Diffuse tenossinovial giant cell tumor: A systematic review on management and treatment strategies

Carlota Espregueira Mendes; Gonçalo Vieira da Silva; Francisco Serra; Érica Marto; João Nelas; Manuel Carrapatoso; Pedro Cardoso; Vânia Oliveira

doi:10.1016/j.jorep.2025.100761

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Review Article

2026

:5;

100761

doi:

10.1016/j.jorep.2025.100761

Diffuse tenossinovial giant cell tumor: A systematic review on management and treatment strategies

Carlota Espregueira Mendes^a,, Gonçalo Vieira da Silva^b, Francisco Serra^b, Érica Marto^b, João Nelas^b, Manuel Carrapatoso^b, Pedro Cardoso^a,b, Vânia Oliveira^a,b

a ICBAS - School of Medical and Biomedical Sciences, Universidade do Porto, Portugal

b Department of Orthopaedics, Centro Hospitalar e Universitário de Santo António, Portugal

⁎Corresponding author: Carlota Espregueira Mendes. u09938@chporto.min-saude.pt

Received: 2025-6-28, Accepted: 2025-8-4, Published: 2025-8-8

The Authors

Disclaimer:
This article was originally published by Reed Elsevier India Pvt. Ltd. and was migrated to Scientific Scholar after the change of Publisher.

Abstract

Diffuse-type tenosynovial giant cell tumor (D-TGCT) is a rare and benign tumor that originates in the synovial lining of joints, tendon sheaths, or bursae. Despite being benign, it is associated with locally aggressive behavior and high risk of recurrence, leading to pain, swelling and significant functional impairment. Several treatment options exist, but there is still no clear consensus on the most effective approach, particularly for recurrent or inoperable cases.

This systematic review explores current evidence on the management of D-TGCT, focusing on treatment strategies, recurrence rates, and outcomes, while also discussing new therapeutic alternatives. By bringing together all recent advances, this review aims to help clinicians make informed and patient-tailored decisions when managing this tumor.

A systematic search was conducted in PubMed, Scopus, and Web of Science, including studies published between 2000 and January 2025. Original articles reporting treatment outcomes in patients with D-TGCT were selected. To ensure accuracy and reduce bias, two reviewers independently selected studies and extracted relevant data. The methodological quality of the included studies was assessed using the JBI Critical Appraisal Checklist for Cohort Studies. Due to the heterogeneity across study methodologies and outcomes, a narrative synthesis was considered the most appropriate method to summarize the results.

Fifty-two studies, including 4279 patients, were reviewed. Surgery, especially open synovectomy, remains the standard of treatment but is associated with considerably high recurrence rates. Adjuvant radiotherapy can help reduce recurrence in selected patients. In inoperable or recurrent tumors, systemic therapies, such as CSF1R inhibitors, have shown some short-term benefits. However, their toxicity and long-term effects are still unclear. For asymptomatic patients, active surveillance can be a viable option.

The management of D-TGCT requires a tailored and multidisciplinary approach, coordinated in a referral center. While treatment options have expanded over the years, there is still no standardized treatment algorithm. Therefore, further research is needed to establish clearer guidelines and treatment protocols. Multimodal strategies combining surgery, radiotherapy, and systemic therapies can offer the best outcomes particularly when individualized to the patient's condition and tumor behavior.

Abstract

Graphical abstract

Diffuse-type tenosynovial giant cell tumor (D-TGCT) is a benign yet aggressive synovial tumor with high recurrence rates. This systematic review analyzed 52 studies involving 4279 patients. Surgery remains the primary treatment, though recurrence is common. Radiotherapy can be beneficial as an adjuvant therapy. In recurrent or inoperable cases, CSF1R inhibitors show promise despite limited long-term data. Active surveillance is viable for asymptomatic patients. A multimodal, individualized, and multidisciplinary approach remains essential for optimizing outcomes in D-TGCT management.Image 1

1 Introduction

Giant cell tumors (GCTs) are rare, locally aggressive neoplasms that, despite their typically benign nature, significantly impact patients' function and quality of life. They are classified into two main subtypes: giant cell tumor of bone (GCTB) and tenosynovial giant cell tumor (TGCT), which differ in anatomical location, clinical presentation, and biological behavior. GCTB primarily arises in the epiphyses of long bones, particularly around the knee, and is driven by dysregulation of the RANK/RANKL/OPG pathway, leading to excessive bone resorption. In contrast, TGCT originates in the synovial lining of joints, tendon sheaths, and bursae. Although these tumors share histological features, their distinct locations and pathogenesis necessitate tailored diagnostic and therapeutic approaches.¹^,²

TGCT, formerly termed pigmented villonodular synovitis (PVNS) in its diffuse form, is a rare, proliferative synovial disease that typically affects a single joint.³ It comprises two subtypes: localized (L-TGCT) and diffuse (D-TGCT), with the latter being the focus of this review. Over the years, inconsistent terminology—such as giant cell tumor of the tendon sheath and PVNS—has caused confusion in the literature. The 2013 WHO classification standardized nomenclature to “localized-type TGCT” and “diffuse-type TGCT,” reflecting their shared histological and molecular characteristics and facilitating clearer clinical communication.¹^,³^,⁴

D-TGCT has an incidence of approximately 5 cases per million person-years. It affects adults aged 30–50, with a slight female predominance. While L-TGCT typically involves small joints of the hands and feet, D-TGCT more frequently affects large joints, particularly the knee (70 %) and hip (15 %).⁵^,⁶ Clinical manifestations are often nonspecific; joint pain is the most common symptom, but swelling, stiffness, hemarthrosis, and restricted range of motion are also reported. The disease may remain asymptomatic for extended periods, contributing to diagnostic delays. Although trauma is occasionally cited, a causal relationship remains unproven.⁶^,⁷

D-TGCT is histologically benign but demonstrates locally aggressive behavior and a high propensity for recurrence.⁸^,⁹ MRI is the diagnostic modality of choice, offering detailed visualization of characteristic features, including synovial proliferation, hemosiderin deposition, joint effusion, and bone erosions.¹⁰ Gradient-echo and contrast-enhanced sequences are particularly valuable. Nonetheless, histological confirmation via image-guided biopsy remains essential for definitive diagnosis.¹¹^,¹²

Surgical resection—typically via radical synovectomy—is the primary treatment. However, the diffuse nature of D-TGCT, its deep anatomical localization, and indistinct margins pose surgical challenges.¹³^,¹⁴ Recurrence rates remain high (23–55 %), particularly in the knee, with only ∼40 % of patients remaining recurrence-free at 10 years. Repeated surgeries increase morbidity, compromise joint function, and diminish quality of life.¹⁵ Adjuvant therapies such as radiotherapy and radiosynoviorthesis (RSO) have been explored to reduce recurrence, though concerns regarding long-term toxicity, including radiation-induced malignancy, limit their routine use.¹⁶^,¹⁷

Recent advances in understanding TGCT pathogenesis—specifically CSF1 overexpression driven by chromosomal translocations—have led to the development of targeted systemic therapies. CSF1 receptor inhibitors (e.g., pexidartinib) offer promising options for inoperable or recurrent disease but require careful risk-benefit assessment due to potential systemic toxicity.¹⁸^,¹⁹ Malignant transformation of TGCT is rare but documented, particularly in cases with longstanding disease or multiple recurrences, underscoring the need for vigilant long-term follow-up.²⁰

Despite its benign classification, TGCT imposes a substantial burden on patients and healthcare systems, driving up costs related to surgery, rehabilitation, and ongoing management. This systematic review aims to summarize current evidence on the management of D-TGCT, highlight emerging treatment modalities, and explore strategies to reduce recurrence and complications, thereby informing more standardized and effective care pathways for this challenging disease.²¹^,²²

2 Materials and methods

The research for this systematic literature review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.²³ The goal was to identify and evaluate the current evidence on the management strategies for Diffuse Tenosynovial Giant Cell Tumor (D-TGCT).

Two reviewers independently screened the abstracts, resolving discrepancies via consensus.

2.1

2.1 Eligibility criteria

We included original studies that evaluated treatment strategies or outcomes in patients diagnosed with Diffuse Tenosynovial Giant Cell Tumor. Eligible study designs included randomized controlled trials, prospective studies, cohort studies, case-control studies, and case series with more than 7 patients to gather the maximum available data. Only articles with full text available were included.

The selected studies had to meet the following criteria: published in English or Portuguese, between 2000 and January 2025 and involving adult human subjects (aged 18 years or older). The studies had to address management approaches (e.g., surgical, medical, or radiotherapeutic interventions) for D-TGCT specifically, and discuss recurrence and its management. Additionally, the tumor location had to be in the appendicular or axial skeleton (excluding tumors located in the head, face, thoracic girdle, or retroperitoneal region).

