Localized tenosynovial giant cell tumors may occur at any age but are most common in patients 30–50 years old. Women are affected about two to three times as often as men. The tumors occur predominantly on the hand, where they represent the most common neoplasm of that region. Less common sites include the feet, ankles, and knees. Overall, roughly 76% involve the hands and 12% the feet, with the remainder occurring in association with various larger joints. Finger lesions are typically located adjacent to the interphalangeal joint, although other sites may also be affected. Occasionally, localized forms of TGCT can arise in an intraarticular location but should be distinguished from the diffuse form clinically and radiographically.

The tumors develop gradually as a painless swelling over a long period and often remain the same size for several years. On physical examination, they are fixed to deep structures but are usually not attached to the skin unless the lesion occurs in the distal portion of the fingers or toes, where the skin is closely related to the tendon ( Fig. 26.4 ). Antecedent trauma occurs in a variable number of patients, but its association with the lesions is likely coincidental. Radiographic studies usually demonstrate a circumscribed soft tissue mass and, occasionally, degenerative changes of the adjacent joint. Only about 10% of patients, however, have cortical erosion of adjacent bone, and bony invasion is exceedingly uncommon ( Fig. 26.5 ).

Localized TGCT of the great toe, demonstrating involvement of both the skin and bone. In the fingers and toes, skin and bone invasion are not necessarily features of a malignant lesion.

Plain radiograph demonstrating one erosion from a localized TGCT of the finger.

Diffuse tenosynovial giant cell tumors most frequently involve large joints, the knee joint being the most common site followed by the ankle and the hip joints. Less often, this disease resides entirely outside a joint, in which case its origin must be ascribed to the synovium of the bursa or tendon sheath. In many cases, it is difficult to define the origin of the tumor. Therefore, the term tenosynovial giant cell tumor of the diffuse type is used when there is a poorly confined soft tissue mass with or without the involvement of the adjacent joint. The term “pigmented villonodular synovitis” is often used to refer to the intraarticular, diffuse form of this disease.

Compared to localized TGCT, the diffuse form is much less common and exhibits clinical differences. These lesions tend to occur in younger persons. In the largest study to date of 50 cases, Somerhausen and Fletcher reported an age range of 4–76 years, with a median age of 41 years. Females are affected slightly more often than males, but not to the degree seen in the localized form. Typically, symptoms are of relatively long duration, often several years, and include pain and tenderness in the affected extremity. The additional presence of joint effusion, hemarthrosis, limitation of joint motion, and locking signify articular involvement. Uncommon locations include the finger, elbow, toe, and temporomandibular joint, as well as the facet joints of the vertebra and sacroiliac areas. Radiographically, an intraarticular or soft tissue mass is usually evident and may be accompanied by osteoporosis, widening of the joint space, and cortical erosion of the adjacent bone ( Fig. 26.6 ).

Radiograph of diffuse TGCT, demonstrating a large soft tissue mass in the ankle region with secondary destruction of the distal tibia and fibula ( arrows ). Minimal changes in the joint space suggest that the tumor arose in an extraarticular location ( A ). MRI of diffuse TGCT of the knee, with replacement of the knee joint by tumor, and extension into the popliteal fossa ( B ).

Localized-type tenosynovial giant cell tumors are circumscribed, lobulated masses, occasionally with shallow grooves along the deep surfaces, created by the underlying tendons ( Fig. 26.7 ). They are usually relatively small, ranging from 0.5 to between 3.0 and 4.0 cm in diameter. Those on the feet are often larger and more irregular in shape than those on the hands. On cut section, the tumors have a mottled appearance: a pink-gray background flecked with yellow or brown, depending on the amount of lipid and hemosiderin. Tumors arising in the large joints are usually larger and more irregular in shape than tumors in the digits.

Gross appearance of localized TGCT ( A ). Scanning magnification view of a localized TGCT, demonstrating lobularity and circumscribed growth ( B ).

