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Soft tissue sarcomas are a diverse category of rare malignant tumors that originate from mesenchymal tissues, such as muscles, nerves, and adipose tissues. They exhibit substantial morbidity and mortality due to the frequent development of advanced and metastatic conditions. Several challenges have been reported in diagnosis and treatment, with a shift toward molecular characterization and subtyping. Targeted therapy for certain forms of soft tissue sarcomas has seen significant advancements in the previous two decades. Many novel therapeutic strategies have been developed and approved as a result of the ability to study these molecular markers linked to the genesis of sarcomas. An overview of soft tissue sarcoma diagnosis and treatment is given in this chapter.
Clinical Oncology, Ain Shams University, Cairo, Egypt
*Address all correspondence to: kelaney.m@med.asu.edu.eg
1. Introduction
Sarcomas are a rare heterogeneous group of malignancies that originated from connective tissues in any organ or at any anatomic location of the body [1]. Their name originates from the Greek term for a fleshy excrescence. In his book Surgical Observations, published in 1816, the Edinburgh surgeon Charles Bell (1772–1842) introduced the term soft tissue cancer. According to the literature, he was the first to use the term soft tissue sarcoma to differentiate it from carcinoma. Despite the diversity of different types of tissues and locations, these soft tissue sarcomas (STS) are grouped because of their overall similarities in natural history and treatment ([2], pp. 1803–21).
Sarcoma accounts for fewer than 1% of all adult cancers and 10% of pediatric tumors. In the US, about 11,000 new cases are diagnosed annually, which accounts for less than 1% of total cancer cases. Approximately 80% of sarcoma originates from soft tissue, and the rest originates from bone. Most sarcomas (about 55%) affect mainly the extremities, mostly the legs, and about 15% affect the head and neck area or trunk; the rest are retroperitoneal or intraperitoneal [3].
With an estimated 27,908 new cases annually in the EU27, the overall crude incidence was 5.6 per 100,000 per year. Of these, 84% were soft tissue sarcomas and 14% were bone sarcomas [4].
The overall incidence of soft tissue sarcoma has increased in the UK over time due to improvements in diagnostic techniques and accurate recording within the cancer registries. It is interesting that over the last decades (between 1999 and 2001 and 2008–2010), incidence rates have increased by 17% in males but have not changed significantly in females (Figure 1) [6].
Figure 1.
Trends in the UK’s sarcoma incidence over time [5].
There are different reasons for these dynamic changes regarding the incidence: one reason is the histopathological reclassification and change of subtype definition; for example, atypical lipomatous tumors have been included in the category of well-differentiated liposarcoma, and therefore liposarcoma incidence rates began to rise. In contrast, gastrointestinal stromal tumors (GISTs) were classified separately from leiomyosarcoma, and consequently, leiomyosarcoma incidence rates began to fall [7]. The second reason is changes in reporting practice using accurate diagnostic tools, which allow more specific coding by cancer registries. A third reason is a change in the etiological factors, for example, the incidence of angiosarcoma of the breast is increasing due to the growing number of women receiving radiotherapy for breast cancer [6].
Rhabdomyosarcoma is most frequently diagnosed in pediatric patients, whereas synovial sarcoma, Ewing sarcoma, osteosarcoma, desmoplastic small round-cell tumors, clear cell sarcoma, alveolar soft part sarcoma, epithelioid sarcomas, and malignant peripheral nerve sheath tumors are more frequently diagnosed in adolescents and young adults [8].
Among adult sarcoma patients, undifferentiated sarcomas, gastrointestinal stromal tumors, leiomyosarcomas, and liposarcomas are the most frequent cancers [9].
Research investigating gender disparities has revealed that males have a greater prevalence of STS in comparison to females. According to Hung et al., it was observed that there was a notable prevalence of males among the 11,393 patients with soft tissue sarcomas (STS) [10].
The development of bone and soft tissue sarcoma has been associated with several inherited genetic disorders, particularly in children and young people [11].
Li-Fraumeni syndrome (LFS) is distinguished by genetic alterations in the TP53 gene. Also, TP53 is the most prevalent germline mutation that predisposes to pediatric sarcomas, including osteosarcoma, undifferentiated pleomorphic sarcoma, rhabdomyosarcoma, leiomyosarcoma, and liposarcoma. The prevalence of LFS in children with soft tissue sarcomas is estimated to be 7% [12]. Among a specific cohort of persons in the International Agency for Research on Cancer (IARC) database, 96% of the sarcomas that developed in individuals with LFS occurred before the age of 50. This is in contrast to the general population, where only 38% of sarcomas occur before the age of 50 [13].
Familial adenomatous polyposis (FAP) is a genetic condition caused by a mutation in the APC gene located at 5q21-q22. Familial adenomatous polyposis (FAP) patients often experience intra-abdominal desmoid fibromatosis, which is also called desmoid tumors. This combination is also known as Gardner syndrome [14].
The retinoblastoma RB1 gene is associated with soft tissue sarcoma, particularly leiomyosarcoma [15].
Double hit inactivation, a condition in which one allele is activated in the germline and the second allele is eliminated by somatic mutation, is the source of mutations in the NF1 gene that results in neurofibromatosis type 1, an autosomal dominant illness. This disease is diagnosed by major criteria, including café-au-lait spots, neurofibroma, plexiform neurofibroma, iris nodules, and bone deformity, as well as other factors [16]. Up to 13% will develop soft tissue sarcoma, mostly in the form of malignant peripheral nerve sheath tumors [17].
2.2 Molecular alternation in sarcomas
The conventional karyotypic analysis derives much of the current molecular understanding of sarcomas [18]. At the cytogenetic level, it discriminated sarcomas into two main categories: sarcomas with a simple karyotype versus those with a complex karyotype. From a biological perspective, there is a greater level of comprehension regarding the oncogenic pathways associated with sarcomas that possess a simple karyotype. These mechanisms may generally be classified into two overarching categories: transcriptional deregulation and unregulated signaling. In contrast to sarcomas characterized by highly complicated karyotypes, which generally lack singular “driver” genetic mutations, sarcomas with nonspecific molecular changes are more prevalent. These changes contribute to the development of oncogenic features, including dysregulation of the cell cycle and genomic instability (Figure 2) [19, 20].
Figure 2.
The copy number patterns of sarcomas characterized by a simple genome (top) and sarcomas characterized by a complex genome (bottom), as determined using a next-generation sequencing platform. The case under consideration involves a 9-year-old male patient who has been diagnosed with Ewing sarcoma. The genetic profile is characterized by its simplicity. The presence of an EWSR1-FLI1 fusion was detected in this tumor using the aforementioned assay. The patient in question is a 60-year-old male who has been diagnosed with a high-risk, spindle cell intestinal gastrointestinal stromal tumor (GIST). The presence of a KIT K642E mutation was identified in the tumor using the test. The observed genomic profile exhibits a very straightforward genetic makeup, featuring a nearly diploid karyotype and the absence of chromosomes 1p, 14q, 15q, and 22q. These chromosomal losses are indicative of advanced gastrointestinal stromal tumors (GIST). C. Undifferentiated pleomorphic sarcoma originating in the deltoid muscle of a 55-year-old male individual, and the case under consideration involves a 7-year-old male patient diagnosed with conventional osteosarcoma in the femur. The genetic analysis of this condition reveals the presence of several chromosomal gains and losses, which occur in a nonrecurrent manner. Both tumors had genetic changes in the TP53 gene, namely including copy number loss and truncating mutations [19].
2.3 Environmental factors
2.3.1 Radiation exposure
Murray et al. [5] revised and updated the original radiation-associated sarcoma (RAS) diagnosis criteria in 1999 to include all varieties of radiation-associated sarcoma. Murray et al. outlined the following requirements: First, the patient must have a historical context that involves the occurrence of sarcoma in the region encompassed by the radiation field and the 5% isodose line. Additionally, it is crucial to establish the absence of any indications of sarcoma prior to the administration of radiation therapy. Furthermore, the sarcomas must be confirmed through histological evidence and exhibit distinct pathological characteristics in comparison to the primary tumor. The latency period for the onset of radiation-induced sarcoma generally ranges from 5 to 20 years [21].
An examination of 20 instances of radiation-induced sarcoma, which includes four instances that were treated using carbon ion radiotherapy, the histological diagnoses of RAS included leiomyosarcoma, undifferentiated pleomorphic sarcoma, rhabdomyosarcoma, angiosarcoma, malignant peripheral nerve sheath tumor, and spindle cell sarcoma, not otherwise specified [22].
