Continuing Education Activity

Synovial sarcoma is a mesenchymal tumor that presents mainly in adolescents and adults younger than 30. It is a relatively rare tumor, with 800 to 1000 cases reported annually. Synovial sarcoma is defined by the translocation between chromosome X and 18, which leads to the expression of SS18:SSX fusion proteins. This activity reviews the presentation, diagnosis, treatment, and role of interprofessional teams in managing patients diagnosed with synovial sarcoma.

Objectives:

• Describe the clinical presentation, evaluation, and pathological findings of synovial sarcoma.
• Review the treatment options available for synovial sarcoma.
• Summarize the latest clinical trials exploring treatment options for synovial sarcoma.
• Explain the role of interprofessional team strategies for improving care coordination and communication to treat patients diagnosed with synovial sarcoma and improve outcomes.

Introduction

Synovial sarcoma (SS) is a mesenchymal tumor with partial epithelial differentiation. It is commonly seen in older children and younger adults. The presence of t(X;18)(p11.2;q11.2) is a pathognomonic feature of synovial sarcoma. Synovial sarcoma is the most well-established 'translocation-associated sarcoma,' and several molecular techniques are used to determine this translocation.[1] 

It is a very aggressive malignancy with a high potential for metastasis. Like other soft-tissue sarcomas (STS), surgical resection (to achieve microscopic negative margins) along with perioperative radiotherapy remains the cornerstone of treatment. The role of neoadjuvant or adjuvant chemotherapy remains controversial in adults but is utilized regularly in the pediatric population.

Etiology

The translocation between the SS18 gene on chromosome 18 and one of the several synovial sarcoma X (SSX) genes on chromosome X is reported in more than 90% of patients. There are no environmental or inheritable factors associated with synovial sarcoma. Radiation-induced synovial sarcoma is an extremely rare entity but has been described in the literature.[2]

Epidemiology

Synovial sarcoma accounts for up to 10% of all STS.[3] In the US, 800-1000 new cases of SS are diagnosed annually. According to an analysis of the Surveillance, Epidemiology, and End Results (SEER) database study, the age-adjusted incidence rate of SS in the US is 0.177 per 100,000 (approximately 580 incident cases) with a prevalence rate of 0.65 per 100,000 (approximately 2129 prevalent cases).

Although SS can affect any age, it is known to occur more commonly in adolescents and adults younger than 30. SS is considered the most common sarcoma in the adolescent age group.[4]

Pathophysiology

The word 'synovial' is a misnomer in synovial sarcoma, as the development of the tumor is not limited to the synovium and can originate anywhere in the body. The pathognomonic translocation between chromosomes X and 18 leads to the expression of several SS18:SSX fusion proteins described in this tumor's pathogenesis. SS18:SSX1 and SS18:SSX2 (and rarely SS18:SSX4) are the fusion proteins expressed in 95% of patients diagnosed with SS and are essential in establishing the diagnosis. The fusion proteins bind to the BAF complex (BRG1- or HBRM-associated factors), which displaces the tumor suppressor BAF47. The modified BAF complex leads to the activation of Sox2 (sex-determine region Y-box 2), which is necessary for the proliferation of synovial sarcoma.[5]

Histopathology

Synovial sarcoma is a heterogenous tumor with uncertain origin. SS is divided into two major subtypes- monophasic and biphasic. The monophasic subtype can either be spindle cell type (most common) or epithelial subtype (rarer and underrecognized). The biphasic subtype includes both fibroblast-like spindle-shaped cells and epithelial cells. Rarely, poorly differentiated (round cell), ossifying, and myxoid subtypes have also been described. SS can present with multiple morphologies, making diagnosing difficult and needing the opinion of a pathologist specializing in sarcoma histology. 

More than 90% of synovial sarcoma have a focal expression of cytoplasmic cytokeratins (CK) and membranous expression of EMA (epithelial membrane antigen). Although many keratins can be expressed in SS (AE1/AE3, CAM 5.2), CK-7 and CK-19 are restricted to patients with SS and help establish the diagnosis. Other markers include: 

• BCL-2 
  • Diffuse expression
  • Present in 98% of patients
• CD-99
  • More commonly cytoplasmic, and some membranous
  • Present in 60% of patients
• Calponin
  • Although present in multiple tumors, it can help in differentiating poorly differentiated SS from small round tumors which lack calponin

Gene expression studies may also help distinguish SS from other tumors. The following genes are noteworthy. 

