Synovial Sarcoma

                                    Dr. KS Dhillon

Introduction

Synovial sarcoma is a malignant neoplasm that can occur throughout the body. Sixty percent of synovial sarcomas arise from the lower limb, especially the thigh. Synovial sarcomas account for about 6% to 10% of all malignant tumors of somatic soft tissues. They have an estimated incidence of 2.75 per 100,000 general population [1,2]. A small but significant number presents with primary lesions that arise on the trunk, especially in the abdominal wall [3], in the head [4], and in the neck [5]. 

Most of these tumors originate close to major articular structures. Sometimes they arise in joint cavities. These lesions do not originate from synovium. They arise from a primitive mesenchymal cell [6]. Previous reviews have suggested that for synovial sarcoma, distal rather than proximal location in the extremities has a more favorable outcome [7,8]. 

Synovial sarcomas are classified into two basic histologic subtypes i.e. monophasic and biphasic. The monophasic type contains a spindle cell population that is arranged in fascicles with tapering nuclei and a pale, poorly-defined cytoplasm [7,9]. In addition to spindle cells, the biphasic lesion also contains well-differentiated cuboidal to columnar epithelium. Synovial sarcomas contain a translocation involving chromosomes X and 18. This translocation results in the fusion of the SSXT gene from chromosome 18 with one of two highly homologous and neighboring genes on chromosome X for the monophasic and polyphasic tumor types [10].

Synovial sarcoma occurs more frequently in the younger age group (range, 10–35 years) and has a male to female gender distribution of 1.2:1. It most often arises in the lower limb, especially the thigh, and it is thought to be the most common soft tissue sarcoma of the foot [11,12]. Pulmonary spread occurs in more than 50% of the patients, and the 5 to 10 year survival rates range from 40% to 76% and 20% to 34%, respectively [7,13,14,15]. 

Clinical Presentation

Many synovial sarcomas originate near articular structures. The name synovial sarcoma is a misnomer because these lesions do not originate from intra-articular synovium but from primitive mesenchymal cells [16]. Synovial sarcomas usually present as soft tissue masses but cases of primary synovial sarcoma of bone have also been reported [17]. These lesions can occur anywhere in the body. The majority, however, arise in the extremities, particularly in the lower extremity in the anatomic structures adjacent to the knee joint [18,19]. Synovial sarcomas are considered the most common soft tissue sarcoma (STS) of the foot [20,21,22].

Synovial sarcomas usually do not present with the typical STS presentation of a large and quickly growing painless mass [19]. The majority of synovial sarcomas are slow growing and the mean duration of symptoms before diagnosis is about 2 years [23]. The duration of symptoms is long and patients may have pain or joint contractures that precede the swelling [24]. About 50% of the patients have clinical findings consistent with STS [23,24]. Given the insidious onset, younger age, and atypical symptoms at presentation, these patients may initially be clinically misdiagnosed with benign processes such as myositis, synovitis, bursitis, or tendonitis.

Imaging

Plain radiographs are not required for the diagnosis of synovial sarcomas. However, they are typically performed as part of the initial workup and can identify adjacent bony remodeling, bone invasion, or calcification of the soft tissue mass [25,26,27]. Synovial sarcoma presents as a well-defined or lobulated soft tissue mass on plain radiographs. In one-third of the patients punctate calcifications, particularly around the periphery of the lesion, are visualized [28]. Sometimes more extensive calcification can be seen that   mimics bone-forming tumors including osteosarcoma and myositis ossificans [28].

Magnetic resonance imaging (MRI) with and without contrast is the gold standard for diagnostic imaging for synovial sarcoma [28]. MRI defines the local extent of the soft tissue mass and surrounding edema. It provides excellent visualization of the mass with respect to the surrounding anatomy, which is critical for preoperative planning. The use of gadolinium contrast can differentiate between hemorrhagic or necrotic areas and areas of viable tumor. Synovial sarcomas are heterogenous with low intensity on T1 and high intensity on T2-weighted images with post-gadolinium enhancement [28].

Synovial sarcomas usually present as well-defined, heterogeneously enhancing solid tumors that are multilobulated in nature [28]. A triple signal intensity demonstrating areas of hyperintensity, isointensity, and hypointensity indicates the mix of cystic and hemorrhagic areas, cellular elements, and fibrotic areas [28]. Smaller tumors, especially those smaller than 5 cm in diameter, often show homogeneous enhancement which can be mistaken for a benign process [29]. Several findings on MRI have been found to be predictive of high-grade lesions including the absence of calcifications and the presence of hemorrhage and the triple signal intensity [30].

