Review Article

Synovial Sarcoma: Clinicopathologic Features, Treatment, and Prognosis

Herrick J. Siegel, MD; Wade Sessions, MD; Mark A. Casillas Jr., MS; Nasser Said-Al-Naief, DDS, MS; Philip H. Lander, MD; Robert Lopez-Ben, MD

  • Orthopedics
  • December 2007 - Volume 30 · Issue 12:
  • DOI:

Named after its microscopic resemblance to normal synovium, synovial sarcoma is a well characterized malignant soft tissue sarcoma that often occurs in close proximity to large joints of the extremities. Although it is often found to be in close association with tendon sheaths, bursae, and joint capsules, it is unusual for it to involve the joint. Several distinct histological types have been described. These include classic biphasic, monophasic fibrous, monophasic epithelial, and poorly differentiated. Synovial sarcoma is the fourth most common type of sarcoma, after malignant fibrous histiocytoma, liposarcoma, and rhambdomyosarcoma. It represents between 5% and 10% of all soft tissue sarcomas, with approximately 800 new cases diagnosed in the United States per year.1-3

Synovial sarcoma is most prevalent in adolescents and young adults aged between 15 and 40 years. Males are more often affected than females, with a male:female ratio of 1.2:1. Synovial sarcoma has no known predilection for a particular race. Synovial sarcoma traditionally has been considered to have a poor prognosis; however, in recent years, not all synovial sarcomas share the same dismal outcome.4,5 Additonally, cytogenetics have proven that certain molecular genetic features are related to the course of the disease and thus may be used as a prognostic indicator.6,7

Synovial sarcoma is the most commonly misdiagnosed soft tissue malignancy, often because it may be slow-growing, have a benign appearance on imaging studies, may vary in size, and may have pain similar to that associated with trauma.2,8 It is essential that the orthopedic surgeon retain an awareness of this tumor, particularly when evaluating young, athletic patients, since this is the age group most commonly involved.

Clinical Presentation

The most common presentation (slightly more than half of cases) is a palpable, deep-seated swelling or mass associated with pain or tenderness. Less frequently, pain or tenderness is the only manifestation of the disease. Secondary involvement of nerves may cause referred pain, numbness, and parathesias. Generally, the tumor grows insidiously, often giving a false impression as to the degree of malignancy, delaying diagnosis and therapy. In the majority of cases the disease duration prior to surgery ranges from 2 to 4 years, but a slow-growing mass or pain at the tumor site has been noted for as long as 20 years prior to surgery.2,8 Not infrequently, these cases are incorrectly diagnosed initially as benign processes such as myositis, hematoma, synovitis, tendonitis, or bursitis.2,8,9

Synovial sarcomas occur predominantly in extremities where they tend to arise adjacent to large joints. They are intimately related to tendons, tendon sheaths, and bursal structures, usually just beyond the confines of the joint capsule. Joint cavity involvement has been reported to occur in <5% of patients.2,10 In the extremities, the single most common site is the knee, followed by the ankle/foot, elbow, and upper arm/shoulder.

The most common site for metastasis is the lung; however, lymph node involvement has been reported in large studies to occur in between 3% and 27% of patients.4,5 Some authors have suggested sentinel node mapping with a sampling of lymph nodes.2,11 Another modality that may be used in the future is computed tomography (CT)/positron emission tomography scanning, which is sensitive in detecting lymphatic involvement in other tumors such as melanoma.

Imaging Studies

Figure 1: T1-weighted MRI shows a painful, superficial popliteal mass measuring 2x2 cm
Figure 1: T1-weighted MRI shows a painful, superficial popliteal mass measuring 2x2 cm. The homogenous, well circumscribed appearance suggests a benign tumor. Pathology showed a monophasic synovial sarcoma.

