Tenosynovial giant cell tumor (TGCT), is a neoplasm derived from the synovium that causes recruitment of immune cells, specifically macrophages, leading to formation of a mass. These tumors are often classified by their growth pattern (localized or diffuse) and site (intra- or extra-articular). These pathological distinctions are important because variability in the clinical and biological features of these neoplasms affect treatment .
Localized TGCT is characterized by a discrete nodule, with a predilection for the radial three digits . Diffuse TGCT (D-TGCT), formerly known as pigmented villonodular synovitis (PVNS), is characterized by a diffuse proliferation in the synovium most commonly occurring in and around the knee (~ 75% of tumors) . While local and diffuse disease occur intra-articularly throughout the body, D-TGCT can also be extra-articular, and, in rare circumstances, can metastasize to adjacent lymph nodes and the lungs.
Both localized and diffuse TGCT occur primarily in the 3rd–4th decades of life with a female:male predominance of 1.6–2.1:1 in the localized type and no sex predilection in the diffuse type. The annual incidence in the United States is approximately 11 per million; of that, 9.2 being localized and 1.8 diffuse types. In a more recent epidemiological study from the Netherlands, the worldwide incidence rate of TGCT (including both localized and diffuse) was estimated to be 43 per million .
Clinical presentation of TGCT is variable. The first sign for patients with pathology in the hand is often a painless, slow-growing, firm nontender mass, which may eventually become painful and edematous as it impinges on anatomic structures . When presenting in the knee, intermittent swelling without antecedent trauma is a common symptom .
In 2006, the landmark article by West et al. shed light on the pathogenesis of TGCT. Chromosomes 1 and 2 undergo a translocation at 1p13, which fuses to 2q35, leading to the fusion of CSF1 to COL6A3 and the overproduction of CSF1. However, in collected samples, elevated CSF1 expression was found in only 2–16% of the cells comprising the tumor. This may be in keeping with the fact that only a small fraction of the TGCT mass is considered the malignant clone. As CSF1R is present on immune cells, specifically macrophages, it has been postulated that overexpression of CSF1 from the malignant component of the tumor causes a tremendous immune infiltrate, which comprises the bulk of the tumor [6, 7].
Historically, TGCT has been treated using surgery with the consideration for adjuvant radiation. Surgical options for TGCT are partial or total synovectomy using arthroscopic or open techniques. While localized disease is readily curable with arthroscopic or open surgery, diffuse disease has shown high recurrence rates with arthroscopy (40%) and open surgery (14%). Open surgery also leads to increased morbidity in the form of stiffness and pain .
Newer systemic treatments are being used for TGCT ranging from less selective tyrosine kinase inhibitors, such as imatinib and nilotinib, to CSF1R inhibitors such as emactuzumab and cabiralizumab (monoclonal antibody) and pexidartinib (a selective tyrosine kinase inhibitor) with encouraging results . In the only published phase 2 study of a drug for TGCT, nilotinib led to a disease stabilization rate in 90% of patients at 6 months, but only 6% of patients had a RECIST 1.1 objective response . In a phase 1 study of emactuzumab, partial responses were seen in 24/28 patients and 2 patients had complete responses . In particular, the CSF1R inhibitors are being evaluated in patients with cases with high operative morbidity. The case presented exemplifies the situation in which CSF1R inhibitors, namely pexidartinib, can be used to effectively reduce the disease burden in a patient with D-TGCT .