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Pigmented villo-nodular synovitis of joints and tendon sheaths
PATHOLOGY
incidence and conflicting evidence for sex ratio.3e5 Typically patients are in the 3rde5th decades of life but numerous examples involving infants, children and adolescents have been reported. GCTTS is the most common tumour found in the hand after ganglia, also affecting adults in the 3rde5th decades, but more commonly in women than men.6 The estimated incidence is one new case annually per 50 000 population.7
Pigmented villo-nodular synovitis of joints and tendon sheaths Jonathan Daniel Stevenson Gillian Cribb Paul Cool
Aetiology and pathogenesis Various patho-aetiologies have been suggested for PVNS. An association with trauma and recurrent haemarthrosis has been suggested as synovial haemorrhage and haemosiderin deposition may contribute to the pigmentation of PVNS lesions.5 Haemosiderin deposition is invariably found within PVNS and could result from synovial absorption of blood following haemorrhage.3 In one large series, 80% of localized PVNS and 62% of diffuse PVNS cases had a positive history of trauma.3 Recurrent haemarthrosis secondary to haemophilia or synovial haemangioma have also been postulated as being causative.5 Indeed synovial haemangiomas can be localized or diffuse lesions and differentiating them from PVNS can be a challenge,3 as both may show histological features similar to PVNS, although giant-cell formation is not associated with haemophilia, and unlike PVNS, the haemosiderin pigment is contained within synovial cells and macrophages.8 Inflammatory arthropathies also give rise to histological synovial changes similar to PVNS, suggesting a possible inflammatory or reactive pathogenesis.3 However, Rao and Vigorita reported no progressive fibrotic changes in serial PVNS samples and the lack of distinctive nodules of mononuclear and giant cells in inflammatory arthropathies in their study which refuted an inflammatory relationship.9 Berger et al reported that the aneuploid cell pattern seen in 20% of diffuse PVNS samples was a feature lacking in rheumatoid arthritis, in spite of their histologically homogenous appearance.7 Chromosomal abnormalities,6 the capacity for autonomous growth,10 bone invasion5 and the identification of (rare) malignant transformation11 are suggestive of a neoplastic aetiology.12 The most common genetic abnormality detected has been the translocation of the colony stimulating factor (CSF1) gene in chromosome 1p13.13 Over expression of the CSF1 gene and the CSF1 receptor has been widely implicated in the pathogenesis of PVNS, and may be a future target for therapy.
Abstract Pigmented villo-nodular synovitis (PVNS) is a rare, benign and aggressive disorder of synovial joints and tendon sheaths which is capable of eroding articular structures and bone. It represents a spectrum of pathological disorders ranging from the most common giant-cell tumour of tendon sheath to localized or diffuse intra-articular PVNS lesions and may be associated with joint erosions. It is best treated surgically but recurs if inadequately excised. Adjunctive therapies include injection of intra-articular radio-isotopic materials and external beam radiotherapy.
Keywords giant-cell tumour of tendon sheath; intra-articular; pigmented villo-nodular synovitis; tumour
Introduction First described by Chassignac in 1852,1 it was Jaffe et al who introduced the term Pigmented Villo-Nodular Synovitis (PVNS).2 It is a rare, benign and aggressive disease of the synovium of joints and tendon sheaths. Classic clinical, radiological and histological features of PVNS and Giant-Cell Tumours of Tendon Sheaths (GCTTS) are described and treatments, including novel therapies, are discussed.
Epidemiology The estimated incidence of articular PVNS is 1.8 new cases annually per million population, highlighting the rarity of this disorder.3 There appear to be no socio-economic factors affecting
Mr Jonathan Daniel Stevenson MBChB BMedSci MRCS(Ed) Specialist Registrar Orthopaedics, Greater Manchester and Oswestry Soft Tissue Sarcoma Service (GMOSS), Robert Jones & Agnes Hunt Foundation Trust, Oswestry, Shropshire, UK. Conflicts of interests: None.
Sub-types Granowicz and Mankin divided intra-articular PVNS into localized and diffuse types.14 GCTTS are considered to be an extraarticular PVNS. It is most commonly observed in fingers, but also along the tendon sheaths of the foot and ankle.15 Each subtype is thought to represent a spectrum of the same pathological process,2,16 though clinical presentation, management and prognosis is widely different. Myers and Masi’s 1980 literature review of 1301 PVNS lesions, showed that 69% were GCTTS, 8% localized PVNS and 29% diffuse type PVNS.13 In the same review 66% of articular PVNS lesions were in the knee, 16% in the hip, and 7% in the ankle with infrequent cases involving the foot, wrist, shoulder or elbow.3 GCTTS occurs in the fingers in 78% of
Ms Gillian Cribb MBChB MRCS FRCS(T&O) Consultant Orthopaedic and Oncological Surgeon, Greater Manchester and Oswestry Soft Tissue Sarcoma Service (GMOSS), Robert Jones & Agnes Hunt Foundation Trust, Oswestry, Shropshire, UK. Conflicts of interests: None. Mr Paul Cool MMedSc(Res) FRCS(Ed) FRCS(Orth) Consultant Orthopaedic and Oncological Surgeon, Greater Manchester and Oswestry Soft Tissue Sarcoma Service (GMOSS), Robert Jones & Agnes Hunt Foundation Trust, Oswestry, Shropshire, UK. Conflicts of interests: None.
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PATHOLOGY
Figure 2 (a and b) AP and lateral radiographs of an effused knee with tibial cysts visible in both views.