Obtaining conventional radiographs initially is essential. In approximately 25% of cases, calcification can be appreciated within the tumor.12,13 This mineralization may range from the appearance of fine stippling to large, very dense, amorphous calcium deposits. The majority of synovial sarcomas appear as round or oval, more or less lobulated, and often in close proximity to a large joint. The underlying bone tends to be uninvolved; however, in 15% to 20% of cases there is periosteal reaction, superficial bone erosion, or invasion.7 Massive bone destruction is rare, and is mostly caused by poorly differentiated synovial sarcomas of long duration and large size. Most changes in the adjacent bone are caused by pressure atrophy and periosteal reaction.

Computed tomography and magnetic resonance imaging (MRI) are valuable tools in determining the site of origin and extent of the lesion. Computed tomography effectively demonstrates the extent of the soft tissue mass, calcifications, and bone invasion. Magnetic resonance imaging usually shows an inhomogeneous septated mass of low to intermediate intensity with infiltrative margins on T1-weighted sequences, displaying a high signal on T2-weighted images.14 Occasionally, the mass will have high signal on both T1- and T2-weighted sequences, and fluid levels consistent with hemorrhage within the tumor. The imaging appearance is nonspecific, and in all cases a biopsy is necessary to confirm the diagnosis. It is not infrequent for the imaging studies to be suggestive of a benign process, such as a cyst or hematoma, which often can lead to inadvertent marginal excisions2,8 (Figure 1).

Pathology

Most synovial sarcomas occur in extra-articular locations and bear no resemblance to synovium, neither ultrastructurally nor immunohistochemically. They are often firmly attached to tendon sheaths, bursae, or joint capsules. It has been suggested that synovial sarcoma arises from the pluripotential mesenchyme of the limb bud. On gross section, they are yellow to gray-white. They may grow to >15 cm, but on average measure 3 to 5 cm in greatest diameter.1-3,15-17 Lesions <1 cm have been reported.18 The less differentiated variants often grow more rapidly and tend to be poorly circumscribed, with multiple areas of hemorrhage, necrosis, and cystic formation.19

Unlike most other sarcomas, synovial sarcoma is composed of two morphologically different types of cells that form a characteristic biphasic pattern: epithelial cells, resembling those of carcinoma, and fibrosarcoma-like spindle cells, sometimes incorrectly designated as stromal cells. Synovial sarcomas may be classified into: biphasic type, monophasic fibrous type, monophasic epithelial type, and poorly differentiated type.

Biphasic Variant

Biphasic is considered the classic type and is generally recognizable by the coexistence of morphologically different but histogenetically related epithelial cells and fibroblast-like spindle cells. The epithelial cells are characterized by large, round, or oval vesicular nuclei and abundant pale-staining cytoplasm with distinctly outlined cellular borders. The cells are cuboidal to tall and columnar, and are disposed in solid cords, whorls, or nests, or they border irregular pseudoglandular, cleftlike, or cystlike spaces. The cleftlike spaces are lined by a single layer of epithelial cells bearing a close resemblance to normal synovium.

The surrounding spindle cell or fibrous component consists mostly of well-oriented, spindle-shaped cells of uniform appearance with small amounts of indistinct cytoplasm and oval dark-staining nuclei. Generally, the cells form solid, compact sheets that are virtually indistinguishable from fibrosarcoma except for the absence of a herringbone pattern and fewer mitotic figures. Mitotic figures in synovial sarcoma occur in both epithelial and spindle-shaped cells, but as a rule only the poorly differentiated forms of the tumor exhibit more than two mitotic figures per high-powered field.19

Monophasic Fibrous Variant

The monophasic fibrous type is another synovial sarcoma variant, and is confirmed not only by the presence of tumors with only a minute focus of epithelial differentiation but also by positive immunostaining of the spindle cells for keratin and epithelial membrane antigen. Since this type is closely related to the biphasic type and merely represents one extreme of its morphological spectrum, it shares identical morphological features to the spindle-cell portion of the biphasic type. Furthermore, there is no definitive evidence that the clinical manifestations of the monophasic fibrous type of synovial sarcoma differ significantly from those of the biphasic type19,20 (Figure 2).