When diffuse tenosynovial giant cell tumors involve the joint space, they appear as multifocal synovial thickening and nodularity, often with a villous appearance ( Fig. 26.3 ). Soft tissue involvement takes the form of a nonspecific mass, varying from white to yellow or brown in color, sometimes with foci of hemorrhage and cystic change.

Microscopically, the earliest lesion of the localized form is a villous structure that projects into the synovial space of the tendon sheath. Limited space prevents continued growth into the cavity, so ultimately, the tumor grows outward in a cauliflower fashion and compresses synovium-lined clefts into its substance. At the stage most lesions are surgically excised, they are exophytic masses attached to the tendon sheath and have smooth but lobulated contours. They are partially invested by a dense collagenous capsule that penetrates the tumor, dividing it into vague nodules. The capsule is not totally confining because isolated nests of tumor can be identified outside its bounds, especially at the deep margin where the tumor blends with the synovial membrane.

The histologic appearance of this tumor varies, depending on the proportion of neoplastic synoviocytes, reactive inflammatory cells (e.g., histiocytes, osteoclast-like giant cells, and foamy histiocytes), hemosiderin deposits, and the degree of collagenization. At low-power magnification, localized TGCT typically displays a “zonated” architecture, with a fibrous capsule, pale staining peripheral areas containing lipidized macrophages, and more cellular central zones, often with abundant hyalinized collagen surrounding pseudoalveolar nests of cells ( Fig. 26.8 ). Most tumors are moderately cellular and are composed of a highly variable admixture of plasmacytoid synoviocytes, smaller nonlipidized macrophages, siderophages, foamy macrophages, and osteoclast-like giant cells ( Fig. 26.9 ). Despite the name of this tumor, the number of osteoclast-like giant cells is highly variable, with some tumors containing few or no giant cells. These osteoclast-like giant cells, which are recruited into these lesions by RANKL expression in the neoplastic synoviocytes, have a variable number of nuclei, ranging from as few as three or four to as many as 50–60. It should be emphasized that the synoviocytes represent the neoplastic cell population , and osteoclast-like giant cells are not required for the diagnosis . Synoviocytes generally represent only a small minority of the total cell mass, although scattered foci containing larger numbers of synoviocytes are often present ( Fig. 26.10A ). The synoviocytes are slightly larger than normal histiocytes, often plasmacytoid in shape, contain a moderate amount of eosinophilic cytoplasm, and sometimes display hemosiderin pigment deposited at the periphery of the cytoplasm (‘ladybug’ cells) ( Fig. 26.10B ). Rarely, the tumors may consist of sheets of small synoviocytes and histiocytes, potentially mimicking some sort of round cell neoplasm, especially when mitotic activity is present ( Fig. 26.11 ) Foamy histiocytes tend to be located at the periphery of the tumor and may be associated with cholesterol clefts ( Fig. 26.12 ). Subsets of clinically benign cases show potentially concerning features, such as elevated mitotic activity ( Fig. 26.13A ), infarct-type necrosis ( Fig. 26.13B ), hyalinization and pseudoalveolar change mimicking rhabdomyosarcoma ( Fig. 26.13C ), and vascular space invasion ( Fig. 26.13D ). Degenerative nuclear atypia may be seen in tumors containing very large amounts of hemosiderin ( Fig. 26.14 ).

Localized TGCT demonstrates “zonation,” with a fibrous capsule, lightly staining peripheral areas containing lipidized cells, and more cellular central areas, often with hyalinized collagen ( A ). Lipidized peripheral zone ( B ). More central area, with nests and pseudoalveoli of synoviocytes, osteoclast-like giant cells, and histiocytes, surrounded by hyalinized fibrous bands ( C ).

Typical localized TGCT with moderate cellularity and a polymorphous population of cells ( A ). Higher-power view of mixed cell types, including siderophages ( B ). Large numbers of foamy macrophages may be present ( C ).

The number of osteoclast-like giant cells is very variable in TGCT, and these cells are not required for diagnosis ( D ).

Higher-power view of synoviocytes, large, plasmacytoid mononuclear cells ( A ). Hemosiderin-laden synoviocytes (“ladybug cells”) ( B ).

