INTRODUCTION — Sarcomas are rare malignant tumors that arise from mesenchymal tissue at any body site. Approximately 9,530 cases are diagnosed annually in the United States, representing only 0.70 percent of all new cancers. The annual incidence is 30 per million population. Roughly 78 percent of sarcomas originate from in soft tissue, the remainder from bone. The histopathologic spectrum of sarcomas is broad, presumably because the embryonic mesenchymal cells from which they arise have the capacity to mature into striated skeletal and smooth muscle, adipose and fibrous tissue, bone, and cartilage. This overview will consider malignant mesenchymal tumors that arise from soft tissues. Although ectodermal in origin, malignant tumors affecting peripheral nerves are included because of similarities in their clinical behavior, management, and outcome. Bone sarcomas are discussed in detail elsewhere. The biologic behavior of soft tissue tumors ranges from completely benign to aggressively malignant, with some intermediate categories that are characterized by locally aggressive behavior, or rarely, metastatic propensity . Malignant soft tissue tumors are referred to as sarcomas. Benign soft tissue tumors outnumber sarcomas by at least 100:1 Compared to other tumor types, the relative rarity of sarcomas, and the wide array of histologic subtypes and biologic behavior, contribute to the difficulty in understanding the natural history and patterns of response to treatment. To illustrate, there are only about 500 thigh liposarcomas diagnosed per year in the United States, compared to more than 212,900 adenocarcinomas of the female breast. Thus, the number of adenocarcinomas arising in one anatomic site in women exceeds by almost 500-fold the number of thigh liposarcomas, and is 22-fold higher than the total number of soft tissue sarcomas of all pathological varieties, at all anatomical sites, all age groups, and in both genders. Because of their rarity and the frequent need for multimodality treatment, evaluation and management of soft tissue sarcomas should ideally be carried out in a center with expertise in the treatment of sarcomas, including surgical, orthopedic, medical, pediatric, and radiation oncology. The multidisciplinary team approach to care of soft tissue sarcomas optimizes treatment planning, minimizes duplication of diagnostic studies, and reduces the time to implementation of the definitive therapeutic protocol. ETIOLOGY AND PATHOGENESIS — In nearly all instances, sarcomas are thought to arise de novo and not from a preexisting benign lesion. There is no clearly defined etiology in most cases of soft tissue sarcoma, but a number of associated or predisposing factors have been identified. These include genetic predisposition, exposure to radiation or chemotherapy, chemical carcinogens, chronic irritation, and lymphedema. In addition, human immunodeficiency virus and human herpesvirus 8 have been implicated in the pathogenesis of Kaposi's sarcoma. These topics are discussed separately. CLASSIFICATION AND HISTOLOGY — The World Health Organization (WHO) classifies soft tissue tumors into one of four categories, based upon their biologic behavior
Sarcomas — The WHO classifies most soft tissue sarcomas according to the presumptive tissue of origin; ie, the normal tissues the tumor most closely resembles. Examples include liposarcoma, synovial sarcoma, leiomyosarcoma (LMS), rhabdomyosarcoma (RMS), fibrosarcoma, and angiosarcoma In some cases, histogenesis is uncertain and the designation reflects the morphologic appearance of the cells or the architectural pattern (eg, alveolar sarcoma of soft parts, epithelioid sarcoma, clear cell sarcoma, Ewing's sarcoma). Clear cell sarcoma (also called malignant melanoma of soft parts) is a soft tissue sarcoma with melanocytic differentiation that affects young adults. It was once thought to be a variant of malignant melanoma due to the occasional presence of melanin pigment, and its phenotypic resemblance to malignant melanoma. However, it is a sarcoma. The presence of melanin may help in its distinction from other soft tissue