Localized pigmented villonodular synovitis of the knee joint: neoplasm or reactive granuloma? A review of 18 cases
C. Perka3,
K. Labs,
H. Zippel and
F. Buttgereit1
Department of Orthopaedics and
1 Department of Rheumatology and Clinical Immunology, Charité University Hospital, Humboldt University, Schumannstrasse 20/21, 10117 Berlin, Germany
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Abstract
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Objective. The localized form of pigmented villonodular synovitis of the knee joint is a rare disease with limited alteration of the synovial membrane, the pathogenesis of which is the subject of controversial discussion.
Methods. Eighteen cases have been documented in our hospital since 1976. All of the patients had additional cartilage or meniscus damage. Treatment consisted of excision of the lesion and the adjacent synovial membrane, as well as therapy of the additional damage.
Results. The patients who had received such therapy were followed for 39 yr, without any clinical, sonographic or magnetic resonance tomographic signs of recurrence. In addition to the lack of a tendency towards recurrence, none of the cases displayed any further characteristics of the diffuse form of villonodular synovitis, such as invasiveness or malignant transformation.
Conclusions. We therefore suggest that pigmented villonodular synovitis of the knee joint should be classified more strictly than before into a potentially neoplastic (diffuse) form and a reactive granulomatous (local) form. From the cases observed, we conclude that degenerative joint lesions may be the cause of the reactive granulomatous form.
KEY WORDS: Pigmented villonodular synovitis, Benign giant cell tumour, Reactive granuloma
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Introduction
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Villous, inflammatory nodular neoplasms of the synovial membrane were first described in the 19th century. Because of their uncertain pathogenetic classification, these lesions of the synovial membrane were given various different names, such as xanthomatous giant cell tumour, histiocytic giant cell tumour, xanthoma, benign synovialoma, haemorrhagic villous arthritis and localized pigmented villonodular synovitis (PVNS). The term PVNS was introduced by Jaffe et al. [1] in 1941 and subsequently gained general acceptance. At present, generalized pigmented villonodular synovitis (GVNS) is differentiated from localized pigmented villonodular synovitis (LVS). LVS is further subdivided into an articular (ALNS) form and an extra-articular (ELNS) form [2]. Myers and Masi [3] describe 166 cases, with ELNS occurring in 70.5%, GVNS in 23.5%, and ALNS in only 6%. ALNS is thus rare, with an estimated prevalence of 1.8/1 000 000 inhabitants. Most patients with PVNS are in their thirties [35]. There is no specific sex predilection [5, 6]. The involvement of several joints has only been described for GVNS [7, 8].
The pathogenetic classification is a matter of contention, due to the different characteristics of the disease entities. On the one hand, invasive growth and a tendency to recur suggest a neoplastic origin [9]. On the other hand, classification as a reactive granuloma would be a logical conclusion on the basis of the histology typical of granulation tissue [6]. Alternatively, a borderline case between a reactive and a neoplastic lesion has also been postulated [10].
In this paper, we present the findings and course of disease of 18 patients with ALNS. First, we recapitulate clinical, technical, laboratory and histopathological findings which confirm the diagnosis of ALNS. Second, we describe surgery as the therapeutic method of choice. Third, and finally, we provide arguments to support our suggestion that PVNS of the knee joint should be classified more strictly than before into a potentially neoplastic (diffuse) form and a reactive granulomatous (local) form.
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Patients and methods
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In 7500 knee joint interventions between 1976 and 1995, ALNS was histologically confirmed in 18 cases. Possible differential diagnoses, such as hemangiopericytoma, synovial membrane changes secondary to haemosideroses, haemophilia or angiomas, were conclusively ruled out. The clinical, radiological and pathohistological data were completely documented in all 18 cases. The average age of onset was 34.9 yr (range 851 yr). The sex distribution was approximately balanced, with a female:male ratio of 10:8. The standardized clinical examination was followed by technical imaging procedures. In all patients, bilateral knee joint images were taken in two planes. Pre-operative sonography was also performed in 10 cases. In a few cases, magnetic resonance tomography (MRT), computed tomography (CT) or scintigraphy (
three each) was also performed. In all patients, the following laboratory parameters were recorded: blood count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), electrophoresis, serum iron, rheumatoid factor (RF), alkaline phosphatase, calcium and phosphate.