Giant cell–poor form of localized TGCT composed exclusively of rounded cells in a richly vascularized background ( A ). In thick sections, areas such as these can be confused with a malignant round cell tumor ( B ), especially when mitotic activity is present ( C ).

Clusters of lipid-laden macrophages ( A ) and cholesterol deposition ( B ) in localized TGCT.

Benign TGCT may have worrisome morphological features, including elevated mitotic activity ( A ), infarct-type necrosis ( B ), hyalinization and pseudoalveolar change mimicking rhabdomyosarcoma ( C ),

and vascular space invasion ( D ).

Degenerative nuclear atypia may be seen in tumors containing very large amounts of hemosiderin.

In contrast to localized TGCTs, the diffuse form is not surrounded by a collagenous capsule. Instead, when it occurs in an intraarticular location, it grows in a striking villonodular pattern, with replacement of the subsynovial connective tissue by an admixture of cells identical to localized tenosynovial giant cell tumor ( Fig. 26.15 ). In extraarticular soft tissue locations, diffuse TGCTs typically grow in an infiltrative fashion, with invasion of skeletal muscle ( Fig. 26.16 ) and fat ( Fig. 26.17 ). Bone invasion may occasionally be present, particularly in large, neglected intraarticular tumors ( Fig. 26.18 ). The morphologic features of diffuse-type TGCT are essentially identical to the localized form, with polymorphous proliferation of histiocytes, larger synoviocytes, osteoclast-like giant cells, siderophages, and foamy macrophages. In general, osteoclast-like giant cells are less conspicuous than in localized tumors, and the relative percentage of synoviocytes is somewhat greater. Rarely, diffuse TGCT may consist predominantly of large, rhabdoid, desmin-positive synoviocytes in association with foamy macrophages; such tumors are easily mistaken for “inflammatory” variants of rhabdomyosarcoma ( Fig. 26.19 ). ^,

Intraarticular diffuse TGCT (pigmented villonodular synovitis) growing in a striking villiform manner ( A ). Higher-power view demonstrating full-thickness replacement of the subsynovial connective tissue by synoviocytes, histiocytes, and osteoclast-like giant cells ( B ).

Extraarticular diffuse TGCTs often grow in an infiltrative manner ( A ), with invasion of skeletal muscle ( B ).

Diffuse TGCT invading fat.

Bone invasion by intraarticular diffuse TGCT.

Some diffuse TGCTs contain large numbers of eosinophilic, rhabdoid synoviocytes ( A ). Such cells may be strongly desmin-positive ( B ), a potentially serious pitfall when the differential diagnosis includes rhabdomyosarcoma. These cells are negative for myogenin and MyoD1. Clusterin expression ( C ) confirms synoviocytic lineage.

The evaluation of certain atypical features in both forms can be problematic. For example, the presence of mitotic figures occasionally leads to a mistaken diagnosis of a malignant neoplasm ( Fig. 26.13A ). Rao and Vigorita documented three or more mitotic figures per 10 high-power fields (hpf) in more than 10% of their cases. Although it may indicate an actively growing lesion that is likely to recur, mitotic activity alone should not be interpreted as evidence of malignancy in these tumors. In about 1%–5% of cases, tumor thrombi are observed in small draining veins ( Fig. 26.13D ). Similarly, vascular invasion does not correlate with the ability to produce metastasis. Focal, or occasionally near-total, infarct-type necrosis may also rarely be seen, especially when arising in large joints such as the knee ( Fig. 26.13B ). In those instances, the diagnosis can be made by identifying the mononuclear and multinuclear ghost cells. Because of the extreme rarity of metastasizing forms of TGCT, it is justifiable to adopt a conservative approach when interpreting these atypical features. The diagnosis of malignant TGCT (see later) requires the identification of nodules or sheets of clearly malignant synoviocytes.

