Timothy L. Frankel
Alfred E. Chang
Presentation
A 35-year-old previously healthy man presents to his primary care physician noting a lump on his anterior leg, present for the past 2 months. It is not tender and he denies any recent trauma to the area. The mass has slowly increased in size over 2 months and is now approximately 5 cm in diameter (Figure 1). Examination reveals a firm lesion fixed to the surrounding tissue with no obvious overlying skin changes. He has full range of motion of his knee and ankle with no obvious neurovascular deficits. There is no inguinal adenopathy or lesions elsewhere.
FIGURE 1 • A 35-year-old man presents with a right leg mass.
Differential Diagnosis
Masses located on either the arm or the leg can arise from a variety of malignant and benign pathologies. Benign lesions include lipomas, sebaceous cysts, neurofibromas, etc. Their treatment involves marginal excision when lesions are symptomatic, growing, or for diagnosis. Occasionally, trauma may result in mass formation from either inflammation or hematoma. A careful history can help identify this diagnosis, but a thorough exam is needed as trauma can often expose a previously unidentified malignancy and can in rare circumstances contribute to their growth as in the case of desmoid tumors.
Malignant lesions are classified according to their tissue of origin and may be initially grouped as either sarcomas of the bone or soft tissue sarcomas (STS). Bony sarcomas include osteosarcomas, Ewing sarcomas, malignant fibrous histiosarcoma (MFH) of the bone, and giant cell tumors. They are distinguished from STS by their firmness and fixation to underlying bone. The principal treatment of bony sarcomas is wide resection or rarely amputation with adjuvant chemotherapy. While primary osteosarcomas are often resistant to radiotherapy, it can be useful in the treatment of Ewing sarcoma when resection is not possible as in the case of axial skeletal involvement.
STS comprise the majority of malignant extremity masses. They often grow silently and only come to attention when they become visible or cause pain and loss of function due to distortion of surrounding structures. It is this reason that retroperitoneal sarcomas can go unnoticed until they are very large in size. The most important characteristics in the prognosis of STS are size, location, and grade. Open or large bore core needle biopsy is needed to make an appropriate diagnosis and guide further therapy. STS can be classified as originating from any mesenchymal structures of the extremity including fat, smooth or skeletal muscle, vessels, or nerves. MFH is the most common STS, accounting for roughly 30% of the annual incidence (Table 1). Typically occurring in the fifth and the sixth decades of life, these tumors are defined by their storiform growth pattern and infiltration of histiocytes. Over the past decade, the incidence of MFH has declined as advances in histology have led to reclassification of tumors to different subtypes.
TABLE 1. Soft Tissue Sarcoma Subtypes with Annual Incidence
Liposarcomas are derived from adipocytes and make up 15% of STS diagnosed in the United States annually. There are a variety of subtypes ranging from the slow-growing well-differentiated and myxoid liposarcomas to the more aggressive dedifferentiated and pleomorphic variants. Because therapy differs depending on which form is encountered, a well-trained pathologist is crucial in ensuring appropriate care is given. Low-grade liposarcomas are treated with surgical resection alone as metastases are rare and chemotherapy and radiotherapy are often ineffective. Higher-grade lesions may benefit from adjuvant or neoadjuvant radiation therapy, which will be discussed later. Leiomyosarcoma is the third most common STS and represents malignant growth of smooth muscle cells. They may occur throughout the body, but are commonly found where smooth muscle cell density is highest, such as the uterus. As with other STS, surgical resection represents the cornerstone of treatment with chemotherapy reserved for advanced disease. Rhabdosarcomas are rarely seen in adults, but represent the most common pediatric solid tumor. They arise from skeletal muscle progenitor cells and grow and metastasize rapidly. Unlike other STS, surgery alone rarely leads to cure, but multimodality therapy with the addition of chemotherapy and radiation has led to a 70% cure rate even in advanced disease. Rhabdosarcomas can be divided into embryonal or alveolar subtypes based on their histology with the former having a more favorable prognosis. Angiosarcomas occur most often on the scalp or the face in the eighth and the ninth decades of life. Risk factors include old age, prior exposure to ionizing radiation, and chronic lymphedema. The latter is an important cause of morbidity following axillary or inguinal lymphadenectomy and is thought to be one factor contributing to a rise in the incidence of this STS. Wide excision followed by adjuvant radiation is the treatment of choice for angiosarcoma, but local recurrence is common and the morbidity from reresection high. Synovial sarcoma is an STS that can occur throughout the body and whose histologic features resemble those of synovial cells. There are two subtypes: monophasic, which are dominated by spindle cells, and biphasic, where spindle and epithelial cell morphologies are present. These lesions have an aggressive behavior and therefore require wide resection and radiation therapy for control (Table 2).
