Tenosynovial giant cell tumors (TGCT): molecular biology, drug targets and non-surgical pharmacological approaches

ABSTRACT

Introduction

Tenosynovial giant cell tumor (TGCT) is a mono-articular, benign or locally aggressive and often debilitating neoplasm. Systemic therapies are becoming part of the multimodal armamentarium when surgery alone will not confer improvements. Since TGCT is characterized by colony-stimulating factor-1 (CSF1) rearrangements, the most studied molecular pathway is the CSF1 and CSF1 receptor (CSF1R) axis. Inhibiting CSF1-CSF1R interaction often yields considerable radiological and clinical responses; however, adverse events may cause treatment discontinuation because of an unfavorable risk-benefit ratio in benign disease. Only Pexidartinib is approved by the US FDA; however, the European Medicines Agency has not approved it due to a uncertain risk-benefit ratio. Thus, there is a need for safer and effective therapies.

Areas covered

Light is shed on disease mechanisms and potential drug targets. The safety and efficacy of different systemic therapies are evaluated.

Expert opinion

The CSF1-CSF1R axis is the principal drug target; however, the effect of CSF1R inhibition on angiogenesis and the role of macrophages, which are essential in the postoperative course, needs further elucidation. Systemic therapies have a promising role in treating mainly diffuse-type, TGCT patients who are not expected to clinically improve from surgery. Future drug development should focus on targeting neoplastic TGCT cells.

KEYWORDS:

• Colony-stimulating factor 1
• colony-stimulating factor 1 receptor
• CSF1
• CSF1R
• drug targets
• drug development
• tenosynovial giant cell tumor
• systemic therapy

1. Introduction

Tenosynovial giant cell tumor (TGCT) is a monoarticular, proliferative lesion located in and around joints throughout the body[1]. According to the most recent ‘World Health Organization Classification of Tumors: Soft tissue and Bone Tumors,’ TGCT comprises a family of lesions originating from the synovium of joints, bursae, and tendon sheaths[2]. TGCT consists of two main subtypes: Localized-type TGCT (L-TGCT) and Diffuse-type TGCT (D-TGCT), previously referred to as Giant Cell Tumor of Tendon Sheath and Pigmented Villonodular Synovitis (PVNS), respectively[3]. Although varieties of names have been used in the past, both subtypes are now unified under one denomination, sharing common pathogenesis and morphology [4,5].

1.1. Epidemiology

TGCT is considered an orphan disease, with reported incidence rates ranging from 30–39 and 5–8 per million person-years for L-TGCT and D-TGCT, respectively [6,7]. There is a female predilection (♂:♀ ratio 1:1.5) and both subtypes affect a relatively young population. TGCT is mainly diagnosed between 40 and 60 years; nevertheless, it can occur at all ages, even in children[8]. L-TGCT is primarily located in the digits of the hand and feet (85%), while D-TGCT is more involved in the large joints, especially the knee[9].

1.2. Clinical presentation

L-TGCT and D-TGCT behave differently and are categorized as separate clinical entities. Common experienced symptoms are pain, swelling, stiffness and limited range of motion. Other functional signs are instability, giving way and joint blockage[10]. However, these nonspecific presentations can lead to a delay in diagnosis and visits to various medical professionals[11]. Additionally, a decrease in quality of life (QoL) and interference with daily activities, leading to work loss and requiring domestic help, are often reported. TGCT’s associated burden on QoL and healthcare emphasize the need for an adequate treatment strategy [12–14].

1.3. Diagnostics

Magnetic Resonance Imaging (MRI) is the state of art imaging technique for TGCT and demonstrates the extent of the disease, presence of joint effusion, and secondary degenerative changes. L-TGCT is characterized by a focal, well-demarcated lesion, whereas D-TGCT is classified as more than one, multilobulated lesions with synovial thickening, villous projections and hemosiderin depositions, often extending both intra- and extra-articular[15]. Additionally, the diffuse-type is often associated with bone erosions, cartilage loss and osteophyte formation. In more progressive stages this leads to secondary osteoarthritis[16]. Histological confirmation of the diagnosis is mainly obtained by either excisional biopsies, arthroscopic biopsies or core needle biopsies[11]. However, since often no clear histological distinction can be made between the two main subtypes, L-TGCT and D-TGCT are mainly differentiated by a radiological distribution of tumor within the joint and clinical characteristics.

1.4. Pathogenesis

The pathogenesis of TGCT has been the subject of debate for a long period. In 1941, Jaffe et al. suggested that TGCT had a reactive or inflammatory origin[17]. Several decades later, cytogenic studies revealed numerical and structural chromosomal alterations, indicating a clonal, neoplastic process [18,19]. In 2006, the main view regarding the pathogenesis changed after West et al. demonstrated the presence of recurrent translocations in several TGCT patients. These translocations involve region 1p11-13, on which the colony-stimulator factor 1 (CSF1) gene is located[20]. CSF1, also known as macrophage colony-stimulating factor (M-CSF), regulates survival, proliferation, differentiation and function of macrophages and their precursors by binding to its receptor (CSF1R) [21,22]. Most cells in TGCT express CSF1R, while CSF1 (the ligand of CSF1R) is only present in a low percentage of cells (2–16%). These neoplastic TGCT cells produce elevated levels of CSF1 as a result of the translocation, leading to an increase in more neoplastic cells (autocrine loop) and an accumulation of non-neoplastic CSF1R-expressing cells of the macrophage lineage (paracrine loop). This is referred to as the landscape effect[20]. The most common translocation partner of CSF1 is collagen type VI alpha-3 (COL6A3), located on chromosome 2p37 resulting in t(1;2)(p13;p37) [23,24]. However, recent studies showed that this fusion is only present in a subset of patients. Also, they showed the involvement of other fusion partners leading to additional underlying mechanisms for CSF1 upregulation [24–27]. More specific, novel fusions result in the deletion of CSF1 exon 9, a negative regulator of CSF1 expression, and truncation of 3’-UTR region may account for CSF1 overexpression in more cases instead of overexpression of full-length CSF1 via promoter swapping [28,29]. Also, CBL (Cas-Br-Murine ecotropic retroviral transforming sequence) mutations are present in more than a third of TGCT cases, although not mutually exclusive to CSF1 fusions [28,29]. CBL is a multifunctional protein that associates with receptor tyrosine kinases and could be the driver event in some cases where CSF1 rearrangements are not present[29]. A consensus regarding the effect of different fusions or truncations and levels of CSF1 overexpression and the role of CBL mutations on clinical behavior is still lacking [30–32].

