Synovial Sarcoma

The American Joint Committee on Cancer (AJCC) or Union for International Cancer Control (UICC) TNM system may be used.

SS cells are dependent on SS18-SSX expression to maintain their transformed phenotype. Conditional expression of SS18-SSX induces SSs in genetically engineered mouse models, supporting its function as an oncogene when expressed in permissive mesenchymal progenitor cells. Additionally, SS18-SSX1 has been shown to transform primary cell lines. Recent evidence suggests that the SS18-SSX fusion protein disrupts epigenetic control and blocks mesenchymal differentiation by complementary mechanisms including competitive binding with, and displacement of, native SS18 in the SWI/SNF chromatin-remodeling complex, inducing dependency on BRD9-containing alternative SWI/SNF complexes (ncBAF complexes) and colocalizing with factors such as the ATF2 transcription factor, TLE1 to repress ATF2 target genes, and the KDM2B lysine demethylase at unmethylated CpG islands to reactivate repressed genes.

Most SSs are 3–10 cm in diameter at diagnosis. Minute lesions < 1 cm occur especially in hands and feet. On cut surface, tumor color and consistency are proportionate to cellularity, collagenization, and myxoid change or hemorrhage. Areas may be tan or grey, yellowish or pink, and soft or firm. SS is frequently multinodular and can be multicystic. Calcification, metaplastic ossification, and necrosis may be present.

Histologically, SSs are classified as biphasic (in approximately one quarter to one third of cases) or monophasic (in the majority). Biphasic SS has epithelial and spindle cell components, in varying proportions. The epithelial cells are arranged in solid nests or cords, or in glands with a tubular or sometimes alveolar or papillary architecture. In glandular areas, epithelial cells are cuboidal or columnar and have ovoid vesicular nuclei, and they typically have more-abundant palely eosinophilic cytoplasm than in the dark-blue spindle cell component. Glandular lumina contain epithelial mucin. Focally, the glandular component can predominate, and it may be confused with adenocarcinoma; however, a scant spindle cell component is virtually always found. Rarely, epithelial cells show (keratinizing) squamous metaplasia or granular cell change.

The spindle cells in biphasic SS resemble the spindle cells found in monophasic SS. These delicate spindle cells are fairly uniform and relatively small, with sparse cytoplasm and ovoid, hyperchromatic nuclei with regular granular chromatin and inconspicuous nucleoli. The N:C ratio is so high that the nuclei can appear to overlap. Typically, in both monophasic and biphasic SSs, the spindle cells are arranged in dense cellular sheets or vague fascicles, with occasional tigroid nuclear palisading or a herringbone architectural pattern. The amount of collagen is variable and usually scant, but SS may contain strands of ropy or wiry collagen, bands of hyalinized collagen, or (especially after irradiation) foci of dense fibrosis. Myxoid change is usually only focally present and rarely predominates, with alternating hypocellular and more-cellular areas, as well as retiform cords or microcysts. Many SSs focally display a staghorn-shaped vascular pattern, reminiscent of solitary fibrous tumor / hemangiopericytoma. Mast cells are variably present. In as many as one third of SSs, areas with calcification and/or ossification are found, which are sometimes abundant. In areas with ossification, the osteoid has a lace-like pattern mimicking osteosarcoma, and bone tissue can mature to the point of being lamellar and trabecular. Metaplastic cartilage is rarely seen.

In otherwise typical biphasic or monophasic SS, poorly differentiated areas with increased cellularity, greater nuclear atypia, and high mitotic activity (> 6 mitoses/mm² or > 10 mitoses per 10 high-power fields of 0.17 mm²) may be found. Poorly differentiated areas may be composed of fascicular spindle cells (reminiscent of malignant peripheral nerve sheath tumor), small round hyperchromatic tumor cells (reminiscent of Ewing sarcoma), or epithelioid cells. Compared with typical biphasic or monophasic SS, poorly differentiated areas more often contain areas of necrosis, a branching vascular pattern, and thin fibrovascular septa separating groups of tumor cells. Poorly differentiated lesions are disproportionately more common in elderly patients.

For FNA material, preparation of a cell block is advocated, because a conclusive diagnosis of SS heavily relies on diagnostic molecular studies (e.g., FISH).

Clinical series of SS patients have reported 5-year and 10-year overall survival rates of approximately 50–60% and 40–50%, respectively. Prognosis depends on factors such as tumor size, location, and the presence of metastasis at diagnosis. The presence of an SS18-SSX2 fusion is associated with a better prognosis compared to SS18-SSX1.

SS harbors a unique t(X;18)(p11;q11) translocation, by which SS18 on chromosome 18 is fused to one of the SSX genes (SSX1, SSX2, or SSX4) on the X chromosome. Although there is some variability, the most common fusion transcript links exon 10 of SS18 with exon 6 of the partner SSX gene. Approximately two-thirds of SS cases carry an SS18-SSX1 fusion, one third carry SS18-SSX2, and only rare cases carry SS18-SSX4 or SS18L1-SSX1 – the latter arising from a t(X:20). SS18-SSX1 SSs show an approximately even sex ratio, whereas SS18-SSX2 SSs are significantly more common in women. Moreover, almost all SS18-SSX2 cases show monophasic histology, whereas SS18-SSX1 cases show an approximate 2:1 ratio of monophasic to biphasic histology. For optimal diagnostic accuracy, molecular confirmation (where available) of an SS18-SSX1/2/4 fusion should ideally be performed.

Essential: monomorphic blue spindle cell sarcoma showing variable epithelial differentiation; diffuse and strong nuclear immunostaining for TLE1.

Desirable (in selected cases): demonstration of SS18-SSX1/2/4 fusion gene by molecular genetic testing.