Synovial Sarcoma

Synovial sarcoma is a high-grade malignant soft-tissue sarcoma that typically arises in the deep soft tissues of the extremities, frequently near tendons and tendon sheaths, rather than within the joint space itself, as the name might imply. The term “synovial sarcoma” was initially used due to the histologic resemblance of this tumor to mature synovium. However, this terminology is considered a misnomer, as the precise cellular origin of synovial sarcoma remains unknown and the tumor’s actual histogenesis is still under investigation.

Epidemiology

Synovial sarcoma accounts for approximately 5% of all soft-tissue sarcomas. It is predominantly found in extremities, with 85% of cases occurring there. The most common location is around the knee, where approximately 30% of cases arise, followed by the foot and ankle, which account for approximately 16% of cases.

Synovial sarcoma is the most common soft-tissue sarcoma in young adults 15 to 40 years old, with a median age at diagnosis of around 35 years. It shows a slight male predisposition in cases with the SS18-SSX2 subtype, while the SS18-SSX1 subtype has equal gender distribution. Notably, synovial sarcoma is also the most frequently encountered soft-tissue sarcoma in the foot.

Clinical Features

The most common presentation of synovial sarcoma is a deep, firm, painless soft-tissue mass, similar to other soft-tissue sarcomas. However, synovial sarcoma can also appear in forms that mimic benign conditions. The three unusual appearances of synovial sarcoma include tumors that demonstrate cystic, calcified or hemorrhagic presentations. The cystic form may resemble a benign synovial cyst, the calcified form can be mistaken for myositis ossificans, and the hemorrhagic form may mimic an acute hematoma.

A small subset of synovial sarcomas present as small, superficial masses that may persist for years without significant growth. The slow, indolent nature of these tumors and minimal symptoms in some cases can contribute to delayed diagnoses.

Radiologic Features

On plain radiographs, synovial sarcoma will not be obvious unless it is calcified. Calcifications within the mass are present in approximately 15% of cases, making this the most frequently calcifying soft-tissue sarcoma. This calcification can range from minimal to very dense, producing focal opacities that may resemble heterotopic ossification (Figure 1). Computed tomography (CT) can also reveal calcifications within the soft-tissue mass.

Figure 1: AP radiograph of the right femur demonstrating soft tissue calcifications of synovial sarcoma within the medial thigh.

Magnetic resonance imaging (MRI) is the most valuable imaging modality for assessing the tumor’s location and its relationship to surrounding osseous and neurovascular structures (Figures 2 and 3). On MRI, synovial sarcoma is hypointense to isointense relative to muscle on T1-weighted images and hyperintense on T2-weighted images. Any stippled calcifications within the tumor will appear dark on both sequences. Post-contrast images typically show internal enhancement, though cystic or hemorrhagic variants may have large, non-enhancing areas of cystic degeneration or fluid, a feature which can complicate interpretation.

Figure 2: T2 fat-suppressed sagittal MRI of the knee demonstrating a synovial sarcoma of the posterior knee.

Figure 3: Post-contrast fat-suppressed T1 axial MRI of the thigh demonstrating a synovial sarcoma within the vastus lateralis muscle.

Pathology

Synovial sarcomas are high-grade, highly cellular tumors with no low-grade or benign counterpart. Despite their high-grade nature, most do not demonstrate significant pleomorphism. A defining genetic feature of synovial sarcoma is the translocation t(X;18), which fuses the SS18 gene (on chromosome 18q11) with either SSX1, SSX2, or, more rarely, SSX4 (all located on chromosome Xp11).

Immunohistochemical staining is crucial for diagnosing synovial sarcoma, as it can resemble other sarcomas on standard H&E staining. Synovial sarcoma typically stains positive for vimentin, epithelial membrane antigen (EMA), S-100, and keratin; the most specific stain, however, is TLE1 which is positive in 90% of synovial sarcomas. Unlike most soft-tissue sarcomas, which stain for mesenchymal markers like vimentin but not epithelial markers, synovial sarcoma is notable for its dual staining of mesenchymal and epithelial markers. This feature is shared with two other tumors, epithelioid sarcoma in soft tissue and adamantinoma in bone, as these two tumors also contain both mesenchymal and epithelial components.

Synovial sarcoma has three main histologic subtypes:

Biphasic Synovial Sarcoma (about 25% of cases): The epithelial component is readily visible on histology, forming whorls or nests of large, round cells with the appearance of a columnar epithelium typically adjacent to cystic spaces, while the mesenchymal component consists of spindle cells with indistinct borders, scant cytoplasm, and dark nuclei. Approximately two-thirds of synovial sarcomas are biphasic (Figure 4).
Monophasic Synovial Sarcoma (about 50% of cases): Composed entirely of spindle cells, with the epithelial component not visible on routine histology and detectable only with immunohistochemistry which demonstrates the occult epithelial cells which stain positively for cytokeratin (Figure 5). The cytogenetic staining profile is identical to the biphasic subtype.
Poorly Differentiated Synovial Sarcoma(about 25% of cases): Poorly differentiated areas, characterized by small, densely packed blue cells with minimal differentiation, may occur in approximately 20% of tumors. These areas are associated with a more aggressive clinical course and can resemble other small round blue cell tumors.