2.3.2 Chemical exposure
Sarcoma development has been linked to several substances. However, it is challenging to identify obvious causal effects due to the limited patient numbers in cohorts. Hepatic angiosarcoma has been linked to the chemical vinyl chloride, which was used in the plastics industry in the 1970s [23].
A review of 31 studies and 29,605 cancer cases found that higher levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin were linked to the development of STS [24].
2.3.3 Trauma exposure
Numerous papers documenting the occurrence of secondary traumatic stress (STS) following traumatic injury, surgical procedures, and other related experiences [25, 26, 27] show that trauma exposure has a causal relationship with the development of STS. However, establishing a causal relationship between the two occurrences is a significant hurdle. This phenomenon can be attributed, in part, to the tendency of trauma to bring attention to a preexisting mass located in the same area.
2.4 Infectious and immunological factors
Despite the role of infectious agents in the development of sarcoma is not well understood, there is strong evidence for the association between viral infection and sarcoma development. HIV infection and human herpes virus 8 are known as causative factors for Kaposi sarcoma. Also, leiomyosarcoma has been connected to Epstein-Barr virus infections in patients with HIV infection [28].
In addition, it has been suggested that the acquired regional immune deficiency in combination with chronic lymphedema after exposure to radiation therapy or an infectious condition may lead to the development of angiosarcoma [29].
It is used to confirm the existence of a soft-tissue mass and determine its size, depth, and consistency to guide core-biopsy sampling of superficial masses [30].
Accuracy improved the distinguishing between the aggressive and benign lesions in the US based on echotexture, in which the large, deep-seeded lesion with internal heterogeneity and mass effect raised suspicion of neoplasia. In addition, the vasculature and the high-grade neoplasm were associated with increased peripheral flow because of neoangiogenic and central avascular areas due to necrosis [25].
3.1.2 Computed tomography (CT)
CT is the most accurate modality for evaluating osseous architecture. In soft tissue sarcoma, CT is a very helpful method for the detection of cortical bone invasion, periosteal reaction, and dystrophic calcification seen in some synovial sarcoma.
Furthermore, CT angiography readily demonstrates the vascular anatomy [26].
3.1.3 Magnetic resonance imaging (MRI)
The most sensitive and accurate imaging technique for assessing soft-tissue masses. It provides the finest delineation of the soft-tissue structures and the relation of the mass to neurovascular structures. Thus, it is the study of choice for the localization and staging of soft-tissue tumors [27].
In magnetic resonance (MR) imaging, commonly employed sequences encompass regular T1 and T2-weighted pictures. The incorporation of fluid-sensitive and fat-saturated sequences serves to enhance specificity. It is worth noting that the MR signal intensity characteristics exhibited by most soft tissue lesions, such as soft tissue sarcomas, and lack specificity. The observed tendency is for moderate signal intensity to be displayed on T1-weighted pictures in comparison to skeletal muscle, whereas high-signal intensity is displayed on T2-weighted images [26].
When considering different subtypes of soft tissue sarcoma, some characteristics observed in magnetic resonance imaging (MRI) scans can potentially indicate the specific subtype of sarcoma. The high amount of myxoid matrix in myxofibrosarcoma has been linked to a higher chance of local recurrence after surgery (see Figure 3). The “tail sign” and “water-like” appearance on fluid-sensitive sequences are signs of this. In cases of undifferentiated pleomorphic sarcoma, the presence of the “tail sign” is also linked to a higher chance of local recurrence after surgery [31, 32].
Figure 3.
Contrast-enhanced MRI scans in a 61-year-old woman with myxofibrosarcoma of the left thigh A, precontract axial short inversion time inversion recovery scan, and B, precontract axial T1-weighted scan, show a neoplastic lesion located above the fascial plane with two components—A main mass (*) and a so-called tail sign (arrow), both with the same signal intensity. C after contrast, an axial T1-weighted scan with fat saturation shows that both the main mass (*) and the tail sign (arrow) have a lot more contrast [31].
The presence of the “triple sign” in magnetic resonance imaging (T2w sequences) of synovial sarcoma patients is linked to reduced disease-free survival. This sign indicates the concurrent existence of solid cellular elements (with intermediate signal intensity), hemorrhage or necrosis (with high signal intensity), and fibrotic regions (with low signal intensity) [31].
3.2 Functional and molecular imaging
The glucose-transporter family (GLUT) found in cellular membranes is one commonly used method for tumor imaging. This family of transporters plays a crucial role in regulating the intake of glucose. Tumors exhibit overexpression of the most significant subtypes, namely GLUT 1 and GLUT 3. Tumor cells exhibit a higher demand for glucose to support their proliferation, which can be attributed to the inefficient process of aerobic glycolysis, also known as the Warburg effect [33].
It has been found that the metabolic features of 18F-FDG PET/CT are strongly linked to the histological grade of soft tissue sarcomas (STS). According to sources [34, 35]. For instance, the utilization of both visual and quantitative analysis of FDG PET images could facilitate the distinction between liposarcomas and lipomas. The average standardized uptake value (SUV) of myxoid-type lipomas and other types of liposarcoma was statistically significantly higher than that of a well-differentiated liposarcoma by two and three times, respectively [36, 37].
The use of whole-body FDG PET-CT has demonstrated its ability to serve as a supplementary tool in the process of staging and restaging many types of malignancies, including STSs. The study results demonstrated that the rates of sensitivity and specificity in detecting lung metastases using FDG PET were 86.7 and 100%, respectively. By contrast, the CT scan by itself exhibited sensitivity and specificity rates of 100 and 96.4%, respectively. In comparison, the CT scan alone had sensitivity and specificity rates of 100 and 96.4%, respectively [38]. The user’s text does not contain any information to rewrite. In addition, the FDG PET-CT scan revealed the presence of 13 additional sites of metastases that were not anticipated. More research has shown that positron emission tomography-computed tomography (PET-CT) can find more lymph nodes and bone lesions when first evaluating a soft tissue sarcoma (STS) compared to using only traditional imaging methods. Nevertheless, it exhibited reduced sensitivity and specificity in detecting pulmonary metastases [39, 40].
3.3 Biopsy
The current recommendation for the detection of soft tissue sarcomas (STS) is percutaneous core needle biopsy (CNB), sometimes referred to as “tru-cut biopsy.” This approach is preferred due to its minimally invasive nature and its ability to preserve the option for future surgical procedures without limitations. The accuracy of this procedure is comparable to that of an incisional biopsy, while offering the advantage of not needing hospitalization [41].
In the most extensive cohort of individuals, core needle biopsy (CNB) demonstrated a sensitivity of 99.4% and a specificity of 98.7% when utilized for the purpose of distinguishing between malignancy (specifically sarcoma) and benign mesenchymal tumors [14]. The observed percentages closely resemble those obtained by utilizing the incisional biopsy technique. Similarly, CNB can accurately determine the histological subtype and grade in 80% of instances [42].
An inappropriate biopsy may lead to excess bleeding with a chance of spreading sarcoma cells by hematoma beyond the original site. Inexpert surgery may lead to the opening of tissue planes permitting further contamination of hematoma, which creates an even greater dilemma if contaminated hematoma involves vital anatomic structures such as nerves, vessels, and joints, for which sacrifice may result in significant functional consequences such as altered limb function or even amputation [43].
For this reason, all biopsies should be undertaken at a center specializing in sarcoma management. At these centers, there will be resources to ensure that the tissue is handled appropriately and expeditiously between the time of biopsy and histological examination. When the biopsy is taken outside of a specialized center, it is advisable that it occur after discussion with experts from a specialized sarcoma center [43].
Using radiological tools like ultrasonography and computed tomography (CT) to guide core needle biopsy (CNB) has greatly improved the effectiveness of diagnostic procedures. The utilization of image guidance facilitates enhanced precision in determining the location of tumors, hence assisting in directing biopsies toward regions containing live cancer cells. When determining the appropriate regions for biopsy, it is imperative to refrain from selecting cystic, necrotic, or hemorrhagic tumor regions. The meticulous evaluation of imaging studies is essential for identifying regions of heightened aggressiveness within tumors, typically characterized by a greater degree of contrast enhancement. This process enables a more precise determination of the cancer grade. The most often employed needle gauges for central neuraxial blocks (CNB) range from 14 to 18 g [44].
Prior to performing a percutaneous biopsy, it is imperative to address any hemostatic issues. Additionally, it is crucial to carefully select the biopsy site to avoid noninvolved anatomical compartments that may pose a risk of contaminating neurovascular structures. Furthermore, it is important to acknowledge that the biopsy path and resulting scar should be surgically resected in a definitive manner (Figure 4) [45, 46].
Figure 4.
