grade fatty tumors such as atypical lipomatous tumors (ALT), especially if such tumors are well circumscribed and fairly homogeneous with an internal signal similar to normal fat (Figure 1).
Contrast-enhanced phases are preferred for malignant masses (Figure 2). STIR phases help to demonstrate the extent of peritumoral edema. If MRI is not available, computed tomography (CT) is the next most useful imaging modality of choice, providing detailed cross-sectional images that can help define the size and extent of the lesion in question. Lymph node involvement is not common in ETSTS, but pathologic lymphadenopathy discovered on physical examination or seen on imaging when present should prompt further diagnostic work-up.
If excessive extremity edema is found on exam, doppler ultrasound should be performed to rule out venous thrombus. If there is concern for bony involvement, plain films should be obtained along with an MRI of the area.
After imaging, histologic confirmation is the next critical step. Either ultrasound-guided biopsy (for more superficial lesions) or CT-guided biopsy are the modalities of choice. Core needle biopsy (CNB) is greatly preferred over fine-needle aspiration (FNA) for ETSTS. Ideally, the biopsy tract should be coordinated between the interventional radiologist and the treating surgeon to ensure that uninvolved muscular compartments are not traversed. Open biopsy should rarely be performed and reserved only for cases where needle biopsy is not possible or repeatedly non-diagnostic. The incision for open biopsies must be carefully planned so that it can be incorporated into and excised with any future resection specimen should pathology reveal a malignant tumor, and tissue planes should be only minimally disrupted.
Once the histologic diagnosis is made, full staging imaging must be obtained to complete the work-up. Table 1 shows the American Joint Committee on Cancer (AJCC) 8th edition staging for ETSTS. For most high-grade sarcomas, CT imaging of the chest is necessary to rule out pulmonary metastatic disease. Additionally, specific sarcoma histologies have individualized imaging needs. For example, in myxoid liposarcoma, CT of the chest, abdomen, and pelvis should be considered, as well as MRI of the spine. MRI of the brain should be considered for alveolar soft parts sarcoma and angiosarcoma. Imaging of nodal basins by CT or ultrasound should be considered for subtypes more likely to have nodal involvement (rhabdomyosarcoma, angiosarcoma, clear cell sarcoma, epithelioid sarcoma).
Table 1: Soft tissue sarcoma of the trunk and extremities AJCC 8th edition staging system.
| T Stage | Primary Tumor |
| TX | Primary tumor cannot be assessed |
| T1 | ≤ 5 cm in greatest dimension |
| T2 | >5 cm and ≤ 10 cm in greatest dimension |
| T3 | >10 cm and ≤ 15 cm in greatest dimension |
| T4 | <15 cm in greatest dimension |
| N Stage | Regional Lymph Nodes |
| N0 | No regional lymph node metastasis or unknown |
| N1 | Regional lymph node metastasis |
| M Stage | Distant Metastasis |
| M0 | No distant metastasis |
| M1 | Distant metastasis |
| Anatomic Stage | Prognostic Groups |
| Stage IA | T1 N0 M0, grade 1 or grade X |
| Stage IB | T2 N0 M0, grade 1 or grade X T3 N0 M0, grade 1 or grade X T4 N0 M0, grade 1 or grade X |
| Stage II | T1 N0 M0, grade 2 or 3 |
| Stage IIIA | T2 N0 M0, grade 2 or 3 |
| Stage IIIB | T3 N0 M0, grade 2 or 3 T4 N0 M0, grade 2 or 3 |
| Stage IV | Any T, N1 or M1, any grade |
Position emission tomography (PET) CT is less commonly used in sarcoma but is an option for staging high-grade tumors. For tumors with a very low risk of metastatic potential (eg ALT/well-differentiated liposarcoma), a plain chest x-ray is sufficient for staging. Table 2 lists the metastatic potential of several common ETSTS histologies.
Table 2: Metastatic potential of common extremity and trunk soft tissue sarcomas.
| Low | Intermediate | High |
|---|---|---|
| Well-differentiated liposarcoma | Myxoid liposarcoma | Undifferentiated pleomorphic sarcoma |
| Dermatofibrosarcoma protuberans (DFSP) | Solitary fibrous tumor | Dedifferentiated liposarcoma |
| Desmoid tumor | Extraskeletal chondrosarcoma | Leiomyosarcoma |
| Myxofibrosarcoma | Alveolar soft part sarcoma | |
| Angiosarcoma | ||
| Clear cell sarcoma | ||
| Epithelioid sarcoma | ||
| Extraskeletal osteosarcoma | ||
| Malignant peripheral nerve sheath tumor | ||
| Pleomorphic liposarcoma | ||
| Rhabdomyosarcoma | ||
| Synovial sarcoma |
Management
Locoregional Therapy
Surgical resection remains the gold standard and the only chance of cure for ETSTS. When feasible, a 2 cm margin is taken around intermediate or high-grade tumors. For certain low-grade or slow-growing tumors (eg ALT), a 1 cm margin or even a “marginal resection” taken at the immediate border of the tumor is acceptable, especially if there are anatomic restraints.