Exclusion criteria were case reports, narrative reviews, editorials, conference abstracts, descriptive only trial designs, animal studies, under 18 years old, in vitro studies, studies focusing exclusively on localized-type TGCT, and studies not reporting treatment outcomes or recurrence treatment. The exclusion of pre-2000 studies is due to non-standardized D-TGCT diagnostics before two critical advances: CSF1/CSF1R immunohistochemistry enabled reliable diagnosis, and standardized fat-suppressed, gadolinium-enhanced MRI protocols improved tumor assessment. Earlier studies used inconsistent methods, compromising data comparability.

2.2

2.2 Information sources and search strategy

A systematic search was conducted in the following databases: PubMed, Scopus, and Web of Science. The last search was made on January 10, 2025.

Ethical approval and informed patient consent was not necessary for this review as all the data included was taken exclusively from previously published, peer-reviewed studies.

The initial search was made using a combination of MeSH terms and keywords including: (“Tenosynovial giant cell tumor, diffuse type” OR “pigmented villonodular synovitis” OR “diffuse TGCT” OR “PVNS”) AND (“treatment” OR “management” OR “therapy” OR “drug therapy” OR “surgical treatment” OR “Radiotherapy” OR “tyrosine kinase inhibitors” OR “immunotherapy").

The initial search across the three selected databases resulted in 2337 articles. These results were narrowed down using a series of filters, based on the previously defined inclusion criteria: publication date between 2000 and 2025, language restricted to English and Portuguese, studies involving human subjects aged 18 years or older, and availability of abstract and full text. The number of records was reduced to 1331. A total of 1050 articles remained for screening, after removing case reports and other non-eligible study types.

To ensure reliable results, two reviewers (CEM and VO) independently screened the titles and abstracts for eligibility, resulting in the selection of 285 articles for further assessment. After removing duplicates using Mendeley reference manager, 174 articles remained. These were retrieved for full-text evaluation. Thereafter, a detailed review and application of the inclusion and exclusion criteria led to the selection of 52 studies that were included in the final qualitative synthesis.

The study selection process is detailed in a PRISMA flow diagram presented in Fig. 1 – PRISMA Flow diagram. While our review adhered to PRISMA guidelines, prospective registration (e.g., PROSPERO) was not performed. We mitigated potential bias via dual independent screening and a predefined protocol.

2.3

2.3 Quality assessment

The methodological quality of the included studies was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Cohort Studies,²⁴ which is appropriate for both prospective and retrospective observational designs. The checklist consists of 11 items assessing risk of bias across the domains of participant selection, exposure and outcome measurement, confounding factors, follow-up, and statistical analysis. The checklist application followed the 2020 JBI Manual for Evidence Synthesis.²⁵

Two reviewers independently assessed each study. Each item was rated as “Yes”, “No”, or “Unclear”. Rather than generating a numerical score, an overall judgment was made for each study. Based on the number and nature of limitations identified, studies were categorized as having low, moderate, or high risk of bias. Discrepancies between reviewers were resolved through discussion and consensus.

A summary of the risk of bias ratings is presented in Table 1: Summary of the Risk of Bias Rating Using the JBI Critical Appraisal Checklist for Cohort Studies. This quality assessment informed the interpretation of the findings but was not used as a criterion for study exclusion.

Table 1 Summary of the risk of bias rating using the JBI critical appraisal checklist for cohort studies.

Study	Q1	Q2	Q3	Q4	Q5	Q6	Q7	Q8	Q9	Q10	Q11	Overall Risk of Bias
Baniel et al. (2023)⁶⁹	N/A	Yes	Yes	Yes	No	No	Yes	Yes	Yes	N/A	No	Moderate (Y = 55 %)
Berger et al. (2007)¹⁶	N/A	Yes	Yes	Yes	No	No	Yes	Yes	Yes	Yes	No	Moderate (Y = 64 %)
Bernthal et al. (2021)²	Yes	Yes	Yes	Yes	U/C	Yes	Yes	Yes	Yes	Yes	Yes	Moderate (Y = 91 %)
Bernthal et al. (2022)⁷⁰	Yes	Yes	Yes	Yes	No	No	Yes	Yes	Yes	Yes	No	Moderate (Y = 73 %)
Brahmi et al. (2020)³⁵	N/A	Yes	Yes	Yes	No	No	Yes	Yes	Yes	Yes	No	Moderate (Y = 64 %)
Brien et al. (2004)⁷¹	N/A	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	N/A	No	Moderate (Y = 64 %)
Cao et al. (2023)²⁸	N/A	Yes	Yes	Yes	U/C	Yes	Yes	Yes	Yes	Yes	Yes	Moderate (Y = 82 %)
Capellen et al. (2018)⁷²	Yes	Yes	Yes	Yes	U/C	U/C	Yes	Yes	Yes	Yes	No	Moderate (Y = 73 %)
Cassier et al. (2015)⁵⁸	Yes	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	No	Moderate (Y = 82 %)
Chien et al. (2021)⁵⁰	Yes	Yes	Yes	Yes	Yes	U/C	Yes	Yes	Yes	Yes	No	Moderate (Y = 82 %)
Chin et al. (2002)⁵⁴	Yes	Yes	Yes	Yes	U/C	Yes	Yes	Yes	Yes	N/A	Yes	Moderate (Y = 82 %)
de Carvalho Jr. et al. (2012)⁷³	N/A	Yes	Yes	Yes	No	No	Yes	Yes	Yes	N/A	No	Moderate (Y = 55 %)
Desai et al. (2025)³⁴	Yes	Yes	Yes	Yes	No	No	Yes	Yes	Yes	Yes	No	Moderate (Y = 73 %)
Dharmani et al. (2024)⁵²	Yes	Yes	Yes	Yes	U/C	Yes	Yes	Yes	Yes	Yes	Yes	Moderate (Y = 91 %)
Dürr et al. (2019)⁷⁴	Yes	Yes	Yes	Yes	U/C	Yes	Yes	Yes	Yes	N/A	Yes	Moderate (Y = 82 %)
Elattar et al. (2020)³⁹	N/A	Yes	Yes	Yes	No	No	Yes	Yes	Yes	Yes	No	Moderate (Y = 64 %)
Gelderblom et al. (2018)³⁷	Yes	Yes	Yes	Yes	No	No	Yes	Yes	Yes	Yes	No	Moderate (Y = 73 %)
Gelderblom et al. (2021)⁴⁶	Yes	Yes	Yes	Yes	U/C	No	Yes	Yes	Yes	Yes	No	Moderate (Y = 73 %)
Gelderblom et al. (2024)⁶⁰	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Low (Y = 100 %)
Gortzak et al. (2018)⁴⁹	Yes	Yes	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	No	Moderate (Y = 82 %)
Griffin et al. (2012)¹⁵	N/A	Yes	Yes	Yes	No	No	Yes	Yes	Yes	Yes	No	Moderate (Y = 64 %)
Healey et al. (2023)³³	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Low (Y = 100 %)
Heyd et al. (2010)²⁹	N/A	Yes	Yes	Yes	U/C	Yes	Yes	Yes	Yes	Yes	Yes	Moderate (Y = 82 %)
Horoschak et al. (2009)⁷⁵	N/A	Yes	Yes	Yes	No	No	Yes	Yes	Yes	Yes	No	Moderate (Y = 64 %)
Kat et al. (2000)⁴⁸	N/A	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	N/A	Yes	Moderate (Y = 73 %)
Koca et al. (2013)⁴²	N/A	Yes	Yes	Yes	No	No	Yes	Yes	Yes	Yes	No	Moderate (Y = 64 %)
Kodiyan et al. (2017)³¹	N/A	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	N/A	No	Moderate (Y = 64 %)
Kotwal et al. (2000)⁷⁶	Yes	Yes	Yes	Yes	U/C	Yes	Yes	Yes	Yes	N/A	No	Moderate (Y = 73 %)
Lee et al. (2005)³⁰	N/A	Yes	Yes	No	No	Yes	Yes	Yes	Yes	N/A	No	Moderate (Y = 55 %)
Li et al. (2015)⁷⁷	N/A	Yes	Yes	Yes	No	No	Yes	Yes	Yes	Yes	No	Moderate (Y = 64 %)
Li et al. (2023)⁵¹	Yes	Yes	Yes	Yes	U/C	Yes	Yes	Yes	Yes	N/A	Yes	Moderate (Y = 82 %)
Lin et al. (2020)⁵⁵	N/A	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Low (Y = 91 %)
Lin et al. (2024)²⁶	Yes	Yes	U/C	Yes	U/C	Yes	Yes	U/C	Yes	Yes	Yes	Moderate (Y = 73 %)
Mastboom et al. (2019)⁷⁸	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Low (Y = 100 %)
Mollon et al. (2016)⁵³	N/A	Yes	Yes	Yes	No	No	Yes	Yes	Yes	Yes	No	Moderate (Y = 64 %)
Nassar et al. (2008)⁷⁹	N/A	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	N/A	No	Moderate (Y = 64 %)
Ottaviani et al. (2011)⁹	Yes	Yes	Yes	Yes	No	No	Yes	Yes	U/C	Yes	No	Moderate (Y = 64 %)
Palmerini et al. (2023)⁸⁰	Yes	Yes	Yes	Yes	U/C	Yes	Yes	Yes	Yes	Yes	Yes	Moderate (Y = 91 %)
Park et al. (2012)⁸¹	Yes	Yes	Yes	Yes	U/C	No	Yes	Yes	Yes	Yes	No	Moderate (Y = 73 %)
Rodriguez Blanco et al. (2001)⁵⁷	N/A	Yes	Yes	Yes	No	No	Yes	Yes	Yes	Yes	No	Moderate (Y = 64 %)
Shabat et al. (2002)⁴¹	N/A	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	N/A	No	Moderate (Y = 64 %)
Spierenburg et al. (2022)⁸²	Yes	Yes	Yes	Yes	U/C	No	Yes	Yes	Yes	Yes	No	Moderate (Y = 73 %)
Tap et al. (2015)³⁶	Yes	Yes	Yes	Yes	U/C	Yes	Yes	Yes	Yes	Yes	Yes	Moderate (Y = 91 %)
Tap et al. (2019)²⁷	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Low (Y = 100 %)
Tie et al. (2023)⁴⁰	Yes	Yes	Yes	Yes	No	No	Yes	Yes	Yes	Yes	No	Moderate (Y = 73 %)
van de Sande et al. (2021)³²	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Low (Y = 100 %)
van der Heijden et al. (2014)⁴⁴	Yes	Yes	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	No	Moderate (Y = 82 %)
van der Heijden et al. (2016)⁴⁵	Yes	U/C	U/C	Yes	Yes	Yes	Yes	Yes	U/C	Yes	Yes	Moderate (Y = 73 %)
Verspoor et al. (2019)⁵⁹	N/A	Yes	Yes	Yes	No	No	Yes	Yes	Yes	Yes	No	Moderate (Y = 64 %)
Yao et al. (2024)⁸³	Yes	Yes	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	No	Moderate (Y = 82 %)
Zhang et al. (2024)⁴⁷	Yes	Yes	Yes	Yes	U/C	U/C	Yes	Yes	Yes	Yes	No	Moderate (Y = 73 %)
Zook et al. (2011)⁴³	N/A	Yes	Yes	U/C	No	No	Yes	U/C	U/C	N/A	No	Moderate (Y = 27 %)

