Soft-Tissue Sarcomas
Tae Won B. Kim, MD, CPE, FAAOS
Christina J. Gutowski, MD, MPH, FAAOS
Gord Guo Zhu, MD, PhD
Dr. Kim or an immediate family member has received royalties from Adler Ortho; is a member of a speakers’ bureau or has made paid presentations on behalf of Daiichi Sankyo and OncLive; serves as a paid consultant to or is an employee of Adler; and serves as a board member, owner, officer, or committee member of American Academy of Orthopaedic Surgeons and Musculoskeletal Tumor Society. Dr. Gutowski or an immediate family member has received royalties from Adler Ortho and serves as a paid consultant to or is an employee of Adler Ortho. Neither Dr. Zhu nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this chapter.
ABSTRACT
Soft-tissue sarcomas represent a heterogeneous group of mesenchymal-derived malignancies with behavior ranging from indolent to highly aggressive. Their clinical presentations vary, although the most concerning masses tend to be large, painless, and deep to fascia, with a history of progressive growth. MRI, with or without contrast, remains the preferred imaging modality, whereas core biopsy is the most commonly used method to establish a tissue diagnosis. Current treatment options include wide surgical resection and radiation therapy. Although systemic treatment options such as chemotherapy and immunotherapy can be used in the management of some soft-tissue sarcomas, they remain controversial in most. Metastatic disease occurs in 10% and 30% of patients with low-grade and high-grade sarcomas, respectively, most commonly in the lungs. Overall survival remains at 60% to 70%, demonstrating a need for more effective therapies, especially for metastatic disease. Knowledge of the genetic basis of these sarcomas continues to grow and hopefully will pave the way to improved outcomes. It is highly recommended that primary orthopaedic surgeons refer all soft-tissue masses concerning for sarcoma to their local orthopaedic oncologist to avoid the complications of inappropriate biopsy or excision.
Keywords: immunotherapy; malignant; soft-tissue sarcoma; targeted therapy; wide resection
Introduction
Soft-tissue sarcomas make up a heterogeneous group of malignancies arising from mesenchymal stem cells. They are rare, with an estimated incidence of 13,460 (0.7% of all new cancers) in the United States in 2021.1 The extremities and retroperitoneum remain the most common sites of disease, accounting for more than 80% of cases (60% extremities, 20% retroperitoneum), with the remaining 20% in the head/neck and trunk.2 An analysis of the National Cancer Database in 2014 showed that soft-tissue sarcomas are more prevalent in males than females, with a ratio of 1.23 to 1.00.3 Localized disease remains the most common stage at initial presentation, with reports of local recurrence from 24% to 40% for low-grade and high-grade tumors, respectively.4 Metastatic disease occurs via hematologic routes, with metastases occurring at 10% and 30% in low-grade and high-grade sarcomas, respectively. More than 80% of metastatic disease is found in the lungs, although certain histologies, such as myxoid liposarcoma, have less predictable metastatic patterns.5,6 Management of metastatic soft-tissue sarcoma is largely palliative. Overall survival is worse with higher grade tumors and has not improved substantially over recent decades.7
Common Sarcoma Types
Soft-tissue sarcomas originate from mesenchymal stem cells and are categorized by their lines of differentiation, such as adipose, neural, or myogenic. According to the World Health Organization, there are more than 100 distinct subtypes of soft-tissue sarcomas.8 Advances in
genomic profiling in cancer have increased knowledge of the genetic pathogenesis of these soft-tissue sarcomas. Undifferentiated pleomorphic sarcoma, formerly known as malignant fibrous histiocytoma, is the most common high-grade soft-tissue sarcoma. It lacks a clear line of differentiation and is driven by extreme genomic instability, rather than a specific mutation.9 Five other major types of soft-tissue sarcoma and the recent genetic advancements associated with them are discussed in the following paragraphs.
genomic profiling in cancer have increased knowledge of the genetic pathogenesis of these soft-tissue sarcomas. Undifferentiated pleomorphic sarcoma, formerly known as malignant fibrous histiocytoma, is the most common high-grade soft-tissue sarcoma. It lacks a clear line of differentiation and is driven by extreme genomic instability, rather than a specific mutation.9 Five other major types of soft-tissue sarcoma and the recent genetic advancements associated with them are discussed in the following paragraphs.
