Synovial Sarcoma

The origin of synovial sarcoma is unclear. Its name notwithstanding, this sarcoma is not associated with synovial joints. The basis for the name synovial cell sarcoma was the similarity between cells of this tumor and primitive synoviocytes.

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

The (X;18)(p11;q11) translocation fuses the SYT gene from chromosome 18 to a homologous gene at Xp11 (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 these two fusion proteins. Biphasic tumors, containing both epithelial and spindle cell components, express the SYT-SSX1 transcript, whereas monophasic tumors with only a spindle cell component may express either transcript.[5, 6, 7, 8, 9]

Synovial sarcoma is characterized by a specific chromosomal translocation, t(X;18)(p11;q11).[10] 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, 6, 7, 8, 9, 11]

The incidence of synovial sarcoma has been estimated to be 2.75 per 100,000.[12] The majority of cases involve the lower extremities. Approximately 800 new cases occur in the United States each year, and this tumor represents around 5-10% of all soft-tissue sarcomas. Synovial sarcoma is the third most common soft-tissue tumor in adolescents and young adults.[13]

Synovial sarcoma has been reported to be particularly likely to metastasize.[14] Many factors modify patient outcome,[8, 15, 16, 17] such as tumor size,[18] 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.

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

• Trunk - Head, ^[19] neck, thorax, abdomen, and pelvis
• Distal extremity - Hands, feet, and ankles
• Proximal extremity - Arms, forearms, thighs, and legs

Distal-extremity tumors have a better prognosis than proximal-extremity or truncal tumors do.[12] Nevertheless, this malignancy can affect any part of the appendicular skeleton.

Synovial 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.

A slight improvement in survival rate has been reported with the use of chemotherapy as adjuvant therapy.[13, 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, 25%).

A study of 130 cases of synovial sarcoma treated by a single surgeon reported a global survival rate of 82% at the latest follow-up.[20]  The local recurrence rate was 19%. In all, 28% of patients were diagnosed with at least a metastasis during follow-up; those with tumors larger than 5 cm were at significantly higher risk for metastasis. 

Campbell et al described prognostic factors that correlated with a better prognosis, including the following[21] :

• 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

Crowson et al conducted a retrospective review of medical records to determine clinical and pathologic factors affecting survival in primary synovial cell sarcoma of the head and neck.[22] The study included 28 patients who underwent surgery for the removal of the primary lesion, of whom nine received adjuvant RT, two received chemotherapy, and 14 received postoperative chemoradiation therapy. The presence of metastases on initial presentation and tumor size exceeding 4 cm were found to be factors associated with decreased survival.[22] The addition of chemotherapy to postoperative RT was not found to improve survival or disease control.

In a study using data from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute (NCI), Aytekin et al found that in a study group of 3228 patients (mean age, 39.3 ± 18.8 y; 47.1% female, 52.9% male) factors associated with a poorer prognosis were male sex, being a person of color, age greater than 35 years at the time of diagnosis, epithelioid type, and localization outside the head and neck region.[23] RT improved survival, but the benefit of chemotherapy was unclear.

The French Sarcoma Group (FSG) assessed outcomes in 417 patients with metastatic synovial sarcoma, either synchronous (n = 79; cohort 1) or metachronous (n = 338; cohort 2).[24] ​ In cohort 1, independent favorable prognostic factors for overall survival were young age, surgery of the primary tumor, and a single metastatic site; in cohort 2, independent favorable prognostic factors were surgery within an expert FSG center, absence of perioperative chemotherapy, the lungs as a single metastatic site, time to first metastasis greater than 12 months, local therapy, and ifosfamide in the first metastatic line.

Synovial sarcoma (also referred to as synovial cell sarcoma) usually occurs within the first three decades of life and generally is associated with a history of a small nodule that has increased rapidly in size.[17]  The mass often is painless 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.

Cytogenetic analysis aids the physician in detecting the specific chromosomal translocation between chromosome 18 and chromosome X—namely, t(X;18)(p11;q11).[25, 26, 27] This translocation produces 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 (and possibly in blood),[7, 8, 28] with a sensitivity of 96% and specificity of 100%. Fusion transcripts can be detected with molecular diagnostic techniques in biopsy samples.

Fluorescence in-situ hybridization (FISH) is less expensive than RT-PCR. It has been suggested as a good method of first choice for synovial sarcoma (also referred to as synovial cell sarcoma).[28] This method has a lower sensitivity than RT-PCR does, but the results of the two methods are concordant in 76% of cases.

Aside from molecular diagnostic tests, no laboratory studies are specific for this diagnosis.

Plain radiographs may aid in the diagnosis. Synovial sarcoma typically produces a spotty calcification (snowstorm) within the matrix of the soft-tissue tumor that may be visualized on plain radiographs (see the image below).

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.

Computed tomography (CT) is used to confirm the presence of a mass, its size, and its location, but it is nondiagnostic. It also may detect secondary bony involvement, which is not uncommon with larger synovial sarcomas. Synovial sarcoma is a malignant disease; therefore, CT of the chest is mandatory to exclude metastatic disease.