Generally, critical nerves and vessels are spared if the tumor can be dissected away, which is in the majority of cases. For neurovascular encasement by tumor, vascular resection and reconstruction and sacrifice of involved nerves may on occasion be necessary for high-grade histologies. If adjacent bone is involved, consultation with an orthopedic oncologist is advisable so that an en bloc resection and functional reconstruction can be achieved. Overall, limb salvage should occur in >95% of extremity sarcomas with amputation reserved for only the minority of cases when a functional limb cannot be preserved with adequate oncologic resection.
In cases with a resulting large soft tissue defect after tumor removal, plastic surgery involvement may be needed for skin graft, rotational, or free flap coverage. Staged surgical resections and reconstructions are frequently used in ETSTS; after resection of the tumor, a temporary dressing such as a negative pressure wound therapy device is placed until final pathologic confirmation of negative margins is obtained. Reconstruction is then performed during a planned second stage, usually 5-10 days after the initial resection.
Surgeons are often faced with referrals for ETSTS after a prior resection for what was presumed to be a benign lesion that returns unexpectedly on pathologic review as a sarcoma (also referred to as an “unplanned excision”). In general, repeat excision is recommended because of approximately a 50% risk of residual tumor in the resection bed. Radiation therapy may be indicated before re-resection, depending upon the histology and size of the lesion (see next section for indications for radiation therapy). If the tumor is in an anatomically sensitive area and resecting additional tissue would cause significant morbidity, radiation alone can be considered if there is no residual tumor visualized on imaging or clinical exam.
Radiation Therapy
Radiation therapy is necessary for all high-grade tumors ≥5 cm in size. In a randomized, controlled trial by Rosenberg et al, patients with high-grade tumors were randomized to either amputation or limb-sparing surgery plus radiation. Both groups received chemotherapy. Recurrence rates were statistically equal (P = 0.06) with no differences in disease-free survival (71% vs. 78% at 5 years, P = 0.75) or overall survival (83% vs. 88% at 5 years, P = 0.99) [3].
This trial established that amputation was not necessary if radiation was added to limb-sparing surgery. Another trial by Pisters et al found that surgery alone with an R0 margin for tumors < 5 cm in size had acceptable recurrence rates (7.9% at 5 years) and very low sarcoma-specific death rates (3.2% at 5 and 10 years), thereby allowing omission of radiation for high-grade T1 (<5 cm) tumors following R0 resection [4].
If adjuvant radiation is anticipated at the time of resection, the surgeon can consider placing metal clips in the periphery of the resection bed to help guide the radiation oncologist. In summary, radiation is indicated for tumors <5 cm with R1 margins after resection and in all high-grade tumors ≥5 cm. It may also be considered very selectively for low-grade tumors that are recurrent or deeply infiltrative.
If radiation therapy is indicated, then the decision for either neoadjuvant or adjuvant radiation must be made. Neoadjuvant radiation allows for smaller cumulative doses and less risk of long-term side effects such as fibrosis and joint stiffness. However, neoadjuvant radiation has double the risk of postoperative wound complications (35% as compared to 17% for adjuvant radiation [5]).
Neoadjuvant radiation is a good option for young patients who have potentially many decades ahead to live with the chronic, irreversible effects of radiation. Adjuvant radiation may be a better option for patients at high risk of wound healing problems to minimize wound complications postoperatively. Both methods have equivalent oncologic benefit with respect to local recurrence. Therefore, the decision for neoadjuvant vs adjuvant may be individualized to the patient based on the pros and cons of each method.
Systemic Therapy
Chemotherapy is considered in patients at high risk of developing metastatic disease or in those with unresectable or metastatic disease. Some centers utilize neoadjuvant chemotherapy commonly for large, high-grade tumors, which has several potential benefits, such as preoperative tumor shrinkage, in situ testing of the tumor, and avoidance of postoperative chemotherapy delays due to complications. When given with neoadjuvant radiation, chemotherapy is usually given first, followed by neoadjuvant radiation, then surgery.
Chemotherapy regimens vary by histology and disease stage, but commonly used regimens include single-agent or combination doxorubicin (75mg/m2)/ifosfamide (with ifosfamide given at adequate doses ≥9 g/m2 per cycle), single-agent dacarbazine, and combination gemcitabine/docetaxel. Some histologies are known to be more chemosensitive, for example, myxoid liposarcoma and synovial sarcoma, while others are generally chemoresistant (clear cell and alveolar soft parts sarcoma). Doxorubicin-based regimens (75mg/m2) is the standard-of-care for first-line treatment in chemosensitive histologies [6, 7].