2.4

2.4 Data extraction and synthesis

A standardized data extraction form was used to collect information from the included studies. This process included various details, such as author, year of publication, study design, patient sample size, anatomical location of the tumor, treatment provided, local recurrence rate, recurrence's treatment, re-recurrence rate, treatment-related complications and mean follow-up time.

3 Results

A total of 52 studies published between 2000 and 2025 were included in this systematic review, encompassing 4279 patients with diffuse-type tenosynovial giant cell tumor (D-TGCT), confirmed by MRI and histopathological analysis. Both prospective (37 %) and retrospective (63 %) designs were represented. The knee was the most commonly affected joint (87 % of studies), followed by the ankle (52 %) and hip (47 %). Less frequent locations included the wrist, hand, shoulder, and spine. Follow-up duration ranged from immediate post-treatment to 528 months²⁶^,²⁷, with the longest reported in Cao et al. (2023),²⁸ which followed patients for up to 44 years.

Table II summarizes the characteristics and key findings of the included studies, detailing sample sizes, treatment modalities, recurrence rates and management strategies, complications, and follow-up duration.

Table 2 Summary of the Main Characteristics and Findings of the Studies Included in the Systematic review.

Author(s)	Year	Study Type	N	Anatomical Location	Treatment	Local recurrence (%)	Treatment of Recurrence	Re-recurrence	Complications	Follow-up Duration (months)	Others
Baniel et al.⁶⁹	2023	Retrospective	30	Knee (73%), ankle (16%), hand (10%)	Surgery followed by postoperative external beam radiotherapy (median dose 36 Gy)	0% after RT (24/30 no relapse; 6 with relapse pre-RT, all controlled)	Salvage therapy post-RT (details not specified)	0% after salvage; 100% local control at last follow-up	No radiation-induced malignancies; 86% good/excellent joint function	82 (3–211)
Berger et al.¹⁶	2007	Retrospective	7	Knee (71%), hip (14.4%), wrist (14.6)	Radical synovectomy + postoperative external beam radiotherapy (30–50 Gy)	0.0%	NA	NA	None reported; excellent tolerance to radiotherapy	29 (3–112)
Bernthal et al.⁷⁰	2022	Prospective	176	Mostly large joints: knee (68%)	Surgery only (open resection/one stage synovectomy), surgery and other treatment systemic therapy (Pexidartinib, imatinib), radiotherapy, or watchful waiting	Observed in 10/75 surgery-only, 7/53 surgery + other treatment, and 2/27 untreated patients = 10,8% total. No recurrence was observed in patients with systemic therapy only	Systemic therapy (mostly Pexidartinib or imatinib), additional surgery	Not explicitly detailed	Not mentioned	24
Bernthal et al.²	2021	Prospective	166	Knee (69%), ankle (11%), hip (7%), others (13%)	Surgery (77.1%) ± systemic therapy: imatinib or Pexidartinib (31.3%), radiation (9%)	42.80%	Repeat surgery (arthroscopic or open), some received systemic therapy or radiation	25.7% of recurrent patients had ≥2 recurrences	Not systematically reported; focus on disease burden and QoL	24
Brahmi et al.³⁵	2020	Retrospective	39	Knee (44 %), ankle (23%), foot (10%), elbow (8%), hip (5%), wrist (5%), hand (3%), finger (2%)	CSF1R inhibitors (imatinib, nilotinib, Pexidartinib, Emactuzumab)	NA	NA	NA	Not mentioned	67	Tumor progression was reported in 87%; worsening symptoms 13%; progression free 56% at 30 months; 83% who received a second line treatment received a 3rd line for a median duration of 5 months; median time to progression of 9 months, 60% progressed: 40% during treatment (imatinib & pazopanib for 1 patient each). 2 patients received 4th line (both imatinib) and one received a 5th line treatment (Sunitinib). First line treatment for a median duration of 7 months; 15 patients had recurrent disease after first line CSF1R inhibitor: 12 (80 %) received a 2nd line treatment for a median duration of 6 months and a median time to progression of 12 months. Progression-free at 30 months in 25% after line 2 and 20% after line 3.
Brien et al.⁷¹	2004	Retrospective	11	Foot and Ankle (10 ankle; 1 case in metatarsophalangeal joint)	Surgical excision, or synovectomy	63.70%	Re-excision or synovectomy ± postoperative radiotherapy (36–40 Gy)	NR	1 ankle fusion due to joint destruction; 1 transient nerve deficit; no RT-related complications	Primary lesions: 112 (36–180); Recurrent lesions: 42¹⁸–⁸¹
Cao et al.²⁸	2023	Retrospective	90	Spine	Gross total resection (81.1%) or subtotal resection (18.9%); perioperative radiotherapy (13%)	17.8% (8,2% with GTR and 58,8% with STR)	Radiotherapy or reoperation ± radiotherapy	50% of patients treated with reoperation alone	Surgical complications in 55.6% of hospital group; higher in GTR (60%) than STR (33%)	36 (3–528)
Capellen et al.⁷²	2018	Retrospective	105	Knee (55%), feet (15 %), hand (11 %), ankle (9 %), hip (4 %), elbow (2 %), sacroiliac (1 %), shoulder (1 %), others (2 %)	Open synovectomy (anterior and posterior for knee); 2 received external beam radiotherapy, 27 radiosynoviorthesis	18% (0% on those who did RT and 32% on those who did radiosynoviorthesis, 17% on those who underwent surgery)	Repeat resection	6 patients (5%) had persistent tumor at last follow-up	Femoral condyle necrosis, nerve palsy, infection, instability of the collateral ligament at the knee, 2 hematomas	71 (13–238)
Cassier et al.⁵⁸	2015	Prospective	28	Knee (52%), hip (14%), foot/ankle (28%), wrist (7%)	Emactuzumab, IV every 2 weeks	NA	NA	NA	Facial edema (64%), asthenia (56%), pruritus (56%), rash (40%); 5 serious AEs including subacute lupus, erythema and dermo-hypodermitis.	12^10–23	Objective response in 86%: partial response in 68% after 6 weeks (three cycles of treatment) Vs 7% complete response and 79% partial response.
Chien et al.⁵⁰	2021	Retrospective	24	Knee	Open or arthroscopic synovectomy ± adjuvant radiotherapy (30–40 Gy)	41.70%	Repeat surgery; 4 eventually required total knee arthroplasty	Not detailed	No significant RT-related complications	72 (24–180)
Chin et al.⁵⁴	2002	Retrospective	40	Knee	Combined anterior + posterior open synovectomy ± intra-articular (75%) or external radiotherapy (12,5%)	18 % (17% of those treated with intra-articular RT and 40% with external beam RT)	Repeat surgery + intra-articular RT; one progressed to ipsilateral hip and lung involvement	NR	Stiffness (7.5%), wound issues (10%), reflex sympathetic dystrophy (2.5%), OA leading to Total Knee replacement (2.5%)	60 (18–96)
de Carvalho et al.⁷³	2012	Prospective	8	Knee	Subtotal arthroscopic and open synovectomy + adjuvant external-beam radiotherapy	12.50%	2 reinterventions for recurrence of effusion, synovitis, and pain	Not specified	3 minor: peripatellar pain, articular effusion, persistent quadriceps atrophy	103.2 (36–168)
Desai et al.³⁴	2025	Prospective	32	Mostly lower joints (knee most common)	Pexidartinib (400, 600 or 800 mg/day), Phase 4	55% on those who discontinued Pexidartinib (at mean 22.8 months) and 0% on those who remained on treatment	Rechallenge with Pexidartinib at the dosage level at which the patient completed the prior trial (3/11)	All those who restarted Pexidartinib achieved disease stabilization	CPK increase, COVID-19, AST/ALT elevation, hypertension (66.7% in the treatment continuation and 100% in retreatment)	24	Disease progression: 55% on those who discontinued Pexidartinib (at mean 22.8 months) and 0% on those who remained on treatment/without restarting Pexidartinib; no significant decrease in EQ‐5D‐5L VAS scores from baseline; one patient had a 10‐point decrease in the PROMIS‐PF score at the 24‐month visit vs. 2 of 3 who restarted Pexidartinib due to symptomatic progression improved PROMIS‐PF or EQ‐5D‐5L VAS scores from baseline.
