Review Article
Synovial sarcoma: defining features and diagnostic evolution

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Abstract

Synovial sarcoma (SS) is a malignant mesenchymal neoplasm with variable epithelial differentiation, with a propensity to occur in young adults and which can arise at almost any site. It is generally viewed and treated as a high-grade sarcoma. As one of the first sarcomas to be defined by the presence of a specific chromosomal translocation leading to the production of the SS18-SSX fusion oncogene, it is perhaps the archetypal “translocation-associated sarcoma,” and its translocation remains unique to this tumor type. Synovial sarcoma has a variety of morphologic patterns, but its chief forms are the classic biphasic pattern, of glandular or solid epithelial structures with monomorphic spindle cells and the monophasic pattern, of fascicles of spindle cells with only immunohistochemical or ultrastructural evidence of epithelial differentiation. However, there is significant morphologic heterogeneity and overlap with a variety of other neoplasms, which can cause diagnostic challenge, particularly as the immunoprofile is varied, SS18-SSX is not detected in 100% of SSs, and they may occur at unusual sites. Correct diagnosis is clinically important, due to the relative chemosensitivity of SS in relation to other sarcomas, for prognostication and because of the potential for treatment with specific targeted therapies in the near future. We review SS, with emphasis on the diagnostic spectrum, recent immunohistochemical and genetic findings, and the differential diagnosis.

Introduction

Synovial sarcoma (SS) is a malignant mesenchymal neoplasm with partial epithelial differentiation, that occurs predominantly in older children and young adults and that has been shown to occur at almost any anatomic site. Accounting for 5% to 10% of all soft tissue sarcomas [1], [2], [3], SS was originally named for its frequent occurrence in the soft tissue around large joints, particularly the knee, and was believed to be of synovial cell origin. It has now been documented in most areas of the body including viscera. Its occurrence within a joint is very rare [4], [5], [6], and as SS neither arise from nor differentiate toward synovium, the name is a historical error [7], [8]. A specific cell of origin is unknown and neural, myogenic, or multipotent mesenchymal stem cells have been considered as putative originators [9], [10], [11], [12]. Synovial sarcoma was initially recognized as a biphasic neoplasm with both epithelial and uniform spindle cell components, but it is now clear that there is considerable morphologic and immunohistochemical heterogeneity within this group of neoplasms. Although the 2 characteristic (spindle or epithelioid) cell types of SS are morphologically distinct, they are histogenetically similar. Synovial sarcoma is defined by the presence of the t(X;18)(p11.2;q11.2) translocation, involving the SS18 (formerly SYT) gene on chromosome 18 and one of several synovial sarcoma X (SSX) genes on chromosome X (usually SSX1 or SSX2), which is seen in more than 90% of SS and results in the formation of SS18-SSX fusion oncogenes. Synovial sarcoma is, perhaps, the most well established “translocation-associated sarcoma,” a neoplasm with defining genetics for which the diagnostic gold standard has long been the use of ancillary molecular and molecular cytogenetic diagnostic techniques, fluorescence in situ hybridization, or reverse transcription–polymerase chain reaction (RT-PCR). There is a large histologic spectrum, with SS showing significant morphologic overlap with a variety of neoplasms, from small round cell tumors to spindle cell sarcomas and carcinoma. We review here the clinicopathologic and genetic features of SS, with emphasis on the diagnostic spectrum and new molecular and immunohistochemical findings.

Section snippets

Clinical and radiologic features

Synovial sarcomas account for between 5% and 10% of all childhood, adolescent, and adult soft tissue sarcomas [1], [2], [3] and occur over a wide age range, having been reported in infants (including congenital cases) [13] and adults up to their eighth and ninth decades [14], [15]. However, SS is predominant in young adults between aged 15 and 40 years, with peak incidence in the third decade and 90% occurring before aged 60 years [7], [15]. Synovial sarcoma is the commonest

Prognosis and treatment

Synovial sarcoma is generally considered a high-grade, aggressive sarcoma, with 5- and 10-year survival rates of approximately 60% and 50%, respectively [60]. It is noted for its propensity for late local recurrence and metastasis, with the latter often occurring after more than 5 years [61]. Metastatic disease occurs in approximately 50% of patients [62] and is more common in adults [63]. Synovial sarcoma commonly metastasizes to the lungs and pleura (which are also known sites for primary

Histopathologic and immunohistochemical findings

Grossly, SS are multinodular masses, ranging in size from minute (<1 cm) to 15 cm in diameter. They can appear relatively well defined but infiltrate irregularly into the surrounding soft tissues and may be adherent to an adjacent tendon or neurovascular bundle [7]. The cut surface varies from solid, firm, and fleshy to smooth and glistening to tan, gritty, and calcified. Calcification is common, but it can be difficult to discern grossly. Occasionally, there is cyst formation, with smooth

Ultrastructure

Monophasic SS shows closely packed cells with focal poorly formed intercellular junctions, along with intercellular spaces with processes present to varying degrees [108], some microvilli, fragments of external lamina, and variable amounts of rough endoplasmic reticulum that may resemble fibroblasts. Biphasic SS shows glands enclosed in continuous external lamina, with well-organized, true epithelial tight junctions [133], [134], junctional complexes, surface microvilli, and tonofilaments.

Molecular genetic and cytogenetic findings

Synovial sarcomas harbor a highly specific, usually balanced and reciprocal t(X;18)(p11.2;q11.2) translocation, in which the SS18 (formerly SYT) gene (at 18q11) fuses with SSX genes: SSX1, SSX2, or rarely SSX4[135] (all at Xp11), leading to the generation of SS18-SSX fusion oncogenes [136], [137], [138], [139]. Nine SSX genes (SSX1-9) have been described to date and are highly homologous [14]. SS18-SSX can be detected in more than 95% of SS [140], for which it is specific and has been seen in

Differential diagnosis

The differential diagnosis of SS is wide and varies according to the specific morphologic pattern. Carcinosarcoma or sarcomatoid carcinoma can be particularly difficult to distinguish from SS, and monophasic epithelial SS may be overlooked as well differentiated adenocarcinoma. Patients with metastatic carcinoma tend to be older than those with SS and often have a history of previous or primary carcinoma. Carcinoma may show features of dysplasia or in situ carcinomatous change in the overlying

Conclusions

Synovial sarcoma shows a wide spectrum of morphologic and immunophenotypic variation, which, along with its propensity to occur at almost any anatomic site, can result in significant diagnostic difficulty. As the subclassification of sarcomas becomes increasingly complex with the incorporation of molecular characteristics alongside histology and immunohistochemistry into routine diagnostic pathology, SS represents a tumor with defining genetics whose molecular features were identified at an

Acknowledgments

We acknowledge support from the National Institute for Health Research Royal Marsden Hospital/Institute of Cancer Research Biomedical Research Centre.

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    Disclosures: The authors have no conflicts of interest or funding to disclose.

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