Computed tomography (CT) with contrast can be used when an MRI is unavailable or contraindicated. Synovial sarcoma appears hypointense compared to muscle with heterogeneity in lesions that are large [20]. CT scan allows for good visualization of soft-tissue calcification and local bone reaction [28].

Diagnosis and Staging

A biopsy and histological examination are required to differentiate synovial sarcoma from other STS subtypes and to define the tumor grade. A biopsy has to be performed prior to definitive surgery to avoid inadequate resection and misdiagnosis [31]. Options for biopsy include core needle biopsies (CNB), incisional biopsies (IB), and fine needle aspirations (FNA).

Historically, open incisional biopsies have been the gold standard for soft tissue lesions since they provide larger volumes of tissue. When compared to CNB and FNA, IB tend to have higher diagnostic accuracy but this comes with a higher rate of complications when compared to percutaneous techniques [32]. Core needle biopsies retrieve more tissue than FNA and have a higher diagnostic accuracy [33]. Fine needle aspirates are rarely used in STS due to the small quantity of sample material obtained and a limited ability to assess the lesional architecture [33]. Advances in diagnostic imaging have allowed for image-guided percutaneous biopsies which have improved the diagnostic accuracy of these techniques [34]. Given the lower morbidity and relatively high diagnostic accuracy of CNB, image-guided CNB is the preferred method of biopsy, particularly for deeper tumors. 

Staging investigations are imperative. They allow for a better understanding of disease prognosis and risk of recurrence or metastases. The tumor stage also helps to formulate a treatment plan.

Staging of synovial sarcoma involves cross-sectional imaging of the affected extremity, systematic staging with a chest CT, and pathologic assessment. The two most commonly utilized staging systems are the American Joint Committee on Cancer (AJCC) system and the Enneking staging system [26,27]. The Enneking staging system has remained largely unchanged since its introduction in 1980 while the AJCC system has evolved significantly and is currently on its Eighth edition. The Enneking staging system relies on tumor grade, local extent of disease, and presence of metastases. The AJCC staging system is based on anatomical site of primary tumor and tumor size (pT) tumor grade, nodal involvement (N), and presence of metastases (M) [27].

Synovial sarcomas are malignant tumours that can metastasize. They most commonly metastasize to the lungs with up to 13% of patients having distant metastases at the time of diagnosis [35]. 

Diagnostic and Molecular Pathology

The gross appearance of synovial sarcoma is usually tan or grey in colour and may be multinodular or multicystic [16]. Most synovial sarcomas are about 3–10 cm in diameter. Lesions smaller than 1 cm can occur in the hands and feet [36,37]. On histological examination, the synovial sarcoma is a monomorphic spindle cell sarcoma with variable epithelial differentiation [36]. There are three variants namely monophasic, biphasic, or poorly differentiated. In the monophasic variant, the tissue is comprised of spindle cells only whereas in the biphasic synovial sarcoma, there are epithelial and spindle-cell components [16]. In about a third of synovial sarcomas, areas of calcifications and/or ossification can be found. In both monophasic and biphasic variants, there may be poorly differentiated areas with increased cellularity, greater nuclear atypia as well as high mitotic activity [36]. Sometimes the entire tumor can show poorly differentiated morphology. On immunohistochemistry, diffuse expression of bcl-2 is seen. In 60% of cases, the tumours stain positive for CD99 [36]. Immunohistochemistry also demonstrates strong and diffuse nuclear staining for the transcriptional corepressor TLE1 that is found in the large majority of synovial sarcomas [36]. NY-ESO-1 is also expressed strongly in most synovial sarcomas and this can help differentiate it from other spindle cell neoplasms [38].

Molecular Pathology

Synovial sarcoma is characterized by a pathognomonic translocation t(X:18) which is present in more than 95% of cases [39]. This translocation leads to the expression of different SS18:SSX oncogenic fusion proteins, that drives sarcomagenesis. The subtypes include SS18:SSX1 and SS18:SSX2 and less commonly SS18:SSX4 [40]. Both the fluorescence in situ hybridization (FISH) and reverse transcription polymerase chain reaction (RT-PCR) testing have been validated in the diagnosis of this translocation [41]. Almost all SS18-SSX2 synovial sarcomas show monophasic morphology and are more common in women. 