Dharmani et al.⁵²	2024	Retrospective	345	Not specified	82 Pexidartinib, 263 other systemic therapies: non-FDA approved agents: imatinib, nilotinib, sunitinib, sorafenib	NA	NA	NA	34.1% required dose reduction; usage limited by REMS program (hepatotoxicity concerns)	12 Pexidartinib, 10 others	Discontinued treatment anytime/Probability remaining on treatment at 12 months: Pexidartinib 40.2%/54% vs Imatinib 55. %/36.4% vs Sorafenib 57.1%/31.7% vs Sunitinib 66.7%/17.1% vs Nilotinib 87.5%/Not estimable. Restarted after discontinuation: 6.3% (Sunitinib) to 21.2% (Pexidartinib).
Dürr et al.⁷⁴	2019	Retrospective	32	Knee	Open synovectomy ± adjuvant radiosynoviorthesis (in 70,3%))	24.00%	Repeat surgery; some underwent second or third resections	11% had recurrence at final follow-up (all had RSO)	None reported; well-tolerated RSO protocol	49 (14–193)
Elattar et al.³⁹	2020	Prospective	12	Knee	Staged synovectomy (arthroscopic anterior + open posterior) + low-dose external radiotherapy (25–30 Gy)	0.00%	NA	NA	Limited range of motion and 3 mild complications: superficial wound infection, repeated effusion, transient neuropraxia	47²⁵–⁷²
Gelderblom et al.⁴⁶	2021	Prospective	130	Knee (56%), ankle (23%), hip (10%), others	Pexidartinib	12.00%	NA	NA	Hair color change (75%), fatigue (61%), nausea (47%), liver abnormalities (92% aminotransferase elevations), 3% mixed/cholestatic hepatotoxicity	39³²–⁸²	Complete or partial response 60% (95% confidence interval, 51.4%–68.0%), stable disease 20%, and progressive disease 1%./65% complete or partial TVS response/initial response at 3.4 months (range, 1.6–38.3 months) via RECIST and 2.8 months (range, 1.6–33.6 months) via TVS, with most responses 77 % within the first 6 months/41% RECIST response by 3 months, 62% by 6 months, and 92% by 18 months/TVS response 60% by 3 months, 77% by 6 months, and 98% by 12 months./RECIST complete response in 26%, 44% by 8 months 76% by 20 months 1 patient at 42 months 11% progressed on treatment, and 2% progressed after treatment, 1% underwent surgery for residual TGCT after a response to Pexidartinib therapy.
Gelderblom et al.³⁷	2018	Prospective	56	Knee (52%), ankle/foot (23%), hip (13%), wrist (4%), hand (5%), ulna (2%), other (2%)	Nilotinib (400 mg BID) for up to 1 year phase 2	NA	NA	NA	96% AEs (most common: headache, nausea and increased ALT concentrations); 11% grade 3 (dizziness, hepatic disorder, pruritius, toxidermia, diarrhea); no grade 4–5	48	Progression-free survival at 12weeks Vs. 48 months: 92.6% vs. 57·1%; after 1year treatment 30% turned operable.
Gelderblom et al.⁶⁰	2024	Prospective	123	Knee (67%), ankle (11%), hip (13%), other	83 with Vimseltinib 30 mg twice weekly vs 40 with placebo for 24 weeks (MOTION phase 3 RCT)	Not reported (40% response rate in the Vimseltinib group; 0% in the placebo group)	NA	NA	Mostly grade 1–2. Most common: periorbital edema (45%), fatigue (33%), facial edema (31%), pruritus (29%), CPK elevation (24%)	6 (Week 25 primary endpoint); extension ongoing	RECIST 40% (5% complete response vs 35% partial response) vs 0% placebo (difference 40% [95% CI 29–51]; p < 0·0001). Tumor volume score at week 25 was significantly higher in the Vimseltinib group (difference 67% [95% CI 56 to 77]; p < 0·0001) with 5% having a complete response and 63% a partial response. Vimseltinib significantly improved physical function as measured by PROMIS-PF (difference 3·3 [1·4 to 5·2]; p = 0·0007). The difference in PROMIS-PF response rate was 18% (p = 0·046). Additionally, the improvement in stiffness was significantly greater with Vimseltinib than placebo (difference −1·8 [−2·5 to −1·1]; p < 0·0001), and the difference in worst stiffness NRS response rates was 24% (8–39; nominal p = 0·0080). The least squares mean change from baseline for EQ-VAS was significantly higher with Vimseltinib than placebo (difference 7·4 [1·4 to 13·4]; p = 0·016). Although the proportion of patients who had an EQ-VAS response did not differ significantly, the result numerically favored Vimseltinib (difference 12% [−5 to 29]; nominal p = 0·16). The difference in BPI worst pain response rate for patients receiving Vimseltinib placebo was 26% (4–42; p = 0·0056).
Gortzak et al.⁴⁹	2018	Retrospective	56	Knee	Surgical synovectomy ± adjuvant 90Y radiosynovectomy	44.1% (with 90Y), 50% (without 90Y)	Further synovectomy; some received second 90Y injection	9 patients in 90Y group had third surgery; none in control group	Very low; one infection, one skin ulcer (both in non-90Y group)	87.6 (30–304)
Griffin et al.¹⁵	2012	Retrospective	50	Knee (40%), hip (8%), ankle (18 %), foot (14%), wrist (8%), hand (12%)	Surgery + external beam radiotherapy	6.00%	Excisional biopsy,² open/arthroscopic synovectomy of the knee + postoperative radiation	NR	Avascular necrosis (4 cases), osteoarthritis leading to total hip arthroplasty,² septic arthritis¹	94 (19–330)
Healey et al.³³	2023	Prospective	120	Lower extremities (92%): knee (61%), ankle (18%)	Pexidartinib (1000 mg/d/800 mg/d), randomized + open-label extension (ENLIVEN)	NA	NA	NA	Hepatotoxicity (13% discontinued), hair color changes, fatigue, nausea	12 (part 1 + part 2 combined)	Decreased in worst-weekly pain: 31% [95% CI 21%–44%] versus 15% [95% CI 8 %–27%] Placebo; Worst pain 26% [95% CI 17%–38%] for Pexidartinib versus 10% [95% CI 5%–20%] for placebo; or the MCID (≥2 points) (31%[95% CI 21%–44%] for Pexidartinib versus 14% [95 % CI 7%–25%] for placebo; (p = 0.02). Difference both groups: baseline to week 25–2.5 [95% CI -3.0 to −1.9] versus −0.3 [95% CI -0.9 to 0.3]; (p < 0.001)/change w25 to w50–3.3 6 1.7 Vs. −2.8 6 3.4 Placebo
Heyd et al.²⁹	2010	Retrospective	41	Knee (61%), ankle (19.5%), hip (7.3%), wrist (7.3%), shoulder (2.4%)	Open or arthroscopic synovectomy + postoperative radiotherapy (30–50.4 Gy; median 36 Gy)	4.90%	Radiotherapy (36.0 Gy)	NR	Mostly mild (≤RTOG Grade II); erythema (26.8%), hyperpigmentation and skin fibrosis (9.7%), 1 lymphedema	6 to >120
Horoschak et al.⁷⁵	2009	Retrospective	17	Knee (67%), ankle (17%), hand (11%), spine (6%)	Cytoreductive surgery + postoperative external beam radiotherapy (mean dose 34 Gy)	25.00%	Repeat resection; all achieved disease control	NR post-resection	No grade III/IV toxicity; no radiation-associated malignancy	46 (8–181)
Kat et al.⁴⁸	2000	Prospective	11	Knee (73%), Hip (27%)	Surgical synovectomy + radiosynovectomy (Y-90 or Re-186)	18.00%	Repeat radiosynovectomy	NR after second RS	None reported; well-tolerated	12
Koca et al.⁴²	2013	Prospective	15	Knee	Arthroscopic synovectomy ± posterior open synovectomy + adjuvant 90Y radiosynovectomy	0.00%	NA	NA	None reported; no leakage or radiation-related side effects	48 (12–86)
Kodiyan et al.³¹	2017	Retrospective	9	Knee (89%), hip (11%)	Postoperative external-beam radiotherapy or radiotherapy alone (19–45 Gy, median 36 Gy)	33.00%	Surgery (e.g., synovectomy, hip replacement); Radiotherapy	Not clearly detailed	None reported (no acute or long-term RT-related toxicity)	66 (25–312)
Kotwal et al.⁷⁶	2000	Prospective	48	Hand: 96% fingers and 4% palm	Surgical excision ± radiotherapy (29% received RT)	4% (0% in the RT group)	NR	NR	No complications from radiotherapy	52 (24–132)
Lee et al.³⁰	2005	Prospective	7	Foot and ankle	Open synovectomy + postoperative radiotherapy (35 Gy in 20 fractions)	0.00%	NA	NA	None reported	24^18–36
Li et al.⁷⁷	2015	Retrospective	28	Knee	Arthroscopic synovectomy + postoperative external beam radiotherapy (26/28 diffuse cases), 2 only surgery	7.1% (those who did not complete post- operative RT).	Repeat arthroscopic resection + post-operative radiotherapy	NR	None reported	54²⁴–⁷²
Li et al.⁵¹	2023	Retrospective	37	Hip	Total hip arthroplasty (n = 17) or Arthroscopy (n = 20)	20% (arthroscopy group only)	All required total hip arthroplasty after failed arthroscopy	NR	THA: 64.7% had ≥1 complications, 3 cases of aseptic loosening; Arthroscopy: 5 patients had complications (including necrosis, OA)	51 (24–94)
Lin et al.²⁶	2024	Retrospective	83	Knee (61%), ankle (12%), hip (12%), foot (8.4%), others	Pexidartinib (mean starting dose 622 mg/d; range 200–800 mg/d)	Not reported as recurrence rate (70.4% of the patients had previous surgery and 25.9% previous systemic therapy)	Pexidartinib	NA	Hair color change (8.4%), liver enzyme changes (6%), fatigue (6%), others mild	6 (0–12)	Stiffness 3.0 vs. 6.2 and worst pain 2.7 vs. 5.7 (p < 0.05). The majority of patients reported clinically meaningful improvement in overall symptoms and physical function during treatment with Pexidartinib.