Magnetic resonance imaging (MRI) is the investigation of choice for soft-tissue sarcomas. Low signal intensity is observed on T1-weighted MRI (see the first image below), and high signal intensity is observed on T2-weighted MRI (see the second image below). The signal from the matrix is fairly homogeneous unless calcification is present.

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

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.

The histologic picture of synovial sarcoma can be confused with those of many other round blue cell tumors. Macroscopically, the tumor is grayish-white and often has a greasy feel. Histologic features of synovial sarcoma are identical in children and adults.

Three types of synovial sarcoma have been described, as follows:

• In the monophasic type, there is a predominance of spindle cells, mixed with round cells (see the image below); cells are arranged in fascicles with a poorly defined cytoplasm; no glandular areas are present
• 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

Although synovial sarcoma typically has a biphasic histology, this disease is often monophasic (lacking glandular differentiation), which produces the picture of a small, round blue cell tumor.

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 of 2 or 3.[12, 6, 7, 29] Punctuate areas of calcification may be observed.

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

There are no contraindications for surgical treatment of synovial sarcoma (also referred to as synovial cell sarcoma), which is potentially life-saving. There is a relative contraindication for treating 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.

Adjuvant chemotherapy and neoadjuvant chemotherapy have been proposed for patients with metastatic soft-tissue sarcomas. Although chemotherapy in the treatment of synovial sarcoma has been controversial, some studies have shown overall survival benefits in selected patients.[30]

Ladenstein et al reported improved survival rates with the use of adjuvant doxorubicin- and cyclophosphamide-based chemotherapy.[13] 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 (G-CSF) may stimulate the bone marrow. Chemotherapy should be considered in patients with extremity tumors larger than 5 cm.[1, 2, 3]

In a study that included 32 patients with advanced synovial sarcoma who had already been treated with first-line chemotherapy (ie, doxorubicin ± ifosfamide) and subsequently received second-line chemotherapy, Kojima et al compared several second-line regimens: doxorubicin ± ifosfamide, ifosfamide + etoposide, docetaxel + gemcitabine, pazopanib, trabectedin, and eribulin.[31]  The rate of response to second-line therapy was poor, at 9.4%.

Some studies showed promising results in the treatment of synovial sarcoma xenografts with a murine monoclonal antibody.[32] This monoclonal antibody attacks a frizzled homologue called FZD10 (a cell-surface receptor), which is present in synovial sarcoma cells and absent in normal organs. Clinical applications of these monoclonal antibodies are not yet available. An additional innovative technique could be an SYT-SSX–derived peptide vaccine.[9]

The efficacy of chemotherapy as adjuvant treatment after surgery has been a controversial aspect of treatment of synovial sarcoma. Chemotherapy has not proved to provide a significant benefit in survival rates in all series.[33]  However, a retrospective analysis of 271 patients with synovial sarcoma, of whom 41% received adjuvant chemotherapy, found that the 5-year metastasis-free survival (MFS) rate was 60% for those who were treated with chemotherapy and 48% for those who were not.[34] The authors recommended that patients with high-risk synovial sarcoma (tumors >5 cm) be the first to be considered for this type of treatment.

A multicenter clinical trial for the treatment of patients with soft-tissue sarcoma included patients with stage IV sarcomas and evaluated the clinical response to treatment with topotecan and carboplatin. Information is available on the clinical trial web site.[35]

Surgical excision is still the cornerstone of treatment for synovial sarcoma. A tumor-free margin of 1-3 cm is recommended.[4] Maximal care must be taken to reduce the risk of local recurrence. Careful preoperative planning is essential. 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.[7] 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.[36]

Preparation for surgery

Because synovial sarcoma spreads along fascial planes, careful preoperative staging is crucial. Radiologic evaluation before treatment is very important. Imaging techniques employed in preoperative evaluation include radiography, magnetic resonance imaging (MRI), and computed tomography (CT).

Synovial sarcoma has the ability to metastasize via the lymphatic system.[15]  Venous metastasis can occur as well. Synovial sarcoma is most likely to invade adjacent bone.

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

Operative details

The ideal surgical approach to synovial sarcoma 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.[37]

RT is usually required in addition to surgery, particularly if the margins are close to vital neurovascular structures. The most common form of RT in this setting is external-beam RT (EBRT) that is directed at the tumor site and that includes a margin of surrounding normal tissue. The timing of RT (ie, before or after surgery) has been debated. A study by Scheer et al found that preoperative RT was associated with greater local relapse-free survival in patients with advanced synovial sarcoma.[38]

The local radiation dose is usually 40-60 Gy. Proximity of vital neurologic structures, open physes, or an extreme peripheral location (hand or foot) can make EBRT potentially hazardous. Brachytherapy (radiation administered by a local implant) is an alternative consideration.[39]  Intensity-modulated radiation therapy (IMRT) has also been proposed.[1]

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. Accordingly, it may be necessary to consider nerve grafting, later muscle transfers, or both in order to allow the wide margin required.

Follow-up involves clinical examination, MRI of the surgical site, and CT of the chest. After surgical treatment, the authors recommend MRI, CT, and a 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 develops within the first 2 years, but late recurrence has been documented.[40]