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Synovial Cell Sarcoma
Article Last Updated: Aug 7, 2008
AUTHOR AND EDITOR INFORMATIONSection 1 of 11 Authors and Editors Introduction RELEVANT ANATOMY Contraindications Workup Treatment Complications Outcome and Prognosis Future and Controversies Multimedia References

Author: Bernardo Vargas, MD, Consulting Staff, Unité Pédiatrique de Chirurgie Orthopédique et Traumatologie (UPCOT), Department of Orthopedic Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

Coauthor(s): Mark Clayer, MD, MBBS, FRACS, FAOrthA, Head of Musculoskeletal Tumor Service, Department of Orthopaedics and Trauma, Queen Elizabeth Hospital; Senior Visiting Medical Specialist, Royal Adelaide Hospital and Women’s and Children’s Hospital, Australia

Editors: Howard A Chansky, MD, Associate Professor, Department of Orthopedics and Sports Medicine, University of Washington Medical Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Sean P Scully, MD, PhD, Professor, Department of Orthopedics, University of Miami; Dinesh Patel, MD, FACS, Associate Clinical Professor of Orthopedic Surgery, Harvard Medical School; Chief of Arthroscopic Surgery, Department of Orthopedic Surgery, Massachusetts General Hospital; Harris Gellman, MD, Consulting Surgeon, Broward Hand Center, Voluntary Clinical Professor of Orthopedic Surgery and Plastic Surgery, Departments of Orthopedic Surgery and Surgery, University of Miami School of Medicine

Author and Editor Disclosure

Synonyms and related keywords: synovial cell sarcoma, synovial sarcoma, synovial cell, connective tissue tumor, connective tissue neoplasm, synovioma, malignant neoplasm, malignant tumor, joint tumors


INTRODUCTIONS
section 2 of 11 Authors and Editors Introduction RELEVANT ANATOMY Contraindications Workup Treatment Complications Outcome and Prognosis Future and Controversies Multimedia References


Synovial cell sarcoma is one of the most common soft tissue tumors in adolescents and young patients, with approximately 1 in 3 cases occurring in the first 2 decades of life. Mean age of patients at diagnosis is approximately 30 years.



Prognosis of this relatively rare tumor is related to initial care. Survival rates have improved in the past 20 years because of treatment with primary radical surgery, along with chemotherapy and radiation.1, 2, 3, 4

Related eMedicine topics:
synovial chondromatosis
Synovial Osteochondromatosis
Synovial Sarcoma Radiology

Related Medscape topics:
Specialty Site Orthopaedics
Specialty Site Hematology-Oncology
Resource Center Joint Disorders
CME Stay Connected: Update on the Management of Sarcoma Slides With Transcript note you must register to access this site. Registration is free.


Problem
The origin of synovial cell sarcoma is unclear. In contrast to its name, synovial cell sarcoma is not associated with synovial joints. Because of the similarity between cells of this tumor and primitive synoviocytes, the term synovial cell sarcoma has been used.

A neurologic origin has been suggested. In fact, there is a histologic resemblance between neural cells of malignant peripherical nerve sheath tumor (MPNST) and synovial cell sarcoma.5 Typically, synovial cell sarcoma is associated with a history of a long-standing nodule, sometimes present for years, which increases rapidly in size over a few months; therefore, it is sometimes overlooked. The tumor spreads along fascial planes and, thus, can be much more widespread than apparent on initial evaluation.

Frequency
The incidence of synovial cell sarcoma has been estimated to be 2.75 per 100000.6 The majority of cases involve the lower extremities. Approximately 800 new cases occur in the United States each year, and it represents around 5-10% of all soft tissue sarcomas. Synovial cell sarcoma is the third most common soft tissue tumor in adolescent and young adults.7



Etiology
Synovial cell sarcoma is characterized by a specific chromosomal translocation t(X;18)(p11;q11). This defect appears to be the underlying cause of the tumor. This specific chromosomal translocation between chromosome X and chromosome 18 has been noted in more than 90% of cases. This fusion gene is called, in genetic terms, the SYT-SSX1, SYT-SSX2, or SYT-SSX4. These terms correspond to a fusion of the SYT gene (chromosome 18) with the SSX gene (chromosome X). Females are more commonly affected than males in both SYT-SSX2 and SYT-SSX1 types. This association is stronger in SYT-SSX2. To our knowledge, the origin of this translocation has not been identified.5, 8, 9, 10, 11