Figure 2A: Monophasic spindle-cell variant

Figure 2B: Monophasic epithelial variant

Figure 2C: Biphasic variant

Figure 2D: Poorly differentiated variant

Figure 2: Hematoxylin-eosin, 133. Monophasic spindle-cell variant (A), with a predominance of spindle cells aligning in multidirectional fascicles. This may be confused with the herringbone pattern seen with fibrosarcoma. Chromosomal analysis showed characteristic translocation synovial sarcoma. Monophasic epithelial variant (B), with a predominance of epithelial cells organizing into gland-like structures, with a paucity of spindle cells. Biphasic variant (C), spindle cell seen (top left) adjacent to epithelial gland-like structures (bottom right). Poorly differentiated variant (D), with randomly organized malignant cells with features neither favoring spindle nor epithelial variant. Often differentiated areas are seen, which assists in establishing the diagnosis of synovial sarcoma.

Monophasic Epithelial Variant

Predominance of epithelial cells often is difficult to differentiate from other more common entities that may display almost identical microscopic features. This type exhibits glandular structures lined with epithelial cells. The histologic differential diagnosis not only includes many metastatic and adnexal carcinomas but also malignant melanoma, malignant epithelioid schwannoma, and epithelioid sarcoma.21,22

Needle biopsy may occasionally be inadequate to make the diagnosis; however, it is not uncommon to proceed to open biopsy.2,8 Needle biopsies of soft tissue masses showing epithelial cells in gland-like arrangements without a known primary carcinoma should be approached with extreme caution. As with the monophasic fibrous type, clinical and imaging information such as patient age, symptoms, location of the tumor, presence of calcification or ossification, and MRI appearance are all essential components in making the diagnosis.

Poorly Differentiated Variant

The incidence of poorly differentiated synovial sarcoma is difficult to estimate because of the crossover with other variants. In that a neoplasm may contain areas well and poorly differentiated, the latter may occasionally be underappreciated and under-reported on histologic examination.19,23 Microscopically, the poorly differentiated type is largely composed of solidly packed oval or spindle-shaped cells of small size that seem to be intermediate in appearance between epithelial and spindle cells, often with little evidence of differentiation, simulating small-cell carcinoma or angiosarcoma. This variant appears to imply a more rapid, aggressive course and a worse prognosis. However, large studies have not shown by univariant or multivariant analysis that the histologic variant of synovial sarcoma has a significant prognostic or therapeutic importance.19,24-26

Immunohistochemistry and Cytogenetics

Both the epithelial and spindle cell elements of synovial sarcoma show reactivity for cytokeratins and, less intensely, for epithelial membrane antigen. Positive immunostaining for keratin is seen in nearly all biphasic synovial sarcomas and in many of the monophasic fibrous type. Synovial sarcoma may also stain for keratins,7,8,18,19 desmoplakin, Leu-7, and S-100 protein.

Synovial sarcoma has a characteristic balanced translocation between chromosomes X and 18, t(X;18)(p11.2;q11.2) in the majority of cases. The translocation fuses the SYT gene from chromosome 18 to either of two highly homologous genes at Xp11, SSX1, or SSX2. SYT-SSX1 and SYT-SSX2 are thought to function in aberrant transcriptional regulation.27-30 This translocation is usually the only abnormality, and occurs in all variants of synovial sarcoma.31

Treatment

Figure 3: A large, deep-seated soft tissue mass on the posterior thigh
Figure 3: T2-weighted MRI shows a large, deep-seated soft tissue mass on the posterior thigh. Periosteal edema and reaction is seen. This patient is an 18-year-old football player treated for 8 months with physical therapy for a pulled hamstring.