TABLE 2. Results of Randomized Trials of Adjuvant Radiation Following Sarcoma Resection
Workup
A thorough history and physical examination is important in differentiating benign versus malignant soft tissue lesions of the extremity. The character and rate of growth of the mass is elicited as well as any overlying skin changes or functional abnormalities of the limb. Lesions that have shown no growth over many years can often be treated with careful observation unless symptomatic. The decision on whether to next proceed directly to biopsy versus radiologic studies depends largely on the suspicion of malignancy. If a benign lesion such as lipoma is suspected, excisional biopsy is both diagnostic and therapeutic avoiding the need for costly imaging. When radiographic studies are needed, magnetic resonance imaging (MRI) is the primary modality for imaging extremity sarcomas. It allows delineation of muscle compartments, measurement of tumor size, and proximity to surrounding structures. Malignant lesions tend to be heterogeneous and enhanced on T2-weighted images, whereas benign masses appear similar to surrounding tissues (Figure 2). When MRI is unavailable or in patients with metallic implants, computed tomography (CT) can be used.
FIGURE 2 • MRI of lower-extremity mass can show features of the tumor, such as necrosis and proximity to surrounding structures such as vessels and bones.
All extremity masses in which malignancy is suspected should be biopsied and the tissue sent for pathologic analysis. There are four accepted methods of biopsy: fine needle aspiration (FNA), core needle biopsy, and incisional or excisional biopsy. FNA is performed by cleaning the skin immediately over the mass and infiltrating the subcutaneous tissue with local anesthetic. Next, a 22-gauge needle attached to a 3-mL syringe is inserted into the mass and negative pressure applied. The needle is retracted and advanced multiple times until debris is seen within the syringe. This is then extruded onto a slide for immediate review by a trained cytopathologist. Benefits of this procedure are its low morbidity and ability to be performed in an outpatient clinic provided a cytopathologist is immediately available. Unfortunately, due to the small amount of tissue obtained, diagnostic uncertainty may still exist and information regarding grade and subtype of tumor may be lacking. Hence, FNA biopsies are reserved to document local recurrence or metastatic lesions. Core needle biopsy is performed in a similar fashion and can also take place in the outpatient setting. A larger bore needle is inserted into the lesion percutaneously and tissue cores removed for histologic analysis. Complication rate is low and the larger volume of tissue and retention of architecture allows for greater diagnostic certainty. When lesions are difficult to palpate or are in close proximity to vital structures, image-guided biopsies may be performed. With both FNA and core biopsy, the insertion point should be immediately above the lesion of interest and the needle tract removed with the specimen during operative extirpation.
Incisional or excisional biopsy is reserved for cases in which FNA and core biopsy fail to establish a diagnosis. Depending on the size of the lesion and proximity to vessels, nerves, and joints, the lesion is either completely removed (lesions <3 cm) or a small wedge taken (lesions >3 cm) for histologic analysis. It is important when performing either incisional or excisional biopsies to orient the incision along the longitudinal axis of the limb to facilitate future re-resection. In addition, meticulous hemostasis should be achieved to avoid a hematoma that may dissect through tissue planes and potentially seed the area with tumor cells. Ideally, the biopsy should be done by the surgeon who will ultimately execute the definitive operation and is trained in the management of STS.