The gene expression profile of TGCT is consistent with apoptosis resistance, inflammation, and matrix degradation, leading to ongoing proliferation and joint destruction. Genes highly overexpressed include CD53, ALOX5AP, SPP1, MMPs 1 and 9[33]. Contrarily, tumor suppressor genes, such as TP53, are downregulated[33].

1.5. Histopathology

TGCT belongs to the so-called fibrohistiocytic tumors according to the 5^th edition of the World Health Organization Classification of Tumors and the tumor microenvironment contains a heterogeneous cell population[2]. Tumors are composed of a variable proportion of mononuclear cells, multinucleated (osteoclast-like) giant cells, foamy macrophages (xanthoma cells), inflammatory cells, and siderophages (hemosiderin-laden macrophages), with stromal hyalinization (Figure 1) [34–36]. Two principle cell types are described, in variable proportion, within the mononuclear cell compartment: small histiocyte-like cells with round to oval nuclei often represent the main cellular component. In addition, larger epithelioid cells with abundant cytoplasm and larger nuclei are seen (Figure 1)[2]. To date, it remains unknown from which lineage these cells are derived. Immunohistochemically, the larger mononuclear cells express clusterin, podoplanin and to lesser extent desmin, highlighting dendritic processes [2,37]. The smaller histiocyte-like cells are positive for CD68, CD163 and CD45[38]. Although osteoclast-like giant cells are the most distinctive histological feature of TGCT, giant cells may be sparse or absent[39]. In the joint fluid, various inflammatory factors are present, such as Interleukine-1β (IL-1β) and Tumor necrosis factor-α (TNF-α), indicating the presence of a highly inflammatory microenvironment within joints affected by TGCT (Figure 2)[40]. Besides the two main subtypes, malignant TGCT is incidentally reported. This aggressive subtype has a high potential for metastasis, mainly in pulmonary and regional lymph nodes[41]. Besides the typical TGCT histology, malignant TGCT displays increased mitotic activity, including atypical mitoses, necrosis, enlarged nuclei with nucleoli, spindling of mononucleated cells, and myxoid change[2]. The malignant TGCT cells are suggested to be derived from clusterin-positive large mononuclear cells[42]. The etiology of malignant TGCT is not well understood.

Figure 1. TGCT H&E stained tissue section showing characteristic histologic features such as small histiocyte-like cells with oval nuclei, larger epithelioid cells of which some contain hemosiderin depositions, multinucleated osteo-clast like giant cells, and stromal hyalinization.

Figure 2. Simplified overview of pathways involved in TGCT chromosomal aberrations of the CSF1 gene lead to an overexpression of CSF1. Elevated levels of CSF1 are suggested to cause an increase in neoplastic TGCT cells (autocrine loop) and accumulate CSF1R presenting cells of the macrophage lineage (paracrine loop). CSF1 is also suggested to be involved with the proliferation of FLS. Monocytes/macrophages can differentiate into osteoclast-like giant cells and foam cells. Monocytes can produce VEGF resulting in angiogenesis and expressing PD-L1, leading to attenuation of lymphocytes. VEGF can also be induced by hypoxic stress by FLS amongst others. Macrophage produced cytokines can strengthen the effect of VEGF. Cadherin-11 can stimulate FLS to produce cytokines, while the cytokines can stimulate FLS through a positive loop. Additionally, the effect of proteins ARRB2, cIAP2, PPARγ and targets over several drugs are depicted. Created with BioRender.com.

1.6. Current gold-standard treatments

Complete excision of TGCT is the primary choice of treatment[43]. L-TGCT is often removed relatively easily by either arthroscopy or open surgery, depending on the localization, with a recurrence rate around 10% [44,45]. Contrarily, adequate removal of D-TGCT can be challenging due to the localization in- and outside the joint and the non-clear-cut boundaries of the tumor. Additionally, D-TGCT has high recurrence rates and often requires re-excision [46,47]. Relapse-free survival rate is estimated at 40% at 10 years[46]. The optimal surgical technique remains to be elucidated[48]. Some specialists claim that open surgery leads to better overview and access, especially in widespread lesions. On the other hand, open surgery may lead to more iatrogenic morbidity, especially in patients having relapses.

The high rate of recurrences in D-TGCT underlines the demand for (neo)adjuvant or new stand-alone treatment approaches[47]. Radiotherapy, consisting of radiosynoviorthesis (RSO) with the injection of intra-articular radioactive isotopes and external beam radiotherapy (EBR), is occasionally performed [49–51]. Only a few studies are available with low-level evidence for both types of radiotherapy. Mixed results have been reported regarding the efficacy of RSO, but this is also associated with serious complications such as skin necrosis [52–54]. A meta-analysis by Mollon et al. suggested that surgery combined with EBR leads to a reduced recurrence rate, but they also concluded that large long-term prospective multicenter studies are required to confirm these findings[55]. Long-term findings are important since EBR is associated with radiation-induced malignancies, especially in a relatively younger patient population. This is regarded as an unacceptable outcome in a benign or intermediate disease[56].

In 2008, Blay et al. were the first to report the effect of the drug imatinib (or imatinib mesylate) in a patient with TGCT, leading to complete remision[57]. This implied a promising role for targeted therapies in TGCT, especially for patients not amenable to surgery. The interest in systemic therapies is increasing more recently, leading to the development and clinical testing of new and available drugs, providing enlargement of the current therapeutic armamentarium.

1.7. Cell line models

Patient-derived tumor cell lines are essential to investigate molecular mechanisms of TGCT pathogenesis and develop novel therapeutic strategies. Recently, a new cell line was established from TGCT tissue[58]. Complimentary use of a culture can be helpful in in vitro studies to gain new insights and increase drug screening reliability[58]. In addition, Tang et al. established the use of patient-derived tumor TGCT xenografts for drug validation in ex vivo models[59].

2. Potential therapeutic targets

Systemic therapies provide a new avenue for patients with inoperable TGCT and are sometimes considered as a last resort[49]. Various underlying molecular pathways have been explored as new therapeutic strategies (Table 1) (Figure 2).

Table 1. (Potential) TGCT drug targets

Molecular target	Biological target	Related drugs applied in TGCT
CSF1-CSF1R axis	Tumor cell proliferation and monocyte/macrophage survival, proliferation and differentiation	Imatinib, nilotinib, pexidartinib*, vimseltinib, lacnotuzumab, emactuzumab, cabiralizumab
JAK2	Cytokine activity	No
cIAP2	Cell apoptosis	No
B-Arrestin2	Cell survival, apoptosis, migration and proliferation of FLS	No
PPARγ	Tumor cell proliferation, invasion, differentiation and apoptosis	Zaltoprofen
TNF-α	Inflammatory conditions and monocyte, macrophage, osteoclast proliferation and differentiation	Infliximab, etanercept
VEGF	Angiogenesis	Bevacizumab
RANKL	Differentiation and activation of osteoclasts	No
PD-L1	Regulation of immune response on tumor cells	No
Cadherin-11	Cytokine and metalloproteinase production and migration and invasion of FLS	No

*Only drug with US FDA approval for TGCT, FLS Fibroblast-like synoviocytes

2.1. Therapeutic targets related to tumor cells

2.1.1. Colony stimulating factor 1

Since the discovery of CSF1 overexpression in TGCT patients, the CSF1-CSF1R axis has been the most studied target[60]. Where in some patients genomic alterations cause overexpression of CSF1 in the neoplastic cells, in other patients, the origin of elevated levels of CSF1 and CSF1R remains unclear [20,26,28]. Nonetheless, targeting the CSF1-CSF1R signaling pathway is suggested to have an anti-tumoral effect by blockade of CSF1R. Different approaches to CSF1R blockade have been investigated, such as CSF1R antibodies and tyrosine kinase inhibitors (TKIs)[27].

2.1.2. Janus-kinase-2

Tsuda et al. found that CBL mutations in TGCT prolong the phosphorylation of tyrosine kinase Janus-Kinase-2 (JAK2), leading to enhanced cell proliferation[28]. They also found that CBL mutations are associated with increased JAK2 expression and worse disease outcomes. Therefore, the authors suggest inhibiting JAK2 as a possible new therapeutic strategy. However, the CBL mutation is not mutually exclusive to CSF1 fusions [28,29]. In cases with the presence of CSF1 rearrangements and CBL mutations, combined treatment might be reasonable.

2.1.3. Cellular inhibitor of apoptosis 2

Cellular inhibitor of apoptosis 2 (cIAP2) is an anti-apoptotic protein, and deregulation of this protein is associated with tumor development and progress[61]. Levels of cIAP2 are significantly higher in D-TGCT compared to the localized-type. Besides, overexpression of cIAP2 is related to ligament, cartilage and bone erosion, and tumor relapses[62]. Since high levels of cIAP2 in TGCT patients were associated with poor prognosis, cIAP2 gene may have a promising role in prognosis prediction and targeted therapy in D-TGCT[62].

2.1.4 β-Arrestin2

β-Arrestin2 (ARRB2) is associated with cell survival, apoptosis, migration, and proliferation in several tumor types. ARRB2 is also highly expressed in TGCT, leading to increased cell proliferation and inhibition of apoptosis through activation of the PI3K-Akt pathway[63]. Cao et al. observed that knockdown of ARRB2 inhibited cell proliferation and increased apoptosis of FLS. They concluded that ARRB2 could be a potential molecular target in TGCT treatment[63].

2.1.5. Proliferator-activated receptor gamma

Proliferator-activated receptor gamma (PPARγ) is a member of the nuclear receptor super family of transcription factors. It is expressed in high levels in adipose tissue and monocyte-derived macrophages and stimulates adipocyte and macrophage differentiation[64]. Ligand activation of PPARγ in monocytes/macrophages inhibits inflammatory mediator and cytokine production. Also, PPARγ is expressed in a variety of cancer cells and specific ligands can induce growth inhibition and apoptosis[65].

2.2. Therapeutic targets related to reactive myeloid cells

2.2.1. Tumor necrosis factor-α

Analysis of the gene expression pattern of TGCT showed elevated levels of macrophages and proinflammatory cytokines, such as TNF-α[33]. Proinflammatory cytokines drive inflammation, which is associated with joint destruction[66]. In addition, the synergistic paracrine loop between TNF-α and CSF1 contributes to monocyte, macrophage, and osteoclast proliferation and differentiation, resulting in tumorigenesis. TNF-α blockade is assumed to antagonize the inflammatory process predominantly[67].

2.2.2. Vascular endothelial growth factor

Vascular endothelial growth factor (VEGF) promotes endothelial cell proliferation and new blood vessel formation. Angiogenesis is crucial for tumor development. In addition, CSF1 can activate multiple cell signaling pathways leading to VEGF production. VEGF inhibition is associated with reducing tumor growth by blocking angiogenesis and, therefore, could be a potential target[68].

