➢ Evidence now exists suggesting a neoplastic origin for pigmented villonodular synovitis, including a thorough description of the translocations involved.
➢ Arthroscopic excision for localized pigmented villonodular synovitis allows for both minimal recurrence and morbidity when compared with open excision; however, open excision still plays an important role in treating posterior compartment nodules.
➢ The optimal surgical treatment for diffuse pigmented villonodular synovitis is still a matter for debate, with combined anterior arthroscopic and open posterior excision being considered the preferred method.
➢ Radiation therapy has re-emerged as an additional treatment method for pigmented villonodular synovitis; however, the potential for serious toxicity makes it a questionable option, especially for such a benign condition.
➢ Small molecule and monoclonal antibody targeted therapies are being investigated as novel treatment methods for pigmented villonodular synovitis, with promising results.
Pigmented villonodular synovitis is a rare benign proliferative disease of the synovial joint, synovial bursa, and tendon sheath. Pigmented villonodular synovitis is typically found as a monoarticular process, with the knee joint being involved most often, followed by the hip, ankle, shoulder, and elbow1,2. This condition most commonly presents in individuals between the ages of 30 and 40 years. Pigmented villonodular synovitis has an estimated incidence of 2 to 8 cases per million per year in the general population, and although some authors have reported male predominance, other authors have reported no difference between sexes3-7. No current data exist about the incidence in children, but it is estimated to be substantially lower than in the general population.
The first documented case of pigmented villonodular synovitis was believed to be in 1852, when Chassaignac8 reported lesions in the flexor tendon sheaths of the fingers. In 1941, Jaffe et al.1 established the current terminology of “pigmented villonodular synovitis,” which was then further expanded by Granowitz and Mankin9 to define the localized and diffuse forms. Currently, a localized type and a diffuse type are recognized. In 2007, Rubin10 suggested that localized pigmented villonodular synovitis and tenosynovial giant cell tumor, a benign soft-tissue tumor of tendon sheaths, be unified in diagnosis and terminology, as both were found to be histologically identical with similar pathogenesis. Currently, localized pigmented villonodular synovitis and tenosynovial giant cell tumor are interchangeably used in the literature. Although the tenosynovial giant cell tumor is found in the extra-articular synovial tissues, such as the tendon sheaths, localized pigmented villonodular synovitis exists as an intra-articular process. Localized pigmented villonodular synovitis and diffuse pigmented villonodular synovitis behave and appear differently, and therefore it is an important distinction to make.
For many years, the treatment for localized and diffuse pigmented villonodular synovitis was surgical excision. However, as we have gained further understanding of the clinical behavior of this tumor, especially the diffuse type, the effects of different types of treatment, and a potential new genetic etiology for this tumor, treatment options have become more sophisticated. This review will focus on providing updated information with regard to the etiology of both types of pigmented villonodular synovitis and new diagnostic and treatment modalities, as well as suggesting a treatment algorithm.
Pigmented villonodular synovitis was historically considered to be an inflammatory process, but there is recent evidence in the literature to suggest a neoplastic origin. In 1999, Sciot et al.11 published a study documenting 19 patients with localized pigmented villonodular synovitis and 16 patients with diffuse pigmented villonodular synovitis, of which 11 (58%) of the 19 patients with localized pigmented villonodular synovitis and 12 (75%) of the 16 patients with diffuse pigmented villonodular synovitis displayed clonal chromosomal aberrations. The investigators found that many of the patients had a 1p11-13 chromosomal rearrangement, suggesting a possible neoplastic transformation. These results were further supported by Nilsson et al.12, who reported that 24 (92%) of 26 patients with localized pigmented villonodular synovitis had a breakpoint in chromosome 1p11-13, and found chromosome 2q35-37 to be the most common translocation partner. These studies, describing clonal processes, along with other studies showing trisomies in chromosomes 5 and/or 73,11-14, provided the foundation for a neoplastic origin for pigmented villonodular synovitis.
More recently, studies have shown that the colony stimulating factor-1 (CSF-1) gene at the 1p13 breakpoint and the COL6A3 gene at 2q35 may play a role in the development of pigmented villonodular synovitis15,16. CSF-1 encodes the CSF-1 cytokine involved in the proliferation and differentiation of monocytes and macrophages, and COL6A3 encodes a type-IV alpha-3 collagen chain. West et al.15 characterized 23 (77%) of 30 patients with localized pigmented villonodular synovitis and 5 (63%) of 8 patients with diffuse pigmented villonodular synovitis and found that 2% to 16% of the mononuclear and multinucleated giant cells carried this common translocation using combined interphase fluorescence in situ hybridization and CSF-1 immunohistochemistry. Although only a small percentage of cells overexpressed the CSF-1 cytokine, the majority of the cells expressed CSF-1R, a receptor tyrosine kinase15,16. Autocrine and paracrine signaling using CSF-1 and its receptor leads to the stimulation and proliferation of macrophages in a neoplastic manner. Additionally, CSF-1 may stimulate the recruitment of other CSF-1R-yielding inflammatory cells, such as histiocytes, lymphocytes, and osteoclast-type multinucleated giant cells.