Both localized and diffuse tenosynovial giant cell tumors contain a mixture of cell types, each with a unique immunophenotype. The small histiocytes show a typical phenotype, with expression of CD45 (weak), CD68, CD163, and CD11c. ^{, , ,} In contrast, the neoplastic cells (synoviocytes) typically lack expression of histiocytic markers and express instead clusterin and podoplanin. Follicular dendritic cell markers, such as CD21 or CD35, are negative, as are markers of epithelial cells (e.g., keratins, EMA) ( Table 26.1 ). The synovial cells of TGCTs also show variable expression of desmin, a potential diagnostic pitfall, especially in diffuse forms where they may be present in large numbers. ^, Desmin-positive synoviocytes often have dendritic morphology, a useful clue to their nonmyogenous nature. It is unclear why desmin expression is seen in the synoviocytes of some TGCTs and not in others; this may represent a different functional state of these cells. These desmin-positive cells do not express MyoD1 or myogenin. ^, Synoviocytes also express RANKL, likely accounting for the numerous osteoclast-like giant cells that typify these lesions. These same cells harbor the CSF1 rearrangement and represent the neoplastic cell population in TGCTs. The CSF1 upregulation can be identified immunohistochemically or by chromogenic in situ hybridization. ^,

A number of studies have found clonal cytogenetic abnormalities in TGCT. Gains of chromosomes 5 and 7 are common, as are rearrangements of 1p11–13. ^, Alterations of the CSF1 gene, located at 1p13–21, have been implicated as central to the pathogenesis of this tumor. This gene encodes for colony-stimulating factor 1 (CSF1), a protein involved in macrophage function, differentiation, and proliferation. It appears that CSF1 rearrangements and CSF1 expression in the synoviocytes create a recruited “landscape” of reactive inflammatory cells, including osteoclast-like giant cells. ^, The majority of mononuclear cells and multinucleated giant cells express the CSF1 receptor, CSF1-R. COL6A3 , located on chromosome 2q37, seems to be the most frequent translocation partner for CSF1 . However, alternative mechanisms of CSF1 overexpression also seem to occur as some tumors show high expression of mRNA and protein without detectable CSF1 rearrangements. Fusions of the CSF1 gene have been reported with a variety of partners, including CSF1::COL6A3 , CSF1::VCAM1 , CSF1::FN1 , and CSF1::CDH1 , among others. ^,

With very rare exceptions, localized tenosynovial giant cell tumors are benign, although they may recur in about 10%–20% of cases. “Benign metastasizing” TGCTs are quite rare, and generally result only in nonprogressive metastases. ^, In the study of Williams et al. of 213 cases of TGCT involving the hand, 27 (13%) locally recurred with a mean follow-up of 51 months. Cases located on the extensor tendon recurred more often than those in other locations. Recurrences are nondestructive and are easily controlled by re-excision. Local excision with a small cuff of normal tissue is usually considered adequate therapy, even for lesions with increased cellularity and mitotic activity. Most are cured by this approach, and more extended surgery can always be planned later for persistently recurring lesions.

Although much has been reported concerning the behavior and treatment of intraarticular diffuse tenosynovial giant cell tumor, there are few data on the extraarticular forms of diffuse-type TGCT. It seems reasonable to assume, however, that the natural history of intraarticular and extraarticular forms of TGCT are similar, with significant potential for local recurrence (sometimes destructive) but without metastatic risk.

Histologic features do not reliably predict local recurrence, which seems to be more closely associated with the adequacy of surgical excision. In the Somerhausen and Fletcher series, follow-up information available in 24 patients revealed recurrences in eight (33%), with a median follow-up of 55 months. All recurrences occurred between 4 and 6 months after the initial excision, and five patients had multiple recurrences. As in localized TGCT, the presence of high cellularity, mitotic activity, and necrosis does not seem to be of clinical significance in the absence of overt cytologic features of malignancy. Four cases from the Somerhausen and Fletcher series showed sarcomatous transformation, and one patient died of disease (see next section). One exceptional, benign-appearing tumor from this series metastasized to lymph nodes.

