NORD gratefully acknowledges 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 (TSGCTs) 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 connect 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. Surgery is the main treatment option, but the tumor tends to recur, particularly in pigmented villonodular synovitis, which is the diffuse-type of giant cell tumor. 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.
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 giant cell tumor: giant cell tumor of the tendon sheath (GCTTS) and pigmented villonodular synovitis (PVNS). GCTTS is a localized form that can occur within the joint (intraarticular, formerly localized PVNS), or outside of the joint (extraarticular, formerly nodular tenosynovitis). Pigmented villonodular synovitis is also called diffuse-type PVNS or diffuse-type giant cell tumor.
The signs and symptoms of tenosynovial giant cell tumors (TSGCTs) can vary depending upon the exact location involved and the subtype present.
PIGMENTED VILLONODULAR SYNOVITIS (PVNS)
(also known as diffuse-type giant cell tumor; formerly, diffuse-type PVNS)
PVNS 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.
PVNS can progress to cause arthritic damage and degeneration to the joint and damage to the surrounding cartilage and bone. If untreated, PVNS 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.
GIANT CELL TUMOR OF THE TENDON SHEATH (GCTTS)
(Intraarticular GCTTS, formerly localized PVNS; Extraarticular GCTTS; formerly nodular tenosynovitis)
GCTTS 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.
Researchers have determined that a minority of the cells that make up a tenosynovial giant cell tumor (TSGCT) carry a specific chromosomal translocation. Chromosomes, which are present in the nucleus of 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. 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. They are no risk factors that have been conclusively shown to be involved with the development of these tumors.
Tenosynovial giant cell tumors mainly affect individuals between 25-40 years of age, with a median age of diagnosis of 30. However, these tumors can affect the elderly and younger children as well. There is a slight female preponderance in some studies. The incidence is estimated to be 1.8 people per 1 million people in the general population based on a study conducted in the United States in 1980.
A diagnosis of tenosynovial giant cell tumor (TSGCT) 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 from the onset of symptoms until a diagnosis is made.
Clinical Testing and Workup
X-rays can help with a diagnosis of these 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. Sometimes, these tumors can show up as soft tissue masses on x-rays. X-rays will not be effective in helping to diagnose all people 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 also 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. An MRI can reveal distinctive changes that indicate a tenosynovial giant cell tumor.
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 TSGCTs, 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.
It is important to differentiate between pigmented villonodular synovitis (diffuse-type giant cell tumor) and giant cell tumor of the tendon sheath as the prognosis and treatment of these conditions can be different.
Treatment
Surgery is the mainstay of treatment. Surgery for giant cell tumors of the tendon sheath tends to be successful with a good prognosis. However, there is a risk of recurrence. Pigmented villonodular synovitis (diffuse-type giant cell tumor) tends to get slowly worse (progressive disease) and often recurs after surgery at a higher rate. Doctors are studying medications that target the underlying defect in colony stimulating factor-1 overproduction (see Investigational Therapies below).
The specific surgical techniques a surgeon will use depend on several factors including the location and extent of the disease. TSGCT is typically treated with partial synovectomy, removing the involved area of the lining. Complete synovectomy, often with arthroscopic or open surgery, is recommended for PVNS or diffuse disease. 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 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. Sometimes, a combination of arthroscopic and open surgery may be used. In severe, resistant cases, total joint replacement has been tried.
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. Originally, external beam radiation was used in recent years, but a newer method called intraarticular radiation, or isotopic synoviorthesis, has been successfully used. The synoviorthesis-surgery sequence is more effective in joints other than the knee, where recurrence is as high as 30%. Intraarticular radiation therapy alone (radiation therapy as a primary treatment) has also been attempted. Information on radiation therapy as a primary or adjuvant therapy is limited to small, single-institution reports and, therefore, has not yet been conclusively established.
In 2019, the tyrosine kinase inhibitor pexidartinib (Turalio) 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.
Several medications have been studied as potential therapies for tenosynovial giant cell tumors (TSGCTs). As of October 2017, 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 and emactuzumab. Monoclonal antibodies are antibodies that are artificially created in a laboratory.
There have also been studies evaluating the efficacy and safety of tumor necrosis factor (TNF-) alpha blockade medications. These drugs did not reduce the tumor mass, but did stabilize inflammation and joint effusion. Since these treatments do not address the underlying CSF1 overexpression, recurrence of the tumor was common.
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
Harrison R. FDA grants orphan drug status to rare joint disease therapy. Rare Disease Report. January 12, 2016. http://www.raredr.com/news/fda-grants-orphan-drug-to-rare-joint-disease-therapy. Accessed October 23, 2017.
Physician’s Guide to Pigmented Villonodular Synovitis. National Organization for Rare Disorders website. Prepublication https://rarediseases.org/for-patients-and-families/information-resources/physician-guides/
Pigmented Villonodular Synovitis. OrthoInfo website. http://orthoinfo.aaos.org/topic.cfm?topic=a00506. Updated November 2014. Accessed October 23, 2017.
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