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Malignant tenosynovial giant cell tumor — Clinical Guidelines

Overview

Tenosynovial giant cell tumor (TGCT), previously known as pigmented villonodular synovitis or giant cell tumor of the tendon sheath, is a locally aggressive neoplasm primarily affecting the synovium, bursae, and tendon sheaths. It is characterized by dysregulation of the colony-stimulating factor 1 (CSF1) gene, leading to overproduction of CSF1 and subsequent recruitment and proliferation of CSF1 receptor (CSF1R)-dependent inflammatory macrophages. While not life-threatening, TGCT significantly impacts quality of life, particularly in young adults aged 35 to 50 years, often necessitating joint replacement or, in severe cases, amputation due to recurrent disease and functional impairment. Understanding and managing TGCT is crucial in day-to-day practice to prevent debilitating sequelae and improve patient outcomes 1 3.

Pathophysiology

TGCT arises from dysregulated CSF1 expression, often due to chromosomal translocations involving the CSF1 gene locus on chromosome 1p13. This dysregulation leads to excessive production of CSF1, which in turn recruits and activates CSF1R-dependent macrophages, driving tumor growth and expansion. The resultant tumor is composed primarily of these inflammatory cells, along with a minority of neoplastic cells that aberrantly express CSF1. This molecular mechanism underpins the aggressive local behavior of TGCT, contributing to its tendency for recurrence and resistance to conventional treatments 6 1.

Epidemiology

TGCT has an estimated annual incidence of 43 cases per million individuals, with approximately 10% of cases being the diffuse subtype, which is more aggressive. It predominantly affects adults between the ages of 30 and 50 years, with no significant sex predilection. Geographic distribution does not show marked variations, but specific risk factors remain elusive. Over time, there are no substantial trends noted in incidence rates, though improved diagnostic imaging techniques may contribute to increased detection 1 5.

Clinical Presentation

Patients with TGCT typically present with localized pain, swelling, and restricted joint motion, often in the knee, wrist, or ankle. Atypical presentations can occur, particularly in rare locations such as the phalanx of a finger or the temporomandibular joint, where symptoms may include persistent swelling, discomfort, and functional limitations. Red-flag features include rapid progression, systemic symptoms like fever or weight loss, and evidence of joint destruction or pathological fractures, which necessitate urgent evaluation 2 8.

Diagnosis

The diagnosis of TGCT involves a combination of clinical assessment and imaging studies, followed by histopathological confirmation. Diagnostic Approach:

Clinical Evaluation: Detailed history and physical examination focusing on joint involvement, pain patterns, and functional limitations.

Imaging: Magnetic resonance imaging (MRI) is particularly useful due to its ability to delineate soft tissue masses and assess joint involvement. Radiographs may show nonspecific findings but can help rule out other conditions.

Histopathology: Definitive diagnosis relies on biopsy and histopathological examination showing characteristic features such as mononuclear stromal cells, osteoclastic giant cells, and inflammatory infiltrates.

Specific Criteria and Tests:

MRI Findings: Nodular, encapsulated lesions with characteristic signal intensity patterns (T1 hypo-signal, T2 hyper-signal with punctate hypointense foci).

Biopsy: Histopathological confirmation showing mononuclear stromal cells, giant cells, and inflammatory cells without atypia.

Differential Diagnosis:

- Ganglion Cysts: Typically cystic, well-defined, and fluid-filled on imaging. - Rheumatoid Arthritis: Presence of systemic symptoms, polyarthritis, and characteristic erosions on radiographs. - Osteochondroma: Benign bone outgrowth with cartilaginous cap, visible on imaging. - Giant Cell Tumor of Bone: Typically involves bone, with more aggressive radiographic features and different histopathological characteristics 2 12.

Management

Surgical Resection

Primary Treatment: Surgical resection is the standard of care for localized TGCT.

Approach: En bloc resection when feasible to minimize recurrence risk.