sarcomas, especially fibrosarcoma and synovial sarcoma. The histologic classification of malignant fibrous histiocytoma (MFH) has evolved over time. The category of MFH, which was established in the 1970s, rapidly became the most common soft tissue sarcoma of adults, coincident with a dramatic decline in the number of cases diagnosed as pleomorphic rhabdomyosarcoma. However, the clinical and prognostic heterogeneity of tumors formerly classified as MFH is now better recognized, as reflected in the 2002 WHO classification. In one a series of 100 tumors initially classified as MFH, a specific line of differentiation could be proven or suggested in the vast majority when the diagnostic material was reanalyzed by histopathologic, immunohistochemical, and ultrastructural techniques. MFH is now regarded as a diagnosis of exclusion, essentially synonymous with an undifferentiated pleomorphic sarcoma. Histologic evaluation should be carried out by an experienced pathologist with a specific interest in bone and soft tissue pathology. Even in the best of circumstances, making a histopathologic diagnosis of sarcoma on the basis of morphology alone may be difficult, and special studies are often required . There may be substantial disagreement among pathologists regarding the specific histologic diagnosis in individual cases The distinction between high grade sarcomas (eg, MFH, extraskeletal osteosarcoma) and nonmalignant conditions such as myositis ossificans can be particularly difficult. Patients with myositis ossificans often present with antecedent trauma, and a large hard mass, that may contain calcifications on plain radiographs. In most cases, the correct diagnosis can be made based upon the plain film or magnetic resonance imaging (MRI). Histologic grade — The histologic type of the sarcoma does not always provide sufficient information to predict the clinical course of an individual tumor. Grading, which is based solely on histologic parameters, is an indicator of the degree of malignancy, and the probability of distant metastases and death from sarcoma. On the other hand, the histologic grade is a poor predictor of local recurrence, which is mainly a function of surgical margins. Several grading systems have been developed to increase the prognostic value of histologic assessment, some of which use a three tier system (ie, grade 1 [well differentiated, low-grade], 2 [moderately differentiated] or 3 [poorly differentiated, high-grade]), and others a four tier system (grades 1 through 4, with grade 4 tumors being poorly differentiated or undifferentiated). The three tiered system is preferred. The impact of histologic grade on prognosis is discussed below The designation of grade is subjective, and dependent to some extent upon the specific pathologist. The two most widely used systems in the United States are those of the National Cancer Institute (NCI), and the FNCLCC (French Federation Nationale des Centres de Lutte Contre le Cancer). The NCI system uses a combination of histologic type, cellularity, pleomorphism, mitotic rate, and extent of necrosis to assign a grade from 1 to 3, while the FNCLCC (also a three-tiered system) is based upon a score obtained by evaluating tumor differentiation, mitotic rate, and the amount of tumor necrosis. Increasing cellularity and cellular pleomorphism characterize progressively higher grades Grading should be used only for untreated primary soft tissue sarcomas. Grade does not differentiate between benign and malignant soft tissue tumors, and is not a substitute for histologic diagnosis. It is not applicable to all soft tissue sarcomas. It is of no prognostic value for MPNST (the majority of which are considered high grade), and it is not recommended for angiosarcoma, alveolar soft part sarcoma, extraskeletal myxoid chondrosarcoma, clear cell sarcoma, and epithelioid sarcoma Immunohistochemistry — In nearly all instances, the pathologist requires a variety of immunohistochemical stains to aid in the identification of the presumptive tissue of origin. The most useful are vimentin, keratin, desmin, S-100, and leukocyte common antigen.