Pathophysiology
The (X;18)(p11;q11) translocation fuses the SYT gene from chromosome 18 to either of 2 homologous genes at Xp11, either SSX1, SSX2, or SSX4. The fusion proteins SYT-SSX1 and SYT-SSX2 are believed to function as aberrant transcriptional regulators, resulting in either activation of proto-oncogenes or inhibition of tumor suppressor genes. A correlation appears to exist between the histologic subtype of the tumor and either of the 2 fusion proteins. Biphasic tumors, containing both epithelial and spindle cell components, express the SYT-SSX1 transcript, while monophasic tumors with only a spindle cell component may express either transcript.5, 8, 9, 10, 11

Clinical
Synovial cell sarcoma usually occurs within the first 3 decades of life and generally is associated with a history of a small nodule that has increased rapidly in size.12 The mass often is painful and deep. Most commonly, it is situated around the knee, but it also can appear in the hands and feet. Patients may show symptoms several months before their diagnosis.



RELEVANT ANATOMY
Section 3 of 11 Authors and Editors Introduction RELEVANT ANATOMY Contraindications Workup Treatment Complications Outcome and Prognosis Future and Controversies Multimedia References --see article for links


Survival analysis is correlated with location of the tumor in 3 anatomic regions:

Truncal location involves the head, neck, thorax, abdomen, and pelvis.
Distal extremity involves the hands, feet, and ankles.
Proximal extremity involves the arms, forearms, thighs, and legs.
Distal extremity tumors have a better prognosis than proximal or truncal tumors.6 Nevertheless, this malignancy can affect any part of the appendicular skeleton. Therefore, relevant anatomy depends on the site involved.


CONTRAINDICATIONS
Section 4 of 11 Authors and Editors Introduction RELEVANT ANATOMY Contraindications Workup Treatment Complications Outcome and Prognosis Future and Controversies Multimedia References


There are no contraindications to surgery, as it is a potentially life-saving procedure. There is a relative contraindication to treat these patients in primary centers. Early referral to tertiary centers for definitive treatment must be preferred. Ideally, treatment should be performed by a multidisciplinary team with personnel experienced in the management of soft tissue sarcomas.



WORKUPSection 5 of 11 Authors and Editors Introduction RELEVANT ANATOMY Contraindications Workup Treatment Complications Outcome and Prognosis Future and Controversies Multimedia References


Lab Studies

Other than molecular diagnostic tests (see below), no laboratory studies are specific for this diagnosis.

Imaging Studies

Plain radiographs may aid in the diagnosis, as synovial sarcoma typically produces a spotty calcification (snowstorm) within the matrix of the soft tissue tumor that may be visualized on plain radiographs (see Image 1).
CT scanning is used to confirm the presence of a mass, its size, and its location, but it is nondiagnostic. CT scan also may detect secondary bony involvement, which is not uncommon with larger synovial sarcomas. Synovial sarcoma is a malignant disease; therefore, CT scanning of the chest is mandatory to exclude metastatic disease.
MRI is the investigation of choice for soft tissue sarcomas. Low signal intensity is observed on T1-weighted images (see Image 2), and high signal intensity is observed on T2-weighted images (see Image 3). The signal from the matrix is fairly homogeneous unless calcification is present.

Other Tests

Cytogenetic analysis aids the physician in detecting the specific chromosomal translocation t(X;18)(p11;q11).13
The chromosomal translocation produces either the SYT/SSX1 or SYT/SSX2 fusion gene, which can be identified by reverse transcriptase-polymerase chain reaction (RT-PCR) in tumor tissue and possibly in blood.9, 10, 14

Diagnostic Procedures
The histologic picture can be confused with many other round blue cell tumors. Cytogenetic analysis aids the physician in detecting the specific chromosomal translocation between chromosome 18 and chromosome X.13 This translocation produces either the SYT/SSX1 SYT/SSX2, or SYT/SSX4 fusion gene. Identification of this anomaly is obtained by reverse transcriptase-polymerase chain reaction (RT-PCR) in tumor tissue, with a sensitivity of 96% and specificity of 100%. Detection of fusion transcripts is possible by molecular diagnostic techniques in biopsy samples. Fluorescence in situ hybridization (FISH test) is less expensive than RT-PCR. It has been suggested as a good method of first choice.14 This method has a lower sensitivity than RT-PCR, but they are concordant in 76% of cases.



Histologic Findings
Macroscopically, the tumor is a grayish-white and often has a greasy feel. Histologic features of synovial sarcoma are identical in children and adults.

