Simple Karyotypic Sarcomas with Specific Genetic Alterations

The first group, those characterized by specific recurrent chromosomal translocations, comprises approximately one third of all sarcomas, and the resulting product of the specific gene fusions usually encode aberrant chimeric transcription factors. These translocations are often the only cytogenetic abnormalities and appear to be pathogenetically important. However, although successful cloning of most genes involved in recurrent translocations has taken place, there remains a paucity of information about the downstream targets mediating oncogenic transformation. In general, the promiscuous pairing of a proximal gene that contributes a promoter and functional domain, with a distal gene possessing a DNA binding domain that confers target specificity, determines the phenotype of various STS.²⁷ Most translocations result in the production of a tumor-specific RNA that encodes a novel transcription factor that plays a role in oncogenesis in mesenchymal cells.

One uncommon mechanism results in a chimeric autocrine growth factor and is evident in dermatofibrosarcoma protuberans (DFSP) in which the t(17;22)(q22;q13) translocation involving the COL1A1-PDGFB genes provides a therapeutic target for response to the tyrosine kinase inhibitor imatinib. Mechanisms such as this represent opportunities for future management. At this time, however, they are typically used in a diagnostic manner to identify a particular subtype of tumor. This is the case for synovial sarcomas, nearly all of which exhibit the t(X;18)(p11;q11) translocation and can be distinguished from other tumors with similar morphology, such as a malignant peripheral nerve sheath tumor. Another example is the fusion product PAX3-FOXO1 arising from the t(2;13)(q35;q14) translocation as well as the t(1;13)(p36;q14) translocation expressed in alveolar rhabdomyosarcoma²⁷ (Table 63-1).

TABLE 63-1 Cytogenetic Abnormalities and Fusion Genes in Soft Tissue Sarcoma

Note: Gene nomenclature evolves at least as rapidly as pathologic terminology.

Modified from Antonescu CR: The role of genetic testing in soft tissue sarcoma, Histopathology 48:13-21, 2006.

Complex Karyotypic Sarcomas without Specific Genetic Alterations

The remaining two thirds of STS lack a recurrent genetic signature and are characterized by numerous aberrations, including chromosomal losses and gains. Most adult spindle cell tumors, leiomyosarcoma, and pleomorphic sarcomas belong to this group. At the molecular level, this sarcoma subset features a high prevalence of TP53 checkpoint alterations, including TP53 inactivating mutations, homozygous deletion of CDKN2A, MDM2 amplifications, and so on. Unfortunately, most cases with complex karyotypes and multiple aberrations do not have a consistent correlation with pathologic or clinical parameters. There also appears to be no indication in most of these lesions that detectable genetic alterations might be useful either for diagnosis or prognosis.²⁹

Genetic Conditions Associated with Sarcomas

Given the genetic information just presented, it is not surprising that STS are associated with several genetic conditions. Patients with neurofibromatosis have a 5% to 10% lifetime risk of developing a malignant neurofibrosarcoma arising in a neurofibroma,^30–33 most commonly in the central nervous system. These patients frequently present the additional diagnostic dilemma of distinguishing between potential metastases or other benign neurofibromas found on staging investigations.

A significant risk for STS is found in individuals with somatic mutations in the TP53 tumor suppressor gene, including Li-Fraumeni syndrome, which is characterized by a familial cluster of sarcoma (12%), breast cancer (25%), leukemia, adrenal carcinoma, brain tumors (12%), lung cancer, skin cancer, and pancreatic cancer.^34,35

Long-term survivors of retinoblastoma with the associated RB gene abnormality often develop tumors later in life, with a risk of 10% to 15%.^36,37 For hereditary retinoblastoma, the cumulative incidence of a second cancer at 50 years after diagnosis is 50% compared with only 5% for nonhereditary retinoblastoma.³⁸ Wong and associates³⁸ showed that the relative risk of STS increases with dose beginning at 5 Gy, rising to 10.7-fold at dose levels exceeding 60 Gy.

Gardner’s syndrome, a subset of familial adenomatous polyposis, is associated with the development of intra-abdominal desmoids.³⁹

Classic Pathology Classification

While originating from the mesoderm and in some lesions from ectoderm, a beguiling feature of the legacy of the nomenclature of sarcoma pathology is the traditional view of histologic subtypes originating from similar-appearing normal tissue counterparts. The most common classification scheme for STS is still based on histogenesis, as described by the World Health Organization (WHO) and others52,53,54 (Table 63-2). However, as the degree of histologic differentiation becomes less apparent, the determination of a putative cellular origin becomes increasingly difficult.

TABLE 63-2 Histologic Classification of Soft Tissue Sarcoma*

Malignant Fibrous Histiocytoma

Since the late 1970s malignant fibrous histiocytoma has borne the mantle of most common STS of middle and late adulthood and therefore warrants specific mention in the chapter. Originally described in the 1960s, the term was used to describe a group of sarcomas deemed to be derived from a mixed histiocytic and fibroblastic lineage. The existence of ‘‘malignant fibrous histiocytoma’’ as a distinct entity is now considered controversial and at best is regarded as a heterogeneous group of tumors without a specific known line of differentiation. Most of these tumors were considered to be either a variable storiform and/or undifferentiated pleomorphic phenotype or one of four rarer additional types: myxoid (the next most common subtype), giant cell, inflammatory, and angiomatoid (a rare variant and the only one to survive contemporary reclassification). Reclassification of many tumors in this group has afforded better prognostication, and the old term “malignant fibrous histiocytoma” now is generally considered obsolete.⁵⁴

Current nomenclature recognizes the entities of undifferentiated high-grade pleomorphic sarcoma (previously storiform-pleomorphic “malignant fibrous histiocytoma”) and myxofibrosarcoma (formerly myxoid “malignant fibrous histiocytoma”), which is now the most common sarcoma of older adults, peaking in incidence in the seventh and eighth decades and presenting most frequently in the lower extremity. Most of these tumors are deep seated, developing in fascia and skeletal muscle, and have a high potential for local recurrence.54,56 Low-grade myxofibrosarcoma is known to have a particularly infiltrative growth pattern, and imaging evaluation with particular attention to tail-like extensions should be considered for management.⁶⁴ This type must be differentiated from other sarcomas containing myxoid areas, such as pleomorphic liposarcoma. The feature that sets malignant fibrous histiocytoma lesions apart is the absence of a defined line of differentiation from which epithelial, melanotic, and lymphoid differentiations have been excluded.⁵²

The natural history is extraordinarily variable, reflecting the heterogeneity of these lesions. The most common site for metastases from pleomorphic sarcomas is the lung (90%), bone (8%), and liver (1%), with rare regional lymph node metastases.⁵⁴

Angiosarcoma

Angiosarcoma is currently included in the seventh edition of the TNM stage classification.⁶³ Particularly unique is the propensity of superficial angiosarcoma to occur in the dermal tissues of the head and neck manifesting typically on the scalp (about 50%) or facial skin. These neoplasms commonly present as purple, bruiselike lesions in elderly white men and are rarely seen in patients of African origin.⁶⁵ The macules usually become nodular, may coalesce, and may ulcerate. Frank bleeding is an ongoing and major problem and often results in chronic oozing through dressings. A particularly difficult aspect of management is the apparent multifocal nature that makes judgment about the area of risk almost impossible from the standpoint of accurate definition of margins for both surgery or RT. The clinical examination must be meticulous because it is the only real means of identifying the deceptive areas of multifocal involvement that may exist.⁶⁶ Frequently, individual patches coalesce into flat masses of substantial size. Involvement of the eyelid and periorbital tissues is particularly troublesome. Metastasis is common if patients survive sufficiently long and occurs most typically in regional lymph nodes and the lung.

The majority of angiosarcomas are considered to originate from the endothelium of the blood vasculature.⁶⁷ Koch and colleagues⁶⁸ have outlined the pathologic features, which can range from well to poorly differentiated lesions. They are typically composed of an accumulation of an irregular or sinusoidal pattern of vessel with vascular spaces lined by a single row of atypical endothelium that may be several layers thick. Highly cellular lesions can manifest as sheets of cells with vascular space obliteration that contribute solid components as vascular channels effaced by the crowding of cells. High-grade, poorly differentiated lesions can be composed of undifferentiated cells and disordered architecture, making them difficult to discern from other histologies, although the hallmark clinical presentation and behavior generally leave little doubt about the diagnosis. On immunohistochemistry, these tumors are usually positive for factor VIII–related antigen, vimentin, CD34, and CD31.