Pathology Macroscopically diffuse PVNS tumours are usually large (>5 cm), firm or sponge-like with pale multicoloured tissue ranging from tan to golden brown.13 The synovial hyperplasia consists of irregular villous projections with larger nodular protrusions. Localized PVNS lesions appear classically yellowbrown, firm, pedunculated lobulated tumours.17 GCTTS are small (0.5 cme4 cm), circumscribed lobulated white/grey tumours arising along the tendon sheaths embedded within a collagenous pseudocapsule.13 The histological appearances are similar across all three PVNS sub-types. They include proliferative synovial-like mononuclear cells, compacted fibrous stromal cells, foam and haemosiderinladen cells, mixed round cell infiltration, mononuclear
Figure 1 (a and b) AP and lateral radiographs of the left ankle showing sub-chondral cysts and articular erosions.
cases, and less frequently in the foot, hand, wrist and ankle. More commonly found volarly (69%) than dorsally (31%) the distribution in fingers is more equal between proximal (58%) and distal (42%).3
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Figure 4 (a and b) AP radiograph of the right hand showing soft tissue swelling radial to proximal phalanx of index finger. Coronal T1 weighted MRI image showing the well circumscribed low signal GCTTS lesion.
ligamentous bone attachments through which bone invasion is thought to occur.17
Figure 3 (a and b) Lateral knee radiograph showing radio-opaque intraarticular localized PVNS lesion inferior to the patella, and the same lesion demonstrating heterogeneous signal on sagittal T2 weighted MRI.
Clinical presentation Intra-articular diffuse PVNS As the diffuse articular type insidiously infiltrates the synovial cavity lining leading to eventual osseous erosions and subchondral cysts, patients present with insidious swelling and/or pain which has been present for months or years. On
polyhedral cells of fibro-histiocytic origin and multinucleated giant cells.2,9,18 Diffuse lesions demonstrate greater vascularity and haemosiderin deposition,3 and have a typically villous pattern lacking in extra-articular disease.13 PVNS may accumulate near the chondro-osseous junction and around vascular and
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Figure 6 Axial image from CT guided biopsy of PVNS involving knee joint.
Intra-articular nodular PVNS The localized articular type manifests itself as a pedunculated nodule within the joint. In the knee PVNS lesions tend to occur at the menisco-capsular junction in the anteromedial compartment.20 Patients may complain of intermittent locking (90%), pain (80%) and episodic swelling (60%).3,8 Localized mobile swellings, mild effusion and limitation of movement may be observed clinically.4 As the symptoms can mimic more common mechanical joint disorders, such lesions are often found unexpectedly after imaging. GCTTS In 99% of cases of GCTTS, the presenting complaint is of a slowgrowing swelling ranging from 1 cm to 4 cm in diameter.7 They tend to involve the radial three digits of the hand, with pain (22%) and limitation of motion (4%) less common features.3 They may also occur along tendon sheaths of the wrist, foot, ankle and knee.7
Investigation Radiology Radiological appearances in early intra-articular PVNS lesions are normal in up to 20% of cases.20 As the disease progresses, early synovial swellings without calcification and effusion with preserved joint spaces are typical, followed by juxta-articular and sub-chondral erosions. Cysts develop in advanced disease (Figures 1 and 2).3,18 Localized intra-articular PVNS most often occurs in the anterior portion of the knee where it may produce a soft tissue mass visible on lateral radiographs because of its contrasting radio-density to Hoffa’s fat pad (Figure 3).17 GCTTS lesions typically give rise to localized soft tissue swellings along the volar aspect of the affected digit with radiological evidence adjacent bone erosion found in 11% cases (Figure 4a).21 Intraarticular lesions demonstrate bone erosions in up to 20% of localized and 50% of diffuse cases respectively.3 Bone invasion is
Figure 5 (a) T2 sagittal MRI (from the same patient as Figure 2) shows the extensive ‘blooming’ low to intermediate signal PVNS lesion within the supra-patellar pouch and popliteal fossa. (b) Axial T1 weighted image showing the sub-chondral cysts of the tibia and the low signal PVNS lesion in the popliteal fossa.