1. TLE1- present ar 9q21.32. It is an excellent marker in distinguishing SS from other soft-tissue malignancies. 
2. NY-ESO-1- diffusely positive in SS
3. Brachyury is consistently negative
4. SMARCB1/INI1 protein expression is reduced.

History and Physical

Typically, synovial sarcoma arises from deep soft tissues of the extremities. SS arises less commonly from the trunk, thorax, and neck regions. Rarely SS has also been reported to arise from pleuropulmonary, cardiac, GI tract, and other body organs.[6] In the extremity, the patient usually presents with a deep-seated enlarging mass that is hard in consistency, usually slightly movable within the muscle (unless fixed to the bone or fascia) and is not tender. Other than these findings, history is typically unremarkable. In patients with visceral SS, the symptoms usually localize according to the organ of involvement. For example, those patients with prostate involvement present with urinary retention; those with lung involvement present with symptoms resembling pneumonia, chest pain, or pulmonary embolism.[7][8] 

It is often not possible to establish a diagnosis of SS clinically. However, the index of suspicion for SS should be high if a previously young, healthy patient in the adolescent/young adult age group presents with a hard mass in the extremity or elsewhere in the body.

Evaluation

The evaluation of a patient with SS includes a biopsy of the mass and radiographic tests. Usually, lab tests are unremarkable, even in patients where SS arises from unusual organs. For example, in patients with prostate involvement of SS, the PSA was reported to be normal. Radiographic tests include computed tomography (CT) scans, Magnetic resonance imaging (MRI), and positron emission tomography (PET) scans.[9]

Biopsy of the Mass

Pretreatment Biopsy

1. To establish the diagnosis, multidisciplinary and interprofessional planning must be pursued to obtain a pretreatment biopsy. A team of musculoskeletal radiologists and interventional radiologists trained in MSK procedures must perform the procedure. Alternatively, an experienced surgeon (preferably with training in orthopedic procedures) can also perform the procedure. Preferably, the surgeon performing the biopsy will also perform the resection.
2. Excisional biopsy is avoided, as it usually results in positive margins and compromises the management of the disease. 
3. Open biopsy has fallen out of favor for core needle biopsy in the extremity, as the amount of tissue excised is minimized when the biopsy tract is resected during surgery.
4. Retroperitoneal synovial sarcoma is diagnosed via a core needle biopsy. However, if the core biopsy is not sufficient, then the resection of the mass may be performed.  

Radiographic Features

1. CT scans show a well-circumscribed mass, usually with punctate and peripheral calcifications.
   • CT chest is needed to stage the disease appropriately.
2. MRI is useful in diagnosing and initial staging of synovial sarcoma
   • Generally, T1-weighted images are dark, and T2-weighted images are bright.
   • T2 weighted images often show hypo-, iso-, or hyperintense fat areas. Areas of high T1 signal intensity represent hemorrhage. 
   • Smaller lesions (less than 5cm) are usually peripheral and often benign appearing (smooth contours, non-infiltrative, homogenous characteristics)
   • Gadolinium-enhanced sequences help in identifying primary cystic synovial sarcoma by demonstrating the solid nodular enhancing component (helps differentiate from periarticular cyst and hematoma)
   • MRI can help identify aggressive features like the involvement of adjacent bone, neurovascular encasement, and muscular invasion. 
   • Resectability of the tumor is also best determined with MRI
3. PET/CT scans are usually ordered to rule out metastatic disease.

Treatment / Management

The treatment of patients with synovial sarcoma is based on the stage of presentation. A patient with SS can either present with localized or metastatic disease. Generally, a localized disease is approached to achieve a microscopic negative margin (R0 resection) surgically. Where neoadjuvant chemotherapy is widely used in the pediatric population, the use of neoadjuvant chemotherapy is controversial in adults. 