Lin et al.⁵⁵	2020	Retrospective	48	Knee (71%), ankle (15%), hip (8%), elbow (4%), shoulder (2%)	Surgery + postoperative RT (83.3%) or definitive RT (16.7%)	14.6% (all from the Surgery + RT group)	Salvage surgery (14.3%), surgery + RT (14.3%), observation (71.4%)	Not specified	Mild RT toxicities: dermatitis (25%), joint effusion (23%), ROM decrease (4%); no surgical complications	52 (14–197)
Mastboom et al.⁷⁸	2019	Retrospective	966	Knee (64%), hip (10%), ankle (14%), foot (5%), others (7%)	Arthroscopic (14%) or open synovectomy: one (54%) or two-staged (16%), excluding prosthesis/amputation cases. 14% received adjuvant therapy	44% (34% of those who underwent open and 46% of those who underwent arthroscopic)	Re-synovectomy; some progressed to prosthesis or multiple surgeries (up to 6)	17% had ≥3 recurrences; location not specified	12% had surgical complications: joint stiffness, infections, hemorrhage, etc. (11% of the open synovectomies and 8% of the arthroscopic)	54
Mollon et al.⁵³	2016	Retrospective	15	Knee	Combined open and arthroscopic synovectomy ± postoperative radiotherapy	13.00%	Repeat synovectomy; one progressed to total knee arthroplasty	NR	Avascular necrosis,¹ lymphedema,¹ wound dehiscence¹	81
Nassar et al.⁷⁹	2009	Retrospective	12	Knee	Combined anterior and posterior open synovectomy + postoperative external beam radiotherapy (26–30 Gy)	0.00%	NA	NA	None; no infection, thrombosis, wound issues, or radiation-related complications	27^20–36
Ottaviani et al.⁹	2011	Retrospective	122	Knee (75%), ankle (16%), hip (6%), others	Surgical synovectomy ± isotopic synoviorthesis (Y-90 or Re-186) (knee:57%; other locations: 74%)	30% (knee), 9% (other locations)	Repeat surgery (some with synoviorthesis); varying approaches	33% of retreated knees recurred again	None reported with low-dose Y-90 under radioscopic control	70 (18–122)
Palmerini et al.⁸⁰	2023	Prospective	176	Knee (68%), ankle (14%), hip (10%), others (8%)	Watchful waiting (44.9%), surgery (23.9%), systemic (27.3%), radiotherapy (3.4%); future surgery (2.8%)	NA	NA	NA	NR	24	Systemic therapy at 1-year FU: BPI Pain Interference (2.79 vs. 5.93), BPI Pain Severity (3.63 vs. 6.38), Worst Pain (4.5 vs. 7.5), and Worst Stiffness (4.0 vs. 7.5)/From 1-year to 2-year FU, EQ-5D VAS scores (77.5 vs. 65.0) systemic treatment Vs. different treatment strategy
Park et al.⁸¹	2012	Retrospective	23	Knee	Synovectomy: arthroscopic (74%) or open (26%) + low-dose external beam radiotherapy (median 20 Gy)	17.00%	Salvage synovectomy in 75%; 25% refused further treatment	0% after salvage treatment	No grade ≥ III toxicity, no radiation-induced malignancy	108 (10–144)
Rodriguez Blanco et al.⁵⁷	2001	Prospective	22	Knee	Partial anterior arthroscopic synovectomy + external beam radiotherapy (26 Gy)	14.00%	Repeat anterior arthroscopic synovectomy	NR	Residual stiffness and swelling in 3 patients; no infections or thromboembolism	33²⁶–⁷⁶
Shabat et al.⁴¹	2002	Retrospective	10	Knee,⁶ ankle,³ hip¹	Debulking surgery + intra-articular yttrium-90 (15–25 mCi) injection (6–8 weeks post-op)	0.00%	NA	NA	None; no systemic leakage or adverse events related to 90Y or surgery	72 (30–144)
Spierenburg et al.⁸²	2022	Retrospective	48	Knee (48%), hip (12.5%), ankle (12.5%), foot (10.4%), ulna (2.1%), wrist (4.2%), hand (6.3 %), TMJ (2.1%)	Nilotinib (400 mg twice daily) for up to 1 year	NA	Synovectomy,¹⁹ other CSF1R inhibitors⁶	NA	No long-term adverse events reported	102 (12–129)	52% progression. Progression-free survival was 77 months. 33% clinical worsening after 11 months 58% received additional treatment, after which 41% had a second relapse. 67% with subsequent treatment (22.2 % other CSF1R inhibitors, 70% synovectomy). 64.6% were operable after systemic treatment
Tap et al.²⁷	2019	Prospective	120	Knee (61%), ankle (18%), hip (11%), wrist (3%), foot (3%), shoulder (2%), spine (2%), elbow (1%), finger (1%)	Pexidartinib 1000 mg/d loading dose/800 mg/d maintenance (ENLIVEN)	NA	NA	NA	Hair depigmentation (67%), elevated liver enzymes (AST/ALT), fatigue, dysgeusia; 13% discontinued due to AEs (mostly hepatic)	22 (0–25)	Week 25 tumor shrinkage RECIST 39 vs 0% Placebo (p < 0·0001)
Tap et al.³⁶	2015	Prospective	23	Mostly knee	PLX3397 (Pexidartinib) 1000 mg/d	NA	NA	NA	Hair color change (74%), fatigue (65%), nausea (39%), dysgeusia (26%), periorbital edema (26%); ALT/AST elevation (9%), hyponatremia (9%)	8 (0.5–19.5)	Partial overall response of 52%; 7/23 stable disease; disease control (complete, partial or stable response) of 83% (95% CI, 67 to 98) median 8 months; reduction in tumor volume of 50% or more in 11/14 patients.
Tie et al.⁴⁰	2023	Retrospective	18	Knee	Complete arthroscopic synovectomy + low-dose external radiotherapy (20 Gy)	0.00%	NA	NA	None during or after surgery or radiotherapy	68 (35–120)
Van de Sande et al.³²	2021	Prospective	120	Lower extremities (92%): knee (61%), ankle (18%)	Pexidartinib (1000 mg/d/800 mg/d); randomized placebo-controlled phase III (ENLIVEN)	NA	NA	NA	Hepatotoxicity (7%); overall AE-related discontinuation 13%	25 (part 1 + part 2 open-label extension)	w25: PROMIS-PF: 3.5 (CI 1.3–5.8) vs. −0.9 (CI −3.0 to 1.3) Placebo; Stiffness: −2.2 (CI −2.8 to −1.6) vs. −0.3 (CI −0.9 to 0.4) Placebo/w25 to w50 improvement: PROMIS-PF: 5.8 (CI 4.1–7.5); stiffness −3.1 (CI −3.9 to −2.3)/PROMIS-PF improvement after w25 correlated with reduction of tumor size (RECIST 1.1) (r = −0.5, p = 0.0008)
van der Heijden et al.⁴⁵	2016	Retrospective	272	Knee (73%), hip (9%), ankle (11.5%), others	Arthroscopic synovectomy (43.4%), open (35.7%), combined (3.7%), others/unknown (17.3%)	58% (arthroscopic), 36% (open), 50% (combined)	Open or arthroscopic re-synovectomy, total knee or hip arthroplasty. Adjuvant therapy with radiation, radioactive colloid instillation with Yttrium, CSFR targeted tyrosine kinase inhibitor, cryosurgery or methotrexate	Not detailed	Not systematically reported	70 (12–374)
van der Heijden et al.⁴⁴	2014	Retrospective	30	Knee	Arthroscopic synovectomy (53%) or open synovectomy (47%)	93% arthroscopic, 29% open	Multiple synovectomies (up to 9 in arthroscopic group)	7% open, 63% arthroscopic	OA in 13%, 10% needed TKR; more functional loss in arthroscopy group	64 (24–393)
Verspoor et al.⁵⁹	2019	Retrospective	58	Knee (56%), ankle (11%), hip (10%), foot (4%), shoulder (1%), elbow (1%), wrist (2%), head/neck (2%)	Imatinib mesylate (400–600 mg daily) for locally advanced or recurrent TGCT	NA	NA	NA	Edema (48%), fatigue (50%), nausea (34%), skin rash and dermatitis (12%); grade III–IV toxicities in 11% (neutropenia, acute hepatitis, facial edema, skin toxicity and fatigue)	52¹⁸–⁸³	4 presented metastatic disease and were excluded. 29% achieved complete response or partial response. One- and five-year progression-free survival rates were 71% and 48%, respectively. 66% patients discontinued Imatinib Mesylate after a median of 7 months.
Yao et al.⁸³	2024	Retrospective	178	Knee	Multiportal arthroscopic synovectomy ± posterior open synovectomy ± adjuvant radiotherapy	12% (at 5 years, Kaplan-Meier estimate)	Repeat surgery in 86% of the recurrences	Not specified	1 vascular injury (no functional loss), 8 joint stiffness, that resolved with rehabilitation	80 (26–149)
Zhang et al.⁴⁷	2024	Retrospective	33	Ankle	Multiportal arthroscopy-assisted synovectomy¹⁵ or combined with open resection¹⁸; 14/33 received postoperative radiotherapy	15.00%	Re-operation and postoperative radiotherapy	NR	None reported (no stiffness, infection, neurovascular damage)	77 (28–142)
Zook et al.⁴³	2011	Retrospective	9	Knee (88.9%), Hip (11.1%)	Surgical resection + intra-articular injection of chromic phosphate (32P)	30.00%	Repeat 32P injection in 2 patients	Not detailed	None reported	20²–⁴⁸

