Epidemiology

Synovial sarcomas constitute ≈8% of soft tissue sarcomas. They can occur at any age, but almost 90% occur in young adults before the age of 50 and most between the ages of 15 and 35 years. There is a slight male preponderance (ratio ≈1.2:1).

Clinical Features

There is usually a mass of 3–10 cm, with or without pain. Location is mainly 71% in the lower and 16% in the upper extremities ( ). Local symptoms in specific sites can also be observed. Growth is often slow, with a mean history of 2–4 years; 20-year histories have been described. Within the soft tissues, the neoplasm is typically situated in deeper structures, such as tendon or muscle rather than the subcutis. General symptoms related to malignancies can be reported, such as fatigue. At the time of diagnosis, ≈10% of cases present with metastases.

The natural course of the disease is such that many patients will experience recurrence of the primary tumor and/or metastatic disease. Up to 50% can recur locally. Metastatic disease occurs in around 50% of patients. The most common sites of metastasis are the lungs, occurring in 74–81% of patients with metastatic disease, lymph nodes, occurring in 3–23%, and bone, occurring in 10–20%.

Among the different grading systems available, the French system, FNCLCC (French Federation of Cancer Centers Sarcoma Group), is the most often used for adult-type soft tissue sarcomas ( ). It is a score system in which the sum of D (differentiation; ‘D3’ by default in synovial sarcoma), M (mitoses: below 10/10 high power fields (HPF); between 10 and 19/10 HPF; more than 19/10 HPF) and N (necrosis: absent; less than 50%; more than 50%) gives the grade 1, 2 or 3. Even if in therapeutic protocols synovial sarcoma is considered among high-grade sarcomas by definition, the FNCLCC grade is reported as its most predictive histological factor. The NCI grading system is more common in the USA ( ).

Radiology

In the case of synovial sarcoma, a computed tomography (CT) scan will identify calcifications in approximately one-third of cases. Only a minority are bone destructive.

The magnetic resonance imaging (MRI) appearance most indicative of the tumor is an inhomogeneous septated mass with well-defined margins in the majority of cases, located close to a joint, a tendon, or bursa. In soft tissue lesions, MRI shows variation in intensity and enhancement. Most tumors are relatively iso- or hypointense compared to muscle and iso- or slightly hyperintense compared to fat and, in cystic areas, show a high fluid signal. Hyperintense lesions in both T1- and T2-weighted images suggest hemorrhage. Such lesions are generally uncommon in most soft-tissue sarcomas other than synovial sarcoma. Triple signal intensity and fluid–fluid levels have been described ( ).

Pathology

Many synovial sarcomas arise near joints. It was initially thought that areas of epithelial differentiation were of synovial origin and hence the name. We now know that synovial sarcoma is unrelated to synovium. It is now thought to arise from primitive undifferentiated mesenchymal cells ( ). Epithelial and some spindle cells of the tumor express cytokeratins and epithelial membrane antigen (EMA), antigens not expressed by synovial cells. Its epithelial cells have ultrastructural features identical to those of normal epithelial cells, such as desmosomes, microvilli, tight junctions and basal lamina. Less than 5% of cases originate within a joint or bursa. Over 80% originate in deep soft tissue of the extremities. Approximately 5% arise in the head and neck region. Any site can be affected. The tumor is usually 3–10 cm in diameter. It can be circumscribed or infiltrative. It is yellow-tan or gray. It can be multinodular, multicystic and can have gross calcification and areas of necrosis.

Histologically, it can be biphasic or monophasic. Biphasic synovial sarcoma has distinct epithelial and spindle cell components, which can merge in some areas. The epithelial cells have ovoid nuclei and abundant cytoplasm. They can form solid nests, glands with lumina or papillary structures. The spindle cells are small, uniform, with sparse cytoplasm and indistinct cell borders. The spindle cell component can exhibit thick collagen bundles, calcification or a hemangiopericytoma-like vascular network, which, when present, is distinctive for the tumor. Monophasic synovial sarcoma resembles the spindle cell component of the biphasic variety. Purely glandular monophasic synovial sarcoma can theoretically exist, but it is indistinguishable from adenocarcinoma without cytogenetics. Poorly differentiated synovial sarcomas constitute up to 20% of cases and exhibit a predominance of areas with high cellularity, closely packed cells, numerous mitoses and often necrosis.

Distant metastases of biphasic synovial sarcoma may contain either component alone or both. In the first case, it is usually the spindle cell component that is solely present. Metastases of monophasic synovial sarcoma almost always remain monophasic.

Approximately, 90% of all synovial sarcomas express cytokeratins, mainly in their epithelial component but also in about 50% of the spindle cells of the monophasic and 70% of the biphasic tumors. Cytokeratins 7 and 19, expressed in synovial sarcoma, are absent in malignant peripheral nerve sheath tumor and Ewing sarcoma, thus helping in the differential diagnosis. Epithelial membrane antigen is also usually expressed and can be especially helpful in the poorly differentiated subtype where 95% of cases are positive. S-100 is detectable in 30% of cases and CD-99 in 60%. BCL2 is diffusely expressed in all cases, especially in spindle cells. CD34 is usually negative. Carcinoembryonic antigen (CEA) is expressed focally in a few cases, mainly in the epithelial cells. Among muscle markers, calponin is usually found, desmin is absent. Vimentin is present in 85% of the spindle and 15–30% of the epithelial component.