examination there may be firm swellings, diffuse tenderness, effusion and restricted movement.4 In one large series, swelling and pain were found in 79% of patients, restriction of movement in 26% and a palpable mass in 6% of cases at presentation.3 Haemarthrosis was present in 75% of patients with diffuse PVNS of the knee in whom synovial fluid was analysed.19
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and 18% in the knee.19,23,24 Open anterior and posterior synovectomy of the knee joint has significantly greater recurrence free survival than anterior arthroscopy and open posterior synovectomy or anterior arthroscopic synovectomy alone.23 However, the additional surgical dissection increases the risk of stiffness, contractures, reflex sympathetic dystrophy (complex regional pain syndrome), neurovascular and wound complications (Figure 7).19,23 Radiotherapy (RT) has been used to augment surgery following incomplete synovectomy and in recurrent PVNS. Blanco et al combined partial arthroscopic synovectomy with low-dose external beam RT in 22 knees with diffuse PVNS, reporting 14% recurrence at 1 year.25 No harmful RT effects were reported and the recurrence rate was comparable to total open synovectomy alone. Adjuvant intra-articular radio-isotopic therapy is also reported to give low recurrence rates.26 However, significant complications have been described; Bickels et al reported three serious complications in series of seven patients with diffuse ankle PVNS, including full thickness skin necrosis and deep sepsis, and the authors have since discontinued using this treatment.27 Chin et al compared the combined use of surgery with and without intra-articular radio-synovectomy or external beam RT in both primary and recurrent diffuse PVNS of the knee.19 All patients had combined open anterior and posterior synovectomy. Seven recurrences (18%) were reported despite adjuvant radiation therapy, and a statistically significant reduction in knee flexion was detected in the external beam RT group. Consequently the authors recommended adjuvant radiation therapy only for symptomatic recurrences, not for the treatment of primary disease. Infrequently later arthroplasty (5%) or arthrodesis (6%) may be necessary after synovectomy of the knee.28 Open synovectomy does not prevent secondary osteoarthritis of the confined hip joint. All the patients in the largest series of hip PVNS to date subsequently required total joint arthroplasty.29
more likely to occur in joints such as the hip which do not have large recesses to accommodate expanding synovial masses.19 Magnetic resonance imaging (MRI) MRI is the investigation of choice9 enabling extent, erosion and invasion to be demonstrated which is crucial in planning surgical approaches. It is reported to be 100% sensitive and specific for detecting diffuse PVNS of the knee pre-operatively.19 It will demonstrate synovially based nodular swellings with heterogeneous low to intermediate signal on both T1 and T2 weighted sequences.8 The difference in magnetic susceptibility between haemosiderin-laden PVNS and surrounding tissue may cause the lesion to appear larger (‘blooming’) on gradient echo images (Figure 5).17 Synovial masses may be extensive in diffuse PVNS involving adjacent synovial structures (semimembranosus, semitendinosus and gastrocnemius bursae), beneath menisci and extending into the popliteal fossa.17 The localized form is usually seen as a single intra-articular nodule or along the tendon sheath in GCTTS (Figure 4b). Biopsy The presence of erosive changes and extensive soft tissue infiltration may lead to the suspicion of soft tissue sarcoma or haemophilic arthropathy, necessitating pre-operative biopsy.14 Biopsies should be taken routinely to confirm diagnosis prior to surgery and may be image (Ultrasound or Computed Tomography) guided (Figure 6) or performed as an outpatient procedure if the lesion is palpable. Differential diagnosis The localized form is often clinically indistinguishable from acute mechanical derangement such as meniscal tears or cysts, loose bodies, osteochondritis dissecans or chondromalacia.4 The diffuse form may be clinically and radiologically similar to haemophilic and inflammatory arthropathies, soft tissue sarcoma and synovial chondromatosis.14,19 GCTTS may be clinically similar in presentation to ganglia, inclusion cysts, sebaceous cysts and rheumatoid synovitis.15
Management In common with other benign aggressive lesions with low propensity for metastasis, PVNS lesions are principally managed surgically.10 The aim is to achieve complete excision with a minimum of soft tissue disruption and to prevent joint erosions and destruction. Incomplete synovectomy is significantly related to recurrence; consequently so-called ‘recurrences’ are thought to represent residual PVNS tissue.19 Arthroscopic excision of localized PVNS lesions of the knee is well established and reported recurrence rates range from 0 to 24%.11,22 In the largest series of localized PVNS of the knee, recurrence free survival with arthroscopic synovectomy has been reported as 91% at 2 years and 73% at 5 years.23 While arthroscopy may have a role to assess the extent of radiologically diffuse lesions which occasionally may originate from one pedunculated stalk and be amenable to arthroscopic excision, the greater propensity of diffuse PVNS than localized PVNS to recur (55% recurrence has been reported with subtotal arthroscopic synovectomy of the knee22), makes open synovectomy preferable.10 The reported recurrence rates are between 8%
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Figure 7 Anterior and posterior clinical photographs right knee 6 months and 2 months following anterior and posterior open synovectomies for diffuse PVNS.