3.1

3.1 Treatment approach

Surgical resection was the predominant first-line treatment, reported in 36 of 52 studies (69.2 %). Among these, open synovectomy was performed in 53 % of cases, arthroscopic synovectomy in 39 %, and combined approaches in 8 %, with the choice dependent on disease extent and anatomical considerations.

Adjuvant radiotherapy—external beam radiotherapy (EBRT) or radiosynoviorthesis (RSO)—was employed in 33 studies (63 %), most often in combination with surgery (92 %), particularly for extensive or recurrent disease. Several studies (Griffin et al., 2012; Heyd et al., 2010; Lee et al., 2005)¹⁵^,²⁹^,³⁰ reported favorable outcomes with low-dose radiotherapy post-surgery. In certain cases of incomplete resection, radiotherapy alone demonstrated efficacy (Kodiyan et al., 2017).³¹

Systemic therapies, particularly colony-stimulating factor 1 receptor (CSF1R) inhibitors, were reported in 15 studies (29 %). These included pexidartinib, imatinib, sunitinib, sorafenib, emactuzumab, nilotinib, and vimseltinib. Pexidartinib was the most extensively studied, appearing in 11 studies, including the pivotal ENLIVEN trial.²⁷^,³²^,³³ Systemic therapies were typically reserved for patients with inoperable, recurrent, or high-morbidity disease.²⁷^,³²

Evidence suggests that CSF1R inhibitors provide meaningful tumor control, reducing tumor size and improving resectability and physical function. Objective tumor response rates (partial or complete) ranged from 60 % to 80 % (Desai et al., 2025; Brahmi et al., 2020; Tap et al., 2015, 2019).²⁷^,³⁴^,³⁵^,³⁶ Improvements in stiffness and physical function (PROMIS-PF and EQ-5D-5L scores) were observed in approximately 40 % of studies. Although 12-week progression-free survival (PFS) exceeded 90 %, PFS declined to 57 % at 48 months (Gelderblom et al., 2018).³⁷ Notably, systemic therapy enabled conversion of inoperable tumors to operable status in some cases (Spierenburg et al., 2022; Gelderblom et al., 2018).³⁷^,³⁸

Regarding symptomatic control, Healey et al. (2023)³³ demonstrated moderate pain reduction with pexidartinib sustained for at least 50 weeks. Thirty-one percent of treated patients achieved clinically meaningful pain improvement versus 14 % with placebo (p = 0.02). Lin et al. (2024)²⁶ similarly reported improvements in pain and stiffness. However, the role of systemic therapy in pain management remains to be fully defined due to data limitations and confounding degenerative joint disease.

Lastly, active surveillance was reported in 3 studies (6 %), reserved for asymptomatic patients with small lesions or when other treatments were contraindicated.

Among the studies using systemic therapies, 80 % administered them as monotherapy, while 20 % combined systemic therapy with surgery or radiotherapy.

3.2

3.2 Recurrences

Local recurrence was reported in 44 of 52 studies (85 %), with rates ranging from 0 % to 93 %, largely influenced by treatment strategy and adherence.

The lowest recurrence rates were associated with combined complete surgical resection and adjuvant radiotherapy. Studies by Berger et al. (2007),¹⁶ Lee et al. (2005),³⁰ Elattar et al. (2020),³⁹ Tie et al. (2013),⁴⁰ and Shabat et al. (2002)⁴¹ reported 0 % recurrence with this approach.

Among the 25 studies utilizing radiotherapy, recurrence rates were generally <20 %. EBRT was used in 19 studies and isotopic RSO in 7 (e.g., Shabat et al., 2002; Koca et al., 2013)⁴¹^,⁴². EBRT demonstrated superior outcomes, with a median recurrence rate of 9.7 % compared to 22.7 % for isotopic RSO.¹⁵^,¹⁶

Surgery alone, particularly arthroscopic synovectomy, was associated with the highest recurrence rates (13.3 %–93 %). Van der Heijden et al. (2014)⁴⁴ reported a 93 % recurrence following arthroscopic treatment versus 29 % for open synovectomy. Similarly, van der Heijden et al. (2016)⁴⁵ observed a 58 % recurrence with arthroscopy compared to 36 % with open surgery.

For systemic therapies, recurrence and progression were closely tied to treatment duration. Desai et al. (2025)³⁴ found that 55 % of patients experienced progression after discontinuing pexidartinib, whereas continuous therapy maintained disease control. Conversely, Brahmi et al. (2020)³⁵ reported high progression rates (87 %) after treatment with various CSF1R inhibitors. Progression-free survival decreased significantly with each subsequent line of therapy. In contrast, Gelderblom et al. (2021)⁴⁶ observed a 60 % objective response and stable disease in 20 %, with progression occurring in 1 % of patients.

Studies by Tap et al. (2015, 2019)²⁷^,³⁶ and van de Sande et al. (2021)³² reported functional improvements paralleling tumor shrinkage, particularly in stiffness and physical function scores.

