Welcome to the NORD Physician Guide to Pigmented Villonodular Synovitis. The NORD Online Physician Guides are written for physicians by physicians with expertise on specific rare disorders. This guide was reviewed by Tom Scharschmidt, MD, FACS, MBOE, Associate Professor, Department of Orthopaedic Surgery, The Ohio State University Wexner Medical Center. (see acknowledgments for additional information).
NORD is a nonprofit organization representing all patients and families affected by rare diseases. The information NORD provides to medical professionals is intended to facilitate timely diagnosis and treatment for patients.
Pigmented villonodular synovitis (PVNS) is a rare disorder characterized by clonal neoplastic proliferation of synovial-like mononuclear cells. These cells are admixed with multi-nucleated giant cells, foam cells, siderophages, and inflammatory cells.1 Although benign, the tumor can be locally invasive. The disorder is usually slowly progressive and if, untreated, can lead to arthritic degeneration and damage to the affected joint and significant disability.2,3
PVNS mainly affects individuals between 25-40 years of age, with a median age of diagnosis of 30. However, the disorder can affect the elderly and younger children as well. There is a slight female preponderance in some studies.1
The incidence is estimated to be 1 in 1.8 million individuals based on a U.S. study in 1980.4
The vast majority of the time the disorder is monoarticular; the knee joint is most commonly affected. Polyarticular (multi-focal) involvement is very rare, but more likely in children.5
Although considered a benign disorder, PVNS can be locally aggressive with a propensity for recurrence and can become destructive and debilitating if untreated. The initial clinical presentation is typically a mono-articular joint effusion with no history of trauma or inciting event.
The mainstay and most effective treatment is complete surgical synovectomy.6 This can be performed either arthroscopically or with an open procedure depending on the extent and location of the disease. Radiation therapy is sometimes but rarely used, most often as an adjuvant treatment. Recurrence after treatment is common.7 Research is underway studying biologic drug therapy (e.g. CSF1R inhibitors) as an alternative treatment option. These medications have shown some promise in treating PVNS.8
For many years, the term pigmented villonodular synovitis has been used as a catchall for any tumor or growth with synovial or synovial-like cell involvement.5 The World Health Organization (WHO) published a classification of tumors in 2013 that classified pigmented villonodular synovitis as synonymous with diffuse-type giant cell tumor (dt-GCT). PVNS is considered a subtype of tenosynovial giant cell tumor (TSGCT).1
Sometimes, the term “localized PVNS” is used by professionals. In the WHO classification, the so-called localized form of PVNS is now called intra-articular giant cell tumor of the tendon sheath (GCTTS) or, tenosynovial giant cell tumor, localized type. Another term, nodular tenosynovitis, is now called extra-articular giant cell tumor of the tendon sheath.1,5 Intra-articular GCTTS is characterized by inflammation and overgrowth of just one area of the joint or the tendons that support the joint. Small nodular or pedunculated masses are seen on the affected area. The localized form typically affects small joints such as those of the hands and feet.3,9
The name pigmented villonodular synovitis was coined by Jaffe et al. in the 1941. This name references the macroscopic signs of pigmented color and varying degrees of villous or nodular changes in the affected joint.10
Synonyms
Pigmented villonodular synovitis (PVNS) is described as a benign tumor of the synovium. The tumors tend to involve a large area of the synovium (often more than 5 cm).1 These growths arise from the synovium, the tendon sheaths, or bursae.5 Most commonly, the knee or hips are involved. Approximately 75% of cases involve the knee. The hip is the next most common site, accounting for about 15% of cases.1 Less often, the ankle, elbow, or shoulder are affected. Although extremely rare, the temporomandibular joint or spinal facet joints can be affected.
Generally, PVNS is intra-articular. In rare cases, extra-articular disease can occur and, usually, presents as a soft tissue mass with or without the involvement of the nearby joint.6,11 The knee, thigh and feet regions are most likely to be affected. Extra-articular PVNS can involve the periarticular soft tissues or be purely intramuscular or predominantly subcutaneous.1
Multi-focal cases can occur, but are also rare. These cases are usually characterized by bilateral involvement of the same joint, most often the knee or ankle.9,12
Malignant transformation, usually sarcomatous, and subsequent metastasis has been reported, but is exceedingly rare and only a few cases have been reported.1,13-14
Symptoms are specific to the area of the body affected.6,15 There is insidious progression of pain, swelling, and stiffness in the affected joint. Sometimes, a painless swelling may be the first sign.8 Sometimes, swelling can be quite significant and dramatic in its appearance. The skin of the affected area may be warm or tender to the touch. A sensation of the joint ‘locking’ or ‘catching’ can occur, and the joint may become unstable.3,15-16 There is often inflammation and recurrent hemarthroses. If untreated, PVNS can progress to cause arthritic degeneration, damage to the surrounding cartilage and bone of the joint and considerable functional impairment.3,6,9,12 Despite treatment, PVNS often recurs. Sometimes, due to anatomic constraints, complete removal with synovectomy cannot be accomplished. These advanced cases can lead to chronic debilitating disease.17
PVNS of the temporomandibular joint is a rare occurrence and can be associated with injury of the middle cranial fossa or intracranial extension.18,19 Symptoms associated with involvement of the TMJ include pain behind the ear on the lesion side, hearing difficulty, swelling in the affected area, and facial paralysis.20
A small number of cells in PVNS have been shown to carry a specific translocation locus [t (1;2) (p13;q37)], which is associated with hyper expression of colony stimulating factor (CSF1). This translocation involves the colony stimulating factor 1 (CSF1) gene on 1p13 and the collagen type VI alpha-3 (COL6A3) gene on 2q35. The CSF1 gene is fused to the COL6A3 gene and this fusion gene results in overexpression of the colony stimulating factor 1 and appears to drive tumor growth and survival. CSF1 overexpression only occurs in neoplastic cells, which make up only a minority of the cell population of the tumor. It is believed that this overexpression leads to the recruitment of CSF1 receptor-expressing cells of the mononuclear phagocyte lineage; these cells make up the bulk of the tumor.7, 21-22 These cells also cause the inflammatory changes that characterize PVNS. This entire process is sometimes termed a “landscape effect.”7
Because inflammatory cell infiltration is a characteristic of PVNS, a significant inflammatory component of the disease is recognized.23
The medical literature is unclear as to whether there are specific risk factors for PVNS. Some studies have noted a history of trauma, or a history of orthopedic interventions in the affected joint in some patients.9,15 However, conclusive evidence of specific risk factors for PVNS is lacking or inconsistent and any associations remain controversial.8
A diagnosis of PVNS may be suspected based on characteristic signs and symptoms. Physicians will conduct a complete physical examination and a detailed patient and family history. The diagnosis is often delayed because the presentation is often vague. The delay in diagnosis can be significant; sometimes there are five to ten years between the onset of PVNS and the diagnosis and initiation of treatment.23
Physicians will order plain radiographs of the affected joint. X-rays can help to rule out other conditions. If PVNS has not caused damage to the surrounding cartilage or bone, the disorder may not show up during x-ray examination.3 Sometimes, PVNS can show up on radiographs as a soft tissue mass with homogenous uptake, with associated effusion.8-9
Advanced imaging techniques, particular magnetic resonance imaging (MRI) are essential in establishing a diagnosis and for surgical planning.9,24-25 An MRI investigation can demonstrate extensive hyperplasia of the synovium or an extensive mass and articular effusion.3,23 An MRI can also reveal destructive bone changes or damage to the cartilage.3 Giant cell tumors will also show reduced or weakened signal intensity in both T1 and T2-weighted images because of hemosiderin deposition.1,23
A sample of the fluid in the joint can be taken because the fluid may contain blood, which can support a diagnosis.3
Sometimes, a biopsy may be necessary to confirm a diagnosis.3,25
It is important to distinguish between the localized and diffuse forms because the treatments are different.2 Histologically, localized and diffuse PVNS are nearly indistinguishable, but can differ in gross appearance.5
Histopathology can be helpful in diagnosing PVNS,25 but the optimal approach has not been addressed.8 Histologic examination of affected tissue can reveal synovial hyperplasia with hemosiderin deposition and hyperpigmentation, lipid-laden macrophages (foam cells), siderophages, multinucleate giant cells, histiocytes, and xanthomatous cells.5,15,22,25
The mainstay of treatment is surgery. The specific surgical technique depends on the location and extent of the disease.6,25 Complete synovectomy, often with arthroscopic or open surgery, is recommended.7,15,26 Complete resection may not always be possible. Sometimes, a combination of arthroscopic and open surgery may be used. In severe, resistant cases, total joint replacement has been tried.8,26Joint replacement is aimed at treating the secondary degenerative changes and really does not directly address the PVNS.
Despite surgical intervention, recurrence is common with reports ranging as high as 50% in patients in whom complete resection is not achieved.7,12 Many patients experience multiple relapses and can require multiple surgeries6,26-27 and some studies have shown that recurrence rates increase and the disease becomes more difficult to treat over time.2
Repeated surgical intervention must balance removal of the diseased tissue versus functional preservation of the joint. More aggressive resections should be postponed as long as possible because of the risk of affecting quality of life.7 Cases with refractory disease or repeated occurrences that have led to osteoarthritis may require total joint replacement.26
Radiation therapy has been used as an adjunct treatment to surgery, particularly in cases where there is incomplete resection of the tumor.9 For years, external beam radiation was used, but a newer method called intra-articular radiation, or isotopic synoviorthesis, has been successfully employed.3,6,9,12 The synoviorthesis-surgery sequence is more effective in joints other than the knee, where recurrence is as high as 30%.9 Intra-articular radiation therapy alone has also been attempted.24 Data on radiation therapy as a primary or adjuvant therapy is limited to small, single-institution cases and, therefore, has not yet been conclusively established.8
A study in 2015 demonstrated that open synovectomy or synovectomy combined with perioperative radiotherapy is associated with a reduced rate of recurrence.27 Other sources have cited lower recurrence rates with arthroscopic surgery.24 And yet other studies have found no difference in recurrence rates between open and arthroscopic methods (Patel et al).
Cryosurgery has also been tried as an adjuvant therapy to surgery.28-29
Despite the treatment approach employed, complete synovectomy is the goal and the procedure most likely to accomplish the goal should be chosen.
Extra-articular PVNS is usually treated with open excision of the extra-articular diseased tissue, followed by consideration for adjuvant radiation therapy.24 PVNS of the temporomandibular joint is treated via surgery with the removal of the entire synovium because of the high risk of recurrence.19
Some researchers recommend that patients with PVNS should receive treatment at tertiary centers because of the rarity and potential destructiveness of the disease.2
There are several medications being studied for PVNS. Some of these medications are currently in clinical trials. The efficacy of these drugs must still be confirmed and the long-term therapeutic benefits established. How to best manage associated side effects also needs to be established.8,22
Information on current clinical trials is posted 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 sponsored by private sources, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
NORD does not endorse or recommend any particular studies.
Resources
National Organization for Rare Disorders (NORD)
55 Kenosia Avenue
Danbury, CT 06810
Telephone: (203) 744-0100 or (800) 999-NORD
E-mail: orphan@rarediseases.org
Web: http://www.rarediseases.org
|
NORD is grateful to the following medical expert for serving as the reviewer of this Physician Guide: Tom Scharschmidt, M.D., FACS, MBOE |
This NORD Physician Guide was made possible by an educational grant from Daiichi Sankyo.
Copyright ©2017 NORD - National Organization for Rare Disorders, Inc. All rights reserved. NORD is a registered 501(c)(3) charity organization. Please note that NORD provides this information for the benefit of the rare disease community. NORD is not a medical provider or health care facility and thus can neither diagnose any disease or disorder nor endorse or recommend any specific medical treatments. Patients must rely on the personal and individualized medical advice of their qualified health care professionals before seeking any information related to their particular diagnosis, cure or treatment of a condition or disorder.