Tenosynovial giant cell tumor (TGCT) is a continuum of diseases that most commonly arise from the synovium of joints and tendon sheaths. This includes the proliferative, hemosiderin-rich conditions previously known as pigmented villonodular synovitis (PVNS) and the localized giant cell tumors of the tendon sheath most commonly seen in the hand. TGCT is typically benign, although rare malignant forms and transformations have been reported. Despite its benign nature, TGCT can be highly symptomatic and locally aggressive, resulting in joint destruction. The spectrum of TGCT can be further characterized by intra-articular versus extra-articular location and by localized or diffuse growth patterns.

Most recent evidence suggests a neoplastic origin of TGCT, in contrast to the historical belief that TGCT/PVNS was an inflammatory process. The precise etiology of TGCT remains uncertain, but current research supports that synovial dysregulation through colony-stimulating factor 1 (CSF-1) and a combination of genetic and environmental factors contribute to the pathogenesis.

Overexpression of CSF-1 drives the changes seen in TGCT and, in most cases, is caused by a translocation involving the CSF-1 and COL6A3 genes.¹ However, even in these clonal cases, only a small proportion of cells (10%) exhibit the CSF-1 overexpression, and it is these multinucleated giant cells that recruit the macrophages and other inflammatory mediators that constitute most of the tumor mass.² The signaling cascade set in motion by CSF-1 overexpression recruits additional inflammatory cells, osteoclast-type multinucleated giant cells, and the production of matrix metalloproteinases that contribute to the locally destructive effect on bones and cartilage. The delineation of this pathway has resulted in recent medical advances in TGCT treatment that target these CSF-1 and CSF-1 receptor pathways (Figure 1).

TGCT is most often seen in patients aged 30 to 50 years;³ however, both diffuse and localized forms can be seen in all ages, including young children. The localized forms, such as giant cell tumor of tendon sheath, are most common and seen with an incidence of 34 per 1 million person-years, whereas diffuse forms are seen in 4 per 1 million person-years.⁴ The most common location for localized TGCT is the hands, where it presents as a painless mass, but it can also occur in the large joints, particularly the knee where it presents as a painless effusion with the intra-articular mass sometimes palpable or causing mechanical symptoms (Figure 2). The diffuse forms, which most commonly affect the knee, present as painful swollen joints that are sometimes tender to palpation and exhibit decreased range of motion. The effusions can be waxing and waning and appear insidiously and have often been present for years before prior to clinical evaluation. If patients present with advanced, diffuse disease, the presentation may be similar to that of advanced osteoarthritis given the bony erosion and joint destruction.

Plain radiographs have limited diagnostic utility in TGCT but may demonstrate an effusion and soft-tissue shadow. In 54% of knee TGCT cases, there are no abnormalities on radiographs.³ Plain radiographs are useful in following the periarticular bone erosion and joint destruction that can occur in more advanced disease. CT can be used in a similar way to assess the bony and articular changes and may be useful in planning joint reconstruction options. CT may also demonstrate the extent of the mass, particularly in patients in whom MRI cannot be performed. Ultrasonography has also been described in the setting of joint effusions to identify the hypoechoic masses and synovial thickening. MRI is the most sensitive imaging modality to evaluate TGCT and can also be used to rule out other causes of joint pain and swelling. On MRI, localized forms of TGCT will present as well-defined masses with relative T1- and T2-weighted signal hypointensity due to the presence of hemosiderin. In diffuse intra-articular forms, MRI demonstrates thickening of the synovium and sometimes formation of fronds. In these tumors, the signal intensity may be more heterogeneous, demonstrating T2-weighted hyperintensity with focal areas of hypointense signal corresponding to the hemosiderin deposits as discussed in a 2023 study.⁵ Contrast enhancement is common given the highly vascularized reactive synovium. A blooming artifact, wherein the mass appears larger and with significantly lower signal intensity, can be seen in certain susceptibility-weighted and gradient echo sequences and is a hallmark of diffuse TGCT⁶ (Figure 3). Occasionally, positron emission tomography may be indicated, particularly if there is concern for malignancy. TGCT can be 18F fluorodeoxyglucose avid with mean maximum standardized uptake values (SUVmax) of 8.7, with SUVmax values as high as 14.5 reported.^7,8

Localized forms of TGCT demonstrate a mixture of multinucleated giant cells, mononuclear cells, and macrophages on histology. Hemosiderin deposits are commonly seen, and it is rare for there to be any tumor necrosis. Hyalinization of the stroma is more common in the localized forms.

Grossly, the localized (nodular) variant presents as a solid mass attached to the synovium that is brownish red. The diffuse form involves the entire joint cavity with a reddish-brown, friable mass that is often multifocal in nature. Adjacent degenerative changes of the joint are seen with erosions and cartilage destruction.

The diffuse forms of TGCT demonstrate highly vascularized and thickened synovium with hemosiderin deposits corresponding to the thickened and brown synovium seen grossly. On high-power fields, the osteoclastlike multinucleated giant cells, mononuclear cells, and macrophages are seen. Some of the histiocytes can have a spindle appearance and there may also be mitotic activity present; consequently, these findings may lead to a mistaken diagnosis of sarcoma or the exceedingly rare malignant PVNS.

The mainstay of treatment for both localized and diffuse forms of TGCT is surgical resection, although advances in medical treatment have shown promise in recurrent and unresectable disease.⁹ The localized forms of TGCT can be monitored with observation if minimally symptomatic or excised marginally around the nodule. When intra-articular in the large joints, this marginal excision is sometimes performed arthroscopically, but intralesional débridement with shavers or piecemeal excision should be avoided if there is no biopsy-confirmed diagnosis. For diffuse intra-articular forms of TGCT, complete open synovectomy is the gold standard of treatment. In the knee, this typically involves combined anterior and posterior approaches to perform a full synovectomy. However, there remains a 15% to 55% recurrence rate.^9,10,11,12 Given the high rate of recurrence, nonsurgical treatment with observation and active surveillance of minimally symptomatic recurrent or primary disease should be considered in select patients. In advanced diffuse forms of TGCT, arthroplasty may be indicated given significant joint destruction, but in contrast to what some clinicians may think, this may not necessarily be curative. In the knee, 5-year implant survival is 89% following total knee arthroplasty for diffuse TGCT and recurrence can be seen in 10% to 20% of patients.^13,14,15,16 Historically, radiation therapy in the form of implanted isotopes or external beam radiation therapy has been used as an adjuvant to surgical treatment and may decrease local recurrence, but significant skin changes, infection, arthrofibrosis, and postradiation sarcoma are potential risks of incorporating radiation therapy into treatment.