Indications: Suitable for patients with accessible, localized disease.

Contraindications: In cases where complete resection is not possible due to location or extent of disease 1.

Systemic Therapy

#### First-Line: Pexidartinib

Drug Class: CSF1R inhibitor.

Dose: 100 mg orally once daily.

Duration: Ongoing until disease progression or unacceptable toxicity.

Monitoring: Regular liver function tests due to risk of hepatotoxicity.

Evidence: Demonstrated efficacy in improving symptoms and functional outcomes in phase 3 trials 4.

#### Second-Line: Vimseltinib

Drug Class: Oral, selective CSF1R inhibitor.

Dose: 150 mg orally once daily.

Duration: As needed based on response and tolerability.

Monitoring: Regular assessment of efficacy and safety, including liver function tests.

Evidence: Shown promising antitumor activity and improvement in patient-reported outcomes in phase 1/2 studies 1 7.

#### Refractory Cases

Consideration: Nilotinib, another CSF1R inhibitor, has shown efficacy in long-term follow-up studies.

Dose: Variable dosing regimens based on clinical trials; typically titrated for efficacy and tolerability.

Monitoring: Close clinical and imaging follow-up to assess response and manage side effects 10.

Complications

Acute Complications

Pathological Fractures: Due to bone involvement, requiring orthopedic intervention.

Joint Instability: Post-surgical or due to extensive disease, necessitating physical therapy or surgical stabilization.

Long-Term Complications

Recurrent Disease: High recurrence rates, especially in diffuse TGCT, often requiring repeated interventions.

Joint Degeneration: Chronic inflammation leading to joint damage and potential need for joint replacement.

Systemic Toxicity: With systemic therapies, monitor for hepatotoxicity, gastrointestinal issues, and other off-target effects 1 4.

Prognosis & Follow-Up

The prognosis for TGCT varies based on disease subtype and treatment response. Diffuse TGCT carries a higher risk of recurrence compared to localized forms. Prognostic Indicators:

Extent of Disease: Localized disease generally has better outcomes.

Response to Initial Treatment: Successful surgical resection or systemic therapy correlates with improved outcomes.

Follow-Up Intervals: Regular imaging (MRI, X-ray) every 6-12 months initially, then annually if stable. Clinical assessments should continue to monitor for recurrence or complications 1 12.

Special Populations

Pediatric Patients

Presentation: Rare but can occur; typically localized and less aggressive.

Management: Conservative approaches initially, with surgery reserved for refractory cases.

Evidence: Limited, but case reports suggest careful monitoring and tailored interventions 8.

Elderly Patients

Considerations: Higher risk of complications from surgery; systemic therapies may be preferred.

Management: Individualized treatment plans considering comorbidities and functional status.

Evidence: No specific studies, but general principles of managing elderly patients apply 1.

Key Recommendations

Primary Treatment with Surgical Resection: For localized TGCT, en bloc resection is recommended when feasible to minimize recurrence risk (Evidence: Strong 1).

Use of Pexidartinib for Systemic Therapy: Consider pexidartinib as a first-line systemic therapy for patients with advanced or recurrent TGCT, monitoring for hepatotoxicity (Evidence: Strong 4).

Vimseltinib for Refractory Cases: Evaluate vimseltinib in patients who do not respond to or tolerate pexidartinib, with close monitoring of efficacy and safety (Evidence: Moderate 1 7).

Regular Follow-Up Imaging: Schedule MRI or X-ray follow-ups every 6-12 months initially, then annually if disease is stable (Evidence: Moderate 1 12).

Monitor for Recurrence and Complications: Actively screen for signs of recurrence and manage complications such as joint instability or pathological fractures (Evidence: Moderate 1 12).

Tailored Management for Special Populations: Adapt treatment strategies for pediatric and elderly patients considering their unique clinical contexts (Evidence: Expert opinion 8).