It is suggested that angiogenesis and vascular permeability play a central role in the development of angiosarcomas. This is likely influenced by vascular endothelial growth factor A (VEGF-A), which plays a significant role in angiogenesis and vascular permeability. VEGF-A induces angiogenesis by acting through a tyrosine kinase receptor predominantly found on vascular endothelial cells, including VEGF receptor-1. VEGF-A acts to enhance the growth of tumors by promoting a more extensive blood vessel supply and increases the probability of hematogenous metastases. Similarly, it has been proposed that angiogenesis and vascular permeability play a central role in development of angiosarcomas, suggesting a role for VEGF-A in the pathogenesis of angiosarcomas,⁶⁷ thereby opening the potential for molecular targeted agents in the future. Bevacizumab, a humanized monoclonal antibody to VEGF, is an attractive agent to consider in angiosarcoma, given its ability to inhibit tumor growth. Koontz and coworkers⁶⁹ have reported promising results in two patients using neoadjuvant bevacizumab combined with RT.

Another rare variant is one complicating the treatment of breast carcinoma, with superficial angiosarcoma appearing extensively within the confines of the previously irradiated volume and a tendency to develop disease in the opposite breast. A further interesting predisposition in angiosarcoma is its tendency to arise in cardiac tissues, where it represents one of the most common pathologic subtypes of a rare presentation of STS.

Rhabdomyosarcoma

Rhabdomyosarcoma is especially important because it is the fifth most common cancer in childhood,⁷⁰ but it also occurs in the adult, where the outcome is significantly less favorable.⁷¹ One feature concerns the “spindle cell rhabdomyosarcoma” that is only rarely described in the adult compared with children and carries a relatively favorable prognosis. In the adult it appears to have a predilection for the head and neck and may be unusually aggressive.^72,73 The rhabdomyosarcoma classification recognizes embryonal, botryoid, alveolar, and pleomorphic subtypes for both childhood and adult cases. Rhabdomyosarcoma can be recognized on light microscopy by the presence of cross striations within cytoplasmic fibrils of spindle-shaped cells that typically demonstrate immunostaining for myogenic markers.⁷⁴ Seventy percent of rhabdomyosarcomas can be classified as embryonal and 20% alveolar, and the remainder are variants, including the uncommon pleomorphic subtype. The pleomorphic subtype is almost never seen in the pediatric population and is not considered in those classifications; there is debate about whether it truly represents part of the disease process and it may fall into the “malignant fibrous histiocytoma” type categories described earlier.

Embryonal rhabdomyosarcoma has variable amounts of primitive spindle or round cells in a myxoid background. These rhabdomyoblasts appear in a variety of unusual shapes called “tadpole” or “strap” cells. Cross striations on light microscopy can be seen in half of these cells. The botryoid rhabdomyosarcoma is thought to be a variant of the embryonal type and only accounts for 5% of cases. It is defined as a tumor having polypoid morphology with the presence of subepithelial aggregates of malignant cells, referred to as the cambium layer. Botryoid tumors have a particularly favorable prognosis.

A diagnosis of alveolar rhabdomyosarcoma is made if the tumor has alveolar-like spaces that are filled with round malignant, eosinophilic cells. Presence of any amount of alveolar morphology in the lesion qualifies it to be alveolar rhabdomyosarcoma, and alveolar morphology has been identified as a poor prognosticator. There is also a solid variant of this tumor that lacks alveolar spaces but is still included in this subtype. The presence of sheets of anaplastic cells warrants a diagnosis of pleomorphic rhabdomyosarcoma. Today the diagnosis of the less favorable alveolar subtype is generally based on the identification of the characteristic chromosomal translocations t(2;13)(q35;q14) and t(1;13)(p36,q14) and their fusion products (see Table 63-1).²⁷

Both translocations may be associated with different clinical phenotypes.⁷⁵ The translocations and the gene fusion products are characteristic, and the PAX3 gene family involved in the disease fingerprint may have a role in muscle development.^76,77

Rhabdomyosarcoma is also one of the sarcomas associated with a risk of lymph node metastasis. Irrespective of age, the alveolar and embryonal subtypes manifest high rates of response to chemotherapy and RT. The initial evaluation of rhabdomyosarcoma is similar to regular STS but should ordinarily include bone marrow examination. Sampling of cerebrospinal fluid should be considered in patients with parameningeal lesions. Rarely, but distinctly, there is a tendency for these lesions to develop synchronous or metachronous metastases in one or both breasts (Fig. 63-2).

Figure 63-2 A, CT of the chest of a female patient presenting with a bilateral breast metastasis of an alveolar rhabdomyosarcoma arising in the left ethmoidal sinus. Note characteristic presentation with orbital invasion (B) and extensive cervical lymphadenopathy (C) shown by coronal MRI. Breast metastasis is not infrequent as a site of relapse in adult females with this disease but also may be seen at initial presentation.

Liposarcoma

Liposarcoma is the second most commonly encountered subtype of STS, and myxoid liposarcoma (MLS) is the most common variant.⁷⁸ Classic MLS has a t(12:16) translocation, resulting in the TLS-CHOP fusion shared with the more aggressive round cell variant and not seen in predominantly myxoid, well-differentiated liposarcoma.⁷⁹ It also has an unusual pattern of recurrence that includes a predilection for soft tissue metastases.^80–83,84

Apparent multifocal presentation or recurrence at two or more anatomically separate soft tissue sites (with predilection for the retroperitoneum and mediastinum) and bone metastases are a striking yet unpredictable feature of myxoid liposarcoma and contrasts to other STS (Fig. 63-3). Surgery and RT may result in relatively long disease-free intervals (e.g., many years). Uncertainty had existed about whether such multifocal lesions represent an unusual pattern of metastasis or multiple separate primary tumors until Antonescu and associates⁸⁵ showed that all cases of multifocal myxoid liposarcoma bore the identical molecular lineage of the parent primary tumor.

Figure 63-3 CT showing isolated mediastinal relapse with tracheal obstruction occurring in a patient who had presented 7 years previously with a myxoid liposarcoma in the popliteal fossa similar to the lesion shown in Figure 63-9. The initial limb lesion was treated with preoperative RT and maintained local control. This patient underwent airway management, preoperative RT, and surgical resection and was disease free with 15 months of follow-up. Isolated soft tissue relapse in this fashion is a hallmark of the behavior of myxoid liposarcoma and may result in long-term remission or salvage of such lesions.

More favorable survival in a large cohort of liposarcoma patients compared with other histologic subtypes has been reported in a series exceeding 1000 cases. The observation was independent of other prognostic factors, including grade, depth, and tumor size.⁸⁶ Myxoid liposarcoma also appears to manifest an unusually sensitive response to RT^87,88 (Fig. 63-4). Two theories, which are not mutually exclusive, of the underlying mechanism have been postulated. RT might cause adipocyte-like maturation/differentiation of tumor cells,⁸⁸ although the time scale of the relatively immediate clinical response suggests it may be the less plausible explanation. Alternatively, radiation-induced damage to the tumor vasculature may lead to tumor cell death.⁸⁹ This radiosensitivity may explain the propensity for unexpectedly favorable local control (>95%) after adjuvant RT.^84,90,91

Figure 63-4 Pretreatment and post-treatment three-dimensional tumor volumes obtained in an identical manner for (A) myxoid liposarcoma (experimental group) and (B) malignant fibrous histiocytoma (control group) treated with preoperative RT (50 Gy in 25 fractions) at the Princess Margaret Hospital. These results provide the first objective data to support the idea that myxoid liposarcoma shows a statistically significant reduction in size when treated with RT and that this response is greater than that of malignant fibrous histiocytoma given the same RT.

Adapted from Pitson G, Robinson P, Wilke D, et al: Radiation response. An additional unique signature of myxoid liposarcoma, Int J Radiat Oncol Biol Phys 60:522-526, 2004.

Dermatofibrosarcoma Protuberans

Dermatofibrosarcoma protuberans is a superficial tumor that often manifests as deceptive dermal, raised, purple/red lesion(s) in the lower neck, upper chest, and shoulder girdle regions, although any site may be involved. This tumor arises from the dermis and exhibits a characteristic slow but persistent growth over many years.