Treating patients with locally advanced unresectable or metastatic synovial sarcoma aims at palliation and prolonging life. The therapy involves using cytotoxic chemotherapy, tyrosine kinase inhibitors, or enrolling the patient in a clinical trial. We will discuss various modalities in the relevant sections.

Differential Diagnosis

On a pathologic level, malignant peripheral nerve sheath tumors (MPNST), solitary fibrous tumors (SFT), small blue round cell tumors (SBRCT), and fibrosarcoma are the top differential diagnosis for a patient with SS. 

1. MPNST- MPNST can be indistinguishable from monophasic synovial sarcoma, especially if the synovial sarcoma arises intra-neurally. Certain features that favor a diagnosis of MPNST are here:
   • The patient has a clinical history of neurofibromas.
   • The presence of several architectural patterns within the same lesion, along with the presence of focal atypia, favor MPNST. Likewise, the presence of goblet-type cells is seen only in glandular MPNST.
   • Focal CD-34 positivity exists (almost never seen in synovial sarcoma).
   • Negative CK-7 and CK-19 are present (most monophasic synovial sarcoma will stain for one or both).
   • SOX-10 stain has up to 63% sensitivity for diagnosing MPNST (positive for 7% synovial sarcoma) but has a very high specificity (93%) for diagnosing MPNST.
   • Lack of SS18-SSX fusions
2. Ewing Sarcoma/ Primitive Neuroectodermal Tumors (PNETs)
   • Can resemble poorly differentiated synovial sarcoma
   • Reticulin stain is positive in synovial sarcoma but negative in PNETs.
   • CD99 staining- Cytoplasmic pattern of staining in synovial sarcoma, vis-a-vis a strong membranous pattern in PNET
   • Expression of CK7 makes PNET less likely.
   • Caveolin-1 is positive in 95% of cases with EFT (membranous and cytoplasmic pattern). However, this is not specific to EFT.
   • TLE1 is rarely positive in EFT.
3. Epithelioid Sarcoma (ES)
   • 50% of ES may express CD34 which is never seen in synovial sarcoma
   • Diffuse expression of low and high molecular weight cytokeratin compared to focal presentation in synovial sarcoma.
4. Solitary Fibrous Tumor 
   • Diffuse expression of CD34 and STAT6 in SFT is almost never seen in synovial sarcoma.
5. Dermatofibrosarcoma protuberans
   • Diffuse expression of CD34 and lack of keratin distinguish this from synovial sarcoma.
6. Gastrointestinal stromal tumor (GIST)
   • Important to know as synovial sarcoma is well characterized in the gastrointestinal tract. Hence, KIT-negative mesenchymal tumors could be synovial sarcoma.
   • DOG-1 is more commonly reported in GIST and is rarely reported in synovial sarcoma.
7. Infantile Fibrosarcoma
   • Occurs in the first two years of life
   • It does not express keratin
   • Characterized by t(12;15)(p13;q25), which gives rise to ETV6-NTRK3 fusion.
8. Spindle cell Rhabdomyosarcoma
   • Express focal myogenin, which is not expressed in synovial sarcoma
9. Leiomyosarcoma - Can show focal dot keratin and rare EMA. Hence, it can be confused with synovial sarcoma.

Surgical Oncology

Limb-sparing surgery is the mainstay of treatment for patients with synovial sarcoma who present with localized disease. Amputation is rarely pursued and reserved for patients where limb salvage is impossible. The goal is to achieve an R0 margin of at least 1 to 2 cm in width.

Alternatively, a fascial plane uninvolved by the tumor is an acceptable margin, regardless of the distance of the tumor from the fascia. In patients with synovial sarcoma, where the tumor is less than 5 cm in size, a wide local resection with a margin of 1-2 cm is adequate.[10] 

Radiation Oncology

In patients with localized synovial sarcoma, radiation therapy (RT) is used either in the preoperative or postoperative setting. In patients with metastatic or those with locally advanced, unresectable tumors, RT can be given for palliative purposes (pain relief, cord compression).[11][12]