Molecular diagnostic techniques — Despite the use of immunohistochemical techniques, some sarcomas remain unclassifiable. In many of these cases, molecular techniques may be diagnostically useful. A number of soft tissue sarcomas display specific nonrandom chromosomal changes which now serve as definitive diagnostic criteria for the tumors in which they occur. Many of these are chromosomal translocations, in which genetic material is exchanged between two chromosomal arms, resulting in the formation of a fusion gene. In several cases, the product of a particular fusion gene is thought to be involved in the molecular pathogenesis of that tumor. Although cytogenetic studies can usually reveal characteristic chromosomal aberrations, they are time-consuming and labor intensive. Rapid automated molecular diagnostic techniques (ie, reverse transcriptase polymerase chain reaction, RT-PCR) can detect transcripts from these fusion genes, a finding which implies the presence of the specific translocation. This topic is discussed in detail elsewhere. Microarray analysis — DNA microarray technology is beginning to be used to molecularly characterize soft tissue tumors by profiling patterns of gene expression, a process termed gene expression profiling (GEP) . Microarray methodology, which permits the expression of thousands of genes to be assayed simultaneously, represents a powerful technique to read the "molecular signature" of individual tumors. Statistical techniques are then applied to data from multiple patients to evaluate genes associated with certain diagnostic groups, and uncover classes of tumors not differentiated by conventional criteria. ( Diagnostic GEPs have been described for RMS and Ewing's sarcoma, GIST, and synovial sarcoma, while MFH has shown considerable heterogeneity . Although molecular classification holds great promise, this field is relatively new, and at present, microarray data cannot be used as a sole means of classifying any malignancy. Microarray analysis of sarcomas may also allow the identification of expressed genes that are inhibited by targeted therapies that have been developed for other, more common cancers. As an example, c-erbB-2 is expressed by the epithelial component of biphasic sarcomas, raising the possibility that trastuzumab, a monoclonal antibody targeting this cell surface receptor, may be of therapeutic value in this disease Anatomic distribution — Soft tissue sarcomas occur at all anatomic body sites, and their frequency is not a simple function of abundance of the tissue type. Liposarcomas are not common in the large fatty deposits of the abdomen; while in the thigh, a frequent site, they often arise deep in the muscle mass, rather than in the subcutaneous fat. However, some histologic types of soft tissue sarcoma have a predilection for certain anatomic sites. As an example, only 14 percent of all soft tissue sarcomas present in the upper extremity. In contrast, 40 to 50 percent of all epithelioid sarcomas arise on the forearm and finger The anatomic distribution of soft tissue sarcomas in 4508 adults reviewed by American College of Surgery was as follows
Distribution of histologic subtypes — The distribution of sarcoma subtypes varies according to age and anatomic location. In adults, the most common histopathologic subtypes of STS are MFH, liposarcoma, and LMS. In children, who account for 10 to 15 percent of all cases, the small cell sarcomas (eg, Ewing's sarcoma, embryonal RMS, and primitive neuroectodermal tumor [PNET]) predominate. Extremity — The most common extremity sarcomas are liposarcoma, MFH, tenosynovial sarcoma, and fibrosarcoma. Retroperitoneum — The majority of retroperitoneal sarcomas are liposarcomas or LMS. Head and neck — In the head and neck region, the main histologic subtypes are RMS (in children), angiosarcoma, the common adult soft-tissue sarcomas (MFH, liposarcoma, fibrosarcoma, LMS), and malignant peripheral nerve sheath tumors (MPNST). In series in which desmoids and dermatofibrosarcoma protuberans (DFSP) are included, these tumors account for a large proportion of cases. Chest wall — Sarcomas involving the chest wall are most often desmoids, liposarcomas, and myogenic sarcomas. GI tract — The majority of gastrointestinal tract sarcomas do not express markers of myogenic differentiation (ie, they are not leiomyosarcomas), and are more appropriately classified as gastrointestinal stromal tumors (GIST), some of which express neural differentiation (eg, schwannomas, gastrointestinal autonomic nerve tumors [GANT]). Genitourinary tract — LMS, the most common genitourinary tract sarcoma affecting adults, may arise in the bladder, kidney, or prostate. LMS and other soft tissue sarcomas may arise in the vulva. . Paratesticular RMS is a disease of young men. Uterus — Three types of uterine sarcoma are recognized: LMS (which arise from the myometrium), endometrial stromal sarcomas (which arise from the endometrial stroma), and mixed mesodermal or Mullerian tumors (which are composed of both carcinomatous and sarcomatous elements). CLINICAL PRESENTATION — The presence of a soft tissue sarcoma is