Infiltration can take place along connective tissue septa, between adnexae and interdigitating with lobules of subcutaneous fat. A uniform population of slender fibroblasts arranged in a monotonous storiform pattern with little nuclear pleomorphism and low mitotic activity is characteristic. Dermatofibrosarcoma protuberans is composed of densely packed spindle cells arranged in a storiform or cartwheel pattern. CD34 staining is extensively positive in nearly all cases and has been used to confirm the diagnosis in less common situations in which the storiform pattern is obscured by myxoid areas. Subtypes include the Bednar tumor, which has melanin-containing cells along with the standard spindle cells of this neoplasm. Ten to 15 percent of all dermatofibrosarcoma protuberans lesions contain areas of fibrosarcoma, and such cases tend to exhibit more aggressive behavior. More than 90% of these tumors are characterized by the t(17;22)(q22;q13) reciprocal chromosomal translocation that is now becoming the hallmark feature of the diagnosis. This rearrangement leads to constitutive activation of the platelet-derived growth factor receptor (PDGFR) as a result of deregulated ligand expression.

The recent observations of response to imatinib (STI 571, Gleevec) in dermatofibrosarcoma protuberans predicted by the presence of the t(17;22) translocation provides possibilities for molecular target therapies in the future.⁹² However, for this tumor one should recall the excellent control rates seen with surgery alone or combined with RT; and these targeted approaches are generally applicable to situations in which surgery and RT are not feasible approaches. For inoperable cases, imatinib has demonstrated antitumor effects in advanced disease harboring t(17;22) and is also active in fibrosarcomatous disease. Two distinct phase II trials of imatinib (400 to 800 mg/day) were conducted by the European Organization for Research and Treatment of Cancer (EORTC) and by the Southwest Oncology Group (SWOG). These trials were combined for analysis to provide more statistical power to assess the clinical response rates of locally advanced and/or metastatic dermatofibrosarcoma protuberans to imatinib and to assess the safety of this therapy.⁹³ Sixteen and eight patients were enrolled onto the EORTC and SWOG trials, respectively, with the objective response rate approaching 50%. These promising response rates in these small studies suggest that median time to progression did not differ between patients taking 400 mg/day and those taking that same dose twice a day.

Synovial Sarcoma

Synovial sarcomas are tumors of pluripotential mesenchymal cells and composed of two morphologically distinct types of cells that form a characteristic biphasic pattern. The biphasic synovial sarcoma includes epithelial cells with a surrounding spindle or fibrous component. The spindle cells stain positive for keratin and epithelial membrane antigen. Vimentin is demonstrable in spindle cells but absent in epithelial cells. S-100 staining may give positive results. Monophasic synovial sarcomas of both fibrous and epithelial types are recognized, although the monophasic epithelial variant of synovial sarcoma is extremely rare. Synovial sarcomas contain a characteristic chromosomal translocation that is the gold standard in establishing the diagnosis, with the observation that 100% of biphasic and 96% of monophasic synovial sarcomas possess the specific t(X;18)(p11;q11) translocation.

Typically occurring in the para-articular areas of the tendon sheaths and joints of young adults, at least 50% of synovial sarcomas are in the lower limbs (especially the knee), and most of the remainder originate in the upper limbs.⁹⁴ Calcification may be apparent. There is little resemblance between synovial membranes and synovial sarcoma, and because the tumor rarely arises from synovial tissue it has been suggested that the name of this subtype should be modified.^95,96 Local treatment follows the general principles of treatment of STS with conservation surgery and RT. This histologic subtype exhibits more favorable responses to chemotherapy than most other histologies.⁹⁷ Nevertheless, the role of chemotherapy still remains unproven and there is a prevailing view that it should not be delivered outside a clinical trials setting.^98,99 A synovial sarcoma–specific nomogram has been developed by Canter and colleagues⁴⁰ based on preoperative variables that may facilitate informed decision making with regard to selecting patients most likely to benefit from adjuvant/neoadjuvant chemotherapy and, in particular, for the typical size cut points clinicians use for consideration of neoadjuvant chemotherapy. The disease also has a reputation for higher risk of lymph node metastasis (<2% to 14%),^100,101 although elective nodal management is not indicated. An increased potential for distant metastases has been observed with larger tumors (>5 cm), local relapse, and age older than 20 years.¹⁰²

Gastrointestinal Stromal Tumors

GIST are rare STS that represent the first solid tumor exhibiting a consistent favorable response to molecular targeted therapy. These tumors may arise anywhere in the gastrointestinal tract but occur predominantly in the stomach or small intestine. They can also develop from omentum and retroperitoneum. Metastases occur predominantly within the peritoneal cavity and the liver. GIST harbor so-called gain-of-function mutations in the KIT or platelet-derived growth factor–alpha receptor (PDGFR-α) genes in 85% and 5% of cases, respectively.103,104 Through these mutations the receptors are constitutively activated. The advent of the tyrosine kinase inhibitor imatinib was a major breakthrough in the management of advanced GIST because the response rates were dramatic and because effective treatment options previously had not been available.^105,106 Patients whose tumors contain exon 11 KIT mutations are more likely to respond to imatinib than those whose tumors have an exon 9 KIT mutations or those with no detectable kinase mutation.¹⁰⁷ The unique behavior of this entity has resulted in the introduction of a new stage classification for clinical use that differs from that employed in regular STS (see later in the section on staging).

Clear Cell Sarcoma (Malignant Melanoma of Soft Parts)

For many years this unusual tumor has also been referred to as malignant melanoma of soft parts or clear cell sarcoma of tendons and aponeuroses. Like true melanoma it has a predilection to develop lymph node metastases but in contrast presents as a deep soft tissue mass rather than a cutaneous lesion. Clear cell sarcoma has a distinct chromosomal translocation, t(12;22)(q13;q12), involving EWS and ATF1 genes. Because of the presence of intracellular melanin, and immunoreactivity for S-100 and HMB45 it has been suggested that this entity is better considered a subtype of melanoma and not a soft tissue sarcoma. Recent analysis by genomic profiling and cluster analysis appears to confirm this view.¹⁰⁸

Local Disease

Most STS tend to spread in a longitudinal direction within the muscle groups where they originate, typically an extremity. As they extend, lesions invade muscle and contiguous structures and may envelop major neurovascular structures. The extending border comprises an outer perimeter of edematous tissue intermixed with a reactive zone of neovascularity with interspersed tumor satellites and pseudopodia. This surrounding area is generally termed the pseudocapsule and may encourage erroneous interpretation of anatomic disease containment and encourage enucleation. Such operations, frequently called “shell outs,” almost invariably mean that residual disease remains.

STS generally respect barriers to tumor spread in the axial plane of the extremity such as bone, interosseous membrane, and major fascial planes, and this feature should be exploited in planning tissue-preserving approaches to management. Thus the margins of RT should be wide in the cephalocaudal direction but in the cross section there may be much greater security in defining nontarget structures. Extremity lesions arising in extracompartmental spaces such as the axilla, femoral triangle, sartorial canal, and popliteal space have the ability to extend proximally and distally at considerable distances with less anatomic restraint and early involvement of the neurovascular bundle.¹⁰⁹ The RT margins should reflect this and include undisturbed tissue planes and barriers to tumor incursion. For nonextremity lesions, the direction of sarcoma growth is also along the involved musculature but care must be taken to ensure that the fascial planes are appropriately recognized and encompassed in surgical or RT target volumes.¹¹⁰

A complete description of all the body’s anatomic planes and fascial compartments is beyond the scope of this chapter. Nonetheless, they guide the principles used to manage these lesions. The importance of the osteofascial compartments of the extremities is that, from an anatomic standpoint, they operate as functional units and are protected from each others’ risks of tumor contamination in the absence of inappropriate violation of the subdividing fascial septa. The latter may occur with misplaced surgical intrusion, including inappropriate placement of drain or biopsy tracts.¹¹¹

The fascial structures are also important because they guard tumors arising superficial to the fascia investing the muscles of the region from the deeper structures. Tumors arising in subcutaneous tissues are staged differently to those arising deep to the fascia. In the event that the fascia has been disrupted, as is often the case after an “unplanned” sarcoma resection with positive margins, it may provide a route for deep contamination by tumor.

Regional Lymph Node Involvement

In STS there is generally no need for any specific regional lymph node treatment. Important exceptions to this generalization include epithelioid sarcoma, clear cell sarcoma, angiosarcoma, and rhabdomyosarcoma^100,101,112 (Table 63-3). More recently, regional lymph node metastases were detected in 28 of 1597 cases treated within a single institution. Results are similar to that reported in Table 63-3, with epithelioid sarcoma and clear cell sarcoma subtypes having the highest lymph node involvement.¹¹² Traditionally, lymph node involvement has been associated with an adverse prognosis rivaling that of distant metastasis. However, data suggest that isolated lymph node metastasis may not be as deleterious a factor.^113,114 This is reflected in the most recent version of the TNM staging system (see later section on staging).⁶³

Distant Metastasis

Most sarcomas present with localized disease, and overt metastasis is present in only 10% of cases at diagnosis. Typically, the patient is asymptomatic and staging investigations are required to demonstrate metastases. The predominant risk is to the lungs. Spread to bone may be seen after lung metastases but is seen with the greatest regularity in myxoid liposarcoma, where it may be the first site of relapse. Myxoid liposarcoma also has the unusual characteristic of developing isolated soft tissue metastases. In patients with retroperitoneal sarcoma and intra-abdominal visceral sarcomas, the liver is a more common site of first metastasis.

