Tenosynovial Giant Cell Tumor

Tenosynovial giant cell tumor is a benign soft tissue tumor arising from the synovium of joints, bursae or tendon sheaths. It can be found in both intra-articular and extra-articular locations. In the past, extra-articular disease was called “giant cell tumor of tendon sheath” and intra-articular disease was called “pigmented villonodular synovitis” [PVNS], either nodular or diffuse. These terms are still frequently used. Since 2013, the term “localized tenosynovial giant cell tumor” has been used to denote giant cell tumors of tendon sheath and nodular tenosynovitis, whereas “diffuse tenosynovial giant cell tumor” has replaced PVNS (though many clinicians still use that term). Although it was previously thought to be a reactive condition, the identification of the t(1p13;2q35) and 5q33 chromosomal rearrangements leading to overexpression of the colony-stimulating factor 1 (CSF-1) gene within tumor cells has confirmed that tenosynovial giant cell tumor is indeed a neoplastic condition.

Epidemiology

Localized tenosynovial giant cell tumor is approximately 3.5 times more common than the diffuse form, with an incidence of 30 cases per million person-years versus 8 cases per million person-years for the diffuse. Females are more often affected than males in the localized form (61%), while there appears to be no gender predilection in the diffuse form. Both forms tend to occur in patients between 30-50 years of age (the average age is 47); however, patients with diffuse tenosynovial giant cell tumor present at a slightly younger age.

Clinical Features

Localized Tenosynovial Giant Cell Tumor

The localized form of this tumor can be either intra-articular or extra-articular and can be found along the tendons of the digits, wrists, and ankles approximately 85% of the time. Most of the remaining intra-articular cases are found in or near the knee. The mass may erode adjacent bone, especially if the tumor is advanced. Patients often present with painless swelling or a slow-growing mass. Localized tenosynovial giant cell tumors in an intra-articular location can cause mechanical symptoms such as popping, catching and locking. Occasionally the tumor within the joint may bleed, resulting in recurrent, atraumatic hemarthroses. Bleeding, however, is more common in the diffuse form.

Diffuse Tenosynovial Giant Cell Tumor

The diffuse form generally exhibits intra-articular involvement and occurs in the large joints, the knee most commonly, followed by the hip, ankle, and elbow. Patients present with joint swelling and pain and may have recurrent atraumatic hemarthroses. Before the availability of CT and MRI scans, the hallmark of this intra-articular process in advanced cases was the presence of cystic changes on both sides of a joint. Patients often describe a decreased range of motion in the affected joint and pain with athletic activities. Symptoms have often been present for many months or years at the time of presentation.

Radiologic Features

Plain radiographs of the affected region may demonstrate cystic erosions of the bone adjacent to the mass, and a key finding is erosions on both sides of the joint in advanced cases as mentioned above. The neoplastic tissue will not calcify. Only 30% of patients will demonstrate abnormal radiographs, therefore the physician must have a high index of suspicion and perform a careful exam of the affected joint as well as ordering advanced imaging in the setting of negative x-rays.

Magnetic resonance imaging (MRI) is the most useful imaging modality. Due to hemosiderin deposition within, the mass will often show low to intermediate signal on T1- and T2-weighted sequences (Figure 1). Localized tenosynovial giant cell tumors will often appear as a well-encapsulated mass along the tendon sheath or within a joint, whereas the diffuse form is often a multilobulated, intra-articular mass that involves multiple compartments of a joint and most of the synovial surface. Gradient-echo sequences demonstrate a “blooming” artifact indicative of hemosiderin within the mass, which is suggestive of tenosynovial giant cell tumor (Figure 2) though histologic confirmation is still usually indicated. Post-contrast MRI sequences will exhibit uniform enhancement throughout the mass.

Figure 1: Axial T1 (left) and axial T2 fat-saturated (right ) MRI sequences of tenosynovial giant cell tumor within the left hip joint.

Figure 2: Axial gradient echo MRI sequence of the left hip demonstrating blooming artifact (red arrows) consistent with tenosynovial giant cell tumor.

Pathology

Grossly, giant cell tumors of tendon sheath appear as a nodular mass (with or without villous extensions) with yellow-brown pigmentation (Figure 3.) Microscopically, it is characterized by synovial-like mononuclear cells with variable amounts of multinucleated osteoclast-like giant cells, foam cells and hemosiderin (Figure 4).

Figure 4: Tenosynovial giant cell tumors, composed of four different cell types: mononuclear neoplastic cells, multinucleated giant cells (arrows), hemosiderin-laden macrophages (arrowheads), and foamy macrophages (not present in current image). (Image courtesy of Dr. Gord Zhu.)

A translocation involving locus 1p13 is found in a minority of cells (2-16%) resulting in overexpression of colony stimulating factor 1 (CSF1). The majority of the tumoral mass is made up of recruited non-neoplastic inflammatory cells expressing the CSF1-receptor.

Differential Diagnosis

Many patients present with recurrent effusions, and therefore the common causes such as rheumatoid arthritis and gout must be considered and excluded. Beyond that, the differential diagnosis of the intra-articular form of the disease includes synovial hemangioma, hemophilia, synovial chondromatosis, tuberculous arthritis, and sarcoma though intra-articular malignancies are quite rare. One must also consider hemophilic arthropathy in the differential diagnosis, a condition which can closely mimic intra-articular Tenosynovial Giant Cell Tumor.