Treatment

The treatment plan for synovial sarcoma is individualized for each patient. Both the patient and tumor variables are taken into account to determine the ideal treatment strategy for each patient.

Synovial sarcomas are treated surgically with negative margins. Radiotherapy and/or chemotherapy are used based on patient and tumour characteristics [31]. Historically, patients were often treated with an amputation but advances in adjuvant therapy and cross-sectional imaging has made it possible for the majority of patients to be treated with limb-salvage surgery [42].

The main aim of limb-salvage surgery is to achieve oncologic control of the tumour while providing the patient with a functional limb. The surgical margins must be free of tumour to prevent local recurrence and improve overall survival [43,44,45]. For superficial tumors or small deep tumors that are less than 5 cm and are not intimately associated with critical structures, a wide excision with negative margins (1–2 cm) could be considered sufficient [46]. 

In patients with tumours that are closely associated with neurovascular structures or bone, the epineurium, adventitia, or periosteum is used as the margin to preserve a functional limb [45,47]. In these cases, microscopically positive margins may be present and radiotherapy is required to decrease local recurrence risk [48,49].

Synovial sarcomas can have an atypical presentation where they grow slowly and present with a painful mass. In such situations, unplanned excision is carried out. Following unplanned excision 50% of patients re-present [23,50]. There is a high rate of residual disease in patients with unplanned excisions of synovial sarcomas. This is especially so for larger and deeper tumors. There is an increased risk for local recurrence even after re-excision [50,51]. Following recurrence after unplanned excision, patients should be re-staged, and the original histology reviewed. Tumor bed excision should be performed in patients with residual disease. The goal is to achieve complete tumor resection and negative margins [52]. These resections are extensive in nature given that areas of potential contamination must be removed. This extensive resection may necessitate reconstructive procedures [51]. There is little data to guide the utilization of radiotherapy in this population. Radiotherapy is, however, recommended as it would be in a primary presentation [52].

In some cases, limb-salvage techniques are not recommended and primary amputation is required [42]. Amputation is needed in patients with tumour location that would necessitate excision of vital structures which would result in poor limb function [42]. In patients with an unplanned excision,  amputation is required if there is extensive contamination of vital structures or major joints [42]. Older patients or those with extensive medical comorbidities may not be able to tolerate a major operation and amputation would be required [42].

Radiation Therapy

Neoadjuvant radiation therapy is recommended for larger tumors that are more than 5 cm in size, or in any case where a close margin may be required to preserve a major neurovascular structure or bone [31]. In large database studies, radiotherapy has been shown to improve local tumour control and may have an overall survival benefit in patients with synovial sarcoma [53,54,55]. Radiotherapy can be administered pre or postoperatively. 

Preoperative radiation is associated with higher wound complication rates. Postoperative radiation can cause fibrosis and joint stiffness which may lead to worse long-term functional outcomes [56]. Intensity-modulated radiation therapy (IMRT) is becoming the preferred method of radiation delivery in patients with STS [31,57]. Intensity-modulated radiation therapy allows for a higher dose of radiation to closely contour the tumor, which reduces the volume of radiation to the surrounding normal tissues.  Preoperative IMRT for STS has been shown to reduce wound complications and the need for reconstructive soft-tissue flaps [58]. Radiation therapy can be considered in isolation in patients with multiple medical comorbidities or patients with metastatic disease where the risks of surgery outweigh the benefits [59].

Systemic Therapies

Synovial sarcoma appears to be more chemosensitive as compared to other STS. There is still controversy surrounding which subgroups of patients benefit from systemic therapy [60]. Chemotherapy is usually reserved for patients with high-risk tumors or advanced disease and is thought to be more effective in younger patients [61,62].

In children and adolescents with intermediate or high-risk tumours i.e. more than 5 cm in size with nodal involvement and positive margins, adjuvant chemotherapy is generally given with the most common agents being ifosfamide and doxorubicin. Prospective multicentred cohort studies have demonstrated adequate response to chemotherapy [63]. Recent data has demonstrated that pediatric or adolescent patients with low-risk tumors can be successfully treated with surgical intervention without systemic therapy [46].

The role of chemotherapy in adult patients with synovial sarcoma is not so clear. Eilber et al showed that chemotherapy improved relapse-free survival in patients with high-risk synovial sarcoma [60]. Canter et al [64] published a synovial sarcoma specific nomogram that supported the survival benefit of ifosfamide-based chemotherapy for certain adult patient populations. Pooled data from 15 trials on advanced STS demonstrated significantly better response to chemotherapy and survival rates when compared to other STS [65]. The French Sarcoma Group, on the other hand, recently demonstrated no overall survival benefit with adjuvant chemotherapy in adult patients with synovial sarcoma [66]. This study, however, included patients with low-risk tumor characteristics in which chemotherapy is unlikely to be of benefit.

