Non-Surgical Targeted Treatments for Patients With Tenosynovial Giant Cell Tumors

Tenosynovial giant cell tumors (TGCTs) are proliferative neoplasms that typically affect the joint synovia, bursae, and tendon sheaths. Although rare and benign, the clinical course of TGCTs is often unpredictable and marked by frequent tumor recurrences and local invasiveness.¹ For patients with TGCTs, the most common symptoms are pain, swelling, stiffness, joint instability, and reduced range of motion.² 

Previously, TGCTs were classified based on their site of origin, such as giant cell tumor of tendon sheath (GCT-TS) and pigmented villonodular synovitis (PVNS).³ In 2013, the World Health Organization (WHO) proposed a new framework for classification based on the localization of the tumor. Localized TGCTs, previously described as giant cell tumor of tendon sheath and nodular tenosynovitis, were 0.5 to 4 cm, lobulated, and well-circumscribed. Under the microscope, localized TGCTs appear as small lesions, encapsulated or pedunculated with alternating yellow and brown areas. Diffuse TGCTs, previously described as pigmented villonodular synovitis, have a multinodular and multi-colored appearance.⁴

The underlying pathophysiology for TGCTs remains poorly elucidated. However, clonal neo-plasticity, inflammation, and traumatic and metabolic pathways have all been implicated.¹ Since the symptoms of TGCTs lack specificity, the tumors are definitively diagnosed via histopathological examinations.

Generally, TGCTs are more predominant in women⁵ and present in individuals between 20 and 50 years of age.⁶ Localized TGCTs account for 80% of cases and are localized in the digits while diffuse TGCTs represent 20% of cases and are found in the larger joints (Figure 1).⁶

The earliest estimates of TGCT incidence came from a study conducted in a county in the United States and found that the incidence rate was 9.2 per million individuals for localized TGCT and 1.8 cases per million for diffuse TGCTs.⁷ However, given the rare nature of the disease and the increased likelihood of misdiagnosis, it became evident that TGCTs were being significantly underreported. A more recent study from the Netherlands places the incidence of TGCTs at a much higher rate (Figure 1).⁴

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Need for Non-Surgical Treatment Options

Currently, no consensus has been established regarding the optimal standard of care for patients with TGCTs. Surgical excision remains the gold standard treatment for both localized and diffuse TGCTs.^8-10

Although the form of surgery is determined based on tumor subtype, location, the skill of the surgeon, and therapeutic availability, most patients are treated with arthroscopic or open surgical excision with partial or extensive synovectomy.⁵

Patient outcomes following surgery vary based on location and progression of the disease, but all forms of surgery have been associated with a high rate of tumor recurrence, particularly in the case of diffuse TGCTs. Furthermore, 59% of patients treated with respective surgery show little improvement in pain.¹¹ Frequent recurrences, especially with diffuse TGCTs of the foot and ankle, are also a concern.¹⁰ Given these considerations associated with surgery, alternative treatment modalities such as radiation has been explored as an adjuvant therapeutic in the treatment of TGCTs.

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Radiosynoviorthesis

Radiosynoviorthesis (RSO) or radiosynovectomy involves the intraarticular injection of radioactive isotopes, facilitating the renewal or reconstruction of the articular mucosa or synovitis. Radionuclides, particularly β emitters, such as yttrium-90, phosphorous-32, rhenium-186, or erbium-169, are directly injected into a joint where they penetrate a few millimeters into the joint tissue. The success rate of RSO ranges from 65% to 80%.¹²

Since the recurrence rate for diffuse TGCTs treated with surgery is between 9% and 70%, RSO may prove beneficial as an adjuvant therapy to surgery in the management of diffuse TGCTs. Studies have shown that the rate of recurrence is much lower when radiotherapy is added to the treatment regimen.¹³ The use of RSO is also indicated in the case of inoperable tumors or when only partial synovectomy is possible surgically.⁵ 

There is no evidence for radiation-induced malignancy, but general radiation safety considerations are warranted. Rare but serious side complications include necroses, thrombosis, joint infections, and injection site drainage leading to chronic pain.^14,15

Although RSO is effective in the treatment of TGCT, surgery still remains the gold standard of treatment.¹⁶

Some studies suggest that RSO can reduce recurrence rates associated with diffuse TGCTs of the ankle.¹⁷ In contrast, other studies show similar rates of recurrence in patients with diffuse TGCTs treated with or without RSO. Patient-reported outcomes and health-related quality of life indicators demonstrate high variability between patients treated with RSO. The benefits of adjuvant treatment have been inconclusive.¹³

External Beam Radiotherapy

External beam radiotherapy (EBRT) involves targeted high-energy irradiation of tumor tissue and has been explored as an adjuvant therapy for the treatment of TGCTs.¹⁸ There is mounting evidence that the rate of recurrence is much lower in patients who receive adjuvant EBRT compared with patients who underwent surgery alone.¹⁹

More recently, rapid technological advances have enabled the targeted and safe delivery of radiation with minimal damage to surrounding soft tissue. As a result, EBRT and RSO have been used either as self-standing agents or in combination in the treatment of recurrent diffuse and symptomatic localized TGCTs.⁹