almost invariably suggested by a mass, which is usually painless. Less commonly, there is pain or symptoms that are secondary to pressure effects on nerve or bone from an unappreciated mass. Differential diagnosis — In addition to sarcoma, the differential diagnosis of a soft tissue mass includes a variety of benign lesions, metastases, lymphoma, and melanoma. Accurate diagnosis requires an adequate biopsy that is representative of the pathologic lesion, and careful histologic and immunohistochemical study of tissue that is well-fixed and well-stained. Pattern of growth and spread — Soft tissue sarcomas grow by direct local extension, infiltrating adjacent tissues and structures, occasionally with skip areas. They generally extend along tissue planes, and only rarely traverse or violate major fascial planes or bone. Spread to regional nodes is infrequent except for certain histologies (RMS, epithelioid sarcoma, and the vascular sarcomas). In a series of 323 patients with soft tissue sarcoma, regional lymph node involvement at diagnosis or as the first metastatic site occurred in 6 percent, and varied according to tumor grade and size
Among patients with high-grade sarcomas, the risk was greatest with RMS (5 of 14) and epithelioid sarcoma (4 of 5). Nodal involvement was uncommon with primary lesions <5 cm in diameter. Although distant metastases at initial presentation are uncommon (7 percent in one series), they often develop later in the course of the disease. As with nodal metastases, the incidence of distant metastasis is a function of histologic grade and tumor size, as illustrated by the following observations:
For patients who develop distant metastatic disease from extremity sarcomas, the first site of metastasis is the lung in 70 to 80 percent. The principal exception is myxoid liposarcoma, in which extrapulmonary metastases (particularly to the retroperitoneum and paraspinous soft tissue) predominate. However, the lungs are ultimately involved in virtually every patient who develops metastatic disease, and this represents the predominant cause of death. DIAGNOSTIC EVALUATION — A complete history and physical examination should focus on defining the anatomic areas of involvement, evidence of skin, major vessel, nerve or bone invasion, the status of regional lymph nodes, and the presence of edema. Radiographic studies provide the best means of assessing the extent of local invasion, and the pattern of metastatic spread. Radiographic studies — Radiologic evaluation should include plain radiographs of the affected area, as well as a CT scan of the primary site and surrounding structures. MRI and CT — Magnetic resonance imaging (MRI) is increasingly considered the imaging method of choice for certain primary locations, such as head and neck, extremity, parameningeal, and pelvic tumors, because of its multiplanar capacity, ability to attenuate bone artifact, and superior soft tissue contrast. MRI is superior to CT for discerning the relationship of the tumor to fascial planes, bones, vessels, nerves, and organs. However, considerable overlap in morphological and signal features limits the ability of MRI to identify subtypes of soft tissue sarcoma, and to distinguish benign from malignant masses. CT of the tumor bearing area is valuable for assessing cortical bone destruction, and for imaging the regional nodes. Although CT cannot accurately predict histology or histologic grade, the presence of tumor necrosis on CT suggests the presence of a high grade tumor (since necrosis is uncommon in low grade tumors) and a poorer prognosis than if this finding is absent. In one study with three year follow-up, metastases developed in 19 of 41 patients with necrotic tumor compared to only one of 10 patients without this finding, even when controlling for tumor size Because the lungs are the predominant metastatic site (except for myxoid liposarcomas, , a chest CT is recommended in newly diagnosed patients with soft tissue sarcoma in guidelines issued by the National Comprehensive Cancer Network (NCCN) and the Society for Surgical Oncology; however, the yield for patients with tumors less than 5 cm in diameter is low. The initial chest CT serves as a baseline for future assessment of the lungs, although in follow-up examinations, plain chest radiographs are often alternated with CT scans. For patients with retroperitoneal sarcoma, the liver should be imaged preoperatively, as it may be the first metastatic site. We also recommend an initial abdominal CT scan in patients with extremity liposarcomas due to their propensity to metastasize intraabdominally ( PET scan — The utility of PET scanning with fluorodeoxyglucose (FDG-PET) as a component of the initial staging evaluation is unclear. The sensitivity of PET scanning for primary sarcomas ranges from 74 to 100 percent and is greater for high and intermediate grade sarcomas, than it is for low grade sarcomas . In one report, 50 percent of low-grade sarcomas did not take up more FDG than adjacent muscle]. On the other hand, reported specificity of FDG uptake is as low as 67 percent. Among benign lesions, high tracer