Chemotherapy is also used in patients with metastatic or unresectable disease [65,67]. Generally, anthracycline-based chemotherapy is the first line for advanced STS and the addition of ifosfamide is dependent on the subtype of STS. Ifosfamide has well-documented efficacy in synovial sarcoma in the palliative setting. It should be considered in patients who undergo chemotherapy if the toxicities can be tolerated 67,68]. Spurrell et al [67] demonstrated median survival of 22 months in patients with advanced disease treated with a combination of doxorubicin and ifosfamide. The combination was superior to either agent given in isolation. 

Novel Agents

There has been interest in the development of new targeted medical therapies for the treatment of synovial sarcoma [69]. New agents such as receptor tyrosine kinase inhibitors, epigenetic modifiers, and immunotherapies have been investigated in clinical trials. Presently only pazopanib, a receptor tyrosine kinase inhibitor is approved for clinical use. Pazopanib has been investigated in patients with advanced disease. It has demonstrated improved progression free survival in a Phase III trial [67,70]. There have been recent advances in cell-based therapies targeting the cancer testis antigen, NY-ESO-1. Early work examining the utility of adoptive T-cell therapy with autologous T cells that have been engineered to express NY-ESO-1 has been promising in patients with metastatic disease [71]. 

Prognosis

The present day five-year survival rates ranges from 59–75% [18,19,35,70,72]. The survival rates have improved over time with early cohorts from the 1960s quoting a 25–51% five-year survival rate. Local recurrence and metastatic relapse of soft-tissue sarcomas generally occur in the first two years following treatment. Hence, surveillance and follow-up are most intensive during this period [73]. Synovial sarcoma, however, is unique in this regard in that it tends to recur much later. Krieg et al [74] showed that local recurrence occurs after a mean of 3.6 years (range 0.5–15 years) and metastases occur at a mean of 5.7 years (range 0.5–16.3 years).

Key prognostic factors include tumor size, grade, anatomical location, patient age at diagnosis, negative surgical margins, and adjuvant radiotherapy [45,61,72,75,76,77]. Neurovascular or osseous invasion, adult age, large tumour size, and unplanned excision have been linked to worse prognosis [72,75,76,77,78]. The role of the subtype of oncogene protein is conflicting. It does not appear to have a definite impact on outcomes [39,79,80,81]. Histologic subtype appears to be prognostic, with the biphasic subtype demonstrating the highest survival rates at both five and ten years [81]. Synovial sarcomas with more than 20% poorly differentiated areas show more aggressive behaviour. The best outcomes are seen with tumors with histologic features of less than 6 mitoses/mm2 and no necrosis [36,82].

Tumor size and grade have been shown to have prognostic value in patients with synovial sarcoma [54,60,75]. Naing et al in a cohort of 1189 patients demonstrated that size predicted worse overall survival [54]. Tumor location has also been demonstrated to be of predictive value, with non-extremity based synovial sarcomas tending to have worse overall survival [35,83]. 

Although synovial sarcoma has a similar clinical presentation in children and adults, there is growing evidence that they have different outcomes.  Children have significantly better survival rates [18,19,46]. Sultan et al [18] demonstrated that the five-year survival rate for children and adolescents is 83% compared to 62% in adults. Smolle et al [19], similarly, demonstrated an 89% five-year cancer-specific survival rate in children compared to 75% in adults. Vlenterie et al [76] demonstrated a stepwise reduction in survival with age, regardless of tumor site, size, and treatment.

Conclusions

Synovial sarcomas (SS) account for 5–10% of all STS. Synovial sarcoma differs from other STS in that they occur at a relatively young age, their location is peri-articular, and they are slow-growing, painful lesions. Synovial sarcomas have unique genomic characteristics and are driven by a pathognomonic t(X;18) chromosomal translocation. Subsequently, there is formation of the SS18:SSX fusion oncogenes. Surgical excision remains the mainstay of treatment. Radiation therapy is utilized in high-risk tumors. Chemotherapy appears to be useful in high-risk tumors in younger patients. In adults, the data remains conflicting. Synovial sarcoma patients require long follow-up due to the risk of late recurrence.

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