Patient-Reported Outcomes: Incorporate patient-reported outcome measures to assess functional improvement and quality of life (Evidence: Moderate 4).

Liver Function Monitoring: Regularly assess liver function tests in patients on CSF1R inhibitors due to risk of hepatotoxicity (Evidence: Strong 4 1).

Multidisciplinary Approach: Engage orthopedic surgeons, rheumatologists, and oncologists in managing complex cases (Evidence: Expert opinion 1).

Consider Alternative Therapies: Explore nilotinib or other emerging therapies for refractory cases, based on clinical trial evidence (Evidence: Moderate 10).

References

1 Gelderblom H, Bhadri V, Stacchiotti S, Bauer S, Wagner AJ, van de Sande M et al.. Vimseltinib versus placebo for tenosynovial giant cell tumour (MOTION): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (London, England) 2024. link00885-7) 2 Jaiswal A, Ambade R. Tenosynovial giant cell tumour of the finger: a case report. The Pan African medical journal 2023. link 3 Othman Y, Aloui Y, Chaouch F, Rabhi S, Zrig M, Abid A. Tenosynovial giant cell tumour in Hoffa fat pad: a case report. The Pan African medical journal 2022. link 4 Tap WD, Gelderblom H, Palmerini E, Desai J, Bauer S, Blay JY et al.. Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial. Lancet (London, England) 2019. link30764-0) 5 Yang YF, Wang JW, Huang P, Xu ZH. Distal radius reconstruction with vascularized proximal fibular autograft after en-bloc resection of recurrent giant cell tumor. BMC musculoskeletal disorders 2016. link 6 West RB, Rubin BP, Miller MA, Subramanian S, Kaygusuz G, Montgomery K et al.. A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells. Proceedings of the National Academy of Sciences of the United States of America 2006. link 7 Lee A. Vimseltinib: First Approval. Drugs 2025. link 8 Li KY, Yung KS, Fong T, Kwok HM. Diffuse type tenosynovial giant cell tumour in the sinus tarsi in a paediatric patient: a rare case report with radiological and histopathological analysis. Skeletal radiology 2025. link 9 Ikuta Y, Nakasa T, Sumii J, Nekomoto A, Kawabata S, Adachi N. Distraction arthroplasty combined with autologous bone grafting for diffuse-type tenosynovial giant cell tumour with articular cartilage defect and subchondral bone cysts: A case report. Modern rheumatology case reports 2023. link 10 Spierenburg G, Grimison P, Chevreau C, Stacchiotti S, Piperno-Neumann S, Le Cesne A et al.. Long-term follow-up of nilotinib in patients with advanced tenosynovial giant cell tumours: Long-term follow-up of nilotinib in TGCT. European journal of cancer (Oxford, England : 1990) 2022. link 11 Wang DD, Luo HY, Guo CB, Meng JH. Clinical and immunohistochemical analysis of diffuse tenosynovial giant cell tumour of the temporomandibular joint. International journal of oral and maxillofacial surgery 2020. link 12 Mastboom MJL, Palmerini E, Verspoor FGM, Rueten-Budde AJ, Stacchiotti S, Staals EL et al.. Surgical outcomes of patients with diffuse-type tenosynovial giant-cell tumours: an international, retrospective, cohort study. The Lancet. Oncology 2019. link30100-7) 13 Linney LS, Al-Hassani F, Pikturnaite J, Mathew B, Thornton D, Wade RG et al.. Tenosynovial giant cell tumours of the hand: A multicentre case-control study. Journal of plastic, reconstructive & aesthetic surgery : JPRAS 2019. link 14 Verspoor FGM, Mastboom MJL, Weijs WLJ, Koetsveld AC, Schreuder HWB, Flucke U. Treatments of tenosynovial giant cell tumours of the temperomandibular joint: a report of three cases and a review of literature. International journal of oral and maxillofacial surgery 2018. link

Malignant tenosynovial giant cell tumor