Three types have been described:


In monophasic type there is a predominance of spindle cells, mixed with round cells. Cells are arranged in fascicles with a poorly defined cytoplasm. The monophasic variant does not have glandular areas.
The biphasic type has a layer of columnar epithelium in addition to spindle cells. It consists of plump, round cells and spindle-shaped fibroblasts alternating with glandular-like areas that are lined by synovial-like cells and contain mucin.
A third type, called poorly differentiated, has numerous mitosis, high cellularity, and tumor necrosis.
The histologic grade is determined by a score of the mitotic activity and tumor necrosis, ranging from grade 1 (differentiated) to grade 3 (poorly differentiated). Synovial sarcoma is very often associated with a grade 2 or grade 3.6, 8, 9, 15 Punctuate areas of calcification may be observed.

Staging
Staging requires local imaging with MRI. The most likely site of distant spread (the lungs) can be observed with CT scanning. Synovial sarcoma is a high-grade lesion.



TREATMENTSection 6 of 11 Authors and Editors Introduction RELEVANT ANATOMY Contraindications Workup Treatment Complications Outcome and Prognosis Future and Controversies Multimedia References


Medical therapy
Adjuvant chemotherapy and neoadjuvant chemotherapy have been proposed for patients with metastatic soft tissue sarcomas. Nevertheless, chemotherapy in the treatment of this sarcoma remains controversial. Ladenstein et al have reported improved survival rates with the use of adjuvant doxorubicin- and cyclophosphamide-based chemotherapy. Other authors have recommended combinations of doxorubicin (75 mg/m2 via continuous infusion over 3 days) and bolus ifosfamide (2.5 g/m2 daily for 4 days, or ifosfamide with liposomal daunorubicin). Granulocyte colony-stimulating factor may stimulate the bone marrow. Chemotherapy should be considered in patients with extremity tumors greater than 5 cm.1, 2, 3, 7

Some studies have shown promising results in the treatment of synovial cell sarcoma xenografts with a murine monoclonal antibody.16 This monoclonal antibody attacks a frizzled homologue called FZD10 (a cell-surface receptor), which is present in the synovial sarcoma cells and absent in the normal organs. Clinical applications of these monoclonal antibodies are not still available. An additional innovative technique could be a SYT-SSX–derived peptide vaccine.11

Another controversial aspect of treatment of synovial cell sarcoma is the efficacy of chemotherapy as adjuvant treatment after surgery. Chemotherapy has not proved to provide a significant benefit in survival rates in all series. A multicenter clinical trial for the treatment of patients with soft tissue sarcoma includes patients with soft tissue sarcoma stage IV and evaluates the clinical response of a treatment with topotecan and carboplatin. Information is available on the clinical trial web site.

Surgical therapy
Surgical excision is still the cornerstone of treatment for synovial cell sarcoma. A tumor-free margin of 1–3 cm is recommended.4 Maximal care must be taken to reduce the risk of local recurrence. As the tumor extends along fascial planes, careful preoperative planning with MRI is necessary before embarking on a wide excision. Because of the tumor’s predilection for the popliteal fossa, limb salvage may not be possible because of the proximity of the neurovascular structures. Even with microscopically negative margins, patients could develop local recurrence. Rare local recurrence has been reported 15 years after the initial treatment.9 Surgical resection of isolated metastases may be possible if the tumor is well controlled. Palliative surgery may also be appropriate, particularly to alleviate pain or achieve hemorrhage control.17

Preoperative details
Staging prior to surgery is essential, as synovial cell sarcoma spreads along fascial planes. Radiologic evaluation before treatment is very important. Imaging techniques employed in preoperative evaluation include radiographs, MRI, and CT scans.

Synovial cell sarcoma has the ability to metastasize via the lymphatic system.18 Venous metastasis can occur as well. Synovial sarcoma is most likely to invade adjacent bone.

Preoperative radiation therapy is associated with an increased rate of wound problems. This neoadjuvant radiotherapy is sometimes proposed before surgery to reduce the size of the tumor.

Intraoperative details
The ideal surgical approach takes into account the location of the lesion and must always include the possibility of amputation in cases of unsuccessful total resection. Thus, a radical or wide resection is indicated, depending on the location of the tumor. The mass may be tagged so that the location of any close or contaminated margins can be identified. A primary amputation is proposed if the location and extension of the tumor do not provide adequate function of the extremity. Primary amputation is required in 20% of patients.1 Vascular resection and reconstruction are most often performed in the lower extremities.19

Postoperative details
Postoperative radiation therapy is usually required, particularly if the margins are close to vital neurovascular structures. The most common radiotherapy is external-beam radiation directed at the tumor site, including a margin of surrounding normal tissue. The decision about the timing of radiation therapy (ie, before or after surgery) is controversial.