Multidisciplinary Management

Consistency in approach to these rare diseases allows comparison of treatment approaches from center to center as well as ensuring quality of care. An essential component to accomplish this is the implementation of multidisciplinary teams consisting of surgeons, radiation oncologists, medical oncologists, pathologists, radiologists, and personnel from support disciplines that allow for the optimal care of these complex cases.¹¹⁵ With a multidisciplinary team, all members ideally would see the patient and participate in formulating a treatment plan before implementation of any component of therapy.

Part of the multidisciplinary approach must also include an appreciation of the principles for safe acquisition of diagnostic tissues as well as review of pathology by an experienced pathologist. Lehnhardt and associates¹¹⁶ showed that expert pathology opinion was essential for optimal treatment of sarcoma and remains a source of concern even when expertise is present. Discordance in diagnosis (tumor entity and grading) was apparent in excess of 70% of cases among pathologists in private clinics, slightly less in general hospital pathology departments, was evident in 66% of cases in an academic environment, and was only improved to 30% in a sarcoma reference center even when punch or needle biopsies were not being considered. Inexperience of the pathologist was considered a strong factor leading to discrepant diagnosis, thereby warranting a recommendation for routine expert second opinion.¹¹⁶

Another practical but important factor is that the radiation oncologist should ideally be aware of and preferably have an opportunity to see the patient before any surgery being performed. Otherwise, imaging and pathology details may be lacking or inadequate and precisely appreciating the original tumor characteristic for accurate postoperative adjuvant treatment may not be possible. The consequence of a fragmented RT service with significantly compromised outcome was evident in a study that addressed an extremity subsite of STS in one center where the local failure was 28% compared with that in two other centers (local failure 5% to 10%) where treatment and consultation were restricted to sarcoma specialist radiation oncologists working in the same multidisciplinary setting as the surgeons.¹¹⁷

A recent report¹¹⁸ evaluated outcome in 4205 operative cases of STS and showed that high-volume centers (those in the upper one third of case of volume in a geographic region) reported better survival outcomes. Smaller centers may have more difficulty formulating a multidisciplinary team with all necessary components of care, including access to an effective multidisciplinary cancer conference that meets frequently and regularly.

Initial Assessment

The overall initial evaluation of a patient with a soft tissue sarcoma is summarized in the diagnostic algorithm (Fig. 63-5). All soft tissue masses deep to the investing fascia should be considered to be sarcoma until proven otherwise. The type of biopsy, or a prior inappropriate excision, may jeopardize the form and outcome of local treatment by contaminating tissues that were uninvolved initially. Before embarking on treatment, histologic confirmation of the diagnosis is necessary. To minimize the risk of undesirable outcome, prebiopsy cross-sectional imaging is necessary to avoid compromising the planning of management.

Figure 63-5 Diagnostic algorithm for the initial evaluation of a patient with soft tissue sarcoma. All soft tissue masses deep to the investing fascia should be considered sarcomatous until proved otherwise. Emphasis is needed on the type of biopsy and pathologic assessment. Most patients require CT or MRI for the local disease assessment, and most patients require CT to exclude metastatic disease. Cerebrospinal fluid analysis for tumor cytology is indicated in parameningeal rhabdomyosarcoma.

In addition to the diagnostic interventions, assessment should include a thorough clinical assessment including history and clinical examination, with particular attention to the relationship to the investing fascia deep to the subcutaneous fat (i.e., whether superficial vs. deep) and adjacent neurovascular structures or bone and lesion size and mobility.

Imaging

Accurate, highly sophisticated imaging to delineate tumor extent for diagnostic, surgical, and RT planning is essential to the management of sarcoma. Plain radiography, bone scintigraphy, angiography, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) are generally not helpful in determining the diagnosis, but all may contribute in different ways to delineation of the extent of local involvement. The authors have recently discussed the imaging characteristics of STS in detail.¹¹⁹

Plain radiography remains useful to establish a differential diagnosis for primary bone tumors but is of little value in the evaluation of STS. Particularly important is the ability of CT to accurately delineate bony anatomy surrounding the tumor. This is crucial in preoperative planning for ablation and reconstruction. CT is also important in assisting in differential diagnosis, because MRI is insensitive to certain features such as calcification. Unfortunately, a limitation of CT is that it acquires and optimally displays images in the axial plane, but sagittal and coronal reformatted images lose detail.

The multiplanar imaging and soft tissue detail rendered by MRI makes this modality ideal for staging and treatment planning of STS. Although MRI is highly accurate in delineating the extent of a soft tissue abnormality, it continues to be nonspecific. Most STS will appear as low signal intensity on T1-weighted images and high signal intensity on T2-weighted images. These features are nonspecific and require a biopsy for diagnosis. MRI is also essential to evaluate peritumoral edema that is not as apparent with CT. In general, a prominent anatomic area (e.g., a joint) should be included in the field of view to permit adequate localization for treatment planning.

A “blinded” study by the Radiation Diagnostic Oncology Group¹²⁰ that compared MRI and CT in patients with malignant bone and soft tissue tumors showed no specific advantage of MRI over CT. Although the diagnostic evaluation may be equally served by both modalities, the treatment planning requirements (for both surgery and RT) frequently require additional information, including advantages through MRI/CT image fusion techniques.

PET has an emerging role in the evaluation of STS.^119,121,122 It uses radiotracers specific for biologic processes to produce images of regional tissue metabolism with ¹⁸F-fluorodeoxyglucose (FDG), the most commonly employed radiotracer for this purpose. New tracers are being evaluated that may refine the differing roles for PET that include evaluation of (1) the grade and extent of local disease, (2) the detection of malignant transformation in neurofibromatosis, (3) the presence of regional or distant metastases, and (4) the response to initial (i.e., neoadjuvant) treatment as a surrogate to prognosticate on future outcome. It does seem that high- versus low-grade lesions may be distinguished and may even provide an imaging technique for biopsy guidance; in addition, response prediction to induction treatments seems to be possible.^{119,121–123,124}

Despite the preceding discussion, the contribution of PET to routine management is currently uncertain. It is clear, however, that radiotracers specific for glucose metabolic imaging or imaging of tumor cell proliferation cannot yet replace biopsy and histopathologic evaluation for sarcoma grading.¹²³

The most common metastatic spread pattern of sarcoma is to the lungs. Consequently, imaging of the chest is necessary using chest radiography in low-grade lesions but CT of the chest is always necessary for high-grade tumors.

Exclusion of Metastasis

For metastatic staging, CT of the chest is required, excepting very low-grade lesions or small lesions where a plain chest radiograph may be sufficient. If the underlying diagnosis is rhabdomyosarcoma, a bone marrow biopsy should be considered as well as cerebrospinal fluid analysis in parameningeal lesions. For retroperitoneal, visceral, and intra-abdominal lesions, the site of metastasis that is most common (i.e., the liver) should be evaluated with the modality that is used for evaluation of the primary lesion.

Rhabdomyosarcoma

For rhabdomyosarcoma two separate classifications of disease extent exist. The original description of disease extent had been by a postoperative surgical classification developed by the North American Intergroup Rhabdomyosarcoma Study Group (IRSG). Currently, such lesions will frequently be treated with induction protocols well in advance of surgery. Therefore, reliance on a surgical staging system is problematic. The International Society of Pediatric Oncology (SIOP) employs a TNM presurgical staging system more in keeping with contemporary TNM staging. Both use a T-category breakpoint at 5 cm, and one of these two pretreatment approaches may be accepted more uniformly in the future.

Proposed Staging for Retroperitoneal Sarcomas

Retroperitoneal sarcomas are currently classified by the TNM system. However, another classification system has been developed based on grade, completeness of resection, and distant metastases.¹³⁰ For class 1 (low grade/grossly complete resection/no metastases) the stage-specific 5-year survival rate was 89%. For class 2 (high grade/grossly complete resection/no metastases) the 5-year survival was 40%. For class 3 (any grade/incomplete resection/no metastases) it was 26%; and for class 4 (distant metastases) it was 17%. These results were obtained from a cohort of patients treated in a single tertiary referral center (n = 107). Five-year OS was 55%. This classification is also problematic from a methodologic standpoint because it requires one parameter (the completeness of resection) to become available after the main treatment has been undertaken and thus cannot be applied at baseline when the patient first presents with sarcoma. Validation is required before it can be considered for general use.