2.2.3. Receptor-activator of nuclear factor kappa-B ligand

Receptor-activator of nuclear factor kappa-B ligand (RANKL) is a cytokine involved in differentiation and activation of osteoclasts, causing bone resorption[69]. The monoclonal antibody denosumab successfully inhibits RANKL in various diseases, such as giant cell tumors of the bone[70]. Yamagishi et al. showed RANKL expression in several soft tissue tumors, for instance, TGCT[69]. RANKL expression can be induced by proinflammatory cytokines, such as TNF-α and interleukins, among others[71]. Although RANKL levels were lower compared to giant cell tumors of the bone, there may be a role for RANKL antibody treatment to inhibit giant cells, although this has not yet been under study [69,72]. However, multinucleated cells such as osteoclast-like giant cells from synovial tumors might represent a different entity than bone tumor-derived multinucleated cells, which may result in different efficacy of RANKL blockage. Additionally, since RANKL antibody treatment targets giant cells and not underlying mechanisms of pathogenesis in TGCT, such as the CSF1-CSF1R axis, this strategy remains uncertain.

2.2.4. Programmed cell death ligand 1

Programmed cell death ligand 1 (PD-L1) regulates immune responses by attenuating lymphocyte activation and stimulating tumor growth. PD-L1 was highly positive in 53% of CSF1-activated TGCT cases, expressed on mononuclear cells, multinucleated giant cells, and foam cells[73]. In addition, a positive correlation was found between PD-L1 expression and larger tumor sizes. Based on their findings, Zheng et al. suggested that anti-PD-L1 immunotherapy in combination with other molecular targeted therapy may possibly improve outcomes of anti-tumor therapy in patients with CSF1/CSF1R signaling[73]. Nonetheless, PD-L1 immunohistochemistry expression can be variable and thus the value of PD-L1 is questionable[74].

2.2.5. Cadherin-11

Cadherin-11 mediates adhesion between FLS and contributes to the formation of the synovium lining layer. Additionally, cadherin-11 can stimulate FLS to produce inflammatory cytokines and MMP[40]. Meanwhile, cytokines IL-1β and TNF-α in the joint fluid can increase cadherin-11 expression through the PI3K-Akt pathway, eventually promoting proliferation, migration, and invasion of FLS through a positive feedback loop. This underlying molecular mechanism can cause joint destruction, relapses, or even metastasis and, therefore, may be used as a prognostic molecular marker for D-TGCT. Finally, cadherin-11 inhibition could present a new promising treatment strategy by weakening the migration and invasion of FLS [40,64,65].

3. Systemic therapies

In the last decade, the safety and efficacy of several drugs regarding TGCT have been investigated (Table 2) (Figure 2). The systemic therapies are categorized by drugs targeting the CSF1-CSF1R axis and other therapeutics and published peer-reviewed data is separated from studies whose results are awaited. Furthermore, studies are presented in chronological order of publication.

Table 2. Systemic treatment studies

Authors	Year	Drug	Class	Therapeutic target	Administration	Company	Funded by company	Type of study	Patients
Blay et al.^[57]	2008	Imatinib	TKI	CSF1R	Oral	Novartis	Yes	Case-report	1
Cassier et al.^[75]	2012	Imatinib	TKI	CSF1R	Oral	Novartis	No	Retrospective cohort	29*
Stacchiotti et al.^[78]	2013	Imatinib	TKI	CSF1R	Oral	Novartis	No	Case-report	2
Verspoor et al.^[76]	2019	Imatinib	TKI	CSF1R	Oral	Novartis	No	Retrospective cohort	62*
Mastboom et al.^[77]	2020	Imatinib	TKI	CSF1R	Oral	Novartis	No	Retrospective cohort	25
Cassier et al.^[80]	2015	Emactuzumab	CSF1R AB	CSF1R	Intravenous	Roche	Yes	Phase I	29
Cassier et al.^[81]	2020	Emactuzumab	CSF1R AB	CSF1R	Intravenous	Roche	Yes	Phase I	63*
Gelderblom et al.^[83]	2018	Nilotinib	TKI	CSF1R	Oral	Novartis	Yes	Phase II	56
Tap et al.^[85]	2015	Pexidartinib	TKI	CSF1R	Oral	Daichii-Sankyo	Yes	Phase I/II	41 + 23
Tap et al.^[86]	2019	Pexidartinib	TKI	CSF1R	Oral	Daichii-Sankyo	Yes	Phase III	120 (59 placebo)
Gelderblom et al.^[87]	2020	Pexidartinib	TKI	CSF1R	Oral	Daichii-Sankyo	Yes	Retrospective cohort	130*
Cheng et al.^[90]†	2015	Lacnotuzumab	CSF1 AB	CSF1	Intravenous	Novartis	Yes	Phase II, abstract	5
Sankhala et al.^[91]†	2017	Cabiralizumab	CSF1R AB	CSF1R	Intravenous	Five Prime therapeutics	Yes	Phase I/II, abstract	22
Smith et al.^[92]†	2021	Vimseltinib	TKI	CSF1R	Oral	Dicephera	Yes	Phase I/II, abstract	3
Gelderblom et al.^[93]†	2021	Vimseltinib	TKI	CSF1R	Oral	Dicephera	Yes	Phase I/II, abstract	68*
Kroot et al.^[94]	2005	Infliximab	Anti-TNF-α	TNF-α	Intra-articular	Unknown	Unknown	Case-report	1
Fiocco et al.^[95]	2006	Etanercept	Anti-TNF-α	TNF-α	Intra-articular	Unknown	Unknown	Case-report	2
Fiocco et al.^[67]	2010	Etanercept	Anti-TNF-α	TNF-α	Intra-articular	Unknown	Unknown	Case-series	4
Nissen et al.^[97]	2014	Bevacizumab	VEGF AB	VEGF	Intra-articular	Roche	No	Case-report	1
Takeuchi et al.^[98]†	2019	Zaltoprofen	NSAID	PPARγ	Oral	Nippon Chemiphar	No	Phase II, abstract	10