Liposarcoma
Liposarcomas are of adipocytic differentiation and account for approximately 15% to 20% of all soft-tissue sarcomas.10,11 There are four distinct types of liposarcomas, including well-differentiated liposarcoma/atypical lipomatous tumor (ALT), dedifferentiated liposarcoma, myxoid liposarcoma, and pleomorphic liposarcoma.12
Well-Differentiated Liposarcoma/ALTs
ALTs and well-differentiated liposarcomas present as slowly enlarging masses within the limbs or retroperitoneum, most commonly diagnosed in the fifth to seventh decades of life.13 On T1-weighted magnetic resonance image, the mass exhibits fat signal with internal stranding (Figure 1, A). Although histologically identical, these tumors are designated ALTs when located in the extremities and well-differentiated liposarcomas when located in the retroperitoneum. They are also distinct in terms of their clinical behavior;14,15 ALTs can undergo marginal surgical excision with low risk of local recurrence, whereas well-differentiated liposarcomas have a higher likelihood of local recurrence (as high as 50%) and dedifferentiation (10%).14,15 Well-differentiated liposarcomas were previously excised with wide margins, potentially including organ resection, but some studies have advocated for a less aggressive surgical approach because visceral involvement is rare.16 Histologically, ALTs and well-differentiated liposarcomas are predominantly composed of variable-sized mature adipocytes with fibrous septa and cells with irregular, enlarged hyperchromatic nuclei17 (Figure 1, B). Genomic analysis of well-differentiated liposarcomas/ALT has shown amplification of chromosome 12q13-15, with MDM2 and HMGA2 most constantly included in this amplicon. In 75% to 90% of cases, CDK4 is also included in the amplicon. Currently, MDM2 (and/or CDK4) amplification by fluorescence in situ hybridization is clinically used to diagnose well-differentiated liposarcomas/ALT.18
 Figure 1 Atypical lipomatous tumors/well-differentiated liposarcomas are shown. A, Coronal T1-weighted magnetic resonance image sequence showing a lipomatous mass within the left thigh. B, Histologic image showing adipocytes of variable sizes, fibrous strands in between, and scattered atypical hyperchromatic nuclei. |
 Figure 2 Dedifferentiated liposarcoma. Histologic slide showing a high-grade, pleomorphic spindle cell sarcoma (right on slide) juxtaposed against a low-grade well-differentiated liposarcoma (left on slide, cellular variant with no fatty formation). |
Dedifferentiated Liposarcoma
Dedifferentiated liposarcomas occur when well-differentiated liposarcomas/ALT undergo progression and lose their adipocytic differentiation. A dedifferentiated liposarcoma can also arise de novo without an associated well-differentiated liposarcoma/ALT component. Histologically, dedifferentiated liposarcoma arising from well-differentiated liposarcoma/ALT shows 2 distinct tissue components: a high-grade, usually pleomorphic undifferentiated spindle cell sarcoma, juxtaposed against a well-differentiated liposarcoma/ALT19 (Figure 2). Dedifferentiated liposarcoma shares the same genetic amplification as well-differentiated liposarcoma/ALT in 12q13-15 but exhibits additional chromosomal
abnormalities that may lead to dedifferentiation. These include the reamplification of 1p32 and 6q23, and overexpression of replication-dependent histone mRNA, all of which have been shown to be associated with poor prognosis.20,21,22 Dedifferentiated liposarcomas are associated with high rates of local recurrence and metastases; they are therefore treated as true soft-tissue sarcomas with wide excision and radiation therapy.
abnormalities that may lead to dedifferentiation. These include the reamplification of 1p32 and 6q23, and overexpression of replication-dependent histone mRNA, all of which have been shown to be associated with poor prognosis.20,21,22 Dedifferentiated liposarcomas are associated with high rates of local recurrence and metastases; they are therefore treated as true soft-tissue sarcomas with wide excision and radiation therapy.