Gastrointestinal Stromal Tumors

For the first time GIST is included in the TNM staging system with separate stage grouping schemes provided for gastric, omental, and small intestinal tumors. This new staging system uses tumor size, dissemination status, and mitotic rate as the staging parameters. Tumor size is partitioned at the 2-, 5-, and 10-cm breakpoints. Mitotic rates are categorized as low and high. Of interest is the use of two stage grouping schemes depending on whether the tumor has arisen in the stomach or omentum as opposed to other sites within the abdomen or esophagus (Table 63-5).

Extent of Surgery and Causes of Different “Resection Margins”

Of more importance than the description of the type of surgery is the actual extent of viable residual disease remaining after surgery. This is not a precise variable but is best represented by expert pathologic assessment of the surgical “resection margin.” Characterization of the margin guides the need for adjuvant RT for those tumors with insufficient normal tissue surrounding tumor to reliably prevent local recurrence. Having positive margins nearly doubles the risk of local recurrence and increases the risk of distant recurrence and disease-related death.¹³⁸ Stoeckle and associates¹³⁹ reported a fourfold difference in local recurrence between resections with negative versus positive margins in their single-center prospective evaluation of 205 patients who underwent surgery for STS of the extremity or trunk wall. Moreover, Gronchi and colleagues¹⁴⁰ found that the quality of surgical margins independently predicted local control and survival but not distant metastases after evaluation of 997 consecutive patients affected by primary extremity STS. These authors reported that survival was directly influenced by local recurrence in pelvic and shoulder girdle sites and maintained that higher surgical aggressiveness is necessary in these situations.

We have shown that positive resection margins may have different causes with potential for different outcome. However, two categories of positive surgical margins are associated with a higher risk of local recurrence despite the use of adjuvant RT: (1) patients who present after pre-referral unplanned excision and who have a positive margin on subsequent reexcision (local recurrence rate: 31.6%) and (2) those with unanticipated positive margins occurring during primary sarcoma resection (local recurrence rate: 37.5%).¹⁴¹ Therefore the policy in STS surgery of attempting to achieve negative surgical margins is sound and this is best accomplished by performing surgery at an experienced referral center. Nonetheless, in this context some caveats exist. For example, patients with microscopically positive margin low-grade liposarcomas have a low risk of local failure (recurrence rate: 4.2%), as do patients in whom a positive margin is anticipated before surgery to preserve critical structures, and RT is able to sterilize the minimal residual disease (recurrence rate: 3.6%). In the latter setting it appears that a small, isolated positive resection margin, planned from the outset by the multidisciplinary team with the intention of sparing a critical anatomic structure (e.g., at a major nerve, vessel, or bone), has a favorable outcome, provided adjuvant RT is appropriately applied, compared with the more extensive margin-positive situations noted earlier in which significant local contamination may be present.¹⁴¹

Although recent data indicate that the unplanned surgery (without reexcision) situation can often be managed successfully with immediate RT,¹⁴² we remain concerned that substantial contamination means that subsequent RT will be less successful. In addition, the burden of residual disease may often be underestimated.¹⁴¹ Chandrasekar and colleagues¹⁴³ found that of 316 reexcisions after an unplanned excision of a soft tissue sarcoma, 188 patients had residual tumor (59%). Furthermore, patients had a higher likelihood of developing a local recurrence if the reexcision specimen contained residual tumor. Cahlon and associates¹⁴⁴ reported the long-term outcomes in extremity STS after pathologically negative re-resection without adjuvant RT. An overall local recurrence rate of 9% was reported for 200 patients. However, patients of older age and/or stage III disease had an increased rate of local recurrence, prompting the authors to comment that treatment decisions especially with regard to the adjuvant use of RT should not be based solely on the finding of a negative re-resection.

Surgery Alone

Amputation

The polar opposite circumstance in which RT is usually omitted is when amputation is performed. There may rarely be a need to deliver RT after amputation when there has been unsatisfactory clearance of at risk tissues, especially in very proximally positioned extremity lesions.

Even in a milieu in which limb preservation with adjuvant RT is a preferred policy, there will always remain a group of patients who are better treated with amputation.¹⁵⁰ At Memorial Sloan-Kettering Cancer Center (MSKCC) from 1968 to 1990 the amputation rate fell from 50% to below 5%¹⁵¹ and at the Princess Margaret Hospital amputation was never popular and only used in 7 of 226 patients with extremity STS treated between 1980 and 1988,¹⁵² both experiences providing strong evidence that the indications for this approach should be rare.¹⁵³ Amputation only should be performed (1) when it is impossible to achieve adequate surgical clearance because the lesion involves major neurovascular structures or multiple compartments (Fig. 63-7); (2) when potential major RT complications would result from dose and volume considerations; and (3) in some lower extremity distal lesions when a below-knee amputation prosthesis may be more serviceable than a limb damaged by extensive surgery and RT.¹⁵⁴

Figure 63-7 A, An axial T1-weighted (TR, 800 msec; TE, 10 msec) image of a complex dedifferentiated liposarcoma of the right thigh necessitating above-knee amputation because of multicompartmental and composite soft tissue involvement. A large multilobulated mass encases the sciatic nerve and femoral neurovascular bundle. The posterior component of the mass was predominantly composed of fat signal (white arrows) and involved the posterior compartment of the thigh. The more anterior and higher-grade component (asterisk) lay predominantly within the vastus medialis muscle and was of intermediate signal. B, A corresponding sagittal view demonstrates encasement of the femoral neurovascular bundle (black arrow) by the dedifferentiated component of the tumor (asterisk).

Adapted from Ghert MA, Abudu A, Driver N, et al: The indications for and the prognostic significance of amputation as the primary surgical procedure for localized soft tissue sarcoma of the extremity, Ann Surg Oncol 12:10-17, 2005. With permission of Springer and Business Media.

Rationale for Adjuvant Radiation Therapy

Adjuvant RT is generally used to permit more conservative tissue resections and therefore less-extensive operations than would have ordinarily been the case. External beam photons delivered preoperatively or postoperatively or by brachytherapy are the usual modes of administration. Strander and colleagues,¹⁵⁵ in a systematic overview involving 4579 patients, employed data from 5 randomized trials, 6 prospective studies, 25 retrospective studies, and 3 additional articles. Adjuvant RT improved the local control rate in combination with conservative surgery in the treatment of STS of the extremities and trunk in patients with negative, marginal, or minimal microscopic positive surgical margins. A local control rate of 90% is expected. More recently, Kim and colleagues¹⁵⁶ reported no significant difference between patients who received RT with R0 margins compared with those treated with close or positive margins combined with RT in terms of local failure free and OS and concluded that margin status did not predict for local failure when adjuvant RT is used. Similarly, the Scandinavian group found that RT improves local control regardless of surgical margin and grade in extremity and trunk wall STS, with the effect being most pronounced in deep-seated, high-grade tumors even if removed with a wide surgical margin.¹⁵⁷ Improvement is obtained with RT after intralesional surgery, but the local control rate is less satisfactory.

For STS in other anatomic sites, such as retroperitoneum, head and neck, breast, and uterus, the benefit in local control with adjuvant RT is less compelling.¹⁵⁵ In the situation in which positive margins remain after surgery, postoperative RT doses greater than 64 Gy, superficial tumor location, and extremity site have been associated with improved local control.¹⁵⁸ For circumstances in which preoperative RT is given and positive margins are found on surgical resection, the effectiveness of a postoperative RT boost is debatable. We retrospectively analyzed 216 patients with positive surgical margins treated with preoperative RT for extremity STS. Fifty-two of these patients were treated with preoperative RT alone (50 Gy) and were compared with 41 who received preoperative RT plus a postoperative boost (80% received 16 Gy postoperatively for a total dose of 66 Gy). The patients who received a postoperative boost had lower 5-year estimated local recurrence-free survival rates (73.8% vs. 90.4% for preoperative RT only). The postoperative boost after preoperative RT did not provide an advantage in preventing local recurrence.¹⁵⁹ We therefore avoid scheduling a postoperative boost owing to the increased risk of difficult-to-treat RT morbidities with the higher radiation doses involved and because of previous clinical experience that patients who could not receive a postoperative boost because of wound healing complications or other contraindications did not seem to be at a higher risk of local recurrence.

