Tumors of Synovial and Tenosynovial Tissue

Normal Anatomy

The synovial intima is composed of two to three layers of specialized connective tissue cells named synoviocytes that form the lining of joints, tendons, and bursae. These cells overlay loose connective tissue that contains the variable elements of fat, collagen, and blood vessels. By light microscopy, quiescent synoviocytes are relatively indistinct, appearing as flattened oval dark staining nuclei with indistinct cytoplasmic borders ( Fig. 13.2 ). However, when they are stimulated, as in reaction to some form of injury, they enlarge and acquire abundant eosinophilic cytoplasm and have a more epithelioid morphology ( Fig. 13.3 ). Although indistinguishable by light microscopy, ultrastructurally and molecularly, intimal synoviocytes lining the luminal aspect of the synovial cavity comprise two distinct cell populations: specialized synovial intimal fibroblasts and macrophages. Synovial intimal fibroblasts, traditionally termed B cells (or fibroblast-like synoviocytes), are responsible for synovial fluid production, secreting high levels of proteoglycans and hyaluronan. By immunohistochemistry, these cells express CD55. Ultrastructurally, synovial intimal fibroblasts have ovoid nuclei, inconspicuous nucleoli, and long cytoplasmic processes that radiate in a tendril-like fashion from the cell body. The cytoplasmic processes contain flattened endoplasmic reticulum, ribosomes, a well-developed Golgi apparatus, and numerous subplasmalemmal pinocytotic vesicles. Although the processes interdigitate extensively, cell junctions are not present. Synovial intimal macrophages are interspersed with fibroblastic cells and are traditionally termed “A cells.” They are involved in synovial fluid turnover, tissue repair, and immune surveillance in the joint. These specialized macrophages lack cytoplasmic processes, but have short filopodia and harbor occasional lysosomes, as well as a similar complement of cytoplasmic organelles as the intimal fibroblasts. These cells express clusterin, and occasionally desmin and podoplanin.

The synovial cells adhere directly to the underlying connective tissue; no basement membrane is present. This absence of basement membrane facilitates the transport of material into and out of the synovial fluid ( Fig. 13.4 ).

Gross Findings

Diffuse TSGCT forms a diffuse villous and nodular red-brown thickening of the synovium and contains finger-like excrescences admixed with 0.5–2.0 cm round nodules. Scattered areas of grossly uninvolved synovium are invariably present. On cross section, the tumor is solid, rusty brown and yellow, with white-grey foci ( Figs 13.7–13.9 ).

Localized TSGCT is well circumscribed and lobulated. Tumors are usually small, and on cross sections are grey-tan with brown and yellow areas, depending on the amount of hemosiderin and lipid-laden macrophages ( Fig. 13.10 ).

Microscopic Findings

TSGCTs are comprised of a variety of monocyte-derived histiocytic cells, including siderophages, foamy macrophages, multinucleated osteoclast-like giant cells, and distinct types of mononuclear cells. One population of mononuclear cells is smaller, with pale cytoplasm, and irregular nuclei which may be grooved. The second population is larger, with abundant pale eosinophilic cytoplasm, and round or grooved, eccentric nuclei, and may contain a rim of cytoplasmic hemosiderin ( Fig. 13.11 ). Mild nuclear pleomorphism and prominent nucleoli may be present. It is these large mononuclear cells which are thought to be the neoplastic cells. Tumor infiltrating lymphocytes may also be present as scattered cells or small aggregates.

Diffuse TSCGT produces widespread thickening of the synovium, which shows a prominent papillary, villous, and nodular architecture ( Fig. 13.12 ; Box 13.4 ). The preexisting synoviocytes overlie a sheet-like proliferation of lesional cells. The osteoclast-like giant cells are not as numerous as in localized TSGCT, and the collagenous or hyalinized matrix is usually less prominent. Mitotic counts rarely exceed 5 per 10 high-power fields (hpf). Necrosis is rare, and when present, it is usually of the infarct type. In rare instances, the tumor can be completely infarcted. The surface synoviocytes are hyperplastic and may contain phagocytized hemosiderin, mimicking hemosiderotic synovitis.

Localized TSGCT is well demarcated, encapsulated, and attached to the adjacent tendon sheath ( Box 13.5 ). Fibrous septa transverse the tumor, giving it a lobulated appearance ( Fig. 13.13 ). In general, while localized TSGCT is identical to the diffuse type, the tumors may contain less hemosiderin and more extracellular collagen. In addition, the number of mononuclear cells, osteoclast-type giant cells, siderophages, and foamy macrophages vary ( Figs 13.14–13.16 ). Mitoses and vascular invasion may be seen, but these features usually do not indicate a more aggressive behavior. Extensive hyalinization and a “pseudoalveolar” pattern of growth may be seen in older examples of localized and diffuse TSGCT.

Immunohistochemistry

Immunohistochemically, the large monocytic cells thought to represent the neoplastic cells of TSGCT express clusterin and podoplanin, and often desmin ( Fig. 13.17 ). On occasion, a very large number of desmin- positive cells are seen; a potentially alarming feature. Non-neoplastic lesional macrophages and osteoclast-like giant cells also stain for CD68, while small non-neoplastic monocytes express CD163.

Genetics

The neoplastic cells, typically comprising less than a quarter of the overall tumor cellularity, demonstrate deletions and rearrangements affecting colony stimulating factor 1 ( CSF1 ) on chromosome 1p13. These alterations result in the deletion of the 3’ untranslated region (UTR) of the CSF1 gene, which in turn is thought to dysregulate mRNA stability and translation, leading to protein overexpression and secretion of high levels of CSF1 protein by neoplastic cells. Consequently, CSF1 promotes survival and proliferation of the neoplastic cells in a paracrine or autocrine fashion, but also recruits and stimulates the differentiation of large numbers of non-neoplastic inflammatory cells expressing the receptor for CSF1. This phenomenon has been termed a landscape effect and is also observed in certain types of lymphomas. Demonstration of CSF1 mRNA expression by chromogenic in situ hybridization (CISH) is a promising new test for the diagnosis of TSGCT, but is not yet widely available outside of research settings.

Gross Findings

The synovium shows a diffuse brown-rust discoloration. In early hemosiderotic synovitis, fine villous projections are present, but the larger nodules and thickened fronds of diffuse TSGCT do not occur (see Box 13.7 ). In the later stages after chronic repeated hemorrhage, the synovium becomes thickened and opaque because of intrasynovial and subsynovial fibrosis. The adjacent articular cartilage may show a greenish-black discoloration.

Microscopic Findings

The synovium is hyperplastic and contains yellow- brown hemosiderin granules. Within the subsynovial connective tissue, hemosiderin-laden macrophages are present, often in association with small blood vessels ( Fig. 13.18 ). Sheets of mononuclear synovial cells, lipid-laden cells, or multinucleated osteoclast-like giant cells, as seen in TSGCT are not a feature of hemosiderotic synovitis. The articular cartilage may show hemosiderin deposition within chondrocyte lacunae and necrosis of the chondrocytes.