3.3

3.3 Management of recurrence

Local recurrences were commonly managed with repeat synovectomy (reported in 48.6 % of studies), frequently combined with adjuvant radiotherapy. Griffin et al. (2012)¹⁵ and Zhang et al. (2024)⁴⁷ demonstrated effective recurrence control using repeat surgery followed by radiotherapy. Patients initially treated arthroscopically often required multiple surgeries; van der Heijden et al. (2014)⁴⁴ reported patients undergoing up to nine procedures.

In a minority of studies (11.4 %), recurrences were treated with radiotherapy alone. Heyd et al. (2010),²⁹ Zook et al. (2011),⁴³ Kat et al. (2000),⁴⁸ and Gortzak et al. (2018)⁴⁹ reported favorable outcomes using either EBRT or RSO as salvage therapy.

Patients receiving systemic therapy for recurrence exhibited lower progression rates. Desai et al. (2025)³⁴ reported that re-challenging with pexidartinib after progression restored disease control in all treated patients, with associated improvements in function and quality of life. No new safety concerns were identified during rechallenge.

In cases of advanced joint destruction or repeated treatment failure, total joint arthroplasty was often required.⁵⁰ Li et al. (2023)⁵¹ reported total hip arthroplasty in all patients with recurrence following failed arthroscopic intervention. Such interventions are typically reserved for patients with severe joint damage.

3.4

3.4 Re-recurrence

Re-recurrence (second recurrence following treatment of initial recurrence) was reported in 9 studies (17.3 %), predominantly in patients treated with surgery alone. Cao et al. (2023)²⁸ reported a 50 % re-recurrence rate with reoperation alone, while Ottaviani et al. (2011)⁹ reported 33 % in re-treated knees. Van der Heijden et al. (2014)⁴⁴ noted significantly higher re-recurrence following repeat arthroscopic synovectomy (63 %) compared to open surgery (7 %).

In Gortzak et al. (2018),⁴⁹ 36 % of patients treated with RSO required a third surgical intervention. Conversely, Desai et al. (2025)³⁴ found that patients re-treated with pexidartinib maintained disease control without further progression. Salvage radiotherapy also demonstrated durable control of re-recurrence in studies by Heyd et al. (2010)²⁹ and Kat et al. (2000).⁴⁸

3.5

3.5 Complications related to treatment

Complications were reported in 63 % of studies, varying by treatment modality. Systemic therapies, particularly pexidartinib, accounted for the majority of adverse events. Desai et al. (2025)³⁴ reported adverse events in 67 % of patients on continuous treatment and 100 % of those re-treated, including liver enzyme elevation, hypertension, and infections. Tap et al. (2019)²⁷ and Gelderblom et al. (2021)⁴⁶ reported hepatotoxicity (13 %), hair color changes (75 %), fatigue (61 %), and nausea (47 %). These side effects necessitated dose reductions in 34 % of patients in Dharmani et al. (2024)⁵² and required REMS monitoring for hepatotoxicity.

Surgical complications were fewer but more severe, including joint stiffness, infection, osteoarthritis, and osteonecrosis. Mollon et al. (2016)⁵³ reported avascular necrosis, lymphedema, and wound dehiscence. Chin et al. (2002)⁵⁴ observed stiffness (7.5 %), wound complications (10 %), and reflex sympathetic dystrophy (3 %). In Cao et al. (2023),²⁸ complications occurred in 56 % of patients, with higher rates following total resection (60 %) versus subtotal resection (33 %).

Radiotherapy was generally well tolerated, with mild complications such as dermatitis (25 %), joint effusion (23 %), and reduced range of motion (4 %) reported by Lin et al. (2020).⁵⁵ No cases of radiation-induced malignancy were reported. Similarly, Ottaviani et al. (2011)⁹ and Shabat et al. (2002)⁴¹ found no systemic complications with yttrium-90 RSO.

4 Discussion

This systematic review examined the management of diffuse-type tenosynovial giant cell tumor (D-TGCT), focusing on recurrence, complications, and patient outcomes. D-TGCT often presents with vague or absent symptoms, contributing to diagnostic delays and negatively impacting quality of life (QoL) and healthcare costs, especially due to repeated recurrences.⁸

4.1

4.1 Surgical treatment

Surgical resection remains the mainstay of treatment. Open synovectomy is generally associated with lower recurrence rates than arthroscopic techniques. For instance, Patel et al. (2017)¹⁴ reported recurrence rates of 44.8 % for open and 83.3 % for arthroscopic synovectomy. Similarly, van der Heijden et al. (2014)⁴⁴ recommended open surgery due to better outcomes. However, Gu et al. (2014)⁵⁶ found no significant difference between approaches. Colman et al. (2013)¹³ reported that combining open posterior and arthroscopic anterior synovectomy reduced recurrence to 9 %, compared to 62 % (arthroscopic alone) and 64 % (open alone). Nonetheless, potential selection bias related to disease severity and anatomy must be considered. Complete resection remains the key objective, irrespective of technique.

While open approaches may carry higher morbidity, especially when dual approaches are required, no randomized controlled trials (RCTs) have confirmed this conclusively. Incomplete arthroscopic synovectomy can lead to fibrous changes and reduced cell yield. Complication profiles appear similar between techniques, and outcomes may be confounded by repeated interventions.

4.2

4.2 Radiotherapy

In this review, studies combining surgery with adjuvant radiotherapy consistently reported 0 % recurrence rates, supporting a multimodal approach for high-risk or diffuse disease. Re-recurrence was more common after repeated surgeries without adjuvant therapy, whereas radiotherapy and systemic treatments provided more durable control in recurrent or inoperable cases.

External beam radiation therapy (EBRT) offered better local control than intra-articular yttrium-90 radiosynoviorthesis, which was associated with complications such as skin necrosis and chronic pain.¹⁷^,⁴⁹

4.3

4.3 Systemic therapies

Systemic therapies, especially CSF1/CSF1R inhibitors like Pexidartinib and Imatinib, are effective for inoperable or treatment-resistant cases. The ENLIVEN trial demonstrated Pexidartinib's superiority over placebo, leading to FDA approval.²⁷ However, due to hepatotoxicity risk, it is available only through a REMS program.¹⁹ Imatinib remains a category 2A recommendation in NCCN guidelines.²⁷^,⁵⁸^,⁵⁹

The optimal duration and safety of systemic therapy discontinuation remain uncertain. Desai et al. (2025)³⁴ showed that Pexidartinib discontinuation may lead to progression, but re-initiation can restore control without new safety concerns, supporting intermittent therapy strategies.

Emactuzumab, another CSF1R inhibitor, showed a 79 % partial response rate in a phase 1 trial. A reduction in CSF1R-expressing monocytes confirmed a pharmacodynamic effect. The ongoing phase 3 TANGENT trial aims to validate these results in patients unfit for surgery. Though peer-reviewed results are pending, the trial's FDA Fast Track status underscores its potential.

Emerging agents include Vimseltinib, a selective CSF1R inhibitor, and Zaltoprofen, a PPARγ-activating NSAID. Vimseltinib showed a 40 % objective response rate and improved patient-reported outcomes in the MOTION phase III trial, leading to its FDA approval in 2025.⁶⁰ Zaltoprofen has demonstrated positive outcomes and tolerability in trials, but further validation is needed.⁶¹

4.4

4.4 Local agents

For asymptomatic or stable patients, active surveillance is a viable option if consistent imaging and follow-up are ensured.¹¹ Innovative local strategies, such as intra-articular TNF-alpha inhibitors and targeted colloidal systems, are being explored for localized immunomodulation.⁶²

Radiofrequency ablation (RFA) may be useful for lesions in surgically challenging areas like the posterior knee. Although it may reduce tumor size and symptoms short term, long-term efficacy remains uncertain due to limited data. RFA risks include injury to neurovascular structures and cartilage.⁶³

4.5

4.5 Outcomes and complications

Systemic therapies can achieve partial responses, but progression remains common, highlighting the need for long-term monitoring.¹ Most recurrences occur within the first two years post-treatment, emphasizing the need for close early surveillance, especially in high-risk patients or those initially treated with arthroscopy.³

Achieving good functional outcomes is a key treatment goal. Surgery and systemic therapies can alleviate symptoms such as pain and stiffness, and improve mobility. Total knee arthroplasty (TKA) can be beneficial in advanced cases, though a history of D-TGCT increases the risk of postoperative complications. TKA is typically reserved for older patients when joint-preserving strategies fail.⁶⁴

QoL impacts must be considered when choosing treatment. Recurrences and repeated interventions can lead to joint damage and functional decline. As people remain active longer, preserving joint function is as important as preventing recurrence. Systemic agents like Pexidartinib have shown improvements in QoL metrics (e.g., PROMIS and EQ-5D), although their use may be limited by toxicity. Active surveillance can preserve QoL in asymptomatic patients but requires vigilant monitoring.²⁷

Despite effective symptom control, structural joint damage and secondary osteoarthritis are common long-term consequences, potentially requiring joint replacement.^{50,51,64–68}Although malignant transformation is rare (<0.1 % incidence), long-term follow-up is warranted. Sarcomatous change renders CSF1R inhibitors ineffective, as noted by Verspoor et al. (2019).⁵⁹

Poor prognostic factors include younger age, obesity, diffuse disease, and extensive joint involvement. Given its inflammatory and neoplastic features, TGCT may benefit from dual-pathway targeted research. For instance, Denosumab (RANK-L inhibitor) has shown limited use in bone-invasive cases, but evidence remains scarce.²⁷^,²⁸^,⁴⁴^,⁵³

Based on our findings, repeat surgery alone is often insufficient after first recurrence. Adjuvant therapies should be incorporated early, particularly in high-risk patients.³ A multidisciplinary team involving orthopedists, oncologists, radiologists, and radiation oncologists is essential. Coordinated care improves outcomes, especially when combining surgery with systemic or radiotherapeutic options.