TNF Tumor necrosis factor, TKI Tyrosine Kinase Inhibitor, VEGF vascular endothelial growth factor, AB antibody, CSF1 Colony-stimulating factor 1, CSF1R Colony-stimulating factor 1 receptor, NSAID non-steroidal anti-inflammatory drug, PPARγ Proliferator-activated receptor gamma, *included patients that were involved in a prior study, † studies representing preliminary results

3.1. CSF1-CSF1R targeted therapies

3.1.1. Imatinib

Imatinib is an inhibitor of a few tyrosine kinases, including Abelson proto-oncogene (Abl), breakpoint cluster region-Abl (Bcr-Abl) complex, c-Kit proto-oncogene (KIT), platelet-derived growth factor receptor (PDGFR) and CSF1R[75]. Before imatinib was applied in TGCT, this oncogene-targeted therapy was already indicated for patients with chronic myeloid leukemia and gastrointestinal stromal tumors[57]. The effect of imatinib on TGCT was first evaluated in one patient, in which complete remission was observed five months after initiation[57]. After treatment interruption, TGCT relapsed both clinically and radiologically, but diminished again after treatment was resumed. After successful treatment of this single patient, a retrospective study reported the effect of imatinib in 29 patients with advanced or metastatic D-TGCT [57,75]. Imatinib is an oral drug, dosed at 400 mg daily. Imatinib led to an objective response rate (ORR) of 20% according to Response Evaluation Criteria in Solid Tumors (RECIST) and symptomatic/functional improvement in 74% of patients. Although a substantial activity against D-TGCT was observed, the effect was less when compared with GIST and dermatofibrosarcoma protuberans, probably due to a lower activity against CSF1-driven chemotaxis[75]. Six patients had to stop due to toxicity (of which three had grade 3 or 4 toxicities), and four without any apparent medical reason[75].

Subsequently, the same study group described the long-term efficacy of imatinib on the initial 29 patients and 33 additional patients. In this cohort, 31% had radiological response and 78% had clinical improvement. A drop-off rate of 59% within a year suggested an unfavorable efficacy/toxicity balance, with grade 3–4 toxicities occurring in 11%. All four patients with metastatic TGCT progressed rapidly on imatinib[76].

Another research group observed partial response in 32% after imatinib use, consistent with the previous reports. Additionally, this study showed a significant decrease in the maximum standardized uptake value (SUV-max) on PET-CT after imatinib. However, 80% of the patients discontinued treatment with imatinib for poor response or intended surgery[77].

Finally, Stachiotti et al. showed anti-tumor activity following imatinib in two patients resistant to prior nilotinib. They assumed that targeted agents with similar profiles could induce different clinical results. However, further research is required[78].

3.1.2. Emactuzumab

Emactuzumab is a recombinant, humanized monoclonal Immunoglobulin 1 (IgG1) antibody directed against CSF1R[79]. In a phase I trial, Cassier et al. determined the safety, tolerability, and clinical activity of emactuzumab in 28 patients[80]. After a median follow-up of 12 months, 86% of the patients showed an objective response, of which 2 achieved complete response; one patient had a relapse. The most frequent adverse events were facial edema, asthenia, pruritus, and rash. Five serious adverse events were reported, of which three were grade 3, including lupus erythematosus twice. Overall, emactuzumab was well tolerated, but 20% of patients dropped out due to adverse events. Eight patients who were resistant to either imatinib or nilotinib or both before achieved objective tumor response. The authors hypothesized that the difference in activity between imatinib, nilotinib and emactuzumab could be attributed to the fact that imatinib and nilotinib are no strong inhibitors of CSF1R.

The same research group performed a subsequent study, including 63 patients, to evaluate the long-term clinical benefit and safety[81]. The best ORR of 71% was observed, and responses were durable at one- and two years at 70% and 64%, respectively. Stable disease was achieved in 98%, which changed to 93% at one- and two-year follow-up. In addition, a significant improvement in the EQ-5D-3 L QoL and WOMAC was observed. Reported AEs were comparable with the previous study. Nine patients (14%) withdrew from the study due to AEs. Finally, a reduction in tumor-associated CD68/CD163-positive and CSF1R-positive cells was shown. Durable responses were seen despite a relatively short treatment duration, which can be interpreted as an advantage.

A third study estimated the optimal biological dose (OBD) based on the previous phase I study. They recommended an OBD of 1000 mg intravenously every two weeks. Dosing flexibility is possible by dosing emactuzumab once every three weeks[82].

3.1.3. Nilotinib

Nilotinib was the first drug whose efficacy and safety was investigated in an open-label, phase II trial for non-resectable D-TGCT[83]. Nilotinib inhibits tyrosine kinases Abl, KIT, PDGFR and CSF1R. Patients received 400 mg orally twice daily until treatment discontinuation or completion of 1 year of treatment. Of 51 evaluable patients, 49 (96%) were progression-free at 12 weeks and 46 (90%) at 24 weeks. After one year of treatment, the best objective response was partial response achieved in three patients (6%) and stable disease in 46 (90%). In total, ten (20%) patients had had disease progression during the 1-year study period. Six patients discontinued nilotinib due to disease progression; five patients due to toxicities. Headache, nausea, increased alanine aminotransferase (ALT) concentrations, fatigue and asthenia, were the most common AEs. Nine grade 3 AEs occurred, including hepatic disorders and toxicodermia. Post-hoc analysis showed progression-free survival in 57% at 48 months. However, secondary resection and nilotinib treatment duration had no additional effect on progression-free survival, although selection biases of patients for surgery are probable.