In the neoadjuvant setting, single-agent chemotherapy should not be administered, as the response rates are significantly lower [8, 9] and the recommended regimen is doxorubicin/ifosfamide in the majority of the common histotypes [10, 11], except for leiomyosarcomas which are resistant to ifosfamide and should be treated with combination of doxorubicin and dacarbazine [12]. In the advanced setting, standard-of-cares vary across centers, although doxorubicin remains the pillar of first-line systemic treatment: the American standard-of-care uses combination regimens [13] whereas the European approach is to use doxorubicin single-agent [14].
This discrepancy is explained by the fact that combination regimens increase response rates but have not shown any overall survival benefit in the advanced setting in pooled cohorts with various histologies. However, combination regimens improve disease control and may provide significant benefit. Notably, doxorubicin/ifosfamide is a particularly toxic regimen and is frequently not well tolerated even in patients with excellent performance status. Cardiotoxicity, nephrotoxicity, and myelosuppression are common side effects.
There is some controversy in administering adjuvant chemotherapy after complete surgical resection as trials have found conflicting results. The Sarcoma Meta-Analysis Collaboration 2008 analysis [15] which included patients from 18 trials found that doxorubicin plus ifosfamide was associated with improved overall survival (30% vs 41% risk of death, OR 0.56, P = 0.01). Subsequent trials have failed to find an overall survival benefit in the adjuvant setting. Therefore, uncertainty remains about the absolute benefit of adjuvant chemotherapy. Involving medical oncologists who frequently treat ETSTS patients and referring patients to centers with clinical trial options is recommended, where available.
Metastatic Disease
Approximately 40-50% of patients with intermediate or high-grade ETSTS will develop metastatic disease at some point in their disease course. In the setting of metastatic disease, the goal is not to cure but rather to prolong life and provide symptom management. This is often achieved with a combination of palliative treatments, including chemotherapy, radiation to symptomatic sites, surgical resection of symptomatic masses, and/or ablation/embolization of hepatic disease.
For select patients with oligometastatic disease and good response to systemic therapy, surgical resection to render the patient disease-free can be considered. For example, in a patient with an operable primary tumor in the extremity and resectable lung oligo-metastases who has had disease stability or response to systemic therapy, surgery to resect both the lung lesions and primary tumor can be considered. Adjuvant or neoadjuvant radiation to the primary tumor should be applied as described above for local disease.
Another option for this same patient with oligometastatic disease but no surgical or systemic options might be definitive radiation to both the lung lesion and primary extremity mass. Selecting between the various palliative options in the metastatic setting is dependent upon the extent and location of metastasis, patient symptoms, rate of growth of disease, and factoring in the known typical course of each particular histology; because of the complexity involved, referral to an experienced sarcoma center is preferred in these situations.
Recurrent Disease
Recurrence in ETSTS can occur at the original site of the primary tumor, occasionally in the lymph node basins, or distantly. The lung is the most common distant site of recurrence, but liver, bone, and subcutaneous lesions are possible. When a recurrence in any location is found, complete re-staging imaging must be obtained.
About 10-20% of patients will develop a local recurrence after appropriate local therapy. Repeat resection should be considered as well as radiation, even if given previously after careful discussion with an experienced radiation oncologist in an expert sarcoma center. Amputation may be required in a minority of patients with a local recurrence.
For those who develop metastatic disease, patients with a disease-free interval of greater than 12 months, age less than 50 years, the absence of a preceding local recurrence, less than 4 pulmonary nodules, and the ability to remove all visible disease are all factors that favor more aggressive intervention.
Surveillance
The National Comprehensive Cancer Network (NCCN) recommends surveillance imaging of the primary tumor site, chest, and all sites at risk every 3-6 months for the first 2-3 years, then every 6 months until 5 years after diagnosis, then annually [16].
For histologies that are low risk for metastasis, imaging of the chest every 6-12 months is adequate, often with a chest x-ray. Otherwise, CT chest is the routine imaging modality of choice. The primary site is generally imaged with MRI although ultrasound can be used for very superficial areas.
Summary
ETSTS are a diverse and challenging set of tumors for clinical teams to manage. Carefully working up each patient to establish the appropriate histology, grade, and stage helps guide the need for radiation, extent of surgery, and potential benefit of chemotherapy.
Amputation is now utilized in a minority of cases, with margin-negative surgery and radiation the standard of care for high-grade tumors >5 cm. Even for those with metastatic or recurrent disease, the available treatment options are ever expanding with new systemic options, regional therapies, and radiation techniques. Referral to a sarcoma center with multidisciplinary expertise is preferred if available.
References
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- Pisters PW, Pollock RE, Lewis VO, Yasko AW, Cormier JN, Respondek PM, et al. Long-term results of prospective trial of surgery alone with selective use of radiation for patients with T1 extremity and trunk soft tissue sarcomas. Ann Surg. 2007;246(4):675-81; discussion 81-2.
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