Supporting this etiology, O’Keefe et al.17 demonstrated intense immunohistochemical and in situ hybridization findings of IL (interleukin)-1β, IL-6, TNF (tumor necrosis factor)-α, and MMP-9 (matrix metalloproteinase-9) expression in 10 (100%) of 10 histologically proven pigmented villonodular synovitis cases. TNF-α stimulates the production of MMPs, which can lead to the cartilage and bone destruction seen in pigmented villonodular synovitis.
The abundance of recent literature supporting a neoplastic origin for pigmented villonodular synovitis has caused other proposed etiologies, including chronic inflammation and trauma-induced hemorrhage, to fall out of favor18. Gaining insight into the molecular pathways induced in pigmented villonodular synovitis has prompted the development of novel therapies, which may serve as potential adjuncts or alternatives to a surgical procedure.
Localized Pigmented Villonodular Synovitis
Localized pigmented villonodular synovitis occurs most often in the hands, but is also seen in large joints, such as the knee and ankle. In the knee, localized pigmented villonodular synovitis presents as a focal lesion, frequently in the anterior compartment. Patients are usually between 30 and 50 years of age. Clinically, the most common presenting symptom is a painless swollen joint, which has been long-standing. In some cases, this form of pigmented villonodular synovitis is found incidentally when ruling out other causes of knee pain. A history of localized trauma is occasionally reported. Radiographically, osseous erosion may be seen resulting from localized pressure. On magnetic resonance imaging (MRI), a well-circumscribed soft-tissue mass is visualized19.
If left untreated, localized pigmented villonodular synovitis can continue to cause discomfort and pain, affecting daily functioning and activity. When treated, localized pigmented villonodular synovitis recurs only about 8% of the time after synovectomy20.
Diffuse Pigmented Villonodular Synovitis
Diffuse pigmented villonodular synovitis is predominantly an intra-articular tumor affecting the knee in 75% of cases. Compared with localized pigmented villonodular synovitis, diffuse pigmented villonodular synovitis tends to occur in patients younger than 40 years of age and carries a slight predominance to females21. Patients present with more concerning symptoms than localized pigmented villonodular synovitis. Swollen joints, which are painful and tender to touch and have limited mobility, are common. Radiographically, degenerative changes of the joint are commonly seen, with changes apparent on both sides of the joint. On MRI, an ill-defined soft-tissue mass rather than a well-circumscribed mass is seen22.
The natural history of diffuse pigmented villonodular synovitis, if left untreated, will lead to continued pain, decreased range of motion, and swelling. The affected joint is preserved early on, but, left untreated, the hypertrophic synovium and multiple soft-tissue masses may lead to joint destruction and osteoarthritis7. When treated, recurrence rates of diffuse pigmented villonodular synovitis can approach 31% to 33%20,23.
Localized Pigmented Villonodular Synovitis or Tenosynovial Giant Cell Tumor
Histologically, localized pigmented villonodular synovitis or tenosynovial giant cell tumor contains a mixture of mononuclear histiocyte-like cells, lymphocytes, and osteoclast-type multinucleated giant cells10. The number of giant cells may vary and they can be hard to distinguish in highly cellular tumors. The mononuclear cells are small and round, but can also be spindle-shaped. Frequently, xanthoma cells are present and tend to be at the periphery of the specimen. Hemosiderin deposition is almost always seen, although in varying amounts22. Hyalinization may be seen in the stroma, and mitotic activity of 3 to 5 per 10 high-power fields can be present. Focal necrosis is rarely seen24.
Diffuse Pigmented Villonodular Synovitis
Compared with localized pigmented villonodular synovitis, the histopathology of diffuse pigmented villonodular synovitis shows an infiltrative pattern. Spaces filled with blood are seen in up to 10% of cases. The osteoclastic giant cells are absent or rare in 20% of cases. The mononuclear cells are of 2 types: small histiocyte-like cells and larger cells. The small histiocyte cells can be round or spindle-shaped, and a predominance of the larger cells may lead this tumor to be mistakenly diagnosed as a sarcoma. Hyalinization of the stroma is also present, although less common than seen in localized pigmented villonodular synovitis. Mitotic activity of >5 per 10 high-power fields can be present (Figs. 1-A and 1-B)24. Lastly, there have been rare reports of malignant transformation of these tumors. Necrosis, >20 mitoses per high-power field, enlargement of the nuclei, abundance of eosinophilic nuclei, and myxoid changes have been seen in those considered to have become malignant24.