Genetics

The t(X; 18) (p11; q11) translocation is present in more than 90% of the reported cases. This translocation probably arises exclusively in synovial sarcomas. Variant, more complex translocations have also been described. The genes affected by the translocation have been described: SS18 (a.k.a. SYT) from chromosome 18 and SSX1, SSX2 and SSX4 from the X chromosome.

The SS18 gene is expressed ubiquitously and codes for a 418 amino acid protein. The SSX gene family encompasses at least five members of 188 amino acid proteins with high sequence homologies. After the translocation, SS18–SSX fusion proteins are identified. During this fusion, the QPGY domain of SS18 is interrupted and may lose its function. The CRAB domain of SSX is also lost during the fusion process.

Biphasic tumors appear uniformly to contain the SS18–SSX1 fusion transcript, whereas equal numbers of monophasic tumor contain the SS18–SSX1 and SS18–SSX2 fusion transcripts.

Patients with SYT–SSX2 expressing tumors have a significantly better prognosis when compared to those with SYT–SSX1 tumors in terms of rates of metastasis and overall survival ( ). There is some debate about whether the molecular observation itself is definitional of synovial sarcoma. Molecular testing is not required if the diagnosis of synovial sarcoma is certain or probable on the basis of clinical, histologic, and immunohistochemical evaluation. However, it proved to be very helpful or necessary when its diagnosis was only possible and was challenged by other tumor types, mainly other spindle cell sarcomas, round cell sarcomas, carcinomas, myoepitheliomas, and epithelioid fibrosarcomas ( ).

Treatment

The main treatment of synovial sarcoma is en bloc surgical resection and radiotherapy. Adequate margins are>1 cm in all directions around the tumor.

At surgery, a positive margin at excision and larger tumor size independently predict adverse local control. In cases of unresected tumor, delayed tumor resection and radiotherapy should be offered. Any influence of delayed definitive surgery in cases of unplanned soft- tissue sarcoma surgery is likely to be of minor clinical importance ( ).

Radiotherapy is offered, especially in adults, and when no negative margin at surgical excision can be obtained. In children, radiotherapy is not standard treatment and must be individualized. It has been shown that postoperative radiotherapy significantly improves local recurrence-free survival, but there is no proof of effectiveness for distant recurrence-free or overall survival ( ).

Evidence for a well-defined role of chemotherapy to improve survival in localized synovial sarcoma remains elusive ( ). Synovial sarcomas are considered to be of medium sensitivity to chemotherapy, between the chemosensitive rhabdomyosarcoma and various non-chemosensitive sarcomas. Chemotherapy is more readily offered to children. The standard first-line therapy is doxorubicin. Compared to doxorubicin alone, combination chemotherapy including ifosfamide significantly improves response rate but not 1-year survival, due to higher rates of adverse effects. Response rates of approximately 50% can be expected.

In cases of advanced disease, surgical removal of metastases is not associated with improved prognosis ( ). Palliative chemotherapy is the mainstay of treatment in the advanced disease setting of locally advanced, inoperable or metastatic cases. In a small subset this treatment can be curative or a response may be observed that may render the disease resectable. More than 20% of soft-tissue sarcoma patients treated with second-line chemotherapy can obtain prolonged benefit for over 6 months ( ).

Future Treatment Issues

As with other soft tissue sarcomas, in the coming years we expect to improve our understanding of synovial sarcoma, and we particularly need novel therapeutic approaches. The specific chromosomal translocation occurring in synovial sarcoma, as well as the tyrosine kinases’ receptors identified, epidermal growth factor receptors (EGFR) and HER-2/neu, may become the targets of new molecular agents specifically designed to influence the tumor’s biology. Clinical investigative trials on targeted therapy are ongoing. Similarly, further studies are needed to investigate the role of the Bcl-2 antisense oligonucleotide therapy, as most tumors overexpress the anti-apoptotic protein Bcl-2 that correlates with tumor growth, chemoresistance and poor outcome in various cancers. Anti-angiogenic agents have also been tried with promising results ( ).

Prognosis

Five-year survival is 36–76% and 10-year survival is 20–63%. Up to 50% of synovial sarcomas recur, usually within 2 years, but sometimes up to 30 years after diagnosis.

About 50% metastasize, mainly to lungs, bone and regional lymph nodes.

A better outcome is obtained when the tumor is totally removed, with postoperative radiotherapy, in childhood patients and younger age, in tumors<5 cm in diameter, in those having<10 mitoses per 10 HPF and in the calcifying variant. It has been suggested that cases of the SS18–SSX2 variant, which is found in monophasic synovial sarcomas, have a better prognosis. A worse prognosis is expected in cases presenting with metastases, in patients with poorly differentiated synovial sarcoma, as well as in cases with extended necrosis. In a major clinical study with 213 children and adolescents and 1055 adults, no major differences in stage distribution (localized, regional, and distant stage) were observed comparing the two age groups. The estimated 5-year cancer-specific survival was 83% for children/adolescents and 62% for adults. Female sex, non-black race, tumors located in the extremities, localized tumors, and tumors <5 cm in size were associated with better survival. In multivariate analysis, adult patients had statistically significantly higher mortality rates than children after adjusting for other variables ( ).