Primary therapy is predicated on surgical resection with an adequate margin and maximal preservation of function. Wide resection consists of removal of the tumor with normal tissue completely surrounding it. The minimal acceptable margin has not been established; however, the surgeon must be aware of the susceptibility for microscopic infiltration of tumor cells into the pseudocapsule of the tumor.2 Dissection through the pseudocapsule often is a plane of least resistance and may facilitate removal, creating a false sense that the tumor has been completely excised. With this approach microscopic and possibly gross residual tumor may be overlooked.2,8 It is not uncommon to find that many patients referred to orthopedic oncology centers have been given a report of “complete” excision, when microscopic disease remains.2 Many centers make it a policy to re-resect all patients independent of reported surgical or pathologic margins.2,11

The adequacy of the margin of resection may be more related to the biologic nature of the tumor than to the depth of the tumor-free margin. Many investigators, based on studies associating positive or negative margins with local recurrence, distant metastasis, and subsequent modalities, have suggested 1- to 2-cm margins.2,11,13,32 Andrassy et al,2 based on their experience, have suggested a tumor-free margin of 1- to 3-cm in adults. This large margin is impossible in most children and in deep-seated tumors adjacent to bone or important neurovascular structures (Figure 3).

Adjuvant chemotherapy for soft tissue sarcoma is controversial and is not a standard option for adult soft tissue sarcoma.16,25,33 However, recent reports have demonstrated a benefit in disease-free state and overall survival in high-risk patients.20,34 Adjuvant chemotherapy, for localized respectable soft tissue sarcomas in adults, has been shown on meta-analysis to improve the time to recurrence, but only a trend toward improved overall survival has been seen.34,35 Unfortunately, other investigators have not been able to appreciate a positive impact of chemotherapy on progression-free survival or overall survival.1-3 Disease-free survival for these 2 groups did not differ (74% versus 76%).36 Multicenter randomized clinical trials are needed to determine the effect of chemotherapy on survival.

Preoperative systemic or isolated limb perfusion chemotherapy may enable limb-sparing surgery in most patients, even if the tumors are located in anatomically difficult areas.37 Local control may be improved with perioperative radiation, especially in those patients with marginal resection. Andrassy et al2 have shown that patients who received radiation therapy in addition to surgery and chemotherapy reported fewer local recurrences than those treated by operation and chemotherapy only. Brennan38 emphasized the importance of a wide surgical margin and reported that local recurrence was the same for adult patients with a positive margins, whether or not they had radiation.

Recommendations for radiation are dependent on the primary site and size of the tumor, histology, patient age, and extent of disease before and after surgical resection. In general, with conventional fractionation (1×1.8 to 2 Gy/day) radiotherapy doses between 50 and 70 Gy should be administered.39,40 In most cases, the radiation field includes the initial tumor plus 2- to 3-cm margins.18,40 The literature demonstrates a benefit in terms of local control from either external beam radiotherapy or brachytherapy in high-grade soft tissue sarcomas39 (Figures 4 and 5). The beneficial effect of radiotherapy on local control has not translated into an increase in disease-specific survival in previous reports. Okcu et al5 performed a meta-analysis including 219 patients treated at 4 oncology centers and found that the lack of radiotherapy was a strong prognostic factor for a poor prognosis. They also found a significant difference in the local recurrence rate in patients who had marginal resections, but no significant difference in those patients who had wide resections. Spillane et al3 found a significant overall decrease in local recurrence with the use of radiotherapy, but when patients with clear margins were compared with those with involved margins separately, it did not reach significance.

Figure 4: Brachycather placement following wide resection for a proximal leg synovial sarcoma

Figure 5: Soft tissue reconstruction was performed using a medial gastrocnemius rotational flap and split thickness skin graft

Figure 4: Brachycather placement following wide resection for a proximal leg synovial sarcoma. The medial collateral ligament was removed with the mass and reconstructed using an allograft. Figure 5: Soft tissue reconstruction was performed using a medial gastrocnemius rotational flap and split thickness skin graft. Adequate soft tissue coverage over the brachycatheters is essential.