Therapy should be based on a desire to remove the tumor as completely as possible without producing severe disability for the patient. Although wide excision or amputation may sometimes be required for local control of the disease, these benign tumors should generally be treated with more conservative surgery, aiming to achieve histologically negative surgical margins. Radiotherapy has been used for the treatment of surgically unresectable TGCT, but there is no significant experience concerning its use for the extraarticular form of TGCT. Inhibitors of CSF1R have recently shown promising results in the treatment of recurrent or unresectable disease. There is also a report suggesting some efficacy for the RANKL inhibitor denosumab in the treatment of these tumors.

Occasionally, other benign lesions located in the vicinity of the tendon sheath are confused with the localized tenosynovial giant cell tumor, including foreign body granulomas, necrobiotic granulomas, tendinous xanthomas, and fibromas of tendon sheath. Granulomatous lesions, however, are less localized and have a greater complement of inflammatory cells. Necrobiotic granulomas are characterized by cores of degenerating collagen rimmed by histiocytes and a prominent zone of proliferating capillaries; giant cells are usually scarce or nonexistent. Although TGCTs with a prominent xanthomatous component and tendinous xanthoma formerly represented a problem in differential diagnosis, this is now seldom a practical problem for the surgical pathologist because of the recognition and early treatment of hyperlipidemia. In contrast to giant cell tumors, tendinous xanthomas that arise in the setting of hyperlipidemia are often multiple and occur in the tendon proper. Histologically, they consist almost exclusively of xanthoma cells, with only a few multinucleated giant cells and chronic inflammatory cells. Fibromas of tendon sheath bear some similarity to hyalinized forms of TGCT, and some once believed that the former represents an end-stage of the latter; this hypothesis has since been contradicted by the observation that fibromas of tendon sheath harbor USP6 rather than CSF1 gene rearrangements. In general, the cells of fibroma of tendon sheath appear myo/fibroblastic and are deposited in a more uniformly hyalinized stroma, although some lesions have areas reminiscent of giant cell tumors. Occasionally, epithelioid sarcomas with numerous giant cells mimic a TGCT. The relatively monomorphic population of cells with dense cytoplasmic eosinophilia, strong and diffuse expression of keratins, and loss of SMARCB1 expression distinguish it from TGCT. Clefted areas of a TGCT may also suggest the glandular component of a biphasic synovial sarcoma. However, the cells lining the spaces are identical to those found in the solid portion of the tumor and lack epithelial features, as determined by IHC. These clefted or pseudoalveolar areas may also suggest alveolar rhabdomyosarcoma, particularly in tumors containing large numbers of desmin-positive cells; thankfully, such tumors are negative for MyoD1 and myogenin. Xanthogranulomatous epithelial tumor/keratin-positive giant cell-rich tumor (giant cell tumors with HMGA2::NCOR2 fusion) may also show expression of CSF1 as is seen in tenosynovial giant cell tumor. However, these tumors usually arise in the subcutaneous tissue or bone and not from synovial lined structures, and usually contain keratin-positive mononuclear cells. ^, This tumor is discussed in Chapter 33 .

Diffuse-type TGCTs usually present greater diagnostic problems than their localized counterparts. The pronounced cellularity, coupled with the clinical findings of an extensive mass, may easily lead to a diagnosis of malignancy. Particular problems arise in the early lesions, which are characterized by a monomorphic population of round cells with a high nuclear/cytoplasmic ratio and a brisk mitotic rate. Focal necrosis or complete infarct-type necrosis may be present. In such cases, attention should be directed to the apparent maturation of these tumor nodules at their periphery, where the cells acquire a more prominent, slightly xanthomatous-appearing cytoplasm. Additional sections sometimes disclose occasional osteoclast-like giant cells, and iron staining may identify modest amounts of hemosiderin not discernible in routine sections. IHC for clusterin and IHC or ISH for CSF1 may also be valuable in identifying the neoplastic synovial cells, particularly when the possibility of a histiocytic sarcoma is considered. Diffuse-type TGCT containing a large number of desmin-positive dendritic cells should be distinguished from pleomorphic rhabdomyosarcoma and the recently described inflammatory rhabdomyoblastic tumor with IHC for skeletal muscle-specific markers, such as myogenin and MyoD1.