Details of the Randomized Trials of Adjuvant Radiation Therapy

As mentioned earlier, adjuvant RT with conservative surgical resection has been evaluated in two randomized clinical trials.^134,135 Yang and associates¹³⁵ at the NCI randomized high-grade extremity lesions after limb-sparing surgery to receive adjuvant RT or no further treatment after the surgery. Concurrent chemotherapy was also used depending on grade. The local control for those receiving RT was 99% compared with 70% in the control group (p = .0001). The results were similar for high- and low-grade tumors. Adjuvant RT, using brachytherapy, was also evaluated in a randomized trial at MSKCC with a similar effect in high-grade lesions.¹³⁴ No improvement in local control was evident with brachytherapy in the low-grade tumors (see Table 63-6), which was attributed to more slowly cycling cells that are thereby excluded from the radiosensitive phases of the cycle during brachytherapy.¹³⁴

Scheduling: Preoperative versus Postoperative Radiation Therapy

The two most common methods of RT delivery are preoperative or postoperative external beam. A Canadian randomized trial compared preoperative and postoperative RT in extremity STS.74,160 Wound complications were twice as common with preoperative RT as with postoperative RT (35% vs. 17%), although the increased risk was almost entirely confined to patients with sarcomas of the lower extremity.⁷⁴ RT toxicity rates in the Canadian trial after 2 years differed between the two arms of the study with a tendency to manifest greater fibrosis in the postoperative arm of the study.¹⁶¹ This analysis suggested strongly that larger treatment volumes were predictive of greater joint stiffness and fibrosis and may also contribute to limb edema. Patients with late treatment responses such as fibrosis, joint stiffness, or limb edema had significantly lower limb function scores at later time points.¹⁶¹

With 3.3 years median follow-up, the initial report of the Canadian trial showed identical local control between the two arms of the trial and identified an early improvement in OS (p = .0481) in the preoperative RT arm⁷⁴ that was not substantiated with 5-year results.¹⁶⁰ The 5-year results for preoperative versus postoperative RT, respectively, were as follows: local control, 93% versus 92%; metastatic relapse free, 67% versus 69%; recurrence-free survival, 58% versus 59%; OS, 73% versus 67% (p = .48); and cause-specific survival, 78% versus 73% (p = .64). Only resection margins were significant for local control. Tumor size and grade were the only significant factors for metastatic relapse, OS, and cause-specific survival. Grade was the only consistent predictor of recurrence-free survival.¹⁶⁰

Recently, a literature-based meta-analysis of oncologic outcomes of preoperative versus postoperative RT in localized resectable STS analyzed five eligible studies that included a total of 1098 patients. This analysis suggested that the risk of local recurrence may be lower after preoperative RT and that the risk of metastatic spread is not increased with the delay in surgical resection necessary to complete preoperative RT.¹⁶² Furthermore, Sampath and associates¹⁶³ assessed the impact of RT sequencing on OS and cause-specific survival. A retrospective analysis was conducted using the National Oncology database and found 1087 patients who received RT with surgery. OS was significantly improved with preoperative RT versus postoperative RT, with a median survival of 124 months and 90 months, respectively (p = .02). Cause-specific survival was also significantly higher with preoperative RT.

Radiation Therapy Alone

Although every effort should be made to attempt resection, there remain patients in whom definitive RT may be considered owing to a combination of unresectability and/or medical comorbidity or to achieve palliation when surgery is not considered appropriate. Tepper and colleagues¹⁶⁴ treated 51 patients with definitive photon beam irradiation to a total dose of 64 to 66 Gy. The 5-year local control and survival rates were 33% and 25%, respectively. Local control was better for tumors less than 5 cm (87.5%) than in tumors 5 to 10 cm (53%) or greater than 10 cm (30%). More recently, Kepka and associates¹⁶⁵ updated this series that now contains 112 patients who underwent RT for gross disease. Local control at 5 years was 51%, 45%, and 9% for tumors less than 5 cm, 5 to 10 cm, and greater than 10 cm, respectively (Fig. 63-8A). Patients who received doses of less than 63 Gy had inferior 5-year outcomes compared with those receiving higher doses, including local control of 22% versus 60% (Fig. 63-8B); disease-free survival (DFS) of 10% versus 36%, and OS of 14% versus 52%. These researchers also noted a rise in complications at doses of 68 Gy or more, which appears to provide a therapeutic window.¹⁶⁵

Figure 63-8 A, Local control according to tumor size of unresected soft tissue sarcoma in a single institution using definitive RT, an uncommon approach in management. B, Local control by total radiation dose partitioned at the 63-Gy level.

From Kepka L, Delaney TF, Suit HD, Goldberg SI: Results of radiation therapy for unresected soft-tissue sarcomas, Int J Radiat Oncol Biol Phys 63:852-859, 2005.

Potentially, higher doses of RT with concurrent dose-intensified chemotherapy regimens, possibly delivered with conformal RT volumes to further protect normal tissues, provide an opportunity to enhance local control in this setting. Preliminary data using a concurrent ifosfamide-based protocol exists and may provide an opportunity to address unresectable disease.¹⁶⁶

Rhomberg and associates¹⁶⁷ prospectively evaluated the radiation sensitizer razoxane in a randomized controlled trial. Among 82 patients with gross disease, RT combined with razoxane demonstrated an increased response rate compared with photon irradiation alone (74% vs. 49%) with improved local control (64% vs. 30%, p <.05). Acute skin reactions were enhanced in the “sensitizer” arm, but late toxicity was not increased. Jakob and colleagues¹⁶⁸ similarly used temozolomide preoperatively in combination with intensity-modulated irradiation (IMRT) for large STS at problematic sites where clear resection margins could not be achieved. An R0 resection was achieved in 7 of 15 cases. The antitumoral effect of temozolomide seems to depend on methylguanine methyltransferase promoter methylation status; and although present in subgroups of STS there are no data available from phase II studies testing the activity of temozolomide in STS. These data will need confirmation with a larger patient population.

Radiation Therapy Modality

External beam irradiation (EBRT) and brachytherapy represent the two common methods of RT for STS, but randomized data comparing these modalities directly are not available.

Radiation Therapy Dose

Radiation Target Volume

The existence of a zone of uncertain size and location that may contain subclinical disease in proximity to the presenting site of the primary tumor presents a frequent dilemma. The size and extent of the putative “risk zone” depends on a number of factors. They include the amount of disturbance of tissue planes and barriers to tumor incursion that may already have taken place, including scars and drain sites. Such areas will need to be included with an appropriate margin. In the preoperative setting the gross tumor volume (GTV) is typically represented by the radiologically defined tumor but the acceptable volume margin remains problematic, depending on the nature of the prior biopsy, the anatomic containment of the lesion, and the imaging characteristics of the lesion. The latter feature concerns the imaging changes evident on MRI beyond the overt tumor evident on clinical examination or even CT and how this information should impact on treatment planning.

The local growth characteristics of STS have suggested that tumor cells may be located in the surrounding soft tissues at some distance from the main tumor mass.^206,207 The original observation led to the development of the concept of a “reactive zone” surrounding the lesion, situated between the tumor margin/pseudocapsule and more remote normal tissues. The reactive zone was described as consisting of a granulation tissue–like proliferation whose characteristics included edema and neovascularity and, in addition, might contain satellite tumor cells.²⁰⁷ MRI has documented high T2-weighted signal changes surrounding STS. These radiographic abnormalities are thought to be caused by increased water content and have, therefore, been labeled “peritumoral edema.” However, it is not clear whether these MRI findings are actually the result of tissue edema and correspond to the reactive zone noted earlier or also contain tumor cells.²⁰⁸

With this in mind, we reported a small series (n = 15) of patients in which we identified if satellite tumor cells can be identified histologically in the tissues surrounding STS and whether their presence correlates with increased T2-weighted signal intensity on MRI (Fig. 63-9). Sarcoma cells were identified histologically in the tissues beyond the tumor in 10 of 15 patients who had not received previous RT. In six cases, tumor cells were located within 1 cm of the tumor margin, and in four cases malignant cells were found at a distance greater than 1 cm and up to a maximum of 4 cm. The location of tumor cells beyond the margin did not correlate with tumor size, nor did it correlate with the location or extent of peritumoral changes.²⁰⁹

Figure 63-9 Sagittal T1-weighted (A), fat-suppressed fast spin-echo T2-weighted (B), and contrast-enhanced fat-suppressed T1-weighted (C) MR images of a liposarcoma of the posterior thigh. Peritumoral increased T2-weighted signal intensity (arrows) seen both proximally and distally to tumor periphery on T2-weighted image (B), with mild corresponding enhancement on contrast-enhanced T1-weighted image (C).