(A), (B) Sagittal enhanced T1-weighted pictures, there is a solid mass present that exhibits heterogeneous enhancement. This mass affects the vastus intermedius and vastus lateralis muscles. The blue and red arrows represent two general potential pathways for performing a biopsy. The blue pathway traverses and interrupts the unaffected posterior compartment, but the red route exclusively passes through the anterior compartment, rendering it the suitable pathway. In this case, a longitudinal ultrasound (US) image was utilized to guide the core needle biopsy (CNB) procedure on the mass, following the red route. In the captured image of the left upper leg, it was observed that the biopsy entry site was situated appropriately within the designated surgical area and aligned with the intended incision line for the scheduled surgery. Blue markers (shown by a blue arrow) delineate the hypothetical path of a blue biopsy. The identification of this tumor has been verified as undifferentiated pleomorphic sarcoma [45].
3.4 Soft tissue tumors pathology
The pathologist initially focuses on comprehending the clinical and radiological aspects of a soft tissue tumor. Understanding these characteristics, along with the evaluation of pathological findings, enables the consideration of potential alternative diagnoses. Relevant factors considered encompass the patient’s age (Table 1), as well as the magnitude and location of the patient’s condition. The following tables demonstrate the common tumors based on age and location.
Age
Soft tissue tumors
Infants (<3 years)
Infantile fibrosarcoma, inclusion body fibromatosis fibrous hamartoma of infancy lipoblastoma Myofibroma
Summary of common soft tissue tumors based on the age of the patient [47].
Obtaining the patient’s past medical history is crucial, as certain cancers may have connections or be linked to a syndrome, as explained in the genetic risk factor. Neurofibromatosis-1 (NF-1) is linked to the presence of neurofibromas and malignant peripheral nerve sheath tumors (MPNST) [17]. Familial adenomatous polyposis (FAP) is associated with intra-abdominal desmoid fibromatosis [14].
Finally, the diagnostic approach for soft tissue tumors is based on cellular morphology and immunohistochemistry (IHC), as well as molecular studies.
3.4.1 Cellular morphology
Spindle cell morphology is one of the most often observed histologic subtypes in soft tissue tumors. It is characterized by cells with thin, elongated nuclei and cytoplasmic borders with pointed or tapering ends.
Examples of spindle cells are smooth muscle tumors, nerve sheath tumors, nodular fasciitis, solitary fibrous tumors, synovial sarcoma, dermatofibrosarcoma protuberans, and fibromatosis. Given the vast and diverse differentials within the spindle cell group of tumors, other histological factors must be assessed to determine the correct diagnosis. This includes consideration of the architectural arrangement of the cells, the growth pattern, associated vascular pattern, background stroma or matrix, mitoses, and necrosis [48].
Epithelioid pattern: Epithelioid refers to cells that resemble epithelial cells in appearance and are spherical or polygonal with lots of cytoplasm. Soft tissue tumors that exhibit epithelioid cytomorphology are uncommon, either in their initial form (such as epithelioid sarcomas) or as the epithelioid variants of mesenchymal tumors, including leiomyosarcoma, fibrosarcoma, GIST, and vascular and neural tumors [48].
Round cell pattern: Small round blue cells are relatively uniform cells with a high nuclear-to-cytoplasmic ratio that appear dark blue on H&E stain. Tumors with round cells are more aggressive and frequently affect pediatrics. Immunohistochemistry is nearly always required for the diagnosis, and molecular methods are often used for gene fusions that characterize round-cell tumors [48].
Round-cell malignancies include both mesenchymal and non-mesenchymal tumors. Non-mesenchymal tumors include lymphoma, melanoma, and some carcinomas (Merkel cell and small cell carcinoma). Mesenchymal round-cell tumors include rhabdomyosarcoma, neuroblastoma, desmoplastic small round-cell tumor, poorly differentiated synovial sarcoma, Ewing’s sarcoma, and undifferentiated round-cell sarcomas (previously called Ewing-like/atypical Ewing), CIC-rearranged sarcoma, and BCOR-rearranged sarcoma. Round cell areas can be seen in myxoid liposarcoma and mesenchymal chondrosarcoma. There is a major role for IHC and molecular typing in this category of tumors.
Myxoid pattern: myxoid tumors of the soft tissue are a broad, heterogeneous group of tumors that are characterized by their abundance of extracellular matrix. These tumors range from benign lesions, such as myxoma, angiomyxoma, and myoepithelioma, to malignant tumors, such as extra-skeletal myxoid chondrosarcoma, low-grade fibromyxoid sarcoma, and myxofibrosarcoma [43].
Adipocytic/lipomatous tumors: adipocytic tumors comprise a large group of heterogeneous tumors that display various pathological appearances and distinct clinical behaviors. These tumors can often present diagnostic challenges due to their overlapping features in histology. Benign fatty tumors include areas of fat necrosis, angiolipoma, hibernoma (brown fat), spindle cell lipoma, intramuscular lipoma, and lipoblastoma. Malignant liposarcoma has three main subtypes: WD/DD liposarcoma (Figure 5), myxoid liposarcoma, and pleomorphic liposarcoma [43].
Figure 5.
Select tumors of adipocytic differentiation [43].
Undifferentiated tumors: undifferentiated or unclassified tumors encompass a subset of tumors that display markedly atypical cells in the absence of any obvious line of differentiation on histology. A prominent example of these tumors is undifferentiated pleomorphic sarcoma (UPS), a highly aggressive tumor that accounts for 5–10% of all sarcomas arising in adults. Previously, UPS belonged to a larger entity called malignant fibrous histiocytoma (MFH), a diagnosis previously given to poorly differentiated mesenchymal tumors that could not be otherwise classified [49]. With the addition of ancillary testing, it is now understood that MFH encompassed a heterogeneous group of both mesenchymal and non-mesenchymal tumors that shared similar histological features [50]. Nowadays, UPS is typically the diagnosis of exclusion for undifferentiated mesenchymal tumors, following immunohistochemical interrogation for other sarcoma entities [51].
3.4.2 Immunohistochemistry (IHC)
Immunoprofiles are not only useful in identifying the lineage of a tumor but also in supporting the diagnosis of rare tumors or tumors that have occurred in unusual situations or sites. The technique employs manufactured antibodies that bind to and identify the proteins (antigens) expressed by cells. The technical aspects of this method will influence its ability to detect an antigen in tumor tissue. Firstly, there needs to be enough representative tissue that is well-processed. Identifiable tumor tissue needs to be present in the sample.
In general, IHC can be used not only in the identification of the line of differentiation, summarized in Table 2, but also as a surrogate to identify specific molecular alterations. See Table 3.
AJCC 8th edition
T1
Tumor ≤5 cm in greatest dimension
T2
Tumor >5 cm and ≤ 10 cm in greatest dimension
T3
Tumor >10 cm and ≤ 15 cm in greatest dimension
T4
Tumor >15 cm in greatest dimension
N0
No regional lymph node metastasis or unknown lymph node status
N1
Regional lymph node metastasis
M0
No distant metastasis
Ml
Distant metastasis
Stage groups
Stage IA
T1; N0; M0; G1
Stage IB
T2, T3, T4; N0; M0; G1
Stage II
T1; N0; M0; G2/3
Stage IIIA
T2; N0; M0; G2/3
Stage IIIB
T3, T4; N0; M0; G2/3
Stage IV
Any T; N1; M0; any G Any T; any N; M1; any G
Table 2.
Staging system for extremity soft tissue sarcoma or trunk [52, 53].
Epithelioid markers
Keratin cytokeratin Ck, pan ck, epithelial membrane antigen EMA
Positive in epithelioid sarcoma, synovial, desmoid round-cell tumor DRCT, epithelioid type leiomyosarcoma, rhabmyosarcoma, angiosarcoma
Desmin positive in smooth & skeletal muscles, DRCT, myofibroblast SMA, H- caldemin positive in leiomyosarcoma Myogenin myod positive in rhabdomyosarcoma
Endothelial markers
CD31, CD34, D2-40
CD34 positive in solitary fibrous tumor SFT, peripheral nerve sheath tumor PNST, dermatofibrosarcoma perturbance DFSP, epithelioid sarcoma, angiosarcoma. Cd31 positive in angiosarcoma, Kaposi, EHE. D2-40 highly specific in Kaposi sarcoma
Neural crest & melanoma markers
S100, Melan-A, HMB-45
S100 positive in schwannoma, neurofibroma, PNST, clear cell sarcoma, extra-skeletal myxoid chondrosarcoma, myoepithelioma. Melan-A positive in PECOMA.
Table 3.
IHC immunohistochemistry in the identification of line differentiation [43].