Myxoid Liposarcoma
Myxoid liposarcoma is a distinct subtype that makes up 30% of all liposarcomas. This variant exhibits an unusual metastatic pattern including the axilla, nonpulmonary soft tissues, and the skeleton.23,24 Staging with CT of the chest/abdomen/pelvis or positron emission tomography (PET) scan, as well as magnetic resonance image of the spinal axis, is indicated to evaluate for atypical metastases. Histologically, immature lipoblasts are seen within a myxoid background on histologic examination (Figure 3). Primitive round cells with large blue nuclei are also seen, with the clinical implications described previously. Myxoid liposarcoma is characterized by a t(12:16) translocation with expression of the fusion protein FUS-DDIT3, which is pathognomonic for this tumor. It has been suggested that the fusion protein prevents adipocytic differentiation, leading to the uncontrolled proliferation of lipoblasts that cannot mature.25 Overall survival of myxoid liposarcoma is associated with the percentage of round cell component, with 5- and 10-year survival at 95% and 87%, respectively, for less than 5% round cell myxoid liposarcoma, compared with 80% and 80%, respectively, in greater than 5% round cell myxoid liposarcoma.26 As such, chemotherapy is indicated if these round cells comprise greater than 5% of the cell population.27
Pleomorphic Liposarcoma
Pleomorphic liposarcoma is a rare, aggressive subtype. Patients typically present with a rapidly enlarging soft-tissue mass in the extremity, although they have been described in the trunk and retroperitoneum.28,29 Histologically, it appears as numerous pleomorphic lipoblasts in a background of high-grade undifferentiated pleomorphic sarcoma (Figure 4). Pleomorphic liposarcoma shows no specific genetic profile, although more gains than losses are noted, and its genome does not share the amplification of 12q13-15 as well-differentiated liposarcomas/ALT.30 Although surgical resection, radiation therapy, and chemotherapy have been used, overall survival is reported to be 57%, which is significantly lower than that of other liposarcomas.30
 Figure 3 Myxoid liposarcoma. Histologic slide showing monomorphic tumor cells in a myxoid background with prominent vasculature and mucin pools that do not exhibit high levels of pleomorphism consistent with a translocation-driven tumor. |
 Figure 4 Pleomorphic liposarcoma. Histologic slide showing highly pleomorphic lipoblastic tumor cells with cytoplasmic vacuoles indenting the nuclei. |
Angiosarcoma
Angiosarcoma is an aggressive soft-tissue sarcoma arising from vascular endothelial cells. It accounts for 2% to 3% of all adult soft-tissue sarcomas and occurs in the sixth and seventh decades of life. Cutaneous and superficial locations make up 60% to 70% of all cases.31 Cutaneous angiosarcomas present as discolored nodules with or without ulceration. Deeper angiosarcomas in the abdomen/pelvis can cause nonspecific symptoms such as abdominal pain, nausea, or vomiting.32 Although there is no definitive cause, chronic lymphedema, radiation exposure, environmental carcinogens, and genetic
syndromes all have been shown to be risk factors.33 The lung and brain are the most common sites of metastasis, and this tumor has the capacity for lymphatic spread as well.34 Overall survival has been reported to be 6 to 16 months, with 5-year survival being 30% to 40%.33,34 Its infiltrative growth pattern within soft tissue makes diagnosis with imaging difficult, as a palpable mass or crisp radiologic border is not always present.
syndromes all have been shown to be risk factors.33 The lung and brain are the most common sites of metastasis, and this tumor has the capacity for lymphatic spread as well.34 Overall survival has been reported to be 6 to 16 months, with 5-year survival being 30% to 40%.33,34 Its infiltrative growth pattern within soft tissue makes diagnosis with imaging difficult, as a palpable mass or crisp radiologic border is not always present.
Histologically, variations in differentiation are visible in the vascular channels that are formed, ranging from well-differentiated to poorly differentiated channels (Figure 5). Polygonal and spindle-shaped cells with epithelioid and round cell features are also visible. Stains for vascular markers are positive, including CD31 (gold standard), CD34, ERG, and vascular endothelial growth factor.35,36
Several genes have been shown to be upregulated in angiosarcoma. The MYC proto-oncogene on chromosome 8q24 is amplified in 90% of secondary angiosarcomas from radiation exposure compared with primary angiosarcomas, where MYC amplification was not a useful diagnostic tool.37,38 Overexpression of the FLT4 gene (encoding for vascular endothelial growth factor receptor 4) has been associated with MYC co-overexpression in angiosarcoma.39 As described in a 2020 study, the Angiosarcoma Project, a total of 47 tumors underwent whole-genome sequencing and showed mutations in the KDR, TP53, and PICK3CA genes.40