Adapted from White LM, Wunder JS, Bell RS, et al: Histologic assessment of peritumoral edema in soft tissue sarcoma, Int J Radiat Oncol Biol Phys 61:1439-1445, 2005.

In the discussion that follows, dose-volume guidelines for both EBRT and brachytherapy are summarized (see Table 63-7) based on parameters used in two randomized controlled trials and bearing in mind anatomic and imaging characteristics of the lesions and normal tissues.

Brachytherapy Volumes

The American Brachytherapy Society has recommended at least a 2- to 5-cm longitudinal margin beyond the CTV and at least 1 cm beyond the lateral edge of the CTV¹⁸³ (Fig. 63-10). These are based on general agreement by experts, although there is no consensus as to the exact size of the margin beyond the tumor bed. The CTV may be difficult to define but in general is represented by the volume of tissue considered at risk for microscopic extension of tumor and includes the tumor bed visualized on radiographic studies and under direct inspection intraoperatively.¹⁸³ The brachytherapy protocol at MSKCC uses margins of 2 cm around the surgical bed.^215,216

Figure 63-10 American Brachytherapy Society guidelines for catheter positioning for soft tissue sarcoma. Catheters are placed 1 to 2 cm beyond the lateral edge of the clinical target volume and 2 to 5 cm beyond the clinical target volume in the longitudinal direction.

From Nag S, Shasha D, Janjan N, et al: The American Brachytherapy Society recommendations for brachytherapy of soft tissue sarcomas, Int J Radiat Oncol Biol Phys 49:1033-1043, 2001.

Combined Preoperative Chemotherapy and Radiation Therapy

Enhancing the local effect of RT with concurrent chemotherapy while also promptly addressing the distant metastasis risk before the surgery is an attractive concept. Strategies include the use of perfusion techniques (see later) as well as a sequential intravenous chemotherapy and RT strategy in patients with localized, high-grade, large (>8 cm) extremity STS described by DeLaney and colleagues.²¹⁷ The protocol involved three courses of doxorubicin (Adriamycin), ifosfamide, mesna, and dacarbazine (MAID) interdigitated with two 22-Gy courses of RT (11 fractions each) for a total preoperative radiation dose of 44 Gy. This was followed by surgical resection. An additional 16 Gy (8 fractions) boost dose was delivered if the surgical margins were microscopically positive. The outcomes of 48 patients treated with this regimen appeared superior to those of a matched cohort of historical controls. The 5-year OS were 87% versus 58% (p = .0003) for the MAID versus control patients cohorts with the difference linked to an improvement in the distant metastases rate (5-year freedom from distant metastasis rate of 75% versus 44% (p = .0016), and the local control was similar in both groups. Febrile neutropenia occurred in 25% of patients receiving the chemotherapy/RT sequential therapy; 14 (29%) of the patients treated with MAID also experienced wound complications. Late fatal myelodysplasia was seen in 1 patient who received chemotherapy.

Because of the promising results seen in this single-institution pilot study, the RTOG initiated a phase II trial to evaluate this neoadjuvant regimen in a multi-institutional intergroup setting. Kraybill and colleagues²¹⁸ reported the short-term results of this phase II study in the management of high-risk, high-grade STS of the extremities and body wall. Patients received neoadjuvant modified MAID, interdigitated preoperative RT (44 Gy administered in split courses), and three cycles of postoperative modified MAID. Estimated 3-year rates for DFS, distant DFS, and OS were 56.6%, 64.5%, and 75.1%, respectively. There were three deaths associated with this protocol (5%). Two were secondary to acute myelogenous leukemia, and the third patient died secondary to leukopenic sepsis and respiratory failure. Grade IV toxicity was experienced by 84% of patients. Five patients required amputations, two of which were related to treatment toxicity. The authors noted the substantial toxicity of this trial, precluding its unmodified use outside of a clinical trial setting. Most recently, the long-term results have been published with a median follow-up for surviving patients of 7.7 years and all but four of the surviving patients having had more than 5 years’ follow-up. The 5-year estimated rates of disease-free and distant DFS, 56.1% and 64.1% respectively, are favorable for disease of this size and grade.²¹⁹ In addition, the incidence of significant toxicity was markedly reduced after 1 year and almost completely resolved after 2 years.

Additional protocols have been developed with adjuvant and neoadjuvant chemotherapy because of the biology of STS and poor outcome. However, concern remains regarding efficacy and toxicity issues concerning these protocols.28,98,220,221

Neoadjuvant Chemotherapy with Regional Hyperthermia

The rationale behind using regional hyperthermia combined with chemotherapy is the theory that heat kills cells by direct thermal toxicity and will concentrate the action of chemotherapy within the heated volume, increase drug efficacy, and induce tumoricidal immune responses. Recently, the results of a randomized phase III multicenter clinical trial were reported that compared the effects of neoadjuvant chemotherapy with and without regional hyperthermia in addition to local therapy (surgery and RT when indicated) for localized intermediate/high-risk STS.²²² Despite nine centers being involved, only three contributed the majority of patients to the trial (310 of 341). Local recurrence rates were high for both extremity and nonextremity tumors; the addition of hyperthermia seemed to benefit patients whose tumors were inadequately managed by surgery alone and who were treated at centers with experience administering this technique.²²³ The precise indications for the use of RT were not defined in the report of this study, although it has been suggested that RT may have been restricted to R1 and R2 resections, which may explain the high rate of local recurrence in this series.²²³

Isolated Limb Perfusion with Extracorporeal Bypass

Isolated limb perfusion (ILP) has been popularized in Europe and was developed predominantly as a means of addressing the more prevalent local control problem of limb threat from satellitosis and in-transit metastases complicating malignant melanoma. The essential requirement is limb arterial and venous access to isolate the limb from the remainder of the body through an extracorporeal circulation system. A heart-lung machine is used to reoxygenate the blood recirculating from the limb. The blood in the extracorporeal circuit is also often warmed to 39°C to 40°C to enhance the effect of chemotherapy.²²⁴ After isolation of the extremity a chemotherapeutic agent is perfused into the limb. Several have been used with the most effective or popular being melphalan with tumor necrosis factor–alpha (TNF-α) at a highly lethal dose under normal circumstances.²²⁵ TNF-α was initially approved in Europe after a multicenter trial²²⁵ in patients with locally advanced STS deemed unresectable by an independent review committee; the response rate to isolated limb perfusion with TNF-α plus melphalan was 76%, and the limb was saved in 71% of patients. Both components of the regimen (melphalan and TNF-α) appear important, and omission of TNF-α has resulted in a decrease in the tissue dose of melphalan, probably from its effects on the tumor vasculature with subsequent treatment failure.²²⁶ Recent efforts, including a randomized trial (see Table 63-6) have focused on attempts to reduce the dose of TNF to try to reduce toxicity.^227,228 Hyperthermic ILP with lower dose TNF-α (1 mg) has been shown to be as effective in terms of response rates and patient outcomes for a group of patients with locally advanced or recurrent STS,²²⁹ including progressive desmoid-type fibromatosis. It has the benefit of lower systemic toxicity rates compared with protocols using higher TNF-α doses. Other authors²³⁰ have reported results using doxorubicin instead of melphalan and higher temperature (42° C).

The major component of the selection for the ILP approach hinges on the decision that patients would otherwise require amputation with marked loss of function if treated in conventional ways. Following this, patients who develop resectable disease usually undergo surgery. The response rates for multiple primary STS and melanoma appear very similar: overall response of 95% and 96% for both diseases and complete response of 69% (in melanoma) and 61% (in multiple primary STS).²²⁴ Grünhagen and associates²³¹ reported the outcome and prognostic factor analysis of 217 consecutive ILPs with TNF-α and melphalan for limb-threatening STS. The overall response rate was 75%, and limb salvage was achieved in 87% of the perfused limbs. The same authors have also reported efficacy of this treatment for locally advanced extremity desmoid tumors in a small study of 11 patients.²³² Amputation was avoided in all cases, and the authors suggest it should be considered when resection without important functional sacrifice may be deemed improbable.

Recently, others have reported long-term damage of ILP to the healthy surrounding normal tissue. Hoven-Gondrie and colleagues²³³ evaluated the long-term morbidity of the combined treatment of ILP and delayed surgical resection followed by EBRT for 32 patients. Serious late toxic effects were seen in two thirds of the patients. Similarly, additional reports have described late morbidity, including critical leg ischemia necessitating limb amputation as well as pathologic fractures 5 to 10 years after treatment.^234,235

Given the complexity and potential toxicity associated with this approach, it is tempting to speculate about how these results would compare with conventional adjuvant RT, and a randomized trial comparing the two approaches would not be unreasonable.

