Historically, orthopaedic surgeons specializing in sports medicine, adult reconstruction, hand surgery, or foot and ankle surgery have had variable experiences with giant cell tumors of tendon sheath (GCTTS) or pigmented villonodular synovitis (PVNS) (nodular or diffuse). In fact, such a diagnosis may present a sense of relief or a sense of dread. More recently, we have come to recognize that these two entities are indeed the same histopathologic process, with PVNS representing the intra-articular form and GCTTS presenting outside the joint along the tenosynovium. In 2013, the World Health Organization formally recognized these entities as being the same disease process, consolidating them to tenosynovial giant cell tumor (TGCT) as the nomenclature to encompass both intra-articular and extra-articular originations.
Presentation of TGCT
Overall, TGCTs are relatively rare and benign, but they are still likely to be seen periodically in orthopaedic practices. A recent population study out of Denmark suggested an overall prevalence of 56 cases of TGCT per 100,000 people, with a slight female predominance. In light of the disparate clinical presentations, perhaps the most important aspect in the management of these patients is ensuring accurate diagnosis. Ultimately, ruling out a soft-tissue sarcoma remains key, as unplanned sarcoma excision may present significant challenges for subsequent limb salvage. Fortunately, intra-articular soft-tissue sarcomas are rare, and extra-articular soft-tissue sarcomas most commonly do not extend along tendon sheaths. However, in a study of 667 tumors around the knee, 3.7 percent were inadvertently recognized during knee arthroscopy, with most of them influencing eventual surgical management.
Patients with extra-articular TGCT often initially present with a soft-tissue mass and swelling or fullness that is rarely painful. In contrast, those with intra-articular TGCT commonly present with pain, effusion, stiffness, or recurrent hemarthroses. Interestingly, the histopathologic appearance of hemophilic synovitis has quite a bit of overlap with that of TGCT, which supported the long-held belief that this may be an inflammatory or reactive condition. More recently, however, we have come to recognize that TGCT is not a reactive condition, but rather a true neoplastic disease with a specific cellular pathway driving tumor growth.
Radiographs will often demonstrate a relatively normal appearance other than a potential soft-tissue shadow. In advanced cases in the joint, osseous erosions may be identified on either side of the articulation. MRI, though, can be very helpful with diagnosis. These typically are relatively dark on T1-weighted imaging, and fluid-sensitive sequences may be bright or dark. The tumors enhance with gadolinium, and gradient echo or diffusion-weighted imaging sequences may demonstrate a “blooming artifact” related to hemosiderin deposition within the tumor (Fig. 1).
TGCT is often classified as being either localized or diffuse. The localized, or nodular, subtype is commonly seen in extra-articular locations, although diffuse involvement can occur along the tenosynovium as well. The overall incidence is about 4:1 localized to diffuse across the population, although the published literature varies widely, likely reflecting marked differences depending upon anatomic sites and referral patterns. Although the localized and diffuse subtypes share histopathologic and molecular biology characteristics, the differences between the two have significant impact on prognosis, with local recurrence rates after surgical excision ranging from 6 percent in mild, localized disease to 64 percent for severe, diffuse TGCT.
Historically, the management of TGCT has been surgical, with marginal excision and tenosynovectomy as the mainstay for extra-articular involvement. Similarly, localized intra-articular TGCT is commonly treated with marginal excision as well. In localized intra-articular TGCT, no clear difference exists regarding local recurrence rates between arthroscopic versus open tumor excision, with some suggesting an earlier return to function and improved early range of motion following arthroscopic excision. Overall, regardless of the approach, operative excision has been shown to improve health-related quality of life and joint function for both localized and diffuse TGCT.
Diffuse intra-articular TGCT, though, is most commonly managed with total synovectomy. For the knee, there are conflicting reports regarding the comparative local recurrence rates between open total synovectomy, all-arthroscopic total synovectomy, and arthroscopic anterior with open posterior synovectomy. Some suggest an improvement in the completeness of excision with open total synovectomy, though at the cost of more extensive surgery and rehabilitation. Patients with posterior extension of tumor around the neurovascular structures, though, are not candidates for posterior arthroscopic synovectomy. Similarly, diffuse TGCT cases around the knee may often invade the proximal tibiofibular joint, extend along the cruciate ligaments, or erode into bone near the gastrocnemius origins—each of which complicates complete surgical removal (Fig. 2, available in the online version).
More recent series of arthroscopy for diffuse TGCT of the hip joint have been compared favorably to surgical hip dislocation, for example. However, anecdotal cases of marked unresectable soft-tissue progression around the hip and pelvis following attempted arthroscopy have tempered some enthusiasm for this approach. Ultimately, regardless of the anatomic location, progressive disease can lead to both massive tumor growth as well as joint degradation (Fig. 3, available in the online version). Those who undergo total joint arthroplasty in the setting of TGCT manifest higher rates of complications, including infection, stiffness, and early revision.
Many patients with TGCT demonstrate a t(1;2) translocation within the tumor cells, resulting in a CSF1-COL6A3 fusion product that causes overexpression of colony-stimulating factor 1 (CSF1). We now recognize CSF1 expression as a key driver of TGCT, leading to efforts to modulate the CSF1/CSF1R axis in patients with advanced TGCT that is not deemed surgically resectable with acceptable morbidity, such as those experiencing multiple local recurrences or extensive diffuse tumor involvement. Initial studies with imatinib mesylate, a receptor tyrosine kinase inhibitor with activity against CSF1R, demonstrated favorable results regarding local control of TGCT in patients whose surgical options were limited or overly morbid.
In 2019, the FDA approved pexidartinib, a novel, orally administered tyrosine kinase inhibitor with high selectivity against CSF1R, for the management of advanced TGCT, following the results of the ENLIVEN study. That international, phase III, double-blind, placebo-controlled, randomized trial enrolled 120 patients. Radiologic measurements of tumor volume demonstrated a response rate of 56 percent at 25 weeks in the pexidartinib group compared to 0 percent in the placebo group, with the majority of patients who responded to pexidartinib maintaining durable disease control while on the medication. However, the durability of tumor response following cessation of the medication remains in question. Furthermore, some dose-related hepatic insufficiency was noted, and the FDA currently requires monitoring of liver function during pexidartinib treatment. Another side effect is hair color changes, which were noted in two-thirds of patients in the trial.
Although surgical management of TGCT remains the standard approach, local control of diffuse involvement is a surgical challenge in many patients. The introduction of the first new medication for locally advanced TCGT has been met with enthusiasm, cautious optimism, and, frankly, relief.
Adam S. Levin, MD, FAAOS, is an associate professor of orthopaedic surgery and oncology at Johns Hopkins University in Baltimore.
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