Localized Synovial Sarcoma

1. Preoperative RT: Delivered prior to surgery targeting a vascularized, well-oxygenated tumor (which helps in the generation of free oxygen radicals). 
   • Advantages
     • Smaller target and the need for a lower dose of RT (usually 50 Gy over 25 fractions)
     • The option of delivering intra-operative RT or postoperative boost remains open (in case of R1 resection), and so does the prospect of postoperative RT in case of an R2 resection (gross residual disease).
     • Long-term side effects are fewer.
   • Disadvantages
     • Wound healing can be compromised/ delayed.
     • Potential delay in surgery (3 to 6 weeks cooling period after finishing RT)
2. Postoperative RT
   • Advantages
     • Lesser wound healing complications
     • RT dose can be tailored according to histology
   • Disadvantages
     • A higher dose is needed for long-term disease control (Up to 76 Gy may be required in patients with R2 resection)
     • A wider area is irradiated.
     • There is a higher risk of long-term complications like pathological fracture, lymphedema, fibrosis, and secondary sarcoma. 

Intensity-modulated RT (IMRT) has become the preferred choice for delivering radiation.[13]

Pertinent Studies and Ongoing Trials

A historical review of radiation studies that are important from the perspective of managing STS of extremities and trunk is necessary. Please be aware that these studies do not apply to visceral and retroperitoneal sarcomas.

Establishing Adjuvant RT as the Standard of Care

1. 1982- National Cancer Institute (NCI) study- randomized 43 patients to amputation or limb salvage surgery (LSS) followed by adjuvant RT and concurrent chemotherapy.
   • The disease-free survival (DSS) and overall survival (OS) at five years were similar.
   • Although four local recurrences (out of 27 patients) occurred in the LSS group, the trend was insignificant compared to amputation (p-0.06).
   • Distant metastasis was more common with amputation alone.
   • After this study, the rates of amputation fell below 10%.[14]
2. 1996- Randomized trial exploring the role of brachytherapy (BRT) in 164 patients undergoing LSS.
   • The patients were randomized to receive brachytherapy via an intraoperatively placed catheter versus no local or systemic treatment.
   • The results were significantly in favor of patients with high-grade STS who received BRT (5 local recurrences out of 56 patients in the BRT group versus 19 local recurrences out of 63 patients in the control arm, P = 0.025).[15]
3. 1998- The NCI trial was a follow-up to the previous trial. It examined the need for adjuvant RT in patients receiving LSS.
   • Ninety-one patients with high-grade STS and 50 patients with low-grade STS were randomized to receive five cycles of adjuvant chemotherapy and RT (44 and 26, respectively) versus chemotherapy alone.
   • At the nine-year follow-ups, only one patient (out of 26) in the low-grade STS group and none in the high-grade STS group experienced a local relapse.
   • On the contrary, in the chemotherapy group, nine patients in the high-grade STS and eight patients in the low-grade STS group experienced local release (P<0.05 for both groups).
   • No difference in the OS and distant metastasis-free survival (DMFS) was noted at the end of 10 years.[16]

The three trials listed above established postoperative adjuvant RT as the standard of care for patients with STS of the extremity or trunk. However, the OS benefit with RT alone remains controversial for patients receiving LSS.

Preoperative versus Postoperative RT

1. 2002- NCI Canada (NCIC) leads the SR2 trial examining the question of preoperative versus postoperative RT in patients with STS.[11] 
   • Patients receiving preoperative RT will be operated upon within 3 to 6 weeks.
   • Patients will receive a boost of 16-20 Gy in the event of a positive margin.
   • The trial was closed early due to a higher number of wound complications in patients undergoing preoperative RT
   • No differences were noted in the local, locoregional, distant failure, and progression-free survival 
2. 2007- In a select group of patients [those with intermediate to high-grade T1a STS (<5 cm in size)], the need for adjuvant RT can be obviated provided the preoperative biopsy identifies the histology correctly and the surgery results in an R0 margin.[17]

Image-guided IMRT

1.  2013- NCIC phase II study to explore the utility of IMRT.[18]
   • Introduced the concept of 'virtual skin flaps'- These are contours designed according to the anticipated suture closure lines
   • Primary closure of the wound was significantly higher with IMRT compared to NCIC SR2 data
2. 2015- Phase II RTOG 0630 evaluated preoperative RT with image guidance and reduced margins. The primary endpoint was late 2-year toxicity. [19]
   • 10.5% of patients experienced grade 2 or later toxicity compared to 37% of patients in the NCIC trial.