accumulation may be seen in giant cell tumors, chondroblastomas, some cases of fibrous dysplasia, and nonossifying fibromas. Because of the correlation between histologic grade and the extent of FDG uptake by sarcomas (typically represented by the semiquantitative Standardized Uptake Value, or SUV), it has been suggested that PET can accurately distinguish benign from malignant soft tissue lesions. Although the distinction between benign and high grade lesions can be made accurately, the ability to differentiate benign from low to intermediate grade sarcomas is limited PET scanning has a greater utility for whole body imaging, and the detection of unsuspected distant metastases. However, it is unclear if the added expense of PET scanning is worthwhile compared to CT alone. The available data are scant
Sarcoma is not a reimbursable diagnosis for PET scanning, at least in Medicare patients. Bone scan — Bone scan is usually not helpful for initial staging. Bone metastases are unusual in adults, in the absence of multiple metastases in other sites, except in myxoid liposarcoma. Furthermore, a positive bone scan adjacent to a soft tissue tumor is insufficient evidence of bone invasion, and instead may represent a reactive process. The diagnosis of bone invasion is best made by demonstration of loss of cortical bone on plain radiographs or CT with bone windows. Biopsy — Biopsy is a critical step in management of the patient with soft tissue sarcoma, and is best performed by experienced surgeons. As with primary bone sarcomas, the diagnostic biopsy must be carefully planned to ensure that adequate tissue is obtained in a manner that does not compromise definitive therapy. A poorly placed initial biopsy may preclude or complicate subsequent surgical resection, preparation of flaps, and/or cosmetic repair. In such patients, a wider surgical excision is required at the time of definitive surgery to attain clean margins than would have been necessary if an appropriate incisional biopsy had been performed at the initial procedure. In two separate series, approximately 20 percent of patients had to undergo a more complex operation or receive adjunctive chemotherapy or irradiation because the biopsy was performed inappropriately Biopsy can be performed by incisional (open) technique, core needle, fine needle aspiration (FNA), or, in special circumstances, excision of the lesion. The most frequent procedure is core needle biopsy, which generally provides adequate tissue for the establishment of the histologic type and grade. Core needle biopsy — Core biopsy (eg, TruCut biopsy) is highly accurate in the diagnosis of malignant soft tissue tumors. The advantages are ease, availability (which minimizes treatment delay), minimal morbidity, and low cost. In one study of 60 core needle biopsies, 93 percent of the specimens were adequate, and the final histologic diagnosis at resection correlated with the biopsy diagnosis for the presence of malignancy, grade, and histologic subtype in 95, 88, and 75 percent of cases, respectively . Frozen section biopsy specimens, while adequate for the diagnosis of malignancy, were insufficiently accurate for grade and histologic subtype. Incisional biopsy — If definitive diagnosis may require flow cytometry, cytogenetics, molecular analysis, and/or in vitro culture , an incisional biopsy is usually preferred. The larger sample obtained by incisional biopsy provides the pathologist with more tissue, and a greater degree of confidence in the diagnosis, in part because of the degree of morphologic heterogeneity throughout the tumor. Incisional biopsy of a soft tissue sarcoma should be appropriately placed, short in length (only a few centimeters, except in unusually deep seated sarcomas), and, for lesions located on the extremities, on the long axis. Open biopsies that are performed with a transverse rather than longitudinal incision may compromise more than one compartment, and contaminate the neurovascular bundle, leaving the patient at risk for needing for amputation when a limb-sparing procedure might have been otherwise possible.. The incision should not be placed over bony prominences, such as the tibial shin or femoral condyle. Following incisional biopsy, meticulous attention must be paid to hemostasis. Ecchymotic areas around the biopsy site must be assumed to contain tumor cells. Extensive areas of ecchymosis make irradiation or reresection more difficult. Fine needle aspiration — FNA is highly accurate for diagnosis of soft tissue sarcomas, but does not usually permit the distinction of histologic subtype or grade of differentiation. It is best suited to diagnosing local recurrence or metastatic disease in patients who have been treated for a sarcoma in the past. In one series of 95 patients undergoing FNA for a suspected local recurrence, 5 percent were cytologically inconclusive, 5 percent were incorrectly labeled benign, and there were no false positive results STAGING — Staging of the extent of tumor spread provides a means for formally assigning prognostic categories, and is of enormous value in comparing results from individual treatment