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7 Berger I, Weckauf H, Helmchen B, et al. Rheumatoid arthritis and pigmented villonodular synovitis comparative analysis of cell polyploidy, cell cycle phases and expression of macrophage and fibroblast markers in proliferating synovial cells. Histopathology 2005; 46: 490e7. 8 Sharma H, Jane MJ, Reid R. Pigmented villonodular synovitis of the foot and ankle: forty years of experience from the Scottish bone tumour registry. J Foot Ankle Surg 2006; 45: 329e36. 9 Rao S, Vigorita VJ. Pigmented villonodular synovitis (Giant-cell tumour of the tendon sheath and synovial membrane). A review of eighty-one cases. J Bone Jt Surg 1984; 66A: 76e94. 10 De St. Aubain Somerhausen N, Dal Chin P. So-called fibrohistiocytic tumours. In: Fletcher CDM, Unni KK, Mertens F, eds. World Health Organisation Classification of tumours. Pathology and genetics of tumours of soft tissue and bone. Lyon: IARC Press, 2002; 109e126. 11 Chin KR, Barr SJ, Winalski C, Zurakowski D, Brick GW. Treatment of advanced primary and recurrent diffuse pigmented villonodular synovitis of the knee. J Bone Jt Surg 2002; 84A: 2192e202. 12 Murphey MD, Rhee JH, Lewis RB, Fanburg-Smith JC, Flemming DJ, Walker EA. Pigmented villonodular synovitis: radiologic-pathologic correlation. Radiographics 2008; 28: 1493e518. 13 Myers BW, Masi AT, Feigenbaum SL. Pigmented villonodular synovitis and tenosynovitis: a clinical and epidemiologic study of 166 cases and literature review. Medicine 1980; 59: 223e8. 14 Granowicz SP, Mankin HL. Localized pigmented villonodular synovitis of the knee. J Bone Jt Surg 1967; 49A: 122e8. 15 Saxena A, Perez H. Pigmented Villonodular Synovitis about the ankle: a review of the literature and presentation in 10 athletic patients. Foot Ankle Int 2004; 25: 819e27. 16 Sciot R, Rosai J, Dal Cin P, et al. Analysis of 35 cases of localized and diffuse tenosynovial giant cell tumor: a report from the Chromosomes and Morphology (CHAMP) study group. Mod Pathol 1999; 12: 576e9. 17 Bravo SM, Winalski CS, Weissman BN. Pigmented villonodular synovitis. Radiol Clin North Am 1996; 34: 311e26. 18 Darling JM, Goldring SR, Harada Y, Handel ML, Glowacki J, Gravallese EM. Multinucleated cells in pigmented villonodular synovitis and giant cell tumor of tendon sheath express features of osteoclasts. Am J Pathol 1997; 150: 1383e93. 19 Ravi V, Wang WL, Lewis VO. Treatment of tenosynovial giant cell tumour and pigmented villonodular synovitis. Curr Opin Oncol 2011; 23: 361e6. 20 Kim SJ, Shin SJ, Choi NH, Choo ET. Arthroscopic treatment for locailsed pigmented villonodular synovitis of the knee. Clin Orthop Relat Res 2000; 379: 224e30. 21 Uriburu IJF, Levy VD. Intraosseous growth of giant cell tumours of the tendon sheath (localised nodular tenosynovitis) of the digits: report of 15 cases. J Hand Surg 1998; 23A: 732e6. 22 Olgivie-Harris DJ, McLean J, Zarnett ME. Pigmented villonodular synovitis: the results of total arthroscopic synovectomy, partial arthroscopic synovectomy and arthroscopic local excision. J Bone Jt Surg 1992; 74A: 119e23. 23 Sharma V, Cheng EY. Outcomes after excision of pigmented villonodular synovitis of the knee. Clin Orthop Relat Res 2009; 467: 2852e8. 24 Flandry FC, Hughston JC, Jacobson KE, Barrack RL, McCann SB, Kurtz DM. Surgical treatment of diffuse pigmented villonodular synovitis of the knee. Clin Orthop Relat Res 1994; 300: 183e92.
GCTTS is exclusively managed with open marginal excision and (non-destructive) recurrences are infrequent (10e20%) and managed with repeat excision.10 More frequent recurrences may occur in lesions with higher mitotic cell counts at histological analysis.13
Future treatments Bone erosion has been noted in up to 25%20 of lesions, which is believed to be due to a complex mechanism related to a Tumour Necrosis Factor (RANKL) e CD14 dependent mechanism involving PVNS phagocytes exhibiting phenotypic osteoclastic features.5,18 Lacunar resorption by PVNS derived giant cells has been abolished ex-vivo with bisphosphonates, suggesting a future role for control of bony erosions. Macrophage Colony Stimulating Factor (CSF) 1 is expressed by some PVNS cells.30 CSF1 receptors are inactivated by Imatinib, a tyrosine kinase inhibitor which therefore may have a future role in refractory PVNS. An international retrospective multi-centre study of imatinib efficacy highlighted symptomatic improvement in 16 of 22 patients, but toxicity in 6 cases and a further four discontinued treatment for no discernible reason.30 This development may be useful for patients unsuitable for extensive surgery or in whom surgical excision could result in functional impairment.
Conclusions PVNS is a spectrum of three distinct clinical entities. GCTTS are by far the most common form, with the least potential for recurrence and morbidity. Insidious intra-articular swellings around joints in young or middle aged adults may suggest the rare articular PVNS. MRI and biopsy are essential to confirm the diagnosis, define the extent of lesions and plan treatment. The potential for joint erosions, particularly in the diffuse form, require total synovectomy to control the disease process and to minimize the risk of recurrence. Adjunctive radiation therapies and new novel therapies may have a role for recurrent or refractory cases. A
REFERENCES 1 Chassaignac M. Cancer de la gaine des tendons (cancer of the tendon sheath). Gaz Hop Civ Milit 1852; 47: 185e6. 2 Jaffe HL, Lichtenstein L, Sutro CJ. Pigmented villonodular synovitis, bursitis and tenosynovitis. Arch Pathol 1942; 31: 731e65. 3 Granowicz SP, D’Antonio J, Mankin HL. Pathogenesis and long-term end results of pigmented villonodular synovitis. Clin Orthop 1976; 114: 335e51. 4 Schnirring-Judge M, Lin B. Pigmented villonodular synovitis of the ankle e radiation therapy as a primary treatment to reduce recurrence: a case report with 8-year follow-up. J Foot Ankle Surg 2011; 50: 108e16. 5 Bisbinas I, De Silva U, Grimer RJ. Pigmented villonodular synovitis of the foot and ankle: a 12-year experience from a tertiary orthopaedic oncology unit. J Foot Ankle Surg 2004; 43: 407e11. 6 Monaghan H, Salter DM, Al-Nafussi A. Giant cell tumour of tendon sheath (localised nodular tenosynovitis): clinicopathological features of 71 cases. J Clin Pathol 2001; 54: 404e7.
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25 Blanco CE, Leon HO, Guthrie TB. Combined partial arthroscopic synovectomy and radiation therapy for diffuse pigmented villonodular synovitis of the knee. Arthroscopy 2001; 17: 527e31. 26 Ward Sr WG, Boles CA, Ball JD, Cline MT. Diffuse pigmented villonodular synovitis: preliminary results with intralesional resection and p32 synoviorthesis. Clin Orthop Relat Res 2007; 454: 186e91. 27 Bickels J, Isaakov J, Kollender Y, Meller I. Unacceptable complications following intra-articular injection of yttrium 90 in the ankle joint for diffuse pigmented villonodular synovitis. J Bone Jt Surg 2008; 90A: 326e8.