Pigmented villonodular synovitis is histologically similar to other disease processes. The giant cell tumor of the tendon sheath shares the polymorphous cell population and hemosiderin deposits with pigmented villonodular synovitis, but is encapsulated and lacks the villonodular architecture25. Additionally, pigmented villonodular synovitis shares the characteristic of hemosiderin deposition with joint synovitis in hemophiliac patients. These patients develop a lobular synovitis with a proliferation of fibroblasts and vascular cells, but lack the giant cells and lipid-laden histiocytes that are present in pigmented villonodular synovitis26,27.
An accurate diagnosis of pigmented villonodular synovitis is based on a combination of physical examination findings, imaging studies, and histologic confirmation. Location of the mass is an important consideration. Masses of the digits of the hand are more likely to be a localized pigmented villonodular synovitis or tenosynovial giant cell tumor, although a swollen, tender larger joint, such as the knee or hip, would be more concerning for diffuse pigmented villonodular synovitis.
On radiographs, degenerative changes may be seen. Changes on both sides of the joint are more likely to be diffuse pigmented villonodular synovitis, but appearances of pressure erosion may be more consistent with localized pigmented villonodular synovitis28,29. It is not possible to differentiate an effusion from synovial thickening and proliferation on radiographs alone28. Additionally, 32% of all pigmented villonodular synovitis cases and 54% of cases of pigmented villonodular synovitis of the knee may appear normal on radiographs (Figs. 2-A and 2-B)28. For these reasons, radiographs are not considered to be diagnostic for pigmented villonodular synovitis.
In many instances, advanced imaging such as MRI is obtained to rule out other etiologies. It is the most sensitive imaging study to evaluate pigmented villonodular synovitis. Ill-defined intra-articular masses involving the entire joint are likely to be diffuse pigmented villonodular synovitis, and well-circumscribed masses are likely to be localized pigmented villonodular synovitis. Pigmented villonodular synovitis is one of the few soft-tissue processes that has a nearly pathognomonic appearance on MRI, presenting with low signal intensity and a “blooming artifact”22,30,31. The blooming artifact, which is characteristic of pigmented villonodular synovitis, is a noticeable signal loss on gradient echo sequences, due to the iron in the hemosiderin deposition (Figs. 3-A and 3-B)31. In 2004, Cheng et al.28 observed hemosiderin deposits in 23 proven cases of pigmented villonodular synovitis, appearing as low-signal regions in T1-weighted and T2-weighted MRI.
Although the combination of physical examination and imaging findings can suggest the diagnosis of pigmented villonodular synovitis, histologic confirmation with biopsy remains the gold standard. Other diagnoses, including amyloid arthropathy, synovial chondromatosis, synovial hemangioma, synovial lipomatosis, synovial sarcoma, and infection, must be excluded. Amyloid arthropathy may present with low signal intensity, but it does not demonstrate the blooming artifact. Synovial chondromatosis differs by its frequent presentation of multiple mineralized intra-articular bodies. Synovial hemangiomas typically present with intermediate T1-weighted image signal intensity with hyperintensity on T2-weighted imaging, in addition to a lobulated intra-articular mass. Synovial lipomatosis often presents with a fatty lobular intra-articular mass with joint effusion and absent hemosiderin32. Lastly, synovial sarcoma typically presents with low intensity on T1-weighted images and high intensity on T2-weighted images33.
Furthermore, with a very large or aggressively behaving tumor, the practitioner must rule out the rare malignant transformations that have been reported34. A needle biopsy of the mass can help to obtain the histologic diagnosis.
Localized Pigmented Villonodular Synovitis
The treatment of localized pigmented villonodular synovitis can entail observation with serial follow-up or surgical excision. In patients with masses of the digits, which are presumed to be a tenosynovial giant cell tumor, that are stable in size and asymptomatic, serial clinical follow-up every 6 months would be warranted. In patients in whom the masses are not easily accessible via clinical examination, serial MRI every 6 months to establish stability would be a reasonable option. Unfortunately, no gold standard for observation of localized pigmented villonodular synovitis has been established.
