NORD gratefully acknowledges Sydney Stern, MS, PhD (c), Department of Pharmaceutical Sciences, University of Maryland Baltimore; Director of Giant Cell Tumor Programs at TGCT Support, and Tom Scharschmidt, MD, FACS, MBOE, Associate Professor, Department of Orthopaedic Surgery, The Ohio State University Wexner Medical Center; Division of Musculoskeletal Oncology, The James Cancer Hospital and Solove Research Institute; Director, Bone Tumor Clinic, Nationwide Children's Hospital, for assistance in the preparation of this report.
Summary
Tenosynovial giant cell tumors (TGCTs) are a group of rare, benign tumors that involve the synovium, bursae and tendon sheath. Synovium is the thin layer of tissue or membrane that covers the inner surface of the joint spaces and the bursae and tendon sheaths. The bursae are small fluid-filled sacs that cushion bones, tendons and muscles around the joints. A tendon sheath is a layer membrane that covers a tendon. Tendons are fibrous tissue that connects muscle to bone.
These tumors cause the affected synovium, bursae or tendon sheaths to thicken and overgrow. They are benign, which means they are not cancerous and do not spread to other areas of the body (metastasize). However, they can grow and cause damage to the surrounding tissue and structures of the body. Symptoms can include pain, swelling and limitation of movement of the joint. Large or small joints can be affected depending upon the tumor subtype. In localized TGCT, smaller joints tend to be affected, such as digits and parts of the foot. In diffuse TGCT, large joints tend to be involved, commonly the knee. Surgery is the main treatment option, but the tumor tends to recur, particularly in diffuse TGCT, which was previously known as pigmented villonodular synovitis. If untreated or if the tumor continually recurs, these tumors can result in damage and degeneration of the affected joint and surrounding tissues or structures. Sometimes, they can cause significant disability. In rare cases, amputation is required.
Introduction
The terminology used to describe these tumors in the medical literature is varied and confusing. The World Health Organization (WHO) classified these tumors in 2013. This classification defines two distinct types of tenosynovial giant cell tumor: localized and diffuse. Localized TGCT encompassed previously known giant cell tumor of the tendon sheath (GCTTS). Diffuse TGCT encompasses formerly known nodular tenosynovitis and pigmented villonodular synovitis (PVNS). Diffuse TGCT was also called diffuse-type PVNS or diffuse-type giant cell tumor.
The signs and symptoms of tenosynovial giant cell tumors (TGCTs) can vary depending upon the exact location involved and the subtype present.
Diffuse TGCT
(also known as diffuse-type giant cell tumor; formerly, PVNS)
Diffuse TGCT usually affects the large joints; the tumor is widespread (diffuse) and affects the entire joint. In most instances, only one joint is involved (monoarticular disease). The knee is most often affected, followed by the hip. The ankle, elbow or shoulder can also be affected. In rare instances, the two joints that connect the jaw bones to the skull (temporomandibular joints) or the joints that connect vertebrae together (spinal facet joints) can be affected.
The initial symptoms are usually pain and swelling of the affected joint. Stiffness of the joint can also occur. Usually, these symptoms have a gradual onset. There may be a feeling of warmth or tenderness on the skin of the affected joint. A painless swelling of the joint is sometimes the first sign. Sometimes, swelling can be significant. Affected individuals may have a sensation of the affected joint ‘locking’ or ‘catching.’ There may be a popping sound on occasion and the joint may be unstable.
Diffuse TGCT can progress to cause arthritic damage and degeneration to the joint and damage to the surrounding cartilage and bone. If untreated, diffuse TGCT can potentially cause chronic, debilitating disease and significant functional impairment of the affected joint. Surgery is the main form of treatment, but the disease often recurs.
Localized TGCT
(Intraarticular GCTTS, formerly localized PVNS; extraarticular GCTTS; formerly nodular tenosynovitis)
Localized TGCT usually presents as a small growth or mass of abnormal tissue (nodules) or as a small growth that is connect to the affected area with a stalk of abnormal tissue (pedunculated mass). These tumors are usually limited to a specific area of the joint (localized) and they typically affect smaller joints such as those of the hands and feet. The initial sign is often a painless swelling. The tumor grows slowly over time. Sometimes they cause pain. Eventually, affected individuals may have a sensation of the affected joint ‘locking’ or ‘catching.’ The affected joint may become unstable. Unlike the diffuse form, these tumors are unlikely to cause destructive changes to the joint or surrounding areas and are less likely to recur after treatment.
A minority of the cells that make up a TGCT carry a specific chromosomal translocation. Chromosomes, which are present in the nucleus of all human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
A chromosomal translocation is when a piece or region of certain chromosomes break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. In these tumors, there is a translocation involving specific regions on chromosome 1 and chromosome 2. This is written as [t (1;2) (p13;q37)]. Cells containing this translocation overproduce a type of protein called colony stimulating factor-1 or CSF-1. These cells only make up a small portion of the cells in the tumor. However, because they overproduce CSF-1, they attract other cells in the body, specifically cells that have a CSF-1 receptor. A receptor is a protein molecule on the surface of the cell that receives chemical signals from outside the cell. CSF-1 binds to a CSF-1 receptor. Cells that have CSF-1 receptors include a type of white blood cell called macrophages and several other cells. It is these other cells that make up the bulk of a tenosynovial giant cell tumor. The TGCT cells use CSF-1 to recruit the white blood cells to incorporate into the tumor. These other cells most likely cause the inflammatory changes that are associated with these tumors.
It is not known what causes the translocation involving chromosomes 1 and 2. It may occur randomly, for no apparent reason. There are no environmental, genetic, occupational, lifestyle, demographic or regional risk factors that have been conclusively shown to be involved with the development of these tumors.
Tenosynovial giant cell tumors mainly affect individuals between 25-50 years of age, with a median age of diagnosis of 40. However, these tumors can affect the elderly and younger children as well. There is a slight female preponderance in localized TGCT; however, in diffuse TGCT, there is no sex predilection. Based on a 2017 Dutch study, the global incidence has been estimated to be 43 cases of TGCT per 1 million people in the general population. For localized TGCT, 39 cases per 1 million are estimated, whereas for diffuse TGCT, 4 cases per 1 million are estimated.
A diagnosis of TGCT is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. The initial symptoms of these tumors are often vague and may go unrecognized. Consequently, there is usually a significant delay, 3-4 years on average, from the onset of symptoms until a diagnosis is made.
Clinical Testing and Workup
X-rays can help with a diagnosis of the damage resulting from the tumors. Plain x-rays, called radiographs, can help to rule out other conditions and can sometimes show damage or degeneration to the surrounding bone or cartilage. X-rays will not be effective in helping to diagnose all patients with these tumors, especially if the tumors have not caused damage to surrounding bone or cartilage.
A specialized imaging technique called magnetic resonance imaging, or MRI, is the most frequently used and this examination can be very effective in helping to diagnose these tumors. An MRI uses a magnetic field and radio waves to produce cross-sectional images of certain organs and bodily tissues. MRI can be used with and without a contrasting dye, allowing the radiologist more insight into blood vessels and other vasculature specific to the joint and tumor growth. An MRI can reveal distinctive changes that indicate a tenosynovial giant cell tumor, such as hemosiderin (iron-containing compound) deposits that become apparent on MRI.
Sometimes, doctors will take a sample of synovial fluid; this is a viscous fluid found in synovial joints that reduces friction between cartilage of the joint during movement. With TGCTs, synovial fluid is often bloody and will indicate a need for further testing. Sometimes, surgical removal and microscopic examination of affected tissue (biopsy), may be necessary to confirm a diagnosis. A biopsy allows doctors to see what kind of cells make up a tumor. However, many patients are diagnosed with MRI alone due to advancements in the imaging resolution.
It is important to differentiate between diffuse TGCT and localized TGCT as the prognosis and treatment of these conditions can be different. There is no microscopic difference between the features of these two subtypes, however, through imaging, cell behavioral changes can be identified.
Treatment
Surgery is the mainstay and frontline of treatment. However, there is no current consensus on the standard of care or the optimal surgical technique. Surgery for localized TGCT tends to be curative. However, there is a risk of recurrence around 15-30%. Diffuse TGCT tends to get slowly worse (progressive disease) and often recurs after surgery at a higher rate around 50-70%.
The specific surgical techniques a surgeon will use depend on several factors including the location and extent of the disease. TGCT is typically treated with synovectomy, removing the involved area of the lining. There is no consensus on the optimal synovectomy technique, whether arthroscopic or open surgery. Synovectomy involves the complete removal of the affected synovium (the membrane lining the inside of a joint). Completely removing the diseased synovium may not always be possible. During open surgery, a surgeon will create an incision (large opening) that allows them full access to the affected joint. This will allow the surgeon to remove the diseased tissue. Arthroscopic surgery involves creating a much smaller incision through which very small instruments are placed. These instruments include a tiny camera that allows the surgeon to see within the diseased joint and surgically remove the diseased tissue.
There have not been formal randomized studies comparing open surgery versus arthroscopic surgery. According to reports in the medical literature, some physicians have had better experiences with open surgery, while others have had better results with arthroscopic surgery. This is based on surgeon’s preference. Sometimes, a combination of arthroscopic and open surgery may be used, especially in the knee. In severe, resistant cases, total joint replacement has been tried to repair the extensive damage to the bone. However, the replacement does not address the tumor itself and is used in combination with a synovectomy to address the tumors and improve joint health.
Radiation therapy has been used as an adjunct treatment to surgery, particularly in cases where there is incomplete removal (resection) of the tumor. An adjunct therapy is one that is used alongside the main (or primary) therapy. There are two types of radiation, external beam radiation and intraarticular radiation, or isotopic synoviorthesis, which has been successfully used. Intraarticular radiation therapy alone (radiation therapy as a primary treatment) has also been attempted but has had inconclusive and variable results. Information on radiation therapy as a primary or adjuvant therapy is limited to small, poor-quality, single-institution reports and, therefore, has not yet been conclusively established. Additionally, there is a risk of secondary radiation-induced sarcoma following radiation. Due to this risk and the lack of established efficacy, radiation treatment is discouraged in young patients.
In 2019, the CSF-1 inhibitor Turalio (pexidartinib) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with symptomatic tenosynovial giant cell tumor associated with severe disease or functional limitations and not amenable to improvement with surgery. Turalio showed over 50% response in TGCT patients, 39% of TGCT patients having partial response and 18% having complete response.
Several medications have been studied as potential therapies for tenosynovial giant cell tumors (TGCTs). As of June 2021, certain medications that block the activity of the CSF1-receptor, known as CSF1R-inhbitors, are being studied for treatment of these tumors. These drugs address the underlying problem (the overexpression of colony stimulating factor 1). They have shown great promise in initial research and are being currently undergoing clinical trials to further determine their long-term safety and effectiveness. These drugs include the monoclonal antibodies cabiralizumab, known as AMB-05X in trial and the small-molecule therapy DCC-3014. Monoclonal antibodies are antibodies that are artificially created in a laboratory to target a protein of interest, such as CSF-1. Small-molecule drugs are formulated differently and can often be taken orally, like with Turalio and DCC-3014. Additionally, different routes of administration (IV vs directly into the joint, vs orally) are being tested to improve the tolerability and selectivity of the drug as well as reduce the side effects.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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INTERNET
TGCT Support. Updated June 1, 2021. https://www.tgctsupport.org/ Accesssed June 4, 2021.
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