Drug Therapies and Colony Stimulating Factor 1 as a Target

The development of TGCTs was previously considered an inflammatory reactive process. However, both cytogenetic and cellular studies have established the role the overproduction of colony stimulating factor 1 (CSF-1) plays in the development of neoplasticism in TGCTs. A few cells in TGCTs contain chromosomal translocations in t(1;2) COL6A3-CSF1. The resulting fusion protein leads to the overexpression of CSF-1. In turn, this leads to the recruitment of CSF-1 receptor containing cells (macrophages, giant cells, and osteoclasts) via a paracrine loop. The tumor cells themselves also express the CSF-1 receptor, leading to the accumulation of neoplastic cells via an autocrine loop.²⁰

Systemic Therapeutic Options

Certain tyrosine kinase inhibitors (TKI; imatinib, nilotinib, pexidartinib) and antibodies (emactuzumab) inhibit CSF-1 receptors and are being explored as systemic drug therapies in the treatment of TGCTs.²¹ In a study with 39 patients with inoperable or diffuse TGCT, patients who received treatment with imatinib, nilotinib, pexidartinib, and emactuzumab did not show progression of TGCT.²²

Imatinib. Imatinib is a TKI and the first CSF-1 receptor antagonist being explored in the treatment of diffuse TGCT of the elbow. Since then, several studies have investigated the use of imatinib in diffuse TGCTs with mixed results. In 6 patients with unresectable and recurrent diffuse TGCTs, use of imatinib at a dose of 400 mg taken once daily led to improvements in pain, swelling, and joint function as well as a reduction in lesion size.²³

Emactuzumab. Emactuzumab, a recombinant monoclonal antibody inhibiting CSF-1 receptors expressed on macrophages, has been explored as an adjuvant treatment in advanced or recurrent diffuse TGCTs and inoperable tumors.²⁴ Use of emactuzumab is contraindicated in patients with autoimmune diseases due to the immunosuppressive nature of the drug. A dose of 1000 mg every 2 weeks is reported to have led to significant improvements in tumor-related outcomes and patient’s quality of life.²⁵

Nilotinib. Nilotinib is a TKI that inhibits several classes of receptors including the CSF-1 receptor. Oral nilotinib at a dose of 400 mg taken twice a day was safely tolerated in patients with advanced and inoperable diffuse TGCTs with minimal side effects. More than 90% of patients with locally advanced unresectable diffuse TGCT achieved disease control within 12 weeks of treatment.²⁶

Nilotinib may be indicated for the treatment of advanced or metastatic diffuse TGCTs, although it may be less effective than both imatinib and emactuzumab. While nilotinib has toxicity concerns, it exhibits less toxic side effects compared with imatinib. Nilotinib can be recommended for patients who are unable to continue imatinib due to intolerable complications.²⁷

Pexidartinib. Pexidartinib a small molecule TKI and has demonstrated the most efficacy in the treatment of TGCTs compared with other systemic drug therapies. Research indicates that a dose of 1000 mg taken once daily can lead to significant reductions in tumor volume within 4 months of treatment.²⁸

The ENLIVEN trial, a double-blinded, randomized phase 3 controlled trial (ClinicalTrials.gov Identifier: NCT02371369), demonstrated that pexidartinib reduced tumor volume and improved patient-reported physical function and quality of life.²⁹ The most common side effects of pexidartinib were fatigue, change in hair color, nausea, periorbital edema, and taste disorders. In rare cases, patients experienced serious and potentially fatal hepatotoxicity.²⁸ The US Food and Drug Administration (FDA) recommends pexidartinib for adult with symptomatic localized TGCTs or advanced diffuse TGCTs who do not qualify for surgical interventions.³⁰

The drug is only available in the United States through the Risk Evaluation and Mitigation Strategy (REMS) program which entails frequent monitoring and patient education. The molecule remains unavailable in Europe, as the European Medicines Agency has determined that the benefits of the drug do not outweigh potential hepatotoxicity.³¹

Immunotherapy

The presence of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) in the TGCT microenvironment has been well established. Consequently, anti-TNF-α drugs have been explored as an adjuvant therapy in the treatment of TGCTs.

Infliximab. Infliximab, an anti-TNF-α monoclonal antibody administered at a dosage of 5 mg/kg/day, has produced significant reductions in macrophages in the synovium, resulting in pain alleviation.³²

Etanercept. Intra-articular injection of etanercept has also resulted in significant reductions in pain for patients with diffuse TGCT of the knee.³² However, there is a lack of evidence conclusively demonstrating the impact of the therapy

Treatment Selection

Currently, there is no structured framework for treatment selection in TGCT because the efficacy of different therapies varies on a case-by-case basis depending on factors such as the location of the tumor, degree of progression, tumor subtype, and presence of preexisting conditions. Ultimately, physicians must balance the potential benefits of each therapy with potential toxicity, risk of reoccurrence, and disease progression (Table).^{1,22,23,26,28,33,34}

While a multidisciplinary therapeutic approach may benefit patients the most, it is also vital to establish a thorough follow-up regimen consisting of imaging and clinical examinations to ensure early detection and management of recurrences.

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Posted by Haymarket’s Clinical Content Hub. The editorial staff of Hematology Advisor had no role in this content’s preparation.

Reviewed May 2022