Retroperitoneal Soft-tissue Sarcomas

The EORTC-62092: STRASS trial was a Phase III trial randomizing patients with retroperitoneal sarcomas between preoperative RT followed by surgery versus surgery alone with a primary endpoint of abdominal recurrence-free survival (RFS).[20]

• Two hundred sixty-six patients enrolled, with 133 assigned to each group. The majority of patients were diagnosed with either liposarcoma or leiomyosarcoma.
• The study excluded patients with GIST, primitive neuroectodermal tumor, rhabdomyosarcoma, small round blue cell tumors, osteosarcoma, chondrosarcoma, aggressive fibromatosis, or sarcomatoid or metastatic sarcoma. 
• The median abdominal RFS was 5.0 years for those who received surgery only compared to 4.5 years for those who received surgery and preop-RT. (P- 0.95). 
• Post-hoc analysis according to different histopathology showed that specific tumor types may still benefit from preop RT and surgery.

Medical Oncology

Systemic therapy is reserved for patients with metastatic or locally advanced unresectable synovial sarcoma. Synovial sarcoma is chemo-sensitive histology. Hence first-line regimen usually involves an anthracycline-based regimen. 

Cytotoxic Chemotherapy

1. Anthracycline based regimens
   • Either used alone or in combination with Ifosfamide
   • The expected response rate is between 25% and 60%.
2. Ifosfamide
   • Has significant activity in patients with synovial sarcoma
   • Primarily used in combination with anthracyclines. 
   • It can be used as a single agent for those not fit to receive anthracyclines. 
   • A recent phase III trial evaluated evofosfamide in combination with doxorubicin versus doxorubicin alone. In the subset of patients with synovial sarcoma, a numerical benefit in the OS was noted in patients receiving both doxorubicin and evofosfamide (22.1 months versus 9.4 months). Although evofosfamide is not approved in the US, this trial does reinforce the activity of Ifosfamide in synovial sarcoma.[21]
3. Trabectedin
   • The drug has demonstrated anti-tumor activity in translocation-driven sarcomas. 
   • Retrospective studies have demonstrated response rates of up to 15%.[22][23]

Targeted Therapy

1. Tyrosine Kinase Inhibitor (TKI)- A functional role of PDGFRA (platelet-derived growth factor alpha) has been described in synovial sarcoma. Hence inhibition of PDGFRA may help achieve a response in patients with synovial sarcoma. Pazopanib is a multi-targeted TKI with several targets, including PDGFRA.
   • Pazopanib is the only USFDA-approved TKI available in the market for patients with synovial sarcoma.
     • PALETTE trial- included 38 patients with synovial sarcoma. An improvement of 3 months was noted in the median PFS with pazopanib versus placebo (4.1 months versus one month).[24]
     • In patients with pleuro-pulmonary synovial sarcoma, a risk of pneumothorax exists. However, some patients can achieve a dramatic response using pazopanib.
   • Regorafenib
     • It was evaluated in the phase II French trial- REGOSARC. All patients in this trial were randomized between regorafenib and placebo.[25] 
     • In the subgroup of synovial sarcoma, a PFS benefit of 4 months was noted (5.6 months versus one month). 

Multiple other molecular targets have been identified in patients with synovial sarcoma, including EZH2 (enhancer of zeste homolog 2), mTOR (mammalian target of rapamycin) pathways, and CDK 4/6 (cyclin D1-cyclin-dependent kinase 4/6) pathways. However, clinical trials investigating these pathways have not resulted in positive results. Most recently, a novel small molecule tyrosine kinase inhibitor AL3818 (APROMISS trial) has shown a progression-free survival benefit compared to dacarbazine.

Promising Ongoing Trials

1. NCT04044768- This phase 2 study evaluating ADP-A2M4 in HLA-A*02 eligible and MAGE-A4 positive subjects with metastatic or inoperable (advanced) synovial sarcoma. This trial uses the novel concept of genetically engineered T-cells to target MAGE-A4 positive cells in the context of HLA-A*02. 
2. NCT03016819- This is a phase 3 trial where a novel small molecule tyrosine kinase inhibitor AL3818 is being tested in patients with advanced synovial sarcoma (APROMISS trial). Preliminary results were presented at ASCO 2021, and authors reported a progression-free survival benefit compared to dacarbazine.