Once tissue is obtained and a diagnosis made, imaging and histology are used to stage the patient for treatment planning. Important characteristics used in STS staging include size (<5 cm or >5 cm), tumor grade (low vs. high), and distant metastatic spread. Patients should undergo imaging of the extremity for operative planning as well as a high-resolution chest CT scan to evaluate for pulmonary metastases. The incidence of regional nodal involvement is very low (<5%). Histologic subtypes that are associated with higher risks for nodal involvement include epithelioid and clear cell sarcomas, which if documented is equated with systemic spread of disease. Ideally, all information should be discussed at a tumor board, where pathology and radiographs can be reviewed and input from surgeons and medical and radiation oncologists can be used to formulate a treatment plan.
Diagnosis and Treatment
Presentation Continued
Core needle biopsy of the mass is performed revealing a high-grade synovial sarcoma. MRI and CT scan confirm the mass to be 6 cm in size and confined to the anterior tibialis with no evidence of metastatic disease found (Table 3).
TABLE 3. Key Technical Steps and Potential Pitfalls to Treatment of Soft Tissue Sarcomas
The treatment of STS depends on the pathologic classification and stage of the tumor. Classically, small, low-grade tumors can be treated with wide excision including 2-cm margins, with no adjuvant therapy needed. For high-grade tumors, or those >5 cm, treatment should be multimodal and include surgical resection with the addition of radiation therapy. Multiple trials over the past three decades have shown improved local control in patients with resected sarcomas when radiation therapy is added. Survival, however, has been unaffected as most patients die of metastatic disease present at the time of primary tumor resection. The decision on preoperative versus postoperative radiation remains controversial and is the subject of ongoing clinical trials. Chemotherapy is used in patients with stage IV disease, large high-grade tumors and occasionally in the neoadjuvant setting to reduce tumor size allowing for a less morbid operation.
The goal of operative intervention should be removal of the tumor to microscopically negative margins while preserving physiologic function. Prior to 1980, the standard therapy for extremity STS was amputation. Marginal resection of the tumor (removing the tumor along the capsule) was associated with a high local recurrence rate of >80%. Wide excision with a rim of normal tissue was associated with a local recurrence rate of close to 50%. Hence, radical excision involving amputation including the joint above the sarcoma or a radical muscle compartment resection was the standard of care, which was associated with a local recurrence rate of 7% to 18%. In the past, single institution studies reported that radiation may be a useful adjuvant treatment to reduce local recurrence rates associated with wide excisions. In 1982, Rosenberg et al. reported a randomized trial of patients undergoing either limb-sparing surgery involving wide excision with radiation therapy versus amputation. Although local recurrence was seen only in the limb-salvage group, there was no difference in overall survival. This study changed the standard of care for sarcoma resection reserving amputation only for those patients in whom potentially curative resection would render the extremity unusable.
As with open biopsies, the initial incision should be made along the longitudinal axis of the extremity allowing for less tension on the skin following closure (Figure 3). If a large defect is anticipated, consultation with plastic surgery should be considered preoperatively and incisions made that facilitate free or rotational myocutaneous flap coverage. This often allows for a superior functional and cosmetic outcome and can be useful when neoadjuvant radiation has been given. The mass is identified and resected along with a 2 cm of surrounding uninvolved tissue. If fascial planes are encountered, these should be removed with the specimen. Nerves and arteries should be preserved if removal will significantly impact limb function. Arterial reconstruction can be considered if gross tumor encasement is found. If bone is encountered, the involved periosteum should be removed and the cortical bone left intact. The skin and soft tissue are reapproximated if possible or reconstruction is performed. Once the specimen is removed, it should be taken to the pathologist with careful inking of all margins to assess if the tumor is close to the margins. If certain margins are felt to be close by gross inspection or frozen section analysis, additional margins can be taken at that time. If margin status is unclear, wounds can be temporarily left open and managed with vacuum-assisted closure devices or cellular collagen matrices until pathologic review is complete and closure can be safely performed. Metallic clips are placed along the borders of the tumor for subsequent radiation therapy if the patient has not received preoperative radiation. Usually, the skin flaps are closed over suction drains with their exit sites placed so that subsequent radiation fields will include them. Depending on the extent of operation, patients typically spend 1 to 2 days in the hospital and are discharged home with physical therapy.
FIGURE 3 • Incisions should be made along the longitudinal axis of the extremity to aid in closing. Exposure of nearby nerves and vessels (vessel loop marks the peroneal nerve and the anterior tibial artery) is crucial to prevent loss of function to the limb.