3.4.3 Molecular testing
There are some chromosomal translocations found in histological subtypes that can be diagnosed by molecular techniques such as FISH and RT-PCR. See Table 3. A prospective multicenter study (GENSARC) showed that molecular methods can modify diagnosis and thus affect management plans [54].
Molecular methods, such as fluorescence in situ hybridization (FISH) and reverse transcriptase polymerase chain reaction (RT-PCR) to find the protein products of these fusion genes, can help with the diagnosis of soft tissue sarcoma because several histologic subtypes are linked to particular chromosomal translocations [54].
3.5 Staging
The tumor, node, metastasis (TNM) approach was created in cooperation between the American Joint Committee on Cancer and the Union for International Cancer Control (UICC) and is the most popular staging method for soft tissue sarcomas (AJCC). The AJCC TNM system divides soft tissue sarcomas into stages based on tumor size (T), lymph node involvement (N), the presence or absence of distant metastases (M), and histologic grade (G) [52].
There are some updates, like the creation of different staging methods at various anatomical regions. It is well recognized that STSs that develop in the head and neck, retroperitoneum, or abdominopelvic cavities, or in the extremities or trunk (see Table 2), and show distinctions in their biological function and clinical outcomes [52].
Delivering treatment necessitates a multimodality team that consists of skilled pathologists, radiologists, orthopedic and reconstructive surgeons, radiation oncologists, medical oncologists, nurses, physical therapists, social workers, and radiation oncologists. The total removal of the tumor with the best possible function preservation and the least amount of side effects are the intended therapeutic outcomes. Due to the complexity of achieving these objectives, a skilled team in a specialized sarcoma center is best suited to handle STS treatment [55].
4.1 Surgery
4.1.1 Principles of surgery for extremity STS
Surgery with a negative margin is the standard primary treatment for most sarcomas. For surgical planning, local disease staging is crucial. Imaging of the affected site should include plain radiography, CT, MRI, or PET, as was previously stated. The precise position and approach to the mass must be carefully planned before proceeding with the biopsy. The following data are essential for designing the surgical margins and reconstructions: size, capsule, consistency, site, shape, edge, and nearby structures, as well as evaluating the response of neoadjuvant therapy [56].
Amputation: Primary amputation may occasionally be the only possible choice or may be required if a serious complication arises. Current indications for primary amputation for soft tissue sarcoma (STS) include massive disease, where a functional limb following resection is not achievable; the need for resection of certain major nerves (e.g., brachial plexus), vessels, and bone; or severely compromised tissue perfusion. Or on local recurrence with widespread lesions and no other options found [57].
The predominant reasons for amputation were patients presenting with either primary localized disease (33.3%) or recurrent disease (52.2%), where there was significant involvement of bone, muscles, and limb-sparing surgery was not feasible. Another sign was the performance of palliative amputation in patients with metastatic disease (14.5%) as a result of fungating lesions, pathologic fractures, or unmanageable pain. Results showed morbidity in 14.5%, and one patient died within 1 month of surgery, while others tolerated the surgery [58].
The typical medical practice for treating localized soft tissue sarcomas is limb-sparing surgery. Over the past three decades, the standard of care has changed from amputation to limb-sparing surgery and radiation therapy, with amputation occurring in less than 10% of cases [59].
The application of radiotherapy in the treatment of both localized and metastatic soft tissue sarcomas (STS) is widely recognized and accepted. Surgery combined with radiotherapy is the most efficient treatment for the majority of localized high-grade STS of the extremity, according to three randomized controlled trials. The 1982 National Cancer Institute experiment revealed that the survival rates for amputation and limb-sparing surgery were equal, establishing limb-sparing surgery in conjunction with radiotherapy as the new standard of practice. In the late 1990s, Yang et al. and Pisters et al. both looked at how adjuvant radiation affected local control in people with high-grade STS who had limb-sparing surgery compared to people who had no surgery [56].
Rosenberg et al., at the National Institutes of Health (NIH), conducted a study on the surgical treatment of STS in the extremities in 1982. A total of 43 patients were randomly randomized to either amputation (N = 16) or limb salvage with adjuvant external beam RT (N = 27) as treatment options. All patients received chemotherapy following surgery. The overall survival (OS) did not exhibit a significant disparity between the two groups, whereas the limb salvage group achieved a local control rate of 85%. The findings supported the practice of limb preservation, which has subsequently become a widely accepted standard of medical treatment [60].
4.1.2 Classification of surgical margins
Surgical margins are assessed and classified as radical, broad, marginal, and intralesional by the Musculo-Skeletal Tumor Society (MSTS) for both conservative resections and amputations (Figure 6) [10].
A marginal resection is the straightforward excision of the tumor and its pseudo capsule sometimes referred to as a “shell-out” or “whoops” procedure. After marginal resection, local recurrence rates can range from 50 to 93%. The fact that microscopic tumor cells can expand beyond the pseudo capsule and up to several centimeters beyond a palpable large tumor is not surprising. Marginal resection is not the proper course of action [62].
Intralesional resection: when dissecting into the lesion, the tumor’s pseudo capsule has been breached and opened during surgery. Typically, microscopic, or macroscopic tumor tissue is left in the margins, and the exposed tissue planes may become contaminated. The most frequent intralesional procedures are subtotal “debulking” resections of the tumor or diagnostic incisional biopsies [62].
A broad resection: the terms “wide resection,” “limb-sparing surgery,” and “function-sparing surgery” are all used to refer to this procedure. En bloc excision of the tumor is required, along with the appropriate margin of normal tissue, which can range in width from a few centimeters to several, depending on the limitations of the anatomic structure. Although this treatment alone is typically associated with somewhat high local recurrence rates, ranging from 25 to 60%, it preserves reasonable function (limb salvage) [63].
The definition of adequate margin means margins of 2 cm or more with respect to anatomical barriers such as the periosteum or fascia [64]. It is generally agreed upon that surgical margins of less than 1.5 to 2 cm increase the chance of local recurrence. Unless further radiotherapy or surgery is done, if a surgical margin is inadequate and surrounded by an intact fascial layer or periosteum, this risk probably does not apply [43].
According to ESMO guidelines, the minimum margin on fixed tissue that should be regarded as adequate may vary depending on a number of variables, such as the histological subtype, preoperative treatments, and the presence of anatomical barriers such as fascia, vascular adventitia, periosteum, and epineurium [65].
Radical resection, which includes the amputation or removal of all the muscles and neurovascular structures within the compartment where the tumor is located. Local recurrence rates are substantially lower and vary from 0 to 18%. Although these local recurrence rates are acceptable, the cost of a limb (or a compartment) being lost is tremendous. Currently, amputations make up <5% of all sarcoma surgeries (Figure 6) [61, 66].
Figure 6.
Schematic diagram of soft tissue sarcoma excision. Cross-section of thigh showing tumor in adductor magnus with surrounding reactive zone, or “pseudo capsule.” Four different classes of surgical excision are depicted, indicating the tissue excised with each type of resection [61].
The American Joint Committee on Cancer (AJCC) classifies margins as negative (R0), microscopically positive (R1), or grossly positive (R2) using the R classification system [67].
The International Union Against Cancer (UICC) has recently modified the R classification to include the “R + 1 mm” classification, where the margin is designated as excessively positive (R2). In the past, specimens were classified as microscopically negative (R0) if there was a minimum of 1 mm of healthy tissue separating the tumor from the inked resection margin. Conversely, they were classified as microscopically positive (R1) if the tumor was located within 1 mm of the inked border. The UICC (R + 1 mm) classification’s R0 margin standards are more stringent than those of the R classification [68].
The Toronto margin context classification (TMCC) identifies four categories of margins: negative margins (R0), unplanned positive margins, planned close margins with ultimately positive microscopic margins along critical structures, and positive margins resulting from tumor bed re-excision in patients initially treated with subpar surgery (the whoops procedure) [69].
4.2 Isolated limb perfusion
Locally advanced sarcomas or local recurrences are commonly treated with isolated limb perfusion. Few changes have been made to the treatment since it was adopted for treating sarcomas in 1992, following the addition of TNF. A significant component of the procedure is a 60-minute perfusion of melphalan and TNF under mild hyperthermia, which results in a 72 to 96% limb preservation rate, a 72 to 82.5% overall response rate, and acceptable toxicity according to the Wieberdink scale [70].