However, in many instances, patients present to the physician for a swollen joint, painful mass, or joint dysfunction. Therefore, operative management is often required. For masses of the digits, open excision is the gold standard. For intra-articular masses, open excision was routinely performed, but now with the advances in arthroscopy, there has been a shift toward arthroscopic excision. The majority of the literature is published on the knee joint, as it is the most common location and the joint most commonly assessed and treated with arthroscopy. In 2007, Sharma et al.35 presented 4 cases of localized pigmented villonodular synovitis in the knee treated with open excision of the nodule. No recurrence was seen after 5 years of follow-up. Dines et al.36 reported 26 cases of localized pigmented villonodular synovitis, of which 14 were treated with open excision and 12 were treated with arthroscopic excision. No recurrences were noted in either cohort, with all patients reporting no pain, locking, clicking, or swelling after a minimum 5-year follow-up. Jain et al.37 reported 40 patients treated by arthroscopic excision, 11 (28%) of whom had localized pigmented villonodular synovitis. The study showed no recurrences in the localized pigmented villonodular synovitis cohort after follow-up of 9 years.
Because of the high efficacy of arthroscopic excision in the knee, some authors advocate that intra-articular localized pigmented villonodular synovitis should be initially treated with arthroscopy because of lower rates of morbidity, pain, and stiffness associated with the procedure37. Additionally, open excision may lead to increased risk of osteoarthritic changes, caused by the additive effects of the pigmented villonodular synovitis disease process, surgical invasion, and muscle weakness postoperatively5,38-40.
Patient selection to undergo arthroscopic excision is an important consideration. Some nodules, such as those that arise behind the anterior cruciate ligament, may be difficult to assess arthroscopically. Large nodules located in the posterior compartment, which require uncommonly used portals (e.g., posteromedial or posterolateral), may put the neurovascular bundle at risk or may be prone to incomplete excision requiring a further open surgical procedure. As such, there is still a role for open excision. This should be considered when arthroscopy would not allow achievement of full excision.
There are limited data on the efficacy of arthroscopic treatment of localized pigmented villonodular synovitis in other joints such as the elbow, ankle, and hip. Although arthroscopy techniques for these joints have improved, ensuring complete excision of the masses may be difficult for a practitioner with limited experience and therefore may be best suited to those with more extensive experience.
Diffuse Pigmented Villonodular Synovitis
The treatment options for diffuse pigmented villonodular synovitis of the knee, which usually involves both the anterior and posterior compartments, have undergone an evolution. Historically, open arthrotomy with complete synovectomy has been viewed as the optimal treatment for diffuse pigmented villonodular synovitis22,41. Studies have shown mixed results with this approach, with recurrence rates as high as 19% to 33%39,42,43. With modern advances in arthroscopy, surgeons are now incorporating this technique into the treatment of diffuse pigmented villonodular synovitis. When evaluating results of arthroscopic excision alone of diffuse pigmented villonodular synovitis, there are documented recurrence rates as high as 92% to 94%39,42, although a combined anterior compartment arthroscopy and posterior open synovectomy had recurrence rates between 9% and 25%42,44. Recurrence rates are similar when the combined arthroscopic and open synovectomy (19%) is compared with complete open synovectomy (25%)42. The combined approach of addressing the anterior disease arthroscopically and the posterior disease with an open approach may be the preferred method, although, because of a lack of Level-I evidence suggesting one technique over another, controversy still remains.
Radiation therapy alone, or as an adjuvant therapy after synovectomy, has been studied and appears to recently have had a resurgence of interest. O’Sullivan et al.45 presented 14 patients with intra-articular and extra-articular diffuse pigmented villonodular synovitis treated with radiation therapy alone or in combination with a surgical procedure. Most patients received either 30 Gy in 15 fractions, 35 Gy in 14 or 15 fractions, or 50 Gy in 25 fractions. After a mean follow-up of 69 months, 13 (93%) of 14 patients showed no disease. That study45 and other, more recent studies (Table I)23,41,46-51 using radiation have shown recurrence rates that are below the rates associated with a surgical procedure alone. However, radiation is not a benign therapy. It can cause permanent skin changes and joint stiffness. Radiation-induced sarcoma is a known complication, which can develop at a mean time of 7 years after treatment, with the possibility of inducing malignant transformation of a locally aggressive but benign entity. Bickels et al.52 reported 3 (43%) of 7 patients treated with intra-articular yttrium-90 into pigmented villonodular synovitis of the ankle joint who experienced serious complications, such as skin necrosis and a draining sinus. With the possibility of serious toxicity, it remains a questionable treatment strategy to use radiation on a benign process such as pigmented villonodular synovitis, especially in adolescents and young adults.