4.6

4.6 Economic evaluation

D-TGCT imposes a substantial economic burden, driven by repeated surgeries, imaging, systemic therapies, and productivity loss due to functional limitations. Drugs like Pexidartinib also require costly safety monitoring. Cost-effectiveness studies and policies to improve access are needed, particularly in resource-limited settings.²⁷^,⁶⁷

4.7

4.7 Clinical algorithm

In conclusion, D-TGCT management should be personalized and multimodal. Open surgical excision remains the gold standard for local control, ideally combined with radiotherapy. Systemic therapies offer alternatives when surgery is not feasible. Novel agents and local interventions such as RFA or surveillance expand the therapeutic arsenal.

Close follow-up, especially in the first two years, is critical. Active surveillance may be appropriate for small, asymptomatic tumors under rigorous follow-up. Current guidelines must be updated to reflect growing evidence in favor of non-surgical approaches.

Based on our findings, we propose two clinical algorithms for managing primary and recurrent D-TGCT (Figs. 2 and 3), summarizing consistent patterns from the literature.

Proposed management approach to primary lesions of D-TGCT based on systematic review findings.

Proposed management approach to recurrences of D-TGCT based on systematic review findings.

4.8

4.8 Limitations

Limitations of this review include heterogeneity in study design, terminology, recurrence definitions, and outcome measures. Most included studies were retrospective, limiting the strength of conclusions. The lack of high-quality RCTs comparing systemic therapy versus surgery plus radiotherapy remains a significant gap.

Future research should prioritize standardized treatment protocols, development of safer systemic therapies, and identification of predictive biomarkers for treatment selection. Studies should clarify the role and timing of radiotherapy and systemic agents, as well as appropriate criteria for surveillance.

Based on this systematic review, several important questions remain unanswered, highlighting clear priorities for future research. These include reconsidering whether the current classification of TGCT as a benign tumor is still appropriate, given its clinical behavior, or if it should be reclassified as an intermediate tumor. The primary focus should be on improving diagnostic accuracy, and how to optimize treatment sequencing. Multicenter prospective trials using consistent diagnostic and outcome criteria are needed. Prognostic tools based on CSF1R rearrangements or monocyte assays could personalize therapy.

Long-term studies should assess systemic therapy duration, durability of response, and QoL impact. Economic evaluations must accompany clinical studies to ensure sustainable, equitable care delivery.

5 Conclusion

This systematic review consolidates current strategies for managing diffuse-type tenosynovial giant cell tumor (D-TGCT), a rare but locally aggressive condition. Effective management requires a multidisciplinary approach in specialized centers, integrating surgery, radiotherapy, systemic therapies, and, in selected cases, active surveillance or localized interventions.

Although open surgery combined with radiotherapy remains a cornerstone of treatment, the approach is increasingly shifting toward personalized care, based on tumor location, disease extent, and patient-specific factors. Despite recent advances, recurrence—especially after arthroscopic or incomplete resections—remains a major challenge.

For patients with inoperable tumors, high surgical risk, or recurrent disease, systemic CSF1R inhibitors offer promising results, though concerns remain regarding long-term efficacy, safety, and cost-effectiveness. Novel targeted agents and minimally invasive techniques, such as radiofrequency ablation, are expanding the therapeutic landscape.

However, the absence of standardized treatment protocols and robust comparative trials limits the ability to define optimal management pathways. Treatment decisions should balance disease control with functional preservation and quality of life.

Further research is essential to determine ideal treatment sequencing, validate predictive biomarkers, and assess long-term outcomes. Large, prospective studies and consensus guidelines will be key to delivering effective, individualized care. By synthesizing the latest evidence and highlighting ongoing uncertainties, this review aims to support informed, collaborative decision-making in D-TGCT management.

Reflecting this need for clarity, the upcoming BOOM Meeting 2026, will focus specifically on TGCT. This review aims to address unsolved issues, establish guidelines, and identify unmet clinical needs. Furthermore, it is expected to encourage collaboration in developing robust, prospective multicenter studies to resolve these critical questions.

CRediT authorship contribution statement

Carlota Espregueira Mendes: Investigation. Gonçalo Vieira da Silva: Writting, Formal analysis. Francisco Serra: Writing – original draft. Érica Marto: Software. João Nelas: Resources. Manuel Carrapatoso: Project administration. Pedro Cardoso: Writing – review & editing. Vânia Oliveira: Conceptualization, Supervision.

Ethical responsibilities

This retrospective study was approved by our institution's Ethics Committee.

Funding statement

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Show Sections

[1] Healey J.H., Bernthal N.M., van de Sande M., . Management of tenosynovial giant cell tumor: a neoplastic and inflammatory disease. J Am Acad Orthop Surg Glob Res Rev [Internet]. 2020 Nov 1;4(11)
[Google Scholar]

[2] Bernthal N.M., Spierenburg G., Healey J.H., et al . The diffuse-type tenosynovial giant cell tumor (dt-TGCT) patient journey: a prospective multicenter study. Orphanet J Rare Dis. 2021 Dec 1;16(1)
[Google Scholar]

[3] Palmerini E., Staals E.L., Maki R.G., et al . Tenosynovial giant cell tumour/pigmented villonodular synovitis: outcome of 294 patients before the era of kinase inhibitors. Eur J Cancer. 2015;51(2):210-217.
[Google Scholar]

[4] St Aubain Somerhausen N., van de Rijn M., . Tenosynovial giant cell tumour. 2020:133-136.
[Google Scholar]

[5] Spierenburg G., Suevos Ballesteros C., Stoel B.C., et al . MRI of diffuse-type tenosynovial giant cell tumour in the knee: a guide for diagnosis and treatment response assessment. Insights Imaging [Internet]. 2023 Dec 1;14(1):1-13.
[Google Scholar]

[6] Mastboom M.J.L., Verspoor F.G.M., Verschoor A.J., et al . Higher incidence rates than previously known in tenosynovial giant cell tumors: a nationwide study in the Netherlands. Acta Orthop [Internet]. 2017 Nov 2;88(6):688.
[Google Scholar]

[7] Ehrenstein V., Andersen S.L., Qazi I., et al . Tenosynovial giant cell tumor: incidence, prevalence, patient characteristics, and recurrence. A registry-based cohort study in Denmark. Journal of Rheumatology [Internet]. 2017 Oct 1;44(10):1476-1483.
[Google Scholar]

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Diffuse tenossinovial giant cell tumor: A systematic review on management and treatment strategies

Abstract

Abstract

Abstract

Graphical abstract

1 Introduction

2 Materials and methods

2.1 Eligibility criteria

2.2 Information sources and search strategy

2.3 Quality assessment

2.4 Data extraction and synthesis

3 Results

3.1 Treatment approach

3.2 Recurrences

3.3 Management of recurrence

3.4 Re-recurrence

3.5 Complications related to treatment

4 Discussion

4.1 Surgical treatment

4.2 Radiotherapy

4.3 Systemic therapies

4.4 Local agents

4.5 Outcomes and complications

4.6 Economic evaluation

4.7 Clinical algorithm

4.8 Limitations

5 Conclusion

CRediT authorship contribution statement

Ethical responsibilities

Funding statement

References

Suggested read for related articles:

We value your privacy

Diffuse tenossinovial giant cell tumor: A systematic review on management and treatment strategies

Abstract

Abstract

Abstract

Graphical abstract

1 Introduction

2 Materials and methods

2.1 Eligibility criteria

2.2 Information sources and search strategy

2.3 Quality assessment

2.4 Data extraction and synthesis

3 Results

3.1 Treatment approach

3.2 Recurrences

3.3 Management of recurrence

3.4 Re-recurrence

3.5 Complications related to treatment

4 Discussion

4.1 Surgical treatment

4.2 Radiotherapy

4.3 Systemic therapies

4.4 Local agents

4.5 Outcomes and complications

4.6 Economic evaluation

4.7 Clinical algorithm

4.8 Limitations

5 Conclusion

CRediT authorship contribution statement

Patient consent statement

Ethical responsibilities

Funding statement

References

Suggested read for related articles: