Tenosynovial giant cell tumor (TGCT) is a non-malignant tumor involving the joint synovium, bursae, and tendon sheath. These rare tumors are sometimes referred to as giant cell tumor of the tendon sheath (GCT-TS) and/or pigmented villonodular synovitis (PVNS).[1-5]
TGCT can appear at any joint. Several studies have examined which joints are most affected and there is yet to be a consensus.[2-7] One of the more comprehensive studies was by Mastboom et al (2017) involving 4,503 cases of TGCT and they found that the majority of tumors were located locally in the digits (68%) followed by those described as localized-extremity (knee, wrist, elbow, hip, etc; 23%), and the remaining 9% were diffuse-type tumors. Within those localized-extremity and diffuse TGCTs, the most dominant joint affected was the knee (48% of localized-extremity TGCTs and 64% of diffuse TGCTs, respectively).
Even though TGCTs are not malignant, they can grow and cause damage to nearby tissue resulting in pain and movement limitations.[2-7]
In most cases, surgery is used to remove the tumor, but the exact type of surgery will be dependent on the size/position of tumor and which joint is involved. For diffuse or localized-extremity tumors, surgery may or may not be an option and other treatment options are in development that may be more applicable. Currently, no systemic treatment is approved for this rare disease.[4,5]
Recurrence rates for localized TGCT can be up to 15% following surgery. For diffuse TGCT, recurrence rates range from 20% to 50% following surgery. Unfortunately, additional surgeries can lead to significant joint damage, debilitating functional impairments, and reduced quality of life.[1,4,8-10]
Pathophysiology and Epidemiology
Overexpression of colony-stimulating factor 1 (CSF-1), as well as the recruitment and accumulation of colony-stimulating factor-1 receptor (CSF-1R) expressing cells, are associated with TGCT. This knowledge has led to a plethora of studies targeting the CSF1/CSF1R axis (e.g, cabiralizumab, imatinib, nilotinib, emactuzumab, lacnotuzumab, and pexidartinib).
The reason(s) CSF1 becomes overexpressed in these tumors is currently not known.
TGCT can occur in both sexes and begin at any age. However, initial diagnoses tend to occur in adults aged 20 – 50 years and it tends to occur more often in women. The estimated incidence is 11 to 50 cases per 1 million people.[6,7,12-14]
Recurrence rates up to 15% are reported for localized TGCT but climbs to 20% – 50% for diffuse TGCT.[1,4,8-10]
Signs and Symptoms
The majority of localized TGCTs occur in the hand and the initial symptom is usually a painless swelling near the joint. Localized TGCTs occur predominantly in the hand with approximately 85% of the tumors occuring in the digits. However, the tumors can occur at other sites, such as the knee, wrist, ankle/foot, and very rarely the elbow or the hip.[2,6]
The swelling can become painful and result in limited joint movement if the tumor is allowed to grow. Since initial symptoms are often innocuous, especially those located in the digits, it may take symptoms of pain and limited joint mobility for a person to seek a diagnosis.
Localized TGCTs may also be subdivided into localized digit tumors and localized-extremity tumors. Microscopically, localized tumors in the digits tend to be characterized as multiple, small (1 cm) nodules surrounded by a fibrous capsule. In contrast, localized-extremity TGCTs (and diffuse TGCT) are typically singular and larger (2 cm) nodules with 1 or more layers of synovial cells.
Diffuse TGCT usually affects larger joints such as the knee or hip. Like the smaller localized form, diffuse TGCT symptoms begin with swelling but in these cases, pain may also be an early symptom. Some patients also report a ‘locking’ or ‘catching’ sensation of the joint. Other joints that may be affected include the elbow, shoulder, ankle or jaw.
Since each tumor is unique, a diagnosis of TGCT usually requires radiography confirmation (most notably a MRI) to support nonspecific evidence obtained from a physical examination. An excellent review of the signs and symptoms of the different TGCT forms was recently written by Gouin and Noailles
The most common treatment is surgical removal of the tumor. Resection may be total or not, depending on the disease’s history, clinical expression, diffuse or localized presentation, and location.
Localized TGCT can usually be removed completely and is at low risk for recurrence if the entire tumor is removed. Most surgical outcomes are positive with the patient having complete or mostly complete use of the joint following surgery.
Surgery for diffuse TGCT tends to be a more complicated with recurrence rates in the 20% to 50% range. The exact surgical procedure will be highly dependent on which joint is affected and the extent of diffusion. Currently, there is no agreement on the most appropriate type of surgery to perform and each case should be evaluated individually.
Pexidartinib is a CSF1R inhibitor and the most studied drug to date for treating TGCT. On August 2, 2019, the Food and Drug Administration (FDA) approved pexidartinib (Turalio) for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Pexidartinib is the first systemic therapy approved for patients with TGCT. The FDA had granted the drug a Priority Review designation, which is given to drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications.