With the discovery of CSF-1 overexpression as the etiology of pigmented villonodular synovitis, new, targeted medical therapies have been developed. Dewar et al.53 published the use of imatinib to inhibit the macrophage (M)-CSF receptor (CSF-1R), c-fms. Imatinib is a tyrosine kinase inhibitor that has been shown to block the Bcr-Abl (breakpoint cluster region-Abelson proto-oncogene) complex, PDGFR (platelet-derived growth factor receptor), c-Kit proto-oncogene, Abl, and ARG (Abl-related gene)53,54. Several small studies have demonstrated a positive response with the use of imatinib and other targeted therapies in pigmented villonodular synovitis54-58; however, the chemotoxic effects of imatinib, when used for a rarely lethal medical condition, must be weighed against its benefits. Potential toxicities associated with imatinib include fatigue, nausea, dermatitis, edema, and myelosuppression53,54. Additionally, the cost of treatment with imatinib for pigmented villonodular synovitis, as reported in 2011, was about $4,600 per month and was not guaranteed to be covered by insurance59.
In 2009, a small molecule labeled PLX3397, a selective inhibitor of c-fms, was put into a Phase-1 clinical trial. At a mean of 166 days of treatment, MRI showed a 50% reduction in tumor volume, and there was substantial clinical improvement in pain, stiffness, and function. Of 11 patients, 7 (64%) noticed partial response and 4 (36%) noticed stable disease60. Because of its Phase-1 success, it is currently undergoing a Phase-3 clinical trial with active enrollment61.
The treatment of diffuse pigmented villonodular synovitis should be individualized and based on the location of the disease, difficulty of local control, and morbidity of operative treatment. In the knee, surgical excision utilizing a combined arthroscopic anterior and open posterior approach should be considered a first-line option. With this surgical approach being technically demanding, community surgeons may consider transferring patients to an academic center with a treating orthopaedic oncologist who is more familiar with this disease process. However, referral to an institution to enroll in the Phase-3 trial may be appropriate for those patients who have aggressive disease in the knee requiring an extensive open anterior and posterior approach, recurrence requiring re-excision causing added morbidity, disease in a joint such as the elbow where extensive open excision can cause substantial morbidity, or disease in a joint that is difficult to access and in which incomplete excision is likely, such as the hip.
We believe that radiation should not be utilized for treating diffuse pigmented villonodular synovitis in light of the new, targeted medical treatments now available.
Figure 4 highlights a proposed algorithm for the diagnosis and treatment of pigmented villonodular synovitis. This algorithm is based on our experience and is aimed at providing a foundation for orthopaedic surgeons who do not regularly treat or evaluate patients with pigmented villonodular synovitis.
In cases of failed surgical treatment, we recommend starting from the beginning of the algorithm and pursuing any further work-up that the surgeon deems necessary. In terms of further treatment options, the surgeon may decide to proceed with the next most invasive surgical procedure or the surgeon may at that point decide that referral to a specialist is warranted.
Pigmented villonodular synovitis is a synovial disorder that commonly affects the knee and can be localized or diffuse in nature. Diagnosis is dependent on a thorough physical examination and advanced imaging, which most often consists of an MRI. Histology is necessary to confirm the diagnosis. Appropriate treatment requires an in-depth understanding of the extent of disease, as localized and diffuse pigmented villonodular synovitis are treated differently.
Surgical treatment for pigmented villonodular synovitis has been established as the standard of care for treatment of these lesions. Numerous studies have evaluated the optimal method of treating localized pigmented villonodular synovitis, with the majority of authors concluding that both open and arthroscopic surgical procedures are efficacious and have low recurrence rates. The surgical treatment of choice for diffuse pigmented villonodular synovitis is still open to debate because of high recurrence rates, although recent studies have demonstrated success with the combination of anterior arthroscopy and posterior open synovectomy. New medical therapies are available and may supplant the need for surgical intervention. Radiation therapy for diffuse pigmented villonodular synovitis is not currently recommended by the authors because of its toxicity and the development of these newer targeted agents. However, more research is required to understand the true efficacy of these drugs, the long-term side effects, and the optimal duration of treatment.
The authors thank Thomas Holdbrook, MD, from the Department of Pathology at Cooper University Hospital, for his assistance in providing histologic images for the manuscript.
Investigation performed at the Department of Orthopaedic Surgery, Drexel University College of Medicine, Philadelphia, Pennsylvania
Disclosure: There was no external funding source for this study. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article.
- Copyright © 2016 by The Journal of Bone and Joint Surgery, Incorporated