3.1.4. Pexidartinib

Pexidartinib is a novel TGCT targeting drug, the first drug approved by the US Food and Drug Administration (FDA)[84]. It was derived from other TKIs, and showed more potential in blocking CSF1R dependent cells and limited cross-reactivity with other kinases. Besides strong selective activity against CSF1R, it also inhibits KIT and fmls-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)[85]. In a phase I study by Tap et al., 41 patients were enrolled in various dose-escalation cohorts. 27% had at least one drug-related adverse event of grade 3 or higher, including anemia, increase in aspartate aminotransferase level (AST), and decrease in lymphocytes. The maximum tolerated dose was set at 1000 mg per day taken orally. In the phase II extension study, 23 patients with D-TGCT were enrolled. Frequently experienced AEs were hair color change, fatigue, nausea, dysgeusia, and periorbital edema. Eight patients had grade 3 or higher AEs, including elevated levels of liver enzymes. Two patients discontinued treatment because of AEs. Disease control was observed in 19 (83%) patients, of which 12 had a partial response. Only one patient with metastatic TGCT had disease progression after a stable period of eight months.

The same study group performed a phase III, randomized, mutational, double-blind, then an open-label trial with pexidartinib[86]. One hundred twenty patients were randomly assigned to pexidartinib (n = 61) or placebo (n = 59) treatment. At 25 weeks, the ORR in the pexidartinib group was 39% according to RECIST and 56% by tumor volume score (TVS) compared to 0% in the placebo group for both measurements. In addition, clinical outcomes were significantly improved in the pexidartinib group compared to the placebo group. However, 98% of the patients in the pexidartinib group experienced AEs. Grade 3–4 AEs occurred in 44% and mainly consisted of increased levels of AST, ALT, alkaline phosphatase (AP) and hypertension. Eight patients (13%) discontinued treatment with pexidartinib due to AEs, of which seven were liver-related (including hepatotoxicity and hyperbilirubinaemia requiring liver dialysis procedures). Subsequently, 30 patients from the placebo group were assigned to a crossover group with 800 mg pexidartinib a day. Of this group, 30% had RECIST response, and 57% had TVS response at week 25. Patients in this group experienced fewer liver enzyme elevations and no bilirubin increases or signs of drug-induced cholestatic hepatotoxicity.

Finally, the same study group described the long-term outcomes of pexidartinib by pooling analysis encompassing the three pexidartinib-treated TGCT cohorts described above[87]. One hundred thirty patients received pexidartinib for a median duration of 19 months at data cutoff. With a median follow-up of 39 months, the RECIST ORR was 60%, the TVS ORR was 65%. Tumor response often occurred within six months after treatment but occurred even more after long-term pexidartinib treatment. The median treatment duration was 19 months. A total of 16 (12%) patients progressed on therapy or after treatment discontinuation. 127 (98%) patients experienced one or more treatment-related AEs; 57 patients (44%) had grade 3 or higher treatment-related AEs of which fourteen had treatment-related serious AEs. 119 (92%) patients had aminotransferase elevations, predominantly AST and ALT. Four (3%) patients experienced mixed or cholestatic hepatotoxicity, which started within eight weeks of the first treatment and was reversible.

Because of the risk of hepatotoxicity, frequent monitoring of liver function is needed to help balance the benefit-to-risk. Since long-term safety data did not show late-emerging or cumulative toxicities, monitoring is especially required in the first two months. In the EU the European Medicines Agency (EMA) refused market authorization due to uncertainties on the risk-benefit ratio. In the US, pexidartinib was FDA approved and available through the risk evaluation management system (REMS) program, which ensures appropriate monitoring [88,89].

3.2. Preliminary results of CSF1-CSF1R targeted therapies

3.2.1. Lacnotuzumab

Lacnotuzumab (MCS110) is a monoclonal antibody against CSF1. Preliminary results of lacnotuzumab in TGCT patients in a phase Ib/II study were presented during a congress[90]. Five patients were treated with a single dose of 10 mg/kg intravenously. Lacnotuzumab was well tolerated with no drug-related AEs. Four weeks after dose administration, the tumor volume by MRI was reduced by 40%. Improvement in clinical symptoms and pharmacodynamics effects were also observed. Results of study extension, with multiple-dose administration and a goal of tumor ablation, are awaited.

3.2.2. Cabiralizumab

In 2017, preliminary results of a phase I/II study of cabiralizumab were presented[91]. Cabiralizumab is a monoclonal antibody that inhibits the interaction of CSF1 and IL-34 ligands with their shared receptor CSF1R. Cabiralizumab was intravenously administered in 22 patients with inoperable D-TGCT every two weeks for six months in different dosages. Positive functional status improvements by Ogilvie-Harris scores (combination of pain, synovitis, range of motion and functional capacity on a scale of 0–12) were noted in objective responders (from 2 to 7). Most reported AEs were creatine kinase elevations, rash and other skin disorders, fatigue and edema; 10 grade 3 AEs were reported. Updated results are awaited.

3.2.3. Vimseltinib

Vimseltinib is a selective, orally administered inhibitor of CSF1R. In contrast to small-molecule inhibitors of CSF1R, this drug is designed to be selective not affecting closely related kinases KIT, FLT3, PDGFRA, PDGFRB, and the rest of the kinome[92]. This selectivity potentially leads to a more optimal CSF1R suppression. It is currently being evaluated in a phase I/II clinical study for the treatment of TGCT. The first three TGCT patients, included in the phase I trial, showed rapid, preliminary anti-tumor activity by three cycles with deepening response over time. Vimseltinib was generally well tolerated in these patients, although the authors concluded it was too premature to draw safety conclusions on this limited data set[92].

Results of the first 68 patients included in this phase I/II clinical study were recently presented at the European Society for Medical Oncology congress 2021[93]. The majority of common treatment-emergent AEs were grade 2 or lower; most common grade 3 or 4 AEs were increased levels of creatine phosphokinase in blood. Two serious AEs were reported, consisting of metabolic encephalopathy and vaginal hemorrhage and three (4%) patients discontinued treatment due to treatment-emergent AEs. The median duration of treatment in the phase 1 cohort was 10.1 months and a high ORR of 50% according to RECIST was observed. In the phase II cohort, an ORR of 42% was seen in evaluable patients. The study is still ongoing with continuing follow-up evaluation and a randomized, placebo-controlled, phase III trial evaluating the effect vimseltinib is started (MOTION-study).