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28 Mankin H, Trahan C, Hornicek F. Pigmented villonodular synovitis of joints. J Surg Oncol 2011; 103: 386e9. 29 Vastel L, Lambert P, De Pinieux G, Charrois O, Kerboull M, Courpied JP. Surgical treatment of pigmented villonodular synovitis of the hip. J Bone Jt Surg 2005; 87A: 1019e24. 30 Cassier PA, Gelderblom H, Stacchiotti S, et al. Efficacy of imatinib mesylate for the treatment of locally advanced and/or metastatic tenosynovial giant cell tumor/pigmented villonodular synovitis. Cancer 2012; 118: 1649e55.
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incidence and conflicting evidence for sex ratio.3e5 Typically patients are in the 3rde5th decades of life but numerous examples involving infants, children and adolescents have been reported. GCTTS is the most common tumour found in the hand after ganglia, also affecting adults in the 3rde5th decades, but more commonly in women than men.6 The estimated incidence is one new case annually per 50 000 population.7
Pigmented villo-nodular synovitis of joints and tendon sheaths Jonathan Daniel Stevenson Gillian Cribb Paul Cool
Aetiology and pathogenesis Various patho-aetiologies have been suggested for PVNS. An association with trauma and recurrent haemarthrosis has been suggested as synovial haemorrhage and haemosiderin deposition may contribute to the pigmentation of PVNS lesions.5 Haemosiderin deposition is invariably found within PVNS and could result from synovial absorption of blood following haemorrhage.3 In one large series, 80% of localized PVNS and 62% of diffuse PVNS cases had a positive history of trauma.3 Recurrent haemarthrosis secondary to haemophilia or synovial haemangioma have also been postulated as being causative.5 Indeed synovial haemangiomas can be localized or diffuse lesions and differentiating them from PVNS can be a challenge,3 as both may show histological features similar to PVNS, although giant-cell formation is not associated with haemophilia, and unlike PVNS, the haemosiderin pigment is contained within synovial cells and macrophages.8 Inflammatory arthropathies also give rise to histological synovial changes similar to PVNS, suggesting a possible inflammatory or reactive pathogenesis.3 However, Rao and Vigorita reported no progressive fibrotic changes in serial PVNS samples and the lack of distinctive nodules of mononuclear and giant cells in inflammatory arthropathies in their study which refuted an inflammatory relationship.9 Berger et al reported that the aneuploid cell pattern seen in 20% of diffuse PVNS samples was a feature lacking in rheumatoid arthritis, in spite of their histologically homogenous appearance.7 Chromosomal abnormalities,6 the capacity for autonomous growth,10 bone invasion5 and the identification of (rare) malignant transformation11 are suggestive of a neoplastic aetiology.12 The most common genetic abnormality detected has been the translocation of the colony stimulating factor (CSF1) gene in chromosome 1p13.13 Over expression of the CSF1 gene and the CSF1 receptor has been widely implicated in the pathogenesis of PVNS, and may be a future target for therapy.
Abstract Pigmented villo-nodular synovitis (PVNS) is a rare, benign and aggressive disorder of synovial joints and tendon sheaths which is capable of eroding articular structures and bone. It represents a spectrum of pathological disorders ranging from the most common giant-cell tumour of tendon sheath to localized or diffuse intra-articular PVNS lesions and may be associated with joint erosions. It is best treated surgically but recurs if inadequately excised. Adjunctive therapies include injection of intra-articular radio-isotopic materials and external beam radiotherapy.
Keywords giant-cell tumour of tendon sheath; intra-articular; pigmented villo-nodular synovitis; tumour
Introduction First described by Chassignac in 1852,1 it was Jaffe et al who introduced the term Pigmented Villo-Nodular Synovitis (PVNS).2 It is a rare, benign and aggressive disease of the synovium of joints and tendon sheaths. Classic clinical, radiological and histological features of PVNS and Giant-Cell Tumours of Tendon Sheaths (GCTTS) are described and treatments, including novel therapies, are discussed.
Epidemiology The estimated incidence of articular PVNS is 1.8 new cases annually per million population, highlighting the rarity of this disorder.3 There appear to be no socio-economic factors affecting
Mr Jonathan Daniel Stevenson MBChB BMedSci MRCS(Ed) Specialist Registrar Orthopaedics, Greater Manchester and Oswestry Soft Tissue Sarcoma Service (GMOSS), Robert Jones & Agnes Hunt Foundation Trust, Oswestry, Shropshire, UK. Conflicts of interests: None.
Sub-types Granowicz and Mankin divided intra-articular PVNS into localized and diffuse types.14 GCTTS are considered to be an extraarticular PVNS. It is most commonly observed in fingers, but also along the tendon sheaths of the foot and ankle.15 Each subtype is thought to represent a spectrum of the same pathological process,2,16 though clinical presentation, management and prognosis is widely different. Myers and Masi’s 1980 literature review of 1301 PVNS lesions, showed that 69% were GCTTS, 8% localized PVNS and 29% diffuse type PVNS.13 In the same review 66% of articular PVNS lesions were in the knee, 16% in the hip, and 7% in the ankle with infrequent cases involving the foot, wrist, shoulder or elbow.3 GCTTS occurs in the fingers in 78% of
Ms Gillian Cribb MBChB MRCS FRCS(T&O) Consultant Orthopaedic and Oncological Surgeon, Greater Manchester and Oswestry Soft Tissue Sarcoma Service (GMOSS), Robert Jones & Agnes Hunt Foundation Trust, Oswestry, Shropshire, UK. Conflicts of interests: None. Mr Paul Cool MMedSc(Res) FRCS(Ed) FRCS(Orth) Consultant Orthopaedic and Oncological Surgeon, Greater Manchester and Oswestry Soft Tissue Sarcoma Service (GMOSS), Robert Jones & Agnes Hunt Foundation Trust, Oswestry, Shropshire, UK. Conflicts of interests: None.