4.3 Adjuvant and neoadjuvant therapy for soft tissue sarcoma
4.3.1 Adjuvant radiotherapy
4.3.1.1 Limb sparing approach for localized extremity STS
Amputation was the standard of care for STS of the extremity until the results of the famous National Cancer Institute (NCI) randomized trial compared amputation to limb-sparing surgery plus postoperative radiation therapy in patients with high-grade STS of the extremity. They used a radiation dose of 50 Gy in a large volume, including the anatomic area at risk for local spread, followed by 10–20 Gy in a smaller volume of the tumor bed. Adjuvant chemotherapy was given to all patients. The trial showed comparable local control rates in both arms. Moreover, disease-free survival (DFS) and overall survival (OS) were not significantly different between the two arms. This trial proposed a new function-preserving option for patients who have a resectable disease with adequate margins and limited the use of amputation [71].
Further two randomized controlled trials tested the additional benefit of postoperative radiotherapy following limb-sparing surgery. The NCI randomized patients with high- and low-grade extremity STS to limb-sparing surgery alone or surgery followed by radiotherapy. Patients with high-grade sarcoma received adjuvant chemotherapy. The radiation was given in two phases. In phase I, a dose of 45 Gy was delivered to a large field, and then a boost dose of 18 Gy was given to the tumor bed. The trial found that adding radiation after limb-sparing surgery significantly decreased local recurrence, regardless of the grade. After a median follow-up of about 10 years, for high-grade STS, the local recurrence rate was 19% with surgery alone, with no local recurrence in the adjuvant radiotherapy arm. While for low-grade STS, the local recurrence rate was 33% after surgery alone, compared to 4% with adjuvant radiotherapy [72]. However, the rate of long-term complications, including worse limb strength, edema, and decreased range of motion, was higher in the radiotherapy arm.
A more recent updated report of the NCI study was published in 2014 with 20-year follow-up data concerning the quality of life. They found an increased rate of pathologic fracture, wound complications, and edema in the radiotherapy arm. In the same report, they confirmed a nonsignificantly better OS favoring adjuvant radiotherapy, although the trial was not powered to detect a survival difference [73].
In the other randomized trial, interstitial brachytherapy was in comparison to limb-sparing surgery alone. Brachytherapy was delivered using iridium-192 needles at a dose of 42–45 Gy over 4–6 days. After a median follow-up of about 6.3 years, they found a higher local recurrence rate in the surgery-only arm. For high-grade STS, the rate of local control was 66% with surgery alone, compared to 89% in the brachytherapy arm (P = 0.0025). In low-grade STS, adjuvant radiotherapy did not improve local control compared to surgery alone (P = 0.49). The trial also showed that adjuvant radiotherapy did not improve survival compared to surgery alone [74].
After a median follow-up of 100 months, a later update of this trial reported a 24% wound complication rate with adjuvant brachytherapy. Wound complications included reoperation for wound problems, wound separation greater than 2 cm, wound infection with purulent discharge, persistent seroma necessitating repeated aspirations, or hematoma formation volume of more than 25 mL. They reported an increased complication rate with large resection specimens [75].
Furthermore, a SEER database analysis found that patients with high-grade STS who received postoperative radiotherapy had better OS compared to surgery alone (HR 0.67, 95% CI 0.57–0.79). On the other hand, no OS benefit was found in patients with low-grade STS [76].
Although adjuvant radiotherapy improves local control over surgery alone, its value in small, low-grade tumors is questionable, especially when adequate tissue margins have been achieved following surgery [77]. A nomogram was made at MSKCC based on a study of recurrence rates among patients who had surgery without radiotherapy. This was done to make the decision of adjuvant radiotherapy more personalized. Five predictive factors were identified, including the patient’s age, tumor size, grade, margin status, and histology [78].
4.3.1.2 Preoperative vs. postoperative radiotherapy
The use of preoperative radiotherapy before limb-sparing surgery was thought to be better than postoperative radiotherapy. For preoperative radiotherapy, a lower radiation dose to a smaller target volume is usually used, which may result in lower rates of long-term side effects. Preoperative radiotherapy may facilitate tumor resection by downsizing the tumor and decreasing the risk of microscopic tumor seeding during surgery. Moreover, delineating a well-visualized tumor volume is much easier than delineating a large area of the postoperative bed [79].
In a large Canadian trial, 190 patients were given either preoperative radiotherapy at a dose of 50 Gy in 25 fractions to the tumor plus a 2 cm expansion with a boost dose of 16 to 20 Gy after resection if the surgical margins were positive or postoperative radiotherapy at a dose of 66 Gy in 33 fractions. The wound complication rates were 35 and 17% in the preoperative and postoperative arms, respectively (P = 0.01). A higher rate of wound complications was seen in patients with lower extremities compared to patients with upper-extremity STS. Moreover, limb function at 6 weeks after surgery was worse in the preoperative arm (P = 0.01). At a median follow-up of 5 years, local control rates (93 vs. 92%) and OS (73 vs. 67%, P = 0.48) were equivalent in both arms [80].
A long-term evaluation of 129 patients found that limb function at 21 to 27 months after surgery was similar in both arms, but there was a statistical trend for more fibrosis, edema, and joint stiffness in the postoperative arm (P = 0.07) [81].
In general, preoperative radiotherapy is preferable, especially for large and/or high-grade STS, to downsize the tumor, decrease treated volumes, and facilitate surgical resection. Preoperative radiotherapy is also recommended for large radiosensitive STS subtypes like myxoid liposarcomas, which respond well to radiation compared to other histological subtypes [82].
4.3.1.3 Impact of margin status
Positive margin is a strong independent predictive factor of local recurrence, regardless of the use of adjuvant radiotherapy. Re-excision is usually indicated to clear margins after initially inadequate surgery. In a retrospective review, the data of 100 patients with high-grade sarcoma who had surgery with positive margins was analyzed. Local recurrence rates following surgery alone or surgery plus radiotherapy were 56 and 74%, respectively [83]. These local recurrence rates are higher than those observed in large series, in which most patients had clear resection margins. Even with the addition of adjuvant radiation, recurrence risk is still higher in the setting of positive margins. If a positive margin cannot be re-excised, a high radiation dose should be used up to 64 Gy due to statistically significant improvements in local control, disease-free survival, and overall survival [84].
4.3.1.4 Radiation therapy alone for unresectable disease
In patients who have initially unresectable disease, radiotherapy may be added for palliation of symptoms and to improve local control. An old study reported a 5-year local control rate of 33% in patients treated with external beam radiation therapy with doses ranging from 64 to 66 Gy [85]. An updated analysis from this study included 112 patients treated with definitive radiotherapy. They reported that the 5-year local control rate was dependent on tumor size and total dose. Regarding the tumor size, at 5 years, the local control rates were 51, 45, and 9% for tumors <5, 5–10, and > 10 cm, respectively. Regarding the total dose, the 5-year local control rate was 60% in patients who received >63 Gy, compared to 22% in patients receiving <63 Gy. The 5-year DFS and OS were also improved with higher doses. However, a higher complication rate was reported for higher doses >68 Gy (26 vs. 8%, p = 0.02) [86].
4.3.1.5 Radiotherapy techniques
External beam radiotherapy using 3D conformal radiotherapy (3DCRT) or intensity-modulated radiation therapy (IMRT) has been used as the gold standard radiotherapy technique. Other modalities, such as brachytherapy and intraoperative radiation therapy (IORT), decreased local recurrence after limb-sparing surgery. However, the local control rates are slightly lower than those reported with EBRT. The 5-year local control rates ranged from 82 to 84% with adjuvant brachytherapy [87]. A study comparing IMRT to brachytherapy found that IMRT improved 5-year local control rates in high-grade STS by 92% compared with 81% (p = 0.04) with brachytherapy. However, the major wound complications rate was 19% with IMRT compared to 11% with brachytherapy. While complications requiring reoperation were observed in 2% of patients treated with IMRT compared with 6% for those treated with brachytherapy [88].
This lower local control rate may be attributed to the smaller treated volume using brachytherapy and IORT alone, which may miss areas of subclinical disease or areas of extra compartmental spread. So, a hybrid treatment using brachytherapy, or IORT, as a boost in combination with EBRT was examined. Collectively, three series showed 5-year local control rates of 63–91.5% with wound healing complication rates of 12–34% [89, 90, 91].
4.3.2 Adjuvant and neoadjuvant chemotherapy
Although limb-sparing surgery preceded or followed by radiotherapy provided excellent long-term local control, up to 50% of patients with high-grade tumors will develop distant metastasis. So, the addition of adjuvant systemic chemotherapy to treat early micrometastatic disease gained a special interest in randomized trials and meta-analyses.
4.3.2.1 Randomized controlled trials of adjuvant chemotherapy
A single-agent doxorubicin was tested in the adjuvant setting in a large study conducted by the Scandinavian Sarcoma Group. After surgery +/− adjuvant radiotherapy, 240 patients were randomized to receive doxorubicin 60 mg/m2 every 4 weeks for nine cycles or no chemotherapy. Data from 181 patients was available at the time of the analysis. After a median follow-up of about 40 months, single-agent doxorubicin did not improve local control, disease-free survival, or overall survival compared to the control arm. Further assessment of the survival data of the entire 240-patient cohort showed no difference in disease-free or overall survival between both treatment arms [92].