All tumours were surgically excised, and concomitant findings were given appropriate intra-operative treatment. The intra-operative site was photographed and the macroscopic findings were recorded descriptively. The diagnosis was verified in all cases by a histopathological examination of the excised material. No additional drug therapy or radiotherapy was given.
The follow-up period was 39 yr (median 5.6 yr). All patients were regularly clinically, sonographically and radiologically monitored over this period. All patients were re-examined by means of a questionnaire and physical and radiographic examinations. The questionnaire included the Lysholm knee score and the evaluation of the patients' activity levels [11]. The physical examination included assessment of the range of motion, swelling, tenderness meniscal, ligamental and patellar disorders. Varus and valgus stress tests with extended and slightly flexed knee and the Lachmann and pivot shift were also performed. Finally, Ahlbäck's classification [12, 13] of arthrosis was used to evaluate the radiographic findings. On the basis of Ahlbäck's classification, patients without changes were allocated to grade 0, patients with a narrowing of the joint space to grade 1, patients with obliteration of the joint space to grade 2 and patients with minor bone attrition to grade 3. Grade 4 patients had a moderate bone attrition, while grade 5 patients had major bone attrition.
In two patients who had questionable findings, an MRT was additionally prepared in order to exclude recurrence.
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Results
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Diagnostic and surgical therapy were performed after a history ranging from 0.1 to 10 yr. After this time, the patients had consulted their attending doctors with mild to moderate pain in a knee joint, recurrent joint swelling, and severely limited mobility. In seven cases, the onset of the complaints was associated with trauma.
The clinical examination revealed a clinically palpable tumour in four patients (Fig. 1
). A trapped tumour mimicking meniscus symptoms was clinically evident in three patients. In the other 11 cases, the complaints suggested that degenerative changes were the cause. The sonography performed on 10 patients within the context of technical diagnostics revealed an echo-intense mass in each case. Radiologically, an intensified soft-tissue shadow around the joint could be found in 11 patients, a widening of the joint cavity in three patients, and an intensified synovial membrane shadow in six patients. Radiologically visible degenerative changes were detected in three cases. No cases of bone erosion, osteoporosis around the joint or loose bodies were observed. A radiological reduction in bone mineral density in the vicinity of the tumour, which has been described for GVNS, was not found. In the MRT, in T1 and T2 weighting the tumours showed a signal which was similar to that of the surrounding skeletal musculature. After gadolinium administration, there was strong enhancement in each case (Fig. 2a
, b). The laboratory findings were normal in all patients. Intra-operatively, a serious joint effusion was found in all cases. The smallest tumours were pea-sized, the largest tumour excised had an extent of 6 x 5 x 4 cm (Fig. 3a
, b). Macroscopically, sessile or pedunculated, pale yellow to brown, elastic and in part deeply flapped nodules were found (Figs 4
and 5
). The secondary destruction of the cartilage, which has been described for GVNS by invasive pannus formation [14] or bone infiltration, was not observed. Figure 6
shows the localization of the tumours in the knee joint. The resection of the tumour and the excision of the surrounding synovial tissue was performed after arthrotomy in 16 cases, and arthroscopically in two cases. The secondary findings were treated appropriately (e.g. abrasion arthroplasty, meniscus resection, plica resection, lateral release). The tumour localizations and the observed degenerative changes listed in Table 1
clearly show that there is no connection between the localization of the tumour and the site and extent of the degenerative changes.

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FIG. 1 Clinically visible tumour in the superior lateral recess, in which the histological diagnosis of ALNS was rendered after surgical excision.
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Fig. 2 Magnetic resonance imaging showing localized villonodular synovitis in (a) sagittal and (b) transversal section.
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Fig. 3 Intra-operative site with image of an approximately 40 x 30 x 25 mm ALNS in