centers. Treatment decisions are strongly influenced by the stage at initial diagnosis. AJCC staging system — The most commonly used staging system for soft tissue sarcomas is that of the American Joint Committee on Cancer (AJCC) (. The AJCC staging system incorporates histologic grade (G), tumor size (T), depth of the tumor (superficial or deep), lymph node metastases (N), and the presence or absence of distant metastases (M) to characterize four stage groupings, I through IV . Each tumor is assigned a grade on the basis of histopathologic characteristics (low-grade being 1 on a three-tier scale or 1 to 2 on a four-tier scale, while high-grade is considered 2 or 3 on a three-tier scale or 3 or 4 on a four-tier scale). Stage IV disease is defined by either regional nodal involvement or evidence of distant metastatic disease, regardless of histologic grade, size, or site. Alternative staging systems — Alternative staging systems are used by some orthopedic surgical units. They include the staging system of the Musculoskeletal Tumor Society (MTS) ], the Memorial Sloan-Kettering (MSK) staging system, and the Swedish SIN (tumor Size, vascular Invasion, and microscopic tumor Necrosis) system The surgical staging system of the MTS assigns disease stage based upon grade (using a two-tiered system, low versus high) and whether the tumor is confined to an anatomic compartment. However, the value of using compartmentality to define prognosis is debatable. Although of value in predicting the probability of local control after surgery alone, compartmentality is not an accurate predictor of local recurrence in patients treated with combined surgery and radiation Moreover, the prognostic value of a sarcoma staging system mainly pertains to its value in predicting the likelihood of distant metastasis, not local failure. In this regard, the important factors are grade and tumor volume or size, not compartmentality When various staging systems for localized extremity soft tissue sarcoma have been directly compared, the AJCC and MSK stage classifications were most predictive of the risk of systemic relapse PROGNOSTIC FACTORS — Several prognostic factors have been identified for survival, as well as distant and local recurrence. In one review of prognostic factors in 1041 patients with extremity soft tissue sarcomas, tumor size and grade were the main predictors of distant recurrence and survival, while age over 50 and the presence of positive resection margins predicted for local recurrence. 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). The worse prognosis of MPNST has been noted by others Grade — For the major histopathologic types, prognosis decreases steeply with increasing grade of differentiation, as illustrated by the following examples:
Tumor size — The frequency of
distant metastasis is related to tumor size (ie, its largest diameter) for
virtually all histologic subtypes of soft tissue sarcoma. The influence of
size on metastatic rate was illustrated in a series of 501 patients with
locally controlled soft tissue sarcomas . For grade 2 or 3 lesions, the
five-year actuarial incidence of distant metastases varied between 3 and
55 to 60 percent as tumor diameter increased from
Other factors — Although histologic grade and tumor size are the most important, other factors influence prognosis, including anatomic site , patient age, and histologic subtype. The combined use of these factors to estimate prognosis in individual patients is discussed below. There is a greater need to predict outcome for individual patients than is now possible. Among the prognostic indicators that may be helpful in individual cases are cellular proliferation kinetics, and genetic changes such as overexpression, amplification, deletions, or mutations. Proliferative activity — The proliferative activity of a tumor is an indicator of its potential for distant metastasis. Several techniques are available to assess proliferative activity, including assay for the fraction of cells in S-phase, and immunohistochemical staining with the monoclonal antibody Ki-67 (MIB-1) , or with the monoclonal antibody PCNA (proliferative cell nuclear antigen) [77,78]. Ki-67 reacts with a nuclear antigen present on cells that are actively progressing through cell cycle, while PCNA is an S-phase-associated nuclear protein. The influence of proliferative activity on prognosis can be illustrated by the following examples:
Despite these data, the use of any measure of proliferative activity has not been evaluated prospectively proliferative activity is not currently assessed as a means of determining the prognostic profile of a tumor. Oncogenes — Several other biologic markers such as p53 abnormalities, p27 expression, and amplification of the oncogene MDM2, which binds to and inactivates p53, have been associated with high grade histology and poor survival ]. In one series, the relative risk of death was markedly elevated in patients who overexpressed both p53 and MDM2 . However, none of these factors has been shown to be an independent prognostic indicator, or validated in prospective clinical studies. At present, none of these factors are used routinely in the grading or staging of soft tissue sarcomas. SYT-SSX fusion transcripts — Synovial sarcomas account for up to 10 percent of soft tissue sarcomas, and include two major histologic subtypes, biphasic and monophasic, defined respectively by the presence or absence of glandular epithelial differentiation. Most are characterized by the translocation t(x;18)(p11.2;q11.2), which functions as an aberrant transcriptional regulator . The breakpoint of this translocation fuses the SYT gene from chromosome 18 to one of two homologous genes, SSX1 or SSX2 on the X chromosome. The type of fusion gene appears to be of both pathogenetic and prognostic significance . This was illustrated in one study of 45 synovial sarcomas, in which all of the biphasic tumors had SYT-SSX1 fusion transcripts, while all tumors with the SYT-SSX2 transcript were monophasic . Moreover, when the 39 patients with localized disease were studied, the metastasis-free survival was significantly greater when the 15 patients with the SYT-SSX2 were compared to the 24 with SYT-SSX1 fusion transcripts (relative risk 3.0). Similar results have been noted by others , although not all reports support a worse outcome for patients with biphasic as compared to monophasic histology, or for those with SYT-SSX1 as compared to SYT-SSX2 fusion transcripts . TREATMENT — Surgical resection is the only potentially curative therapy for soft tissue sarcomas regardless of their site of origin. However, due to anatomic constraints, sarcomas arising in some sites (eg, the head and neck) are less often amenable to complete excision. Adjuvant radiation therapy — Adjuvant radiation therapy is commonly recommended for patients with high-grade resected soft tissue sarcomas involving the extremity, retroperitoneum, trunk, or head and neck region. The main benefit of radiation is improved local control, and no meaningful impact on survival has been shown. The optimal timing of radiation therapy is unclear. Compared to postoperative treatment, preoperative (neoadjuvant) radiation therapy has the advantage of smaller treatment fields and lower doses, but the potential for wound complications is higher. Adjuvant chemotherapy — With the exception of the childhood soft tissue sarcomas such as RMS and extraskeletal Ewing's sarcoma (see below), the benefit of adjuvant chemotherapy for other histologic subtypes of soft tissue sarcoma is controversial. While no clear benefit has been shown for adjuvant chemotherapy in patients with retroperitoneal or uterine sarcomas, a survival benefit for adjuvant doxorubicin-based regimens has been suggested in some but not all trials involving patients with extremity soft tissue sarcomas. A meta-analysis included 1568 adults with localized resectable soft tissue sarcoma of the extremities or retroperitoneum who were enrolled in 14 trials that randomly assigned patients to receive or not receive adjuvant doxorubicin-containing chemotherapy. The following benefits were noted in the chemotherapy group:
These data have been interpreted by some as supporting the routine use of doxorubicin-based adjuvant chemotherapy for patients with resected high-grade extremity sarcoma, and by others as not supporting such use. This topic is discussed in detail elsewhere. Rhabdomyosarcoma — For patients with localized RMS (the majority of whom are children), postoperative multiagent chemotherapy (typically vincristine, dactinomycin, and cyclophosphamide) contributes significantly to cure, and this represents the standard of care. Extraskeletal Ewing's sarcoma and PNET — Because of the high relapse rate (80 to 90 percent) in patients undergoing local therapy alone, it is surmised that the majority of patients with both skeletal and extraskeletal Ewing's sarcoma as well as PNET have subclinical metastatic disease at the time of diagnosis. Chemotherapy can successfully eradicate these deposits, and modern treatment plans all include chemotherapy, usually administered prior to and following local treatment.
Neoadjuvant therapy — Benefit for
neoadjuvant (preoperative) doxorubicin/ifosfamide-based chemotherapy with
or without radiation therapy in patients with large (
Definitive radiation therapy —
Definitive radiotherapy may be considered in clinical situations where no
acceptable surgical option is available ]. The largest published
experience is a series of 112 patients with soft tissue sarcomas arising
in the extremity, retroperitoneum, or head and neck (excluding desmoid
tumors, dermatofdibrosarcoma protruberans, rhabdomyosarcoma and PNET
tumors) who had radical irradiation for gross disease over a 30 year
period at a single institution Five-year rates of local control
(LC), disease-free survival (DFS), and overall survival (OS) were 45, 24,
and 35 percent, respectively. Outcomes were better in patients receiving
|
2.5
cm to >20 cm
8
cm), high-grade extremity sarcomas has been suggested in prospective
studies as well as retrospective series. However, randomized trials have
not been conducted, and this approach should ideally be considered in the
context of a clinical trial.