Combination chemotherapy for truncal and extremity soft tissue sarcomas was tested in a study by the Italian Sarcoma Study Group. After surgery +/− radiotherapy, 104 patients received either no chemotherapy or received ifosfamide (9 g/m2 split over 5 days) and epirubicin (120 mg/m2 split over 2 days) with filgrastim. Early termination of the study was decided after interim analysis, which showed that the primary endpoint of improved DFS was met. After a median follow-up of 36 months, OS was 72 vs. 55% in the chemotherapy arm and the no chemotherapy arm, respectively (p = 0.002). However, with longer follow-up, DFS did not reach a statistical significance level of p = 0.05, but 5-year overall survival was significantly better with chemotherapy [93]. This was the first study that showed a survival benefit for chemotherapy with ifosfamide-anthracycline-based therapy.
The EORTC conducted the largest randomized trial of adjuvant combination chemotherapy. The EORTC 62029 trial recruited 351 patients over 8 years. Patient characteristics were balanced between the treatment arms; about 47% of patients were > 50 years old, and about 54% were male. Histological subtypes included leiomyosarcoma 15%, liposarcoma 13%, MFH 11%, synovial 11%, with 60% of high-grade tumors, and two-thirds with an extremity primary. About 88% of patients received adjuvant radiotherapy. There was no significant survival benefit from adjuvant chemotherapy, with an equivalent 5-year DFS of 52% in both arms. The 5-year OS was comparable with 69% (observation) and 64% (chemotherapy) [94].
4.3.2.2 Meta-analyses of adjuvant chemotherapy
According to the Sarcoma Meta-analysis Collaboration (SMAC) group, data from different studies of adjuvant chemotherapy were put together in an old meta-analysis to make the case for using it stronger. They revised 23 studies but included 14 studies in the final analysis. Histological subtypes for each patient were reported but without a central pathological review. After a median follow-up of 9.4 years, 10-year DFS was superior to chemotherapy compared to no chemotherapy (55 vs. 45%, p = 0.0001). The 10-year local recurrence-free survival was also improved with chemotherapy (81 vs. 75%, p = 0.016). The 10-year OS was better with chemotherapy (54 vs. 50%), but not statistically significant (p = 0.12). A subgroup analysis of about 886 patients with extremity STS found a statistically significant improvement in overall survival: 46% of patients received chemotherapy compared to 39% of those who did not (p = 0.029) [95].
A more recent SMAC meta-analysis was published in 2008, which included modern studies using ifosfamide as part of adjuvant or neoadjuvant chemotherapy [96]. Most patients (about 95%) had STS in the extremity or trunk, where adequate surgical margins are most likely achieved. They reported a statistically significant reduction in local, distant, and overall recurrence for patients who received chemotherapy, compared to patients who did not receive chemotherapy. There was an absolute risk reduction of death of 6% (95% CI 2–11%; p = 0.003) favoring adjuvant chemotherapy. The 5-year survival rate was 46% for patients who received chemotherapy and 40% for those who did not. There were similar outcomes for patients who were treated in the ifosfamide-anthracycline-containing studies when analyzed alone or in combination with the older doxorubicin-based studies where ifosfamide was not used.
In conclusion, most individual clinical trials of adjuvant chemotherapy were negative. The encouraging results from the meta-analyses, however, might balance this. So, there is a small benefit from chemotherapy.
4.3.2.3 The patient selection for adjuvant chemotherapy
Based on the small benefit of adjuvant chemotherapy, defining a group of patients who may gain the biggest advantage from chemotherapy is critical. The chemosensitivity of different histological subtypes was not addressed in either meta-analyses or clinical trials, as no histological subtype represents the majority in any of these studies. Given the higher sensitivity of myxoid-round cell liposarcoma and synovial sarcoma to chemotherapy in metastatic soft tissue sarcoma (STS) compared to other subtypes, it is reasonable to anticipate potential benefits from adjuvant chemotherapy in individuals with these specific histological subtypes. A combined data analysis from two EORTC randomized trials of adjuvant therapy included 819 patients; no specific histological subtype gained a higher benefit from chemotherapy compared to others. In the same analysis, men appeared to benefit more than women, and patients under age 40 had worse outcomes than older patients, which is surprising since most patients under age 40 are diagnosed with chemotherapy-sensitive STS like synovial sarcoma and myxoid liposarcoma [97].
Two nomograms for predicting OS and distant metastases were developed based on retrospective data from 1452 extremity STS patients who had an operation at the Istituto Nazionale Tumori (Milan, Italy) from 1994 to 2013. The external validation of these nomograms was performed in three groups of patients from France, Canada, and the UK. The author confirmed the utility of these nomograms in predicting the risk of distant metastases and death after surgery. This information may help make decisions regarding the use of adjuvant chemotherapy in high-risk patients [98].
4.3.2.4 Neoadjuvant systemic chemotherapy
The role of neoadjuvant chemotherapy is debated, particularly for patients with large, unresectable, high-grade STS, to downsize the tumor. However, the data supporting the use of neoadjuvant chemotherapy for STS is scarce and mainly derived from retrospective series and small phase II trials [99, 100].
A new phase III RCT was done in Italy, France, and Poland to find out which is better for treating high-risk trunk and extremity STS: traditional anthracycline-ifosfamide-based neoadjuvant therapy or histology-based therapy. The study enrolled 287 patients who had nonmetastatic high-risk soft tissue sarcoma (STS) with a grade of 3 and a size of 5 cm or larger. These patients were classified into five histological subtypes: undifferentiated pleomorphic sarcoma (UPS) accounted for 33.8% of the cases, synovial sarcoma (SS) accounted for 24.4%, high-grade myxoid liposarcoma (HG-MLPS) accounted for 22.6%, leiomyosarcoma (LMS) accounted for 9.8%, and malignant peripheral nerve sheath tumor (MPNST) accounted for 9.4%. The control arm received three cycles of epirubicin 60 mg/m2/d short infusion for 2 days and ifosfamide 3 g/m2/d for 3 days. The investigational arm received histology-based regimens including gemcitabine 900 mg/m2 on days 1 and 8 administered IV over 90 minutes, docetaxel 75 mg/m2 on day 8 administered IV over 1 hour for UPS, The administration of ifosfamide at a high dosage of 14 g/m2 is done over a period of 14 days using an external infusion pump for SS, trabectedin 1.3 mg/m2, given by 24-hour continuous infusion for HG-MLPS, gemcitabine 1800 mg/m2 on day 1 administered intravenously (IV) over 180 minutes, and dacarbazine 500 mg/m2 on day 1 administered IV over 20 minutes for LMS, and etoposide 150 mg/m2/d on for 3 days and ifosfamide 3 g/m2/d on days for 3 days for MPNST. After a median follow-up of 52 months, there was no difference in 5-year DFS and OS, and no treatment-related deaths were observed between both arms [101].
The Japanese JCOG1306 phase II/III randomized trial compared gemcitabine-docetaxel to standard adriamycin-ifosfamide and concluded that the anthracycline-ifosfamide combination should still be the standard regimen for neoadjuvant chemotherapy in high-risk extremity and trunk STSS [102].
In the absence of strong evidence, a multidisciplinary team discussion is essential to select patients for neoadjuvant chemotherapy. Patient factors, such as age and comorbidity, together with the tumor characteristics, including histology, subtype, stage, and resectability, should all be considered in discussing the appropriateness of this approach on a case-by-case basis.
4.3.3 Special consideration for retroperitoneal STS
Retroperitoneal sarcomas (RPS) pose several challenges in management. They are a group of rare, heterogeneous tumors that often present with large masses. The risk of complete surgical eradication is high due to its critical proximity to abdominal organs. So, the local recurrence rate is higher than the extremity and trunk STS. Local recurrence rates are common with high-grade tumors and following macroscopically incomplete resections [103].
4.3.3.1 Adjuvant radiotherapy
Pre- or postoperative EBRT and/or IORT are usually used in combination with surgery to decrease the risk of local recurrence. Several retrospective database studies confirmed the positive impact of preoperative or postoperative radiotherapy on survival compared to surgery alone. A US National Cancer Data Base study investigated the added role of preoperative compared to surgery alone in retroperitoneal liposarcoma. Preoperative radiotherapy followed by resection improved survival compared to surgery alone, with a median overall survival of 129.2 versus 84.3 months, respectively (P = 0.046). The effect of preoperative radiotherapy on survival was more apparent in large, advanced tumors with organ invasion. The median overall survival was not reached in the preoperative radiotherapy cohort versus 63.8 months in the surgery-only cohort (P = 0.044) [104].