Staging

Staging of soft tissue sarcomas utilizes the TNM system as well as tumor grading. The T-staging is based on size and location (i.e., trunk/extremity, retroperitoneal, head and neck, etc.). The size cutoffs for T-staging vary based on tumor location. Nodal staging (N0 or N1) is straightforward and merely indicates the involvement of regional lymph nodes. Certain sarcoma subtypes have a propensity for lymph node metastasis, such as epithelial sarcomas, clear cell sarcomas, angiosarcomas, and rhabdomyosarcomas. Metastasis (M0 or M1) could be fulfilled either through non-regional adenopathy or with spread to visceral organs.

Tumor grading is also essential for staging. Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading utilizes a point system based on necrosis (no necrosis – 0 pts, <50% necrosis – 1pt, or ≥50% necrosis – 2 pts), differentiation (resembling normal adult mesenchymal tissue – 1pt, Sarcomas with definite histologic typing – 2pts, and undifferentiated – 3pts), and mitotic count (0-9 mitosis/hpf – 1 pt, 10-19-mitosis/hpf – 2pts, ≥20 mitosis/hpf – 3 pts). The sum of these factors determines the tumor grade ranging from 1-3 (1- 2-3pts, 2- 4-5 pts, 3- 6-8 pts). Grading and nodal/metastatic status are what primarily drive staging, while tumor size plays a smaller role.

Although sarcomas can be divided between stages I to IV as per the eight editions of the AJCC (America joint committee for cancer) guidelines, they are either localized (stages 1 to 3) or metastatic (Stage 4). This oversimplified staging is essential in determining if the tumor is resectable or not.

Prognosis

Synovial sarcoma is an aggressive malignancy with a poor prognosis. Synovial sarcoma is a high-grade malignancy by definition.[26] The expected 5-year survival is between 50-60% in adults, and 5-year metastasis-free survival is between 40 to 60%. The European Pediatric Soft Tissue Sarcoma Study Group reports a 90% 5-year survival. 

Other prognostic factors include

1. Younger age is a favorable prognostic factor.[27][28]
2. Tumor size- A smaller size of the primary tumor is associated with better outcomes. 
3. Tumor site- Synovial sarcoma originating in the extremities has a much better prognosis.[29]
4. Perioperative Radiotherapy- is associated with a better prognosis.[30]
5. Osseous invasion or neurovascular invasion is associated with poor outcomes.[31]
6. Unplanned resections are associated with poor outcomes.

Complications

Compression of the nearby structures due to the "mass effect" of the growing tumor can lead to various compressive issues. Synovial sarcoma rarely metastasizes to the brain and can lead to seizures and other neurologic complications. Clot-formation can occur due to compressive effects or secondary to the presence of a tumor in the body. The complications from the use of chemotherapy include myelosuppression, hair loss, nausea, vomiting, and dysgeusia.

Many adverse events are specific to the class of the drug used. For example, anthracycline can cause cardiac complications, ifosfamide can cause neurotoxicity and nephrotoxicity, pazopanib can cause cardiac and hepatic toxicity, and trabectedin can lead to cardiac, hepatic, and myelotoxicity. All providers must be aware of potential toxicities from the various chemotherapy regimens.

Deterrence and Patient Education

Synovial sarcoma is more common in children and young adults. Hence, it is prudent to involve the parents/ guardians in the discussion of the management of this rare yet aggressive malignancy. The diagnosis and treatment pose a particular challenge to the clinician of this tumor, which has proven resistant to multiple treatment regimens. Therefore, all patients and parents/ guardians must receive education on the importance of surgical resection and RT's role in managing SS.

In addition, the patient, parents, and guardians should understand the pros and cons of neoadjuvant or adjuvant chemotherapy in managing SS. A decision regarding the treatment of SS must only be made only with the consensus of parents/guardians. Finally, If a clinical trial is available at the institution or nearby, the patients, parents, and guardians must be encouraged to explore that opportunity.