The approval was largely based on the safety and efficacy of pexidartinib in an international, multicenter, randomized (1:1), double-blind, placebo-controlled trial enrolling 120 patients with TGCT not amenable to surgical resection (ENLIVEN). The patients were randomized to receive pexidartinib (1000 mg/d for 2 weeks followed by 800 mg/d for 22 weeks) or placebo. The primary endpoint – overall response rate (ORR) at week 25 based upon central review of MRI scans using Response Evaluation Criteria in Solid Tumors – was met in the study with 39% of pexidartinib-treated patients having a response compared to 0% of the placebo-treated patients (P < .0001).
Regarding safety, hepatic toxicities were more frequent in pexidartinib-treated patients and 8 patients discontinued pexidartinib due to hepatic adverse events.
For a more extensive review of the different procedures used for the various TGCTs, readers are encouraged to read recent reviews by Gouin and Noailles or Noailles and colleagues. Due to the limited success that often occurs with diffuse TGCT, alternative therapies are being developed to either avoid surgery (and its obvious risks) or improve outcomes following surgery.
TGCT Can Be a Chronic Disease
Patients with recurrent TGCT will likely need ongoing care. Surgery can often be curative for patients with TGCT—especially for localized tumors. The same is not true for diffuse TGCT where recurrence can be as high as 50%.
Recurrent TGCT will likely require multiple surgeries leading to substantial morbidity of the joint, secondary osteoarthritis and possibly joint arthroplasty.[11,12,16]
Health care providers often need work across specialties to manage some recurrent, diffuse, or difficult-to-treat TGCT cases. For patients with recurrent, diffuse, or difficult-to-treat TGCT, a team-based approach to care is beneficial.
Academic centers can be a source of expertise in these tumors. Referring your patients with recurrent TGCT to a specialized oncology or sarcoma center can support their potential long-term management needs and likely improve outcomes.
Every patient with TGCT is different, and several specialists may be involved throughout the disease course, including:
- Hand surgeon, orthopedic surgeon, or sports medicine
- Medical and surgical oncologists, as well as oncology nurses
- Radiologists and pathologists
- Physical and occupational rehabilitation therapists
Radiation therapy (RT) can be used as adjuvant therapy with surgery. Evidence for its efficacy is limited but it does appear to reduce recurrence rates for patients with diffuse TGCT.
Other CSF1 Focused Treatments
Numerous drugs that can influence CSF1 have been investigated to treat TGCT, including cabiralizumab, imatinib, nilotinib, emactuzumab, lacnotuzumab, and pexidartinib.
Cabiralizumab. A phase 1/2 study testing the safety, tolerability, and pharmacokinetics of the anti-CSF1 receptor antibody cabiralizumab is currently in the planning stages but is not yet enrolling any patients. No further information is currently available at this time.
Imatinib. A proof of concept study was published in 2012 involving 29 patient with locally advanced or diffuse TGCT that were given imatinib (400 mg/day or 600 mg/day) for 4.7 to 10 months. In that study, 73% of accessible patients (16/22) showed symptomatic improvement. During the study, 15 patients discontinued treatment (6 due to treatment-related side effects, 3 due to disease progression, 4 due to surgery, 4 for personal reasons). The authors of that study concluded that “the benefits of alleviating morbidity in patients with localized PVNS/TGCTs must be balanced against the potential toxicity of chronic drug therapy.” Since that published study in 2012, no further studies have been reported.
Nilotinib. A phase 2 open-label, single-arm study was published in 2018 involving 56 TGCT patients treated with nilotinib (400 mg twice per day) and after 12 weeks, 92.6% of the patients were progression free. Regarding safety, 11% of patients reported at least 1 grade 3 level treatment-related adverse. The authors concluded that a randomized clinical is warranted.
Emactuzumab. A phase 1 study was published in 2015 testing various dosages of emactuzumab in 12 patients with locally advanced, diffuse-type TGCT. In that study, 86% of the patients achieved an objective response and 7% had a complete response. Five grade 3 level adverse events were reported. The authors also concluded that further studies are warranted.
Lacnotuzumab. A proof of concept, phase 2, randomized, double-blind, placebo-controlled study testing the safety, tolerability, and efficacy of lacnotuzumab (MCS110) was recently completed in 36 patients with TGCT (referred to as PVNS in their study). No further information is currently available at this time.
Clinical Trial Information
Please visit Clinicaltrials.gov to research clinicals trials currently underway.
The Liddy Shriver Sarcoma Initiative
The Liddy Shriver Sarcoma Initiative is an organization dedicated to improving the lives of people with sarcomas. On its website, you can find information about sarcoma diagnosis, treatment, and research. You can also search for sarcoma centers across many different countries.
National Organization for Rare Disorders (NORD)
Provides a unified voice for the 30 million people who wake up every day to fight the battle with a rare disease, including parents and caregivers.
SARC is a nonprofit organization dedicated to the development and support of research for the prevention, treatment, and cure of sarcomas. Visit the website for a list of SARC Centers, sarcoma research locations across the United States.
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