A separate case-control study examined a cohort of 9068 individuals diagnosed with localized retroperitoneal sarcoma, sourced from a comprehensive clinical oncology database, and who had treatment between 2003 and 2011. Both preoperative and postoperative radiotherapy were significantly linked to a better overall survival rate (OS) compared to surgery alone [105].
Preoperative radiotherapy is usually preferred over postoperative radiotherapy since radiation enteritis is significantly lower as the tumor mass displaces the small intestine away from the radiation beam. Moreover, it is easier to treat a small tumor volume than a large operative bed. A radiation dose of 45 to 50 Gy is recommended for preoperative radiotherapy. VMAT or IMRT, is vastly superior to 3DCRT in terms of radiation dose homogeneity and dose to organs at risk [106].
The latest phase III randomized STRASS trial (EORTC-62092) revealed that preoperative radiation does not provide therapeutic benefits for retroperitoneal sarcoma. The study comprised a cohort of 266 patients diagnosed with nonmetastatic retroperitoneal soft tissue sarcoma (STS). Its objective was to examine the effect of combining preoperative radiation with surgery, as opposed to surgery alone, on the rate of abdominal recurrence-free survival. The administration of radiotherapy involved delivering a total dose of 50·4 Gy in 28 fractions, utilizing either 3DCRT or IMRT techniques. This was followed by the surgical removal of the tumor mass, ensuring complete removal of the visible tumor along with the adjacent organs if required. Following a median follow-up period of 43.1 months, the projected median duration of survival without abdominal recurrence was 4.5 years in the group that had radiotherapy in addition to surgery and 5.0 years in the group that underwent surgery alone. The hazard ratio was 1.01, with a 95% confidence interval of 0.71–1.44. The log rank p-value was 0.95. Higher toxicity was also seen in the radiotherapy arm [107].
4.3.3.2 Adjuvant chemotherapy
Most of the trials addressing the role of postoperative chemotherapy have been performed in the setting of advanced-extremity STS. Data to support the usability of chemotherapy following resection in retroperitoneal STS is very limited, and the extrapolation of data from extremity trials may not be appropriate. Since mortality in RPS often occurs in the absence of distant metastases, the priority should be eliminating the risk of local recurrence. The use of preoperative chemotherapy alone or in combination with radiotherapy was tested in several studies.
An Italian study reported on the long-term outcomes of 83 patients treated with neoadjuvant high-dose long-infusion ifosfamide along with preoperative radiotherapy followed by surgery for localized retroperitoneal STS. About 72% of the patients completed the neoadjuvant chemoradiotherapy regimen. With 91.7 months of median follow-up, the DFS and OS were 46.6 and 63.2% at 7 years, respectively. This study confirmed the long-term feasibility and safety of this approach [108].
A NCD analysis study included patients with localized retroperitoneal STS who received different regimens of pre- or postoperative chemotherapy. The study showed a worse median OS in the chemotherapy group compared to surgery alone (40 vs. 68.2 months; p < 0.01). Even after propensity score matching, lower OS in the chemotherapy group persisted (40 vs. 52.4 months; p = 0.002). However, it is difficult to draw firm conclusions from these data since patients with large, high-grade tumors were more likely to receive chemotherapy [109].
In conclusion, the available data in retroperitoneal STS demonstrated the feasibility of preoperative chemotherapy or chemoradiotherapy. However, there are concerns about toxicity, which may interfere with the patient’s definitive surgical treatment afterward. So, preoperative treatment may be considered in borderline resectable tumors, particularly in high-grade, relatively chemo-sensitive subtypes such as leiomyosarcomas, undifferentiated pleomorphic sarcomas, and grade 3 dedifferentiated liposarcomas [110].
5. Systemic therapies in advanced and metastatic soft tissue sarcoma
Since the first studies in the 1970s, doxorubicin has been and remains the single most active agent for the treatment of STS. There is much variation in its reported response rate given the underlying tumor heterogeneity of early trials, which predominantly included multiple STS subtypes. Modern-day studies in unselected STS reported response rates of 10–25% [111].
It is important to recognize that there is a dose-response relationship with doxorubicin, seen at doses between 60 and 75 mg/m2 per cycle [112]. Other agents have been investigated to try and avoid dose-limiting cumulative cardiotoxicity [113]. Epirubicin has an equal dose, less cardiotoxicity, and a similar toxicity profile and response rate. However, most of the data were collected using doxorubicin, so in most parts of the world, doxorubicin is still the more well-known treatment. Alternatively, liposomal doxorubicin, in phase II studies, has similar activity to doxorubicin with response rates between 10 and 50% and an improved toxicity profile [114].
Multiple randomized trials have looked at the combination of doxorubicin and ifosfamide, but they have not found any clear, useful evidence to show that the combination approach is better than using doxorubicin alone. While these combinations are associated with higher response rates (range of 15–46%) when compared with single-agent doxorubicin (10–18%), they have not improved overall survival. Moreover, toxicity was significantly greater for the combination group [115, 116].
So, the choice of combination versus single-agent therapy in the first line must be designed exclusively for the patient, suggesting that the combination may have a role to play in selected patients where tumor shrinkage is an important goal of treatment, for example, neoadjuvant chemotherapy, or in patients with highly symptomatic lesions but minimal other comorbidities, allowing them to tolerate a more aggressive approach [43].
The GeDDiS trial was a phase 3 randomized controlled trial performed at 24 institutions in the UK and one hospital connected with the Swiss Group for Clinical Cancer Research (SAKK). Patients needed to have histologically proven locally advanced or metastatic soft tissue sarcoma and have never received doxorubicin or sarcoma treatment before. Patients were given either six cycles of doxorubicin or six cycles of gemcitabine/docetaxel at random. Results showed that gemcitabine/docetaxel was not superior to doxorubicin for either PFS or OS, so it can be an alternative when anthracycline is clinically contraindicated [117].
More recently, LMS-04, a randomized multicenter phase III trial that included 150 patients from 20 centers of the French Sarcoma Group, compared doxorubicin alone to doxorubicin and trabectedin as first-line therapy for advanced leiomyosarcoma. Inclusion criteria were patients with age >/= 18 years old, ECOG 0-1, metastatic or unresectable leiomyosarcoma of soft tissue or uterine, who had not received chemotherapy before. Doxorubicin/trabectedin in first-line therapy increased PFS compared to doxorubicin alone and could be considered as a first-line treatment for metastatic leiomyosarcoma [118].
5.1 Second-line systemic therapies
Other systemic medications are thought of as second-line medications. Gemcitabine is effective in treating refractory STS and more effective in treating leiomyosarcoma, angiosarcoma, and, to some extent, pleomorphic sarcoma. There is conflicting evidence on the benefits of a gemcitabine dacarbazine GD regimen over gemcitabine alone, despite its higher tolerability in a palliative setting [119].
In terms of PFS, OS, and RR, gemcitabine with docetaxel is more successful than gemcitabine alone, but with higher toxicity. Phase II studies of the combination showed an overall response rate as high as 53%. In uterine leiomyosarcomas, studies including other soft tissue sarcomas showed a response rate of 14–53% [120].
Trabectedin is an alkylating agent (a tetrahydroisoquinoline alkaloid) that is thought to work by attaching to the minor groove of DNA and damaging the machinery that fixes DNA nucleotides. It is suggested for people who did not respond to anthracycline-based therapy [121]. A PFS of 3.3 months and an overall survival of 13.9 months were found in research on trabectedin 24-hour infusion. These studies’ findings led to the approval of trabectedin for treatment in patients who had progressed on doxorubicin or ifosfamide in Europe in 2007, particularly in cases with myxoid liposarcoma and leiomyosarcoma, so-called “histocyte-specific cytotoxic agents” [122].
Another example of histocyte-specific cytotoxicity in patients with advanced STS is eribulin, a microtubule inhibitor. In a phase II study, the EORTC examined the efficacy of eribulin in people with adipocytic, leiomyosarcoma, and synovial sarcomas. Eribulin 1.4 mg/m2 was administered to 115 patients on days 1 and 8 of a 21-day cycle for analysis and treatment. Patients with leiomyosarcoma had a PFS of 31.6%, those with adipocytic sarcoma had a PFS of 46.9%, and those with synovial sarcoma had a PFS of 21.1% at 12 weeks. Patients with adipocytic sarcomas had a median PFS of 2.6 months, whereas those with leiomyosarcoma and synovial sarcoma had median PFS of 2.9 months each [123]. Patients with advanced liposarcoma and leiomyosarcoma who received eribulin had longer overall survival (OS) than those who received dacarbazine in a phase 3 trial (13.5 vs. 11.5 months, respectively; P = 0.0169). Patients with liposarcoma had the greatest benefit (median OS, 15.6 vs. 8.4). Median PFS was comparable in both treatment groups (2.6 months) [124].