3.3. Other therapeutics

3.3.1. Tumor necrosis factor-α blockage

Three studies have reported the effect of TNF-α blockade treatment, with only seven patients in total receiving this treatment [67,94,95]. Off-label intra-articular infliximab injection was administered in one patient and etanercept in six. Improvement in knee function, regression in synovial stromal fibrosis and vasculogenesis, reduction of cellularity and synovial fluid and decreased thickness were observed. On the other hand, no decrement in CSF1 protein of mRNA expression nor synovial tumor shrinkage was seen after infliximab administration. TNF-α blockade treatment affects the reactive component of TGCT but less likely the neoplastic cells. Although Fiocco et al. considered anti-TNF-α antibody injections as a possible neoadjuvant treatment before synovectomy, they concluded that TNF-α blockade alone does not seem to lead to stable remission of D-TGCT and is ineffective in blocking CSF1 secretion[67].

3.3.2. Bevacizumab

Among other activators such as hypoxic stress, CSF1 is also reported to induce angiogenesis via vascular endothelial growth factor (VEGF) expression in monocytes, essential for tumorigenesis [68,96]. Bevacizumab is a humanized monoclonal VEGF antibody and thus inhibits angiogenesis. Nissen et al. investigated the effect of intra-articular injections with bevacizumab as adjuvant therapy after arthroscopic synovectomy in one patient with relapsing D-TGCT located in the knee[97]. During follow-up, complete response was observed, and the patient reported no symptoms nor adverse events (AEs). However, dosage and number of injections and total follow-up duration were not described. Additionally, the effect of synovectomy prior to bevacizumab is unknown. To our knowledge, this is the only report regarding bevacizumab applied for TGCT.

3.4. Preliminary results of other therapeutics

3.4.1. Zaltoprofen

Based on the approaches with zaltoprofen in rheumatoid arthritis and targeted therapy activating PPARγ in other types of cancer, the anti-tumor effect of zaltoprofen was investigated on primary cultured TGCT cells[98]. Zaltoprofen, a non-steroidal anti-inflammatory drug (NSAID), was found to inhibit cell proliferation via activation of PPARγ. Subsequently, a pilot study of zaltoprofen in D-TGCT affecting the knee and ankle joints was conducted, including ten patients. Oral zaltoprofen was given daily for 48 weeks or until disease progression. At 48 weeks, eight patients had stable disease, and one patient showed progressive disease at 72 weeks. Zaltoprofen was well-tolerated. With the results of this pilot study, a study protocol of a double-blind phase II study of zaltoprofen for D-TGCT and unresectable L-TGCT was published. Results are awaited.

4. Conclusion

To date, the preferred choice of treatment for TGCT remains surgical excision. However, there is a need for other therapeutic strategies in patients where local tumor control cannot be achieved and (repeated) surgery is associated with iatrogenic morbidity. Furthermore, the role of (neo)adjuvant radiotherapy is disputed, because it is associated with unacceptable long-term side effects. A better understanding of the pathogenesis of TGCT led to opportunities for the development of medical therapies. In the last decade, new drug targets were discovered, and the efficacy and safety of several drugs have been studied. Currently, pexidartinib is the only drug approved for TGCT by the US FDA. Pexidartinib showed significant radiological and clinical efficacy, but also severe adverse events occurred, including hepatotoxicity. Therefore, active monitoring of liver functions is mandatory. Contrarily, the EMA refused marketing authorization because it was unclear how long treatment effects would last and because of an unbalanced risk/benefit ratio. More recently, new treatments are under research and recent discoveries regarding new therapeutic targets are promising for the development of drugs with even better tolerability and higher efficacy.

5. Expert opinion

Several efforts have been made during the past years to augment the treatment armamentarium for TGCT, especially for patients with relapsing or inoperable D-TGCT. Also, for orphan diseases, such as TGCT, there is a need for tailored therapy. After the discovery of the presence of CSF1 translocations in TGCT, the CSF1-CSF1R axis became the main pathway to target. Imatinib was one of the first TKIs regularly used off-label[57]. Nilotinib was assumed to have a favorable tolerability profile, especially concerning edema. However, the radiological response was inferior to imatinib and a substantial number of patients discontinued treatment[83]. With both drugs, more patients discontinued treatment without tumor progression than usually in oncology trials, which could be attributed to the nonmalignant character of TGCT and thus lower patient-acceptance rate of side-effects. Pexidartinib, another TKI, was designed to have higher selectivity against CSF1R, leading to better response[85]. Nonetheless, rare but serious liver injuries occurred in patients on pexidartinib treatment, resulting in marketing authorization refusal by the EMA. Of the reviewed therapeutic strategies, drugs targeting the CSF1/CSF1R axis showed potential in tumor size reduction and improving quality of life. However, most CSF1R inhibitors also target closely related tyrosine kinases next to CSF1, leading to off-target activity and causing an unfavorable risk-benefit ratio for a subset of patients[92]. Also, the long-term efficacy of most of the CSF1R inhibitors is still unknown to date. The evidence regarding other therapeutic strategies is limited and therefore their efficacy cannot be accurately assessed. Currently, new drugs, such as vimseltinib, are being investigated, aiming to have less interference with other tyrosine kinases than CSF1R, resulting in a more favorable safety profile[92].^{, 93} Secondly, the effect of intra-articular injections with CSF1R inhibitors is being studied, hoping to cause less systemic adverse events but having at least comparable local efficacy[99]. Finally, blockage of other targets than CSF1 or overlapping pathways may provide new solutions in the future [28,40,62,63,98].

