Tenosynovial Giant Cell Tumor

Not clinically relevant

Cytogenetic studies have demonstrated relatively simple structural changes that most often involve a translocation of the CSF1 gene, encoding colony stimulating factor 1 (CSF1). Cells with this translocation synthesize large amounts of the CSF1 protein. Within tumors that have this translocation, only a small subset of cells actually harbor the translocation, with the majority of the cells that make up the tumor mass consisting of macrophages that are apparently there as a result of the high CSF1 levels.

Grossly, most tenosynovial giant cell tumors of localized type are small (0.5–4 cm), although lesions of greater size may be found in large joints. tumors are well circumscribed and typically lobulated and white to gray with yellowish and brown areas. Diffuse-type tenosynovial giant cell tumors are usually large (often > 5 cm), firm, or sponge-like. The villous pattern is usually present in intra-articular tumors, whereas extra-articular tumors have a multinodular appearance and a variegated color, with alternation of white, yellowish, and brownish areas. Malignant tenosynovial giant cell tumors are usually large, fleshy, and poorly circumscribed, with areas of hemorrhage and necrosis.

The microscopic appearance of tenosynovial giant cell tumors is variable, depending on the proportions of mononuclear cells, multinucleated giant cells, foamy macrophages, inflammatory cells, and haemosiderin, as well as the degree of collagenization of the stroma. Two principal cell types are identified within the mononuclear component: small histiocyte-like cells, with pale cytoplasm and round or reniform nuclei, and larger epithelioid cells, with amphophilic cytoplasm and rounded vesicular nuclei. These larger cells often contain a peripheral rim of haemosiderin granules. Most tumors contain a majority of small histiocyte-like cells, but larger cells may predominate. In both types, mitotic activity may be brisk. Necrosis can be present. Chondroid metaplasia can be seen in tenosynovial giant cell tumors of the temporomandibular joint.
Localized-type tenosynovial giant cell tumors are lobulated and well circumscribed. Osteoclast-like giant cells are usually readily apparent, but they may be inconspicuous in some tumors. Xanthoma cells are frequent, tend to aggregate locally near the periphery of nodules, and may be associated with cholesterol clefts. Haemosiderin deposits are virtually always identified. The stroma shows variable degrees of hyalinization.
Diffuse-type tenosynovial giant cell tumors are infiltrative and grow as diffuse, expansile sheets. Osteoclast-like giant cells are less common in the diffuse form than in the localized form, and they may be absent or extremely rare in as many as 20% of cases. Cleft-like spaces are common and appear either as artefactual tears or as synovial-lined spaces. Blood-filled pseudoalveolar spaces are seen in approximately 10% of cases.
Most malignant tenosynovial giant cell tumors are composed of sheets and nodules of enlarged mononuclear cells. These neoplasms tend to show significantly increased mitotic count, including atypical mitoses, necrosis, enlarged nuclei with nucleoli, spindling of mononucleated cells, and myxoid changes. Less commonly, these tumors contain areas resembling undifferentiated pleomorphic sarcoma or myxofibrosarcoma.
The larger mononuclear cells express clusterin, and in 45–80% of cases a small subset of these cells stain for desmin, which highlights their dendritic processes. The smaller histiocyte-like cells are positive for CD68, CD163, and CD45. Multinucleated giant cells display an osteoclastic phenotype.

The presence of large mononuclear cells with eccentric nuclei, finely granulated cytoplasm, and a cytoplasmic rim of haemosiderin is distinctive.

Tenosynovial giant cell tumor of localized type is a benign lesion with a capacity for local recurrence. Although 4–30% of cases recur, these recurrences are usually non-destructive and are controlled by surgical re-excision. Recurrences are more common in diffuse-type tumors, and repeated recurrences may severely compromise joint function. The recurrence rate has been estimated at 40–60%. In addition, rare cases with benign histology may develop metastatic disease (in the lungs or lymph nodes). Malignant tenosynovial giant cell tumor is an aggressive neoplasm, with substantial mortality (roughly one third of cases). Approximately 50% of cases metastasize to lymph nodes (inguinal and pelvic) and the lungs. Surgery is the mainstay of the treatment of tenosynovial tumors. Molecular targeted therapy targeting the CSF1/CSF1R pathway has shown promising results for unresectable or metastasizing tumors.

Not clinically relevant

Essential: intra- or extra-articular location; varying proportions of small histiocytic cells, large amphophilic cells, foam cells, multinucleated giant cells.

Desirable: demonstration of CSF1 rearrangement (selected cases)