Limb Perfusion without Extracorporeal Bypass

Techniques of percutaneous instillation of chemotherapy into the vessels of the affected limb have been employed for decades. Eilber and colleagues¹⁹⁰ first described the use of preoperative intra-arterial chemotherapy with doxorubicin combined with RT. This infusional approach is conceptually attractive because it provides high doses of chemotherapy directly into the affected limb but, as noted later, was later found equivalent to intravenous chemotherapy. A feature of the protocol described by Eilber and colleagues is the use of higher dose per fraction (3.5 Gy per fraction) compared with more conventional preoperative approaches. The total dose used in the protocol also has varied over the years with doses of 17.5 Gy, 28 Gy, and the original protocol of 35 Gy preceded by a 3-day infusion of intra-arterial doxorubicin. In the first of two randomized trials, the 17.5-Gy regimen was evaluated in combination with additional postoperative chemotherapy but it had no additional benefit compared with no further chemotherapy.²³⁶ In the second trial (n = 99), the intra-arterial approach with 28 Gy was compared with an intravenous approach and they were found not to be different.²³⁷

More recently, Hegazy and associates²³⁸ reported the results of 40 patients with locally advanced extremity STS (28 lower limbs, 12 upper limbs) who received preoperative isolated limb infusion with doxorubicin and external irradiation for limb-threatening STS. Isolated limb infusion was started 3 to 7 days before EBRT to a total dose of 35 Gy in 10 fractions. After a 3- to 7-week interval before surgery, tumor response was seen in 85% of patients, histologic response was seen in 80%, and limb salvage was achieved in 82.5% at a median follow-up of 15 months. One advantage advocated by Hegazy and associates²³⁸ is its use in limb-threatening presentations as opposed to limiting it to conventional adjuvant use. These promising results for this indication require validation in larger patient cohorts.

Particle Radiation Therapy

There is substantial interest in the use of heavier charged particles, in particular, carbon ions, because of their excellent physical dose distribution and higher relative biologic effectiveness in some situations. Serizawa and colleagues²³⁹ have reported the results of carbon ion RT for 24 patients with unresectable high-grade retroperitoneal sarcomas: 16 had primary disease and 8 had recurrent disease. The dose ranged from 52.8 to 73.6 GyE (Gy-equivalent) in 16 fixed fractions over 4 weeks with OS at 2 and 5 years of 75% and 50%, respectively. Local control rates were 77% and 69% at 2 and 5 years. Of interest were the low toxicities seen, with no gastrointestinal tract complications encountered and no observed toxicity greater than grade II. Others^240,241 have reported similar survival for low-grade chondrosarcomas, locally advanced sarcomas not suitable for surgery, and recurrent tumors with low toxicity rates.

Spot scanning proton beam therapy has been used in the curative treatment of STS located in the vicinity of critical structures such as the spinal cord, optic apparatus, bowel, and kidney with comparable local control to EBRT approaches as well as acceptable toxicity levels. Experience is limited.^242,243

Promising results were achieved in a phase II study of high-dose photon/proton RT with modern surgical techniques in the management of nonmetastatic spine and paraspinal sarcomas, particularly for primary spine tumors. For a total of 50 patients with a median follow-up of 48 months, the 5-year actuarial local control, recurrence-free survival, and OS were 78%, 63%, and 87%, respectively. Three sacral neuropathies appeared after 77.12 to 77.4 Gy relative biologic effectiveness.²⁴⁴

Meta-analysis of Randomized Trials

The results from 14 randomized trials performed over three decades were comprehensively combined from 1568 patients in a landmark meta-analysis¹²⁴ that used individual patient data. This study addressed the role of doxorubicin-based adjuvant chemotherapy in STS. In the meta-analysis, the figures for distant relapse-free interval and overall recurrence-free survival were significantly in favor of the use of adjuvant chemotherapy. However, and most importantly, the difference in OS, the ultimate aim of adjuvant chemotherapy, was not significantly different between the chemotherapy and the control groups (p = .12).

Only three trials^245–247 in the meta-analysis had a relatively large sample size. The inclusion of cases with minimal or only small risk of metastatic failure may have diluted the power of the studies to detect an effect that could only realistically apply to those patients who have a genuine risk of metastasis.

Studies Since the Individual Patient Data Meta-analysis

Since the publication of the meta-analysis, an important study was reported from Italy. The inclusion criteria for this trial were appropriately restricted to very adverse tumors (large high-grade lesions) and a very intensive cytotoxic regimen (five cycles of 4′-epidoxorubicin 60 mg/m² days 1 and 2 and ifosfamide 1.8 g/m² days 1 through 5, with hydration, mesna, and granulocyte colony-stimulating factor) compared with no systemic treatment.²⁴⁸ DFS and OS were statistically improved at preliminary analysis. However, by the time of publication, the metastatic rate in both study arms was virtually identical (44% and 45%), and it can be expected that the ultimate survival rate will also be the same.²⁴⁸ Unfortunately, this raises the question whether the potential value of aggressive chemotherapy may largely be in delaying the manifestation of distant metastasis but not its prevention.

Recently, a literature-based meta-analysis was performed including the 14 trials mentioned earlier with an additional 4 randomized trials included, for a total of 1953 patients.²⁴⁹ A combination of doxorubicin and ifosfamide was used in 5 trials. The mean follow-up was 4.9 years, and the absolute improvement for OS was 6% in favor of chemotherapy (40% vs. 46%, p = .003). Chemotherapy also reduced local recurrence by 4% (19% vs. 15%) and distant recurrence by 9% (37% vs. 28%). These results need to be verified in a further individual patient data meta-analysis.

Recent Analyses of Multicenter Data

Recently, several attempts have been made to pool data from large established cancer centers in the United States. One such study included all patients treated or not treated with adjuvant or neoadjuvant chemotherapy at M.D. Anderson Cancer Center and MSKCC but showed no statistical difference in OS for patients treated with chemotherapy versus no adjuvant chemotherapy.²⁵⁰ In contrast, combined nonrandomized data from the University of California, Los Angeles, and MSKCC showed that adjuvant chemotherapy may be useful for some STS subsets, including myxoid/round cell liposarcoma.²²⁰ Moreover, data from the MSKCC and the Dana-Farber Cancer Center institutional databases have suggested a significant improvement in disease-specific survival in patients with high-grade extremity STS greater than 10 cm.²⁵¹ In interpreting such data it is important to recognize biases that may exist, and it seems clear that randomized trials should continue.

Influence of Chemotherapy on Local Control

The largest trial in the meta-analysis (EORTC 62771) compared the outcome of adjuvant CYVADIC chemotherapy (utilizing cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dacarbazine [DTIC]) with controls in 468 patients.²⁴⁶ The relapse-free survival was significantly better after the CYVADIC regimen (56% vs. 43% for controls; p = .007), and local recurrence was significantly reduced (17% vs. 31%; p = .01). This favorable result in this subset analysis was confined to head, neck, and trunk tumors. In contrast, distant metastases rates were similar in both study arms as were OS (63% vs. 56%; p = .64). Thus adjuvant chemotherapy may improve local control in high-risk groups of STS, where local control has traditionally not been as satisfactory.

More recently, the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) reported the preliminary results of a large adjuvant trial of chemotherapy with doxorubicin and ifosfamide (EORTC-STBSG 62931)²⁵² that failed to demonstrate any significant difference in the relapse free survival or OS. More patients received RT in this recent trial compared with the EORTC-STBSG 62771 trial (73% vs. 42%), and, notably, outcome was improved in the EORTC-STBSG 62931 trial participants. Whether the composition of the trial will permit the final report to again address the interplay between anatomic complexity (especially in head and neck sites where surgery is frequently compromised because of functional and cosmetic considerations) and RT with or without chemotherapy and local control remains uncertain.

Summary of Evidence About Adjuvant Chemotherapy

Overall, even contemporary trials seem to provide conflicting results, leading to the conclusion that adjuvant chemotherapy has not proven to improve the outcome for patients with STS.²⁸ For the high-risk patients, those presenting with large, high-grade and deep lesions (stage III disease), a benefit to adjuvant chemotherapy appears to be small if present at all. For this reason we tend to individualize treatment for a given clinical setting. Younger patients with relatively chemotherapy-sensitive subtypes such as myxoid/round cell liposarcoma and synovial sarcoma may experience benefit, and it has also been our policy to advise chemotherapy in patients presenting with lymph node involvement and in adverse presentations of head and neck or torso sarcoma when surgery and RT delivery are compromised.