Prognosis

Historically, the prognosis for synovial sarcoma has been poor. In recent large studies, using chemotherapy and radiation is advantageous, particularly in high-risk patients.17,20,34,35 The factors determining high risk include: size >5 cm, deep seated, inadequate surgical resection, and local recurrence.41 Other indicators of a poor prognosis suggested in other studies include: patient age >20 years, monophasic subtype, and mitotic activity of >10 per high power field.26

Synovial sarcomas are characterized by the t(X;18)(p11;q11) translocation. Many studies have delineated the 5-year overall survival rates and 5-year metastasis-free survival rates in patients containing two gene mutations, SYT-SSX1 and SYT-SSX2.27-31 Two studies with cohorts of 104 and 243 synovial sarcoma patients showed the overall 5-year metastasis-free survival for patients with SYT-SSX1 ranged from 42% to 53% versus 73% to 89% for those with SYT-SSX2.30,42 Thus, detection of the presence and type of SYT-SSX fusion may be important for diagnosis and prognosis.

The heterogeneity of soft tissue sarcomas makes the diagnosis and therapy particularly difficult and should be reserved for specialized centers with expertise in treating cancer. Major progress in the accuracy of diagnosis and classification has been made by the identification of specific, recurring genetic alterations. Data on 128 patients with nonmetastatic synovial sarcoma established that the 5-year disease-specific survival rate for this series of patients with localized synovial sarcoma was 62.9%.1

In a 2004 study of 271 patients with synovial sarcoma treated at a single institution, Ferrari et al34 reported the 5-year overall survival and the 5-year metastatic-free survival rate in 215 patients with nonmetastatic surgically resected disease as 71% and 51%, respectively. The metastatic-free survival rate was 60% for patients who received chemotherapy compared to 48% for those who did not. Adult patients who received chemotherapy did better than those who did not, especially among those who had tumors measuring >5 cm (metastatic-free survival, 47% versus 27%). The investigators concluded that their retrospective findings suggest that all patients with tumors >5 cm should receive chemotherapy.34

Summary

Synovial sarcoma is a characteristic subtype of soft tissue sarcomas with a predilection for young people. There may be a long delay in diagnosis or misdiagnosis, because of its insidious growth, varied presentation on imaging studies and associated joint pain, which can be confused with trauma. Diagnosis requires a tissue sample in the form of a needle or open biopsy. The needle biopsy may not be representative of the tumor, particular if it is biphasic, and it may be necessary to proceed to open biopsy. Ideally, the biopsy should be performed by the surgeon who will be performing the definitive surgical resection. Although treatment is predicated on surgery, adjuvant radiation and/or chemotherapy may be beneficial, particularly in high risk patients. Significant prognostic factors include: size >5 cm, deep-seated location, adequacy of surgical margins, and history of recurrence. In the future, multi-institutional prospectively randomized, controlled studies will be needed to better define the role of adjuvant chemotherapy. Currently, outcome may be optimized by early suspicion and detection with referral to an orthopedic oncology specialist prior to the biopsy.

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Authors

Drs Siegel and Sessions and Mr Casillas are from the Department of Surgery, Dr Said-Al-Naief is from the Department of Radiology, and Drs Lander and Lopez-Ben are from the Department of Pathology, University of Alabama at Birmingham, Alabama.

Drs Siegel, Sessions, Said-Al-Naief, Lander, and Lopez-Ben and Mr Casillas have disclosed no relevant financial relationships. Dr Morgan, CME Editor, has disclosed the following relevant financial relationships: Stryker, speakers bureau; Smith & Nephew, speakers bureau, research grant recipient; AO International, speakers bureau, research grant recipient; Synthes, institutional support. Dr D’Ambrosia, Editor-in-Chief, has disclosed no relevant financial relationships. The staff of Orthopedics have disclosed no relevant financial relationships.

The material presented at or in any Vindico Medical Education continuing education activity does not necessarily reflect the views and opinions of Vindico Medical Education or Orthopedics. Neither Vindico Medical Education or Orthopedics, nor the faculty endorse or recommend any techniques, commercial products, or manufacturers. The faculty/authors may discuss the use of materials and/or products that have not yet been approved by the US Food and Drug Administration. All readers and continuing education participants should verify all information before treating patients or utilizing any product.

Correspondence should be addressed to: Herrick J. Siegel, MD, Section of Orthopedic Oncology, Dept of Surgery, University of Alabama at Birmingham, 510 20th St South, Ste 920, Birmingham, AL 35294.

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