Local radiation is usually 40-60 Gy. Vital neurologic structures, open physes, or an extreme peripheral location (hand or foot) can make external-beam radiation therapy potentially hazardous. Brachytherapy (radiation administered by a local implant) is an alternative consideration.20 Intensity-modulated radiation therapy (IMRT) has also been proposed.1

Follow-up
Follow-up involves clinical examination, MRI of the surgical site, and CT scan of the chest. After surgical treatment, the authors recommend an MRI, a CT scan, and patient review every 3-6 months for the first 2 years and then every 6 months for the next 3 years. Most recurrent metastatic disease occurs within the first 2 years, but late recurrence has been documented.21



COMPLICATIONS Section 7 of 11 Authors and Editors Introduction RELEVANT ANATOMY Contraindications Workup Treatment Complications Outcome and Prognosis Future and Controversies Multimedia References


The surgical complications are related to the site involved but include the general complications of wound infection, wound breakdown, neurologic or vascular injury, and hematoma or seroma formation.

Specific complications associated with this tumor are local recurrence and distant metastases. The risk of local recurrence is directly proportional to the adequacy of surgical clearance. Therefore, a wide excision is mandatory to reduce this risk. Essential neurologic structures may make a wide clearance impossible, especially in the popliteal fossa. Nerve grafting and/or later muscle transfers may need to be considered to allow the wide margin needed.



OUTCOME AND PROGNOSIS
Synovial cell sarcoma has been reported to be a particularly metastasizing tumor.22 Many factors modify patient outcome,10, 18, 23, 12 such as tumor size, anatomic localization, and histologic grade. Nevertheless, histologic criteria such as nuclear grade, measures of mitotic count, and amount of necrosis are subjective and sometimes difficult to compare. Synovial cell sarcoma has survival rates of 50-60% at 5 years and 40-50% at 10 years. However, advances in oncologic therapy, particularly the development of monoclonal antibodies, may improve survival rates (see Future and Controversies).

A slight improvement in survival rate has been reported with the use of chemotherapy as adjuvant therapy.7, 2, 3 Recurrence has been reported up to 69 months after treatment and suggests a worse prognosis with low survival rates. Distant metastases at presentation suggests a bad prognosis (2-year survival rate of 25%)

Prognostic factors that correlate with a better prognosis have been described24 and include the following:

Biphasic histologic pattern
Patients with SYT/SSX2 fusion genes
Location in the hand or foot
Size < 5 cm
Female sex
Age < 50 years
Negative resection margins

FUTURE AND CONTROVERSIES
Some studies have shown promising results in the treatment of synovial cell sarcoma xenografts with a murine monoclonal antibody.16 This monoclonal antibody attacks a frizzled homologue called FZD10 (a cell-surface receptor), which is present in the synovial sarcoma cells and absent in the normal organs. Clinical applications of these monoclonal antibodies are not still available. An additional innovative technique could be a SYT-SSX–derived peptide vaccine.11

Another controversial aspect of treatment of synovial cell sarcoma is the efficacy of chemotherapy as adjuvant treatment after surgery. Chemotherapy has not proved to provide a significant benefit in survival rates in all series. A multicenter clinical trial for the treatment of patients with soft tissue sarcoma includes patients with soft tissue sarcoma stage IV and evaluates the clinical response of a treatment with topotecan and carboplatin. Information is available on the clinical trial web site

Multimedia

Media file 1: Lateral radiograph depicts a synovial sarcoma of the dorsum of the hand. A small nodule, present for 5 years, rapidly enlarged to the present size over 2 months.
File 1

Media file 2: T1-weighted MRI depicts a synovial sarcoma of the dorsum of the hand. The tumor has low signal on T1 weighting.


Media file 3: T2-weighted MRI depicts a synovial sarcoma of the dorsum of the hand. The tumor has a heterogeneous signal on T2 weighting, indicative of a variable growth pattern.


Refrences
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Zagard G. Ballo M., Pisters P.et al. Prognostic factors for patients with localized soft tissue sarcoma treated with conservation surgery and radiation therapy. Cancer. 2003;97. 10:2530-2543. [Medline].
Ladanyi M, Antonescu CR, Leung DH, and als. Impact of SYT-SSX fusion type on the clinical behavior of synovial sarcoma: a multi-institutional retrospective study of 243 patients. Cancer Res. 2002;62(1):135-40. [Medline].
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