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Figure 2 (a and b) AP and lateral radiographs of an effused knee with tibial cysts visible in both views.
Pathology Macroscopically diffuse PVNS tumours are usually large (>5 cm), firm or sponge-like with pale multicoloured tissue ranging from tan to golden brown.13 The synovial hyperplasia consists of irregular villous projections with larger nodular protrusions. Localized PVNS lesions appear classically yellowbrown, firm, pedunculated lobulated tumours.17 GCTTS are small (0.5 cme4 cm), circumscribed lobulated white/grey tumours arising along the tendon sheaths embedded within a collagenous pseudocapsule.13 The histological appearances are similar across all three PVNS sub-types. They include proliferative synovial-like mononuclear cells, compacted fibrous stromal cells, foam and haemosiderinladen cells, mixed round cell infiltration, mononuclear
Figure 1 (a and b) AP and lateral radiographs of the left ankle showing sub-chondral cysts and articular erosions.
cases, and less frequently in the foot, hand, wrist and ankle. More commonly found volarly (69%) than dorsally (31%) the distribution in fingers is more equal between proximal (58%) and distal (42%).3
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Figure 4 (a and b) AP radiograph of the right hand showing soft tissue swelling radial to proximal phalanx of index finger. Coronal T1 weighted MRI image showing the well circumscribed low signal GCTTS lesion.
ligamentous bone attachments through which bone invasion is thought to occur.17
Figure 3 (a and b) Lateral knee radiograph showing radio-opaque intraarticular localized PVNS lesion inferior to the patella, and the same lesion demonstrating heterogeneous signal on sagittal T2 weighted MRI.
Clinical presentation Intra-articular diffuse PVNS As the diffuse articular type insidiously infiltrates the synovial cavity lining leading to eventual osseous erosions and subchondral cysts, patients present with insidious swelling and/or pain which has been present for months or years. On
polyhedral cells of fibro-histiocytic origin and multinucleated giant cells.2,9,18 Diffuse lesions demonstrate greater vascularity and haemosiderin deposition,3 and have a typically villous pattern lacking in extra-articular disease.13 PVNS may accumulate near the chondro-osseous junction and around vascular and
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Figure 6 Axial image from CT guided biopsy of PVNS involving knee joint.
Intra-articular nodular PVNS The localized articular type manifests itself as a pedunculated nodule within the joint. In the knee PVNS lesions tend to occur at the menisco-capsular junction in the anteromedial compartment.20 Patients may complain of intermittent locking (90%), pain (80%) and episodic swelling (60%).3,8 Localized mobile swellings, mild effusion and limitation of movement may be observed clinically.4 As the symptoms can mimic more common mechanical joint disorders, such lesions are often found unexpectedly after imaging. GCTTS In 99% of cases of GCTTS, the presenting complaint is of a slowgrowing swelling ranging from 1 cm to 4 cm in diameter.7 They tend to involve the radial three digits of the hand, with pain (22%) and limitation of motion (4%) less common features.3 They may also occur along tendon sheaths of the wrist, foot, ankle and knee.7
Investigation Radiology Radiological appearances in early intra-articular PVNS lesions are normal in up to 20% of cases.20 As the disease progresses, early synovial swellings without calcification and effusion with preserved joint spaces are typical, followed by juxta-articular and sub-chondral erosions. Cysts develop in advanced disease (Figures 1 and 2).3,18 Localized intra-articular PVNS most often occurs in the anterior portion of the knee where it may produce a soft tissue mass visible on lateral radiographs because of its contrasting radio-density to Hoffa’s fat pad (Figure 3).17 GCTTS lesions typically give rise to localized soft tissue swellings along the volar aspect of the affected digit with radiological evidence adjacent bone erosion found in 11% cases (Figure 4a).21 Intraarticular lesions demonstrate bone erosions in up to 20% of localized and 50% of diffuse cases respectively.3 Bone invasion is
Figure 5 (a) T2 sagittal MRI (from the same patient as Figure 2) shows the extensive ‘blooming’ low to intermediate signal PVNS lesion within the supra-patellar pouch and popliteal fossa. (b) Axial T1 weighted image showing the sub-chondral cysts of the tibia and the low signal PVNS lesion in the popliteal fossa.