5.2 Tyrosine kinase inhibitors (TKIs) or multi-targeted kinase inhibitors
TKIs are small, multifunctional molecules that induce downstream effects such as inhibition of angiogenesis, cell growth, and proliferation.
Pazopanib was the first targeted substance to be approved in non-GIST STS and was indicated in patients who had demonstrated poor response to earlier chemotherapy. In an early EORTC study, 62,043 was conducted for Pazopanib in patients with relapsed or refractory advanced soft tissue sarcoma. In total, 140 patients with intermediate- or high-grade soft tissue sarcoma were enrolled, including adipocytic STS, leiomyosarcoma, synovial sarcoma, and other STS types. Results showed that pazopanib was well tolerated in patients with relapsed, advanced STS but had insufficient activity on the liposarcoma subtype [125].
The Spanish Sarcoma Group and the German interdisciplinary Sarcoma Group established a phase II trial (NCT01692496) to monitor the activity of pazopanib on liposarcoma in two cohort groups: well-differentiated or dedifferentiated liposarcoma and myxoid or round-cell liposarcoma. Results showed that pazopanib was well tolerated in well-differentiated and dedifferentiated subtypes but not in myxoid liposarcoma [126].
A phase II trial was established by the Spanish Sarcoma Group and the German interdisciplinary Sarcoma Group (NCT01692496) that was designed to observe the activity of pazopanib on liposarcoma in two cohort groups: well-differentiated differentiated/dedifferentiated liposarcoma and myxoid or round-cell liposarcoma. Results showed that pazopanib was well tolerated in well-differentiated and dedifferentiated subtypes, but not in myxoid liposarcoma [127].
The EPAZ trial showed that pazopanib was just as effective as doxorubicin in treating STS in older patients. This suggests that pazopanib could be used as the first treatment for STS in people aged 60 and up. There was superiority with pazopanib in terms of neutropenia and febrile neutropenia in elderly patients with STS. The overall incidence of toxicity remained similar for both treatments, but there were differences in the AE profiles that may help tailor treatment to individual needs in this population [128].
5.3 Immune checkpoint inhibitors (ICIs)
A treatment option for individuals with advanced and metastatic cancer is pembrolizumab, an anti-PD-1 antibody that exhibits encouraging action in undifferentiated sarcomas [129].
Studies have also been done on the effects of pembrolizumab and nivolumab, two humanized monoclonal IgG4 antibodies that target the PD-1 cell surface receptor. These antibodies may be used alone or in combination with cytotoxic and antiangiogenic medications. In the SARC028 phase 2 study, pembrolizumab worked well as a single drug for all types of undifferentiated STS, with an ORR of 17.5 and a 55% 3-month PFS. Undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma seemed to benefit the most [130].
Patients with alveolar soft part sarcoma (ASPS) showed outstanding outcomes with ICIs. A single-center phase II study with axitinib and pembrolizumab was presented by Wilky and colleagues. Eleven of the patients had been diagnosed with ASPS. Six (54.5%) of the 11 patients showed an objective response, and the median PFS was 12.4 months (95% CI, 2.7–22.3) [131].
5.4 Systemic treatment for certain benign or malignant soft tissue tumors
Because we know more about the different types of STS histology and because of the results of many retrospective reviews and prospective randomized studies, it is important to treat these types of histology with care [132].
Angiosarcoma is highly sensitive to taxanes. Gemcitabine is an alternative, either as a single agent or in combination with docetaxel [133].
Perivascular epithelioid cell tumor (PEComa) is a family of rare mesenchymal tumors consisting of perivascular epithelioid cells. TSC1 and TSC2 mutations disrupting the mTOR signaling pathway led to the exploration of mTOR inhibitors in PEComas [134]. Activity of sirolimus and temsirolimus has been reported in small case series [135].
Dermatofibrosarcoma protuberans (DFSP): Imatinib is the usual first-line medicinal treatment [136]. DFSPs are characterized by a unique translocation t (17;22) (q22; q13), resulting in the COL1A1/PDGFB fusion gene, responsible for platelet-derived growth factor beta receptor activation, hence the imatinib activity [137].
Desmoid tumors DTFs are benign fibroblastic proliferations characterized by infiltrative growth. There are two different types of DTF that have been described: sporadic DTF linked to the CTNNB1 mutation and DTF linked to the APC germline mutation. Wnt/APC/β-catenin pathway alterations are considered to be the drivers of tumor proliferation [138]. For those who fail the “wait and see” management, pazopanib, and sorafenib showed activity with a good response rate in progressive symptomatic patients [139, 140]. Also, there are better data for liposomal doxorubicin, single-agent vinorelbine, and combination methotrexate/vinorelbine or methotrexate/vinblastine [141, 142]. More recently, nirogacestat is an oral, specific, and small-molecule gamma-secretase inhibitor. There was a statistically significant improvement in the risk of disease progression in patients who were randomly assigned to nirogacestat compared to placebo in a DeFi study. On average, the risk of disease progression dropped by 71% [143].
Pigmented villonodular synovitis (PVNS), otherwise known as tenosynovial giant cell tumor, is a rare but well-recognized proliferative disorder of synovial tissue. It is considered a benign neoplasm, lacking malignant and metastatic potential. A translocation in CSF1-COL6A3, t (1;2) (p13; q35), leads to overexpression of the colony-stimulating factor 1 receptor (CSF1R) [144]. Imatinib and nilotinib showed some CSF1R inhibitor activity [145]. The more potent CSF1R inhibitor, pexidartinib, showed an impressive overall response rate but also had significant hepatic toxicity [144].
Solitary fibrous tumor (SFT): the more potent CSF1R inhibitor, pexidartinib, showed an impressive overall response rate but also had significant hepatic toxicity [146]. Anti-angiogenetic agents such as pazopanib, sunitinib, and sorafenib are shown to be active in this entity [147]. It tends to be refractory to doxorubicin, but there has been a variable response seen with other cytotoxic agents, including dacarbazine and trabectedin [148].
Alveolar soft part sarcoma (ASPS) is a rare subtype of soft tissue sarcoma (STS) that is caused by a specific genetic abnormality known as t(X;17) (p11; q25) translocation. ASPS is known for its slow-growing nature, yet it tends to spread to the lungs and brain. It is regarded as inherently resistant to chemotherapy. Tyrosine kinase inhibitors, including sunitinib, cediranib, and pazopanib, have demonstrated efficacy in over 50% of instances, resulting in tumor responses or disease stability [149]. Immune checkpoint inhibitors have also shown promising activity in ASPS based on early-phase immunotherapy trials [150].
Endometrial stromal sarcoma (ESS) Low-grade ESS is the most common subtype of ESS. They are indolent tumors characterized by strong expression of the hormone receptors CD10 and Bcl2. At a molecular level, JAZF1 rearrangements are common and are regarded as diagnostic [151]. They are highly sensitive to progestins, such as medroxyprogesterone (Provera), and hormonal therapy is preferred over cytotoxic agents in the first line. Chemotherapeutic agents are generally reserved for patients with hormone-resistant diseases [152]. High-grade ESS has an aggressive natural history, is characterized by a lack of hormone receptor and CD10 expression, and may have a translocation that results [153].
Soft tissue sarcoma (STS) is a group of diseases with varying biological characteristics and particular responses to treatment based on their location and histological type, rather than a single entity. Surgery is the primary treatment for limited primary disease. The strategy that is advised is to undergo scheduled surgery with the objective of achieving microscopically negative margins. Neoadjuvant and/or adjuvant chemotherapy and radiation therapy are frequently employed to enhance treatment outcomes and optimize the quality of surgical margins although emerging research is showing the importance of using multiple treatment methods for these tumors. To optimize patient care, it is imperative that cases be deliberated upon in a multidisciplinary team (MDT) setting. Furthermore, treatment strategies should be tailored to the individual patient, considering a comprehensive understanding of the distinct behavioral patterns exhibited by specific pathologic types, with particular emphasis on infiltrative variants.
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Written By
Mohamed Kelany, Ahmed R. Eldesoky, Asmaa A. Abdeltawab and Noha Mohamed
Submitted: 28 August 2023Reviewed: 06 September 2023Published: 17 May 2024
Open access peer-reviewed chapter - ONLINE FIRST