A limitation in all studies is the lack of an appropriate method to monitor the medical treatment effect on TGCT tumor growth. TGCT treatment response is predominantly scored by RECIST, which evaluates target lesions over time by one-dimensional criteria (maximum diameter), although TGCT has an irregular shape and no clear tumor margins. TVS was explicitly developed for TGCT for volumetric quantification of tumor in relation to the maximally distended synovial cavity and is mainly used for tumor assessment in the knee[85]. Still, TVS is an unvalidated, semiquantitative scoring approach. This underlines the need for future approaches for volume measurement in TGCT.

Until now, only patients with inoperable D-TGCT or patients with expected morbidity of operative treatment qualified for TKI therapy, yet inoperable TGCT is not clearly defined. At present, multidisciplinary tumor boards are best capable of determining which patients should receive systemic treatment. Looking at the future, it would be a massive step in the tailored treatment of TGCT to identify predictive and/or prognostic markers to select patients who would benefit from specific drug agents.

Besides not knowing which patients will benefit the most, questions remain about treatment tendencies. Little is known about the optimal treatment duration or length of response. In pexidartinib, tumor response often occurred within six months after the first treatment, but even more tumor responses occurred after long-term treatment[87]. However, in a relatively young population, chronic treatment is undesirable. Emactuzumab showed durable responses despite a relatively short treatment duration, which could also be an advantage for intermittent treatment. A study to evaluate discontinuation and re-treatment with systemic therapy in patients with TGCT is now open to inclusions[100]. Finally, since complete response is not very common, perhaps studies should focus more on partial response, achieving a stable state of disease or improving QoL. Current systemic therapies target the CSF1/CSF1R axis and may not eliminate the neoplastic cells, making it impossible to achieve a true, complete response. Drug cessation is expected to result in a return of the reactive cells and subsequent lesion growth. Therefore, future studies should focus on targeting the neoplastic cell components.

Although systemic therapies are primarily used as a stand-alone treatment in patients with advanced TGCT, their role as (neo)adjuvant therapy and in an earlier stage of the disease is yet to be explored. Starting earlier with such treatment could prevent disease worsening and even secondary joint deterioration. In addition, these therapies may be used for surgical downstaging in inoperable cases or to decrease expected morbidity. However, post-hoc analysis showed no additional effect of surgery performed directly after nilotinib treatment.⁸³ Secondly, the effect of CSF1R inhibition on angiogenesis and the role of macrophages, which are essential in the postoperative course, needs to be further elucidated[60]. Besides the role as (neo)adjuvant therapy, the efficacy of CSF1R inhibitors combined with other therapies, such as anti-VEGF therapy, requires further investigation.

Medical treatment paved the way for those patients not amenable to surgery, despite the uncertainties regarding the optimal treatment. There is an unmet medical need for broader availability of TGCT related drugs, but drug approval can be challenging in rare diseases[101].

Article highlights

• TGCT is a monoarticular neoplasm driven by an overexpression of CSF1, leading to an increase in neoplastic TGCT cells and an accumulation of CSF1R presenting cells.

• TGCT is mainly treated by surgery, but achieving a cure can be challenging, requiring additional therapies for relapsing or inoperable tumors.

• Several molecular pathways have been suggested as drug targets, but the CSF1-CSF1R axis is most targeted to date.

• CSF1R inhibitors can have anti-tumor activity, but adverse events often occur.

• Only one CSF1R inhibitor is available in the US to date, but new therapies are being investigated.

• Future drug development should focus on targeting neoplastic TGCT cells.

List of abbreviations

TGCT	=	Tenosyonvial giant cell tumor
CSF1	=	Colony-stimulating factor 1
CSF1R	=	Colony-stimulating factor 1 receptor
D-TGCT	=	Diffuse-type tenosynovial giant cell tumor
L-TGCT	=	Localized-type tenosynovial giant cell tumor
PVNS	=	Pigmented villonodular synovitis
M-CSF	=	Macrophage colony-stimulating factor 1
COL6A3	=	Collagen type VI alpha-3
CBL	=	Cas-Br-Murine ecotropic retroviral transforming sequence
ALOX5AP	=	Arachidonate 5-lipoxygenase–activating protein
SSP1	=	Osteopontin
MMP	=	Matrix metalloproteinase
TP53	=	Tumor suppressor protein p53
FLS	=	Fibroblast-like synoviocytes
IL-1β	=	Interleukine-1β
TNF-α	=	Tumor necrosis factor-α
MRI	=	Magnetic resonance imaging
QoL	=	Quality of life
RSO	=	Radiosynoviorthesis
EBR	=	External beam radiotherapy
Abl	=	Abelson proto-oncogene
Bcr-Abl	=	Breakpoint cluster region-Abl
KIT	=	c-Kit proto-oncogene
PDGFR	=	Platelet-derived growth factor receptor
TKI	=	Tyrosine kinase inhibitors
JAK2	=	Janus-Kinase-2
PD-L1	=	Programmed cell death ligand 1
RANKL	=	Receptor-activator of nuclear factor kappa-B ligand
cIAP2	=	Cellular inhibitor of apoptosis 2
ARRB2	=	β-Arrestin2
VEGF	=	Vascular endothelial growth factor
AE	=	Adverse events
GIST	=	Gastrointestinal stromal tumors
ORR	=	Objective response rate
RECIST	=	Response evaluation criteria in solid tumors
IgG1	=	Immunoglobulin 1
OBD	=	Optimal biological dose
FDA	=	Food and Druga Administration
ALT	=	Alanineaminotransferase
FLT3-ITD	=	Fmls-like tyrosine kinase 3 internal tandem duplication
AST	=	Aspartate aminotransferase level
TVS	=	Tumor volume score
REMS	=	Risk evaluation management system
PPARγ	=	Proliferator-activated receptor gamma
NSAID	=	Non-steroidal anti-inflammatory drugs
EMA	=	European Medicines Agency

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

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