examination there may be firm swellings, diffuse tenderness, effusion and restricted movement.4 In one large series, swelling and pain were found in 79% of patients, restriction of movement in 26% and a palpable mass in 6% of cases at presentation.3 Haemarthrosis was present in 75% of patients with diffuse PVNS of the knee in whom synovial fluid was analysed.19
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and 18% in the knee.19,23,24 Open anterior and posterior synovectomy of the knee joint has significantly greater recurrence free survival than anterior arthroscopy and open posterior synovectomy or anterior arthroscopic synovectomy alone.23 However, the additional surgical dissection increases the risk of stiffness, contractures, reflex sympathetic dystrophy (complex regional pain syndrome), neurovascular and wound complications (Figure 7).19,23 Radiotherapy (RT) has been used to augment surgery following incomplete synovectomy and in recurrent PVNS. Blanco et al combined partial arthroscopic synovectomy with low-dose external beam RT in 22 knees with diffuse PVNS, reporting 14% recurrence at 1 year.25 No harmful RT effects were reported and the recurrence rate was comparable to total open synovectomy alone. Adjuvant intra-articular radio-isotopic therapy is also reported to give low recurrence rates.26 However, significant complications have been described; Bickels et al reported three serious complications in series of seven patients with diffuse ankle PVNS, including full thickness skin necrosis and deep sepsis, and the authors have since discontinued using this treatment.27 Chin et al compared the combined use of surgery with and without intra-articular radio-synovectomy or external beam RT in both primary and recurrent diffuse PVNS of the knee.19 All patients had combined open anterior and posterior synovectomy. Seven recurrences (18%) were reported despite adjuvant radiation therapy, and a statistically significant reduction in knee flexion was detected in the external beam RT group. Consequently the authors recommended adjuvant radiation therapy only for symptomatic recurrences, not for the treatment of primary disease. Infrequently later arthroplasty (5%) or arthrodesis (6%) may be necessary after synovectomy of the knee.28 Open synovectomy does not prevent secondary osteoarthritis of the confined hip joint. All the patients in the largest series of hip PVNS to date subsequently required total joint arthroplasty.29
more likely to occur in joints such as the hip which do not have large recesses to accommodate expanding synovial masses.19 Magnetic resonance imaging (MRI) MRI is the investigation of choice9 enabling extent, erosion and invasion to be demonstrated which is crucial in planning surgical approaches. It is reported to be 100% sensitive and specific for detecting diffuse PVNS of the knee pre-operatively.19 It will demonstrate synovially based nodular swellings with heterogeneous low to intermediate signal on both T1 and T2 weighted sequences.8 The difference in magnetic susceptibility between haemosiderin-laden PVNS and surrounding tissue may cause the lesion to appear larger (‘blooming’) on gradient echo images (Figure 5).17 Synovial masses may be extensive in diffuse PVNS involving adjacent synovial structures (semimembranosus, semitendinosus and gastrocnemius bursae), beneath menisci and extending into the popliteal fossa.17 The localized form is usually seen as a single intra-articular nodule or along the tendon sheath in GCTTS (Figure 4b). Biopsy The presence of erosive changes and extensive soft tissue infiltration may lead to the suspicion of soft tissue sarcoma or haemophilic arthropathy, necessitating pre-operative biopsy.14 Biopsies should be taken routinely to confirm diagnosis prior to surgery and may be image (Ultrasound or Computed Tomography) guided (Figure 6) or performed as an outpatient procedure if the lesion is palpable. Differential diagnosis The localized form is often clinically indistinguishable from acute mechanical derangement such as meniscal tears or cysts, loose bodies, osteochondritis dissecans or chondromalacia.4 The diffuse form may be clinically and radiologically similar to haemophilic and inflammatory arthropathies, soft tissue sarcoma and synovial chondromatosis.14,19 GCTTS may be clinically similar in presentation to ganglia, inclusion cysts, sebaceous cysts and rheumatoid synovitis.15
Management In common with other benign aggressive lesions with low propensity for metastasis, PVNS lesions are principally managed surgically.10 The aim is to achieve complete excision with a minimum of soft tissue disruption and to prevent joint erosions and destruction. Incomplete synovectomy is significantly related to recurrence; consequently so-called ‘recurrences’ are thought to represent residual PVNS tissue.19 Arthroscopic excision of localized PVNS lesions of the knee is well established and reported recurrence rates range from 0 to 24%.11,22 In the largest series of localized PVNS of the knee, recurrence free survival with arthroscopic synovectomy has been reported as 91% at 2 years and 73% at 5 years.23 While arthroscopy may have a role to assess the extent of radiologically diffuse lesions which occasionally may originate from one pedunculated stalk and be amenable to arthroscopic excision, the greater propensity of diffuse PVNS than localized PVNS to recur (55% recurrence has been reported with subtotal arthroscopic synovectomy of the knee22), makes open synovectomy preferable.10 The reported recurrence rates are between 8%
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Figure 7 Anterior and posterior clinical photographs right knee 6 months and 2 months following anterior and posterior open synovectomies for diffuse PVNS.