Figure 4: H&E stain, biphasic synovial sarcoma, demonstrating both spindle cell component and epithelial component with glandular formation. (Image courtesy of Dr. Gord Zhu.)

Figure 5: H&E stain of monophasic synovial sarcoma, showing hypercellular fascicles of spindle cells intersecting at acute angles (herringbone pattern) in the fibrotic stroma. (Image courtesy of Dr. Gord Zhu.)

This classification is crucial, as the presence and visibility of epithelial components aid in diagnosis and may have prognostic implications.

Differential Diagnosis

The differential diagnosis for synovial sarcoma includes a broad range of benign and malignant soft-tissue tumors, as many of these present similarly with MRI findings of hypointense signals on T1 and hyperintense signals on T2 sequences. Histopathologic examination significantly narrows the differential but each of the three subtypes mentioned above has its own histologic differential diagnostic considerations.

Biphasic Subtype: This subtype is relatively distinct due to its epithelial (gland-forming) component, which is verified by positive cytokeratin staining. Few other soft-tissue tumors exhibit this combination of spindle and epithelial cells.
Monophasic Subtype: Monophasic synovial sarcoma, composed solely of spindle cells, can be more challenging to differentiate from other spindle cell tumors histologically. However, immunohistochemical staining for cytokeratin should reveal an occult epithelial component. Cytogenetic testing can confirm the diagnosis with the identification of the characteristic t(X;18) translocation.
Poorly Differentiated Subtype: Poorly differentiated synovial sarcoma may resemble other high-grade spindle cell sarcomas, given its lack of distinct histologic features. Cytogenetic testing for the typical translocation is essential in confirming the diagnosis.

Again, recall that certain variants of synovial sarcoma may mimic benign conditions:

Cystic Variant: This form can resemble a benign synovial cyst but typically includes a solid component within the cystic mass.
Calcified Variant: Calcifications within synovial sarcoma can mimic other conditions, such as myositis ossificans.
Hemorrhagic Variant: Due to its hemorrhagic nature, this form can resemble an acute hematoma. It is distinctly unusual for a simple hematoma, which is usually post-traumatic, to exist without the associated finding of adjacent ecchymosis. As such, a mass labeled as a hematoma without a history of ecchymosis should raise a concern for a more ominous lesion.

Disease Course: Treatment and Prognosis

All suspected synovial sarcomas require biopsy, either needle or open, along with staging through chest, abdomen, and pelvis CT or PET-CT scans once a diagnosis is verified. The lungs are the most common site for metastasis, but synovial sarcoma also has a propensity to spread to lymph nodes. Lymph node metastasis occurs in approximately 10% of cases. Evaluation of the sentinel lymph node basin through imaging or physical examination and possible biopsy may be indicated if masses suggesting lymphatic metastases are noted. (The mnemonic “SCARE” identifies the five sarcomas that can spread to lymph nodes: Synovial sarcoma, Clear cell sarcoma, Angiosarcoma, Rhabdomyosarcoma, and Epithelioid sarcoma).

Treatment of synovial sarcoma is multimodal. Surgical resection is the standard of care, with surgery involving wide excision. Ideally, negative margins should be attained; positive margins increase the risk of recurrence and metastasis and lower survival rates. Radiotherapy is recommended, especially for deep tumors larger than 5 cm, and can be used preoperatively or postoperatively. Amputation may be necessary when neurovascular involvement or insufficient soft-tissue coverage is present. Below-knee amputation is often used for foot or ankle tumors as wide surgical margins are difficult to obtain in the very distal extremity. Chemotherapy, typically ifosfamide-based, is effective for synovial sarcoma and is used as neoadjuvant or adjuvant therapy in patients with deep tumors over 5 cm or metastatic disease.

Prognostic factors include tumor size over 5 cm, recurrence, invasion of vital structures, positive margins, and metastasis, all of which negatively impact survival. The SYT-SSX2 fusion type is associated with a better prognosis than SYT-SSX1. The ten-year cancer-specific survival for patients with localized synovial sarcoma treated with negative-margin resection is approximately 45%.

Key Test Topics

Synovial sarcoma does not form within joints or from synovial tissue.
It is the most common soft-tissue sarcoma of the foot/ankle.
It is one of the few soft-tissue sarcomas that can metastasize to the lymph nodes (“SCARE” mnemonic).
It has three atypical presentations: cystic, calcified or hemorrhagic.
Chemotherapy is included in the standard treatment paradigm for synovial sarcoma, along with surgical resection and radiation. This is somewhat unique because most soft-tissue sarcomas are relatively insensitive to chemotherapy.