Pearls and Other Issues

• Synovial sarcoma is a high-grade sarcoma with an aggressive course and a high potential to metastasize early.
• Synovial sarcoma is the most well-defined 'translocation-associated sarcoma,' identified by the presence of translocation involving the SS18 gene on chromosome 18 and one of the several synovial sarcoma X genes on chromosome X.
• The word synovial is a misnomer, as SS not only arises from the articular surface but can occur in any part of the body.
• SS is a biphasic tumor with both epithelial and spindle cell components. However, it exhibits morphologic and immunohistochemical heterogeneity. 
• Patients diagnosed with SS must be treated at centers that experience a high volume of such patients.
• All patients diagnosed with SS must be discussed in a multi-disciplinary tumor board, including surgical oncologists/orthopedic oncologists, radiation oncologists, pathologists trained in diagnosing sarcoma, medical oncologists, and musculoskeletal radiologists.  
• Surgical resection with a negative margin translates into the best outcomes in terms of overall survival and is the goal of surgical resection.
• Perioperative RT reduces the local recurrence rate and increases local disease-free survival. However, this has not translated into a better distant relapse-free survival or overall survival.
• Preoperative RT is associated with fewer complications than postoperative RT, although wound complications are higher with preoperative RT. A 4 to 5 weeks gap between surgery and RT seems to reduce wound complications with preoperative RT.
• Neoadjuvant or adjuvant chemotherapy affords better survival in children (based on non-randomized retrospective data) but remains controversial in adults. Hence, neoadjuvant or adjuvant chemotherapy is offered more commonly in the pediatric age group. 
• Anthracycline-based regimens are the first choice in treating patients with SS in the neoadjuvant, adjuvant, or metastatic setting.

Enhancing Healthcare Team Outcomes

Synovial sarcoma is one of the most common subtypes of soft-tissue sarcoma. The clinical presentation is non-specific, and the most common presentation is secondary to the mass effect of a growing lesion. Uterine LMS may present with abnormal uterine bleeding. Diagnosis follows histopathology, and clinical imaging helps determine the tumor's stage. A pathologist trained in diagnosing STS is needed to establish histology and accurately grade cancer. Similarly, a team of musculoskeletal radiologists and interventional radiologists must interpret the images (CT scans and MRI) and determine the best region/route to biopsy the mass. An experienced surgeon can also pursue an open incisional biopsy, which is seldom needed. 

Patients diagnosed with synovial sarcoma should receive treatment at centers that regularly experience a high volume of such patients. The principles of treating a patient diagnosed with synovial sarcoma require close coordination of interprofessional team members between the surgical oncology, radiation oncology, and medical oncology teams. Where early-stage synovial sarcoma (also called localized synovial sarcoma) is almost always treated surgically with perioperative radiation, metastatic synovial sarcoma is incurable and is treated with chemotherapy.

Adjuvant chemotherapy is more prevalent in pediatrics and young adults. Hence a pediatric oncologist must be included in the tumor board. A team of skilled surgical oncologists/ orthopedic oncologists trained in the management of soft-tissue sarcoma is critical in caring for a patient diagnosed with synovial sarcoma. Radiation oncologists decide the best modality of RT that would be necessary for the patient's treatment. In addition to this, they also coordinate with surgeons to deliver intra-operative RT.

Synovial sarcoma is quite sensitive to chemotherapy. The medical oncologist ensures that a proper regimen gets chosen according to the presentation of the patient. The drugs involved in treating synovial sarcoma include a host of cytotoxic and targeted agents that come with unique toxicities. A board-certified oncology pharmacist trained in managing chemotherapy and nurses trained in delivering chemotherapy are critical parts of the interprofessional team that will improve patient outcomes by assisting with the coordination of care and patient education. The pharmacist will verify all dosing, assist in specific agent selection and alternate regimens, counsel on adverse effects, and collaborate with nursing on administration. Nursing staff will monitor patients' responses and adverse effects following administration. These examples of interprofessional coordination will optimize results for patients with synovial sarcoma. [Level 5]

The treatment modalities used for patients with synovial sarcoma have undergone testing in phase II and III trials with Level I evidence described above.