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7 Berger I, Weckauf H, Helmchen B, et al. Rheumatoid arthritis and pigmented villonodular synovitis comparative analysis of cell polyploidy, cell cycle phases and expression of macrophage and fibroblast markers in proliferating synovial cells. Histopathology 2005; 46: 490e7. 8 Sharma H, Jane MJ, Reid R. Pigmented villonodular synovitis of the foot and ankle: forty years of experience from the Scottish bone tumour registry. J Foot Ankle Surg 2006; 45: 329e36. 9 Rao S, Vigorita VJ. Pigmented villonodular synovitis (Giant-cell tumour of the tendon sheath and synovial membrane). A review of eighty-one cases. J Bone Jt Surg 1984; 66A: 76e94. 10 De St. Aubain Somerhausen N, Dal Chin P. So-called fibrohistiocytic tumours. In: Fletcher CDM, Unni KK, Mertens F, eds. World Health Organisation Classification of tumours. Pathology and genetics of tumours of soft tissue and bone. Lyon: IARC Press, 2002; 109e126. 11 Chin KR, Barr SJ, Winalski C, Zurakowski D, Brick GW. Treatment of advanced primary and recurrent diffuse pigmented villonodular synovitis of the knee. J Bone Jt Surg 2002; 84A: 2192e202. 12 Murphey MD, Rhee JH, Lewis RB, Fanburg-Smith JC, Flemming DJ, Walker EA. Pigmented villonodular synovitis: radiologic-pathologic correlation. Radiographics 2008; 28: 1493e518. 13 Myers BW, Masi AT, Feigenbaum SL. Pigmented villonodular synovitis and tenosynovitis: a clinical and epidemiologic study of 166 cases and literature review. Medicine 1980; 59: 223e8. 14 Granowicz SP, Mankin HL. Localized pigmented villonodular synovitis of the knee. J Bone Jt Surg 1967; 49A: 122e8. 15 Saxena A, Perez H. Pigmented Villonodular Synovitis about the ankle: a review of the literature and presentation in 10 athletic patients. Foot Ankle Int 2004; 25: 819e27. 16 Sciot R, Rosai J, Dal Cin P, et al. Analysis of 35 cases of localized and diffuse tenosynovial giant cell tumor: a report from the Chromosomes and Morphology (CHAMP) study group. Mod Pathol 1999; 12: 576e9. 17 Bravo SM, Winalski CS, Weissman BN. Pigmented villonodular synovitis. Radiol Clin North Am 1996; 34: 311e26. 18 Darling JM, Goldring SR, Harada Y, Handel ML, Glowacki J, Gravallese EM. Multinucleated cells in pigmented villonodular synovitis and giant cell tumor of tendon sheath express features of osteoclasts. Am J Pathol 1997; 150: 1383e93. 19 Ravi V, Wang WL, Lewis VO. Treatment of tenosynovial giant cell tumour and pigmented villonodular synovitis. Curr Opin Oncol 2011; 23: 361e6. 20 Kim SJ, Shin SJ, Choi NH, Choo ET. Arthroscopic treatment for locailsed pigmented villonodular synovitis of the knee. Clin Orthop Relat Res 2000; 379: 224e30. 21 Uriburu IJF, Levy VD. Intraosseous growth of giant cell tumours of the tendon sheath (localised nodular tenosynovitis) of the digits: report of 15 cases. J Hand Surg 1998; 23A: 732e6. 22 Olgivie-Harris DJ, McLean J, Zarnett ME. Pigmented villonodular synovitis: the results of total arthroscopic synovectomy, partial arthroscopic synovectomy and arthroscopic local excision. J Bone Jt Surg 1992; 74A: 119e23. 23 Sharma V, Cheng EY. Outcomes after excision of pigmented villonodular synovitis of the knee. Clin Orthop Relat Res 2009; 467: 2852e8. 24 Flandry FC, Hughston JC, Jacobson KE, Barrack RL, McCann SB, Kurtz DM. Surgical treatment of diffuse pigmented villonodular synovitis of the knee. Clin Orthop Relat Res 1994; 300: 183e92.
GCTTS is exclusively managed with open marginal excision and (non-destructive) recurrences are infrequent (10e20%) and managed with repeat excision.10 More frequent recurrences may occur in lesions with higher mitotic cell counts at histological analysis.13
Future treatments Bone erosion has been noted in up to 25%20 of lesions, which is believed to be due to a complex mechanism related to a Tumour Necrosis Factor (RANKL) e CD14 dependent mechanism involving PVNS phagocytes exhibiting phenotypic osteoclastic features.5,18 Lacunar resorption by PVNS derived giant cells has been abolished ex-vivo with bisphosphonates, suggesting a future role for control of bony erosions. Macrophage Colony Stimulating Factor (CSF) 1 is expressed by some PVNS cells.30 CSF1 receptors are inactivated by Imatinib, a tyrosine kinase inhibitor which therefore may have a future role in refractory PVNS. An international retrospective multi-centre study of imatinib efficacy highlighted symptomatic improvement in 16 of 22 patients, but toxicity in 6 cases and a further four discontinued treatment for no discernible reason.30 This development may be useful for patients unsuitable for extensive surgery or in whom surgical excision could result in functional impairment.
Conclusions PVNS is a spectrum of three distinct clinical entities. GCTTS are by far the most common form, with the least potential for recurrence and morbidity. Insidious intra-articular swellings around joints in young or middle aged adults may suggest the rare articular PVNS. MRI and biopsy are essential to confirm the diagnosis, define the extent of lesions and plan treatment. The potential for joint erosions, particularly in the diffuse form, require total synovectomy to control the disease process and to minimize the risk of recurrence. Adjunctive radiation therapies and new novel therapies may have a role for recurrent or refractory cases. A
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25 Blanco CE, Leon HO, Guthrie TB. Combined partial arthroscopic synovectomy and radiation therapy for diffuse pigmented villonodular synovitis of the knee. Arthroscopy 2001; 17: 527e31. 26 Ward Sr WG, Boles CA, Ball JD, Cline MT. Diffuse pigmented villonodular synovitis: preliminary results with intralesional resection and p32 synoviorthesis. Clin Orthop Relat Res 2007; 454: 186e91. 27 Bickels J, Isaakov J, Kollender Y, Meller I. Unacceptable complications following intra-articular injection of yttrium 90 in the ankle joint for diffuse pigmented villonodular synovitis. J Bone Jt Surg 2008; 90A: 326e8.
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28 Mankin H, Trahan C, Hornicek F. Pigmented villonodular synovitis of joints. J Surg Oncol 2011; 103: 386e9. 29 Vastel L, Lambert P, De Pinieux G, Charrois O, Kerboull M, Courpied JP. Surgical treatment of pigmented villonodular synovitis of the hip. J Bone Jt Surg 2005; 87A: 1019e24. 30 Cassier PA, Gelderblom H, Stacchiotti S, et al. Efficacy of imatinib mesylate for the treatment of locally advanced and/or metastatic tenosynovial giant cell tumor/pigmented villonodular synovitis. Cancer 2012; 118: 1649e55.
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