Following surgery, patients are given time to recover and external-beam radiation therapy initiated 4 to 6 weeks after surgery. The standard dose is 60 to 70 Gy in 1.8 to 2.0 Gy/d fractions to an area 5 to 7 cm surrounding the original tumor. Preoperative radiation has shown some benefit as tissue oxygenation is improved and margin assessment easier. There is an association, however, with greater surgical morbidity and no proven increase in efficacy.
The role of adjuvant chemotherapy for STS remains controversial. Although strong data exist in pediatric rhabdosarcomas, reports in adult tumors have been conflicting. In a randomized trial comparing anthramycin- and ifosfamide-based chemotherapy to surgery alone, there was an improvement in disease-free and overall survival. However, a large meta-analysis of 14 trials evaluating the use of adjuvant chemotherapy for STS found an improvement in disease free survival but no change in overall survival. The standard approach for most centers is doxorubicin and ifosfamide-based chemotherapy for four to six cycles in high-risk patients without significant medical comorbidities.
Isolated limb perfusion (ILP) is a way to deliver high-dose chemotherapy to an affected limb with minimal systemic exposure. The technique involves isolation of the inflow and outflow vessels to the limb and cannulation with large infusion catheters. The inflow and outflow cannulas are connected to a heart lung bypass machine equipped with a membrane oxygenator, heater, and roller pump. High-dose chemotherapy can then be administered to the leg and cleared from blood prior to returning to the systemic vasculature. During ILP, doses in excess of 10 times the maximal tolerated systemic dose can be achieved with a fraction of the systemic short- and long-term toxicities. When adverse events are encountered, they typically involve burns or blistering to the extremity occasionally requiring amputation.
In 1988, Di Filippo et al. published a series of 64 patients with extremity sarcomas treated with hyperthermia and melphalan, actinomycin, or cisplatinin. Of the 55 patients available for evaluation, 29 were deemed initially unresectable operative candidates (locally advanced disease with no extralimb metastases). Following ILP, 17 (59%) of these patients had sufficient tumor reduction to allow limb-sparing surgery, while 12 went on to amputation. A similar study by Eroglu et al. reported on 37 patients with STS of extremity, 14 of which were considered unresectable at the time of presentation. Patients were treated with ILP using a combination of cisplatin and doxorubicin and followed for response and toxicity. The objective response in this group was 78.6% with a complete response (CR) of 14.3% and a partial response (PR) of 64.3%. Very little systemic toxicity was noted and wide excision was possible in 11 of the 14 patients (78.6%).
Postoperative Management
After resection and adjuvant therapy, patients with STS should be routinely surveyed for evidence of local and distant recurrence. Evidence shows that early recognition and prompt treatment of recurrent disease can improve long-term survival. Patients should be seen every 3 months for the first 2 years with thorough history and physical exams. Any abnormalities should be followed up with imaging and biopsy when necessary. Because lungs represent the most common site of disease spread, patients should receive a high-resolution chest CT scan and extremity MRI semiannually for 2 years.
When patients recur locally, they should be aggressively treated with re-resection or amputation. If adjuvant radiation therapy was not given, it can be used following re-resection to improve local control. Despite aggressive local control, overall mortality is dictated by the development of metastatic disease. Between 20% to 40% of patients with resected STS will develop distant metastases, typically in the first 2 to 3 years. The standard treatment for disseminated disease is chemotherapy, typically with doxorubicin and ifosfamide. When patients present with limited number of metastases to a single body compartment, surgical metastasectomy represents the only option for cure. For this to be considered, the patient must be sufficiently fit for surgery and have a reasonable disease-free interval. In a retrospective review of data from a multi-institutional European sarcoma study, 255 selected patients underwent metastasectomy for STS. The 3- and 5-year overall survival rates were 54% and 38%, respectively, and early stage primaries with long disease-free periods were independent predictors of survival.
Case Conclusion
Following resection with adjuvant radiation therapy, imaging surveillance was performed semiannually. During his 18-month visit, he was found to have two suspicious lesions on chest CT located in the right lower lobe. He underwent successful thoracoscopic wedge resection of the two lesions and has remained free of disease.
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