The differential diagnosis of extra-articular tenosynovial giant cell tumor includes fibroma of tendon sheath, ganglion cyst, and desmoid tumor as well as soft tissue sarcomas.

Disease Course: Treatment and Prognosis

Localized Tenosynovial Giant Cell Tumor

Complete surgical excision is the treatment of choice for localized tenosynovial giant cell tumor, whether it is in an intra- or extra-articular location. The local recurrence rate has been reported to be between 0-15%. Recurrences can be treated with a second excision.

Arthroscopic partial synovectomy of tumor nodules in easily accessible locations is minimally morbid and can be effective (Figure 5). Arthroscopy of the posterior compartment of the knee is technically difficult (as the standard portals are made in the front of the knee, away from the neurovascular bundle). As such, partial synovectomy in the posterior compartment of the knee is often performed through an open approach and represents a technically difficult procedure. Local recurrence risk after treatment of nodular pigmented villonodular synovitis is around 10%.

Figure 5: Arthroscopic view of nodular tenosynovial giant cell tumor.

Diffuse Tenosynovial Giant Cell Tumor

Diffuse Tenosynovial giant cell tumor is often very locally aggressive, causing damage to the articular cartilage, subchondral bone, and ligaments. Despite aggressive treatments with surgery and now targeted therapies, local recurrence remains a problem. Radiation therapy has been utilized occasionally but is not optimal considering the possible late complications of fibrosis and secondary sarcoma.

Surgery is still the mainstay of treatment despite high local recurrence rates reported in the literature (8-75%). Complete synovectomy offers the best local control but is very difficult to achieve. In the knee, debate exists over the best surgical method: all-arthroscopic synovectomy, all-open synovectomy or a combined anterior arthroscopic plus posterior open approach to the knee (Figures 6 and 7). Most studies have found that the lowest rates of local recurrence in diffuse tenosynovial giant cell tumor of the knee are achieved with the combined approach. Again, the challenges of posterior knee arthroscopy are encountered when all compartments must be accessed for thorough synovectomy.

Figure 6: Arthroscopic view of diffuse tenosynovial giant cell tumor.

Figure 7: An open surgical view of diffuse tenosynovial giant cell tumor seen in Figure 6.

Radiation

Radiation in the form of external beam radiation therapy (EBRT) and intra-articular injections of radioisotopes have been used as an adjuvant to incomplete surgical excision or to treat recurrent disease not amenable to surgery. While EBRT can be effective at reducing the risk of local recurrence, side effects include joint stiffness, osteonecrosis and secondary malignancies. Intra-articular injections of yttrium-90 have also been used as an adjuvant or alternative to surgery, however, skin necrosis and draining sinuses have been reported. As such, radiation is not commonly used for these tumors.

Targeted Therapy

The discovery of the 1p13 translocation and overexpression of CSF1 in the neoplastic cells has allowed the development of targeted treatments for diffuse tenosynovial giant cell tumor that block CSF1R. Pexidartinib, which is a selective CSF1R inhibitor, is now approved by the United States Food and Drug Administration (FDA) for use in “recurrent tenosynovial giant cell tumor in which repeat surgery is not possible.” Results from a phase 3 placebo-controlled study showed that patients receiving pexidartinib had a 39.3% overall response rate at 25 weeks compared to 0% in the placebo group. They also reported improved PROMIS and functional scores. However, severe liver toxicities were seen in some patients. [Tap, et al. Final results of ENLIVEN: A global, double-blind, randomized, placebo-controlled, phase 3 study of pexidartinib in advanced tenosynovial giant cell tumor. Journal of Clinical Oncology 2018 36:15_suppl, 11502-11502]. Therefore, all patients prescribed pexidartinib must be enrolled in a Risk Evaluation and Mitigation Strategy (REMS) program.

Key Test Topics

The 1p13 translocation is found in a minority of cells which are considered the neoplastic cells. This results in over-expression of CSF1, which through a paracrine effect recruits inflammatory cells with the CSF1R.
New tyrosine kinase inhibitors targeted at CSF1R are being developed to treat recurrent diffuse tenosynovial giant cell tumor. Pexidartinib is a selective CSF1R inhibitor recently approved by the FDA to treat tenosynovial giant cell tumors causing significant morbidity that cannot be improved with surgery, but patients must be enrolled in a REMS program due to the concern for liver toxicity.
Localized tenosynovial giant cell tumors tend to occur in the digits and wrist and follow a fairly benign course with a 15% local recurrence rate following excision.
Pigmented villonodular synovitis (intra-articular tenosynovial giant cell tumor) is most common in the knee and is monoarticular.
X-ray findings are usually normal and MRI with gradient echo sequences (“blooming artifact”) is the imaging study of choice.
Classic histologic findings: hemosiderin-laden macrophages, giant cells, foam cells.
Diffuse tenosynovial giant cell tumors can be very locally aggressive requiring complete surgical synovectomy; the local recurrence rate following resection ranges from 8-75% depending on surgical technique.