Tenosynovial giant cell tumor is a neoplasm of synovium in which dysregulation of the colony-stimulating factor 1 (CSF1) axis attracts immune cells, particularly macrophages, leading to the formation of a mass [1]. Clinically and radiographically, TGCT is divided into localized type – characterized by a well-circumscribed nodular appearance comprising 90% of cases – and diffuse type, characterized by an expansive villous proliferation within joints that can extend extra-articularly. Diffuse TGCT (dTGCT) is locally aggressive and frustrating to manage. Surgery is the mainstay of treatment but, while curative for localized disease, it is associated with failures above 50% for diffuse cases [2]. Local recurrence of disease has been shown to be a risk factor for subsequent failures of operative treatment, and repeated surgical interventions contribute to overall morbidity, joint stiffness, and impaired quality of life [3,4]. Because of this, multiple adjuvant therapies – including external beam radiotherapy, isotopic synoviorthesis, and cryotherapy – have been utilized attempting to limit local recurrences, but each have limited success and associated risks along with complicating future joint arthroplasty procedures [3,5].

Medical therapy became possible once the molecular mechanism driving TGCT was elucidated. The neoplastic clone within TGCT overexpresses CSF1, frequently due to a t(1; 2) translocation creating the chimeric protein COL6A3-CSF1, leading to the recruitment of reactive inflammatory cells expressing the CSF1-receptor (CSF1R) forming the tumorous mass [6]. Thus, blocking the CSF1/CSF1R axis can target the underlying cause of the disease [7]. After modest clinical success with imatinib and nilotinib [[8], [9], [10]], agents with specific activity against CSF1R were created [11,12].

Pexidartinib (Daiichi Sankyo, Tokyo, Japan) was designed as a selective CSF1R inhibitor capable of stabilizing the autoinhibited conformation of the kinase [12]. The randomized phase III ENLIVEN study demonstrated dramatic treatment responses over placebo at the 25-week primary endpoint in patients with unresectable dTGCT [13]. Subsequently, pexidartinib became the first systemic treatment FDA-approved for adult patients with TGCT not amenable to improvement with surgery, and it was added to the National Comprehensive Cancer Network (NCCN) clinical practice guidelines as a category 1 recommendation [14,15].

Now, clinicians are tasked with investigating how to best incorporate this new tool in treatment strategies for a challenging disease. Pexidartinib is an option when surgery cannot eradicate dTGCT without excessive morbidity, but medical treatment alone may be insufficient for some aggressive cases and cannot reverse structural damage. In these instances, combinations of medical and surgical approaches may be most effective. Here we present the first published case employing pexidartinib in the neoadjuvant setting to facilitate limb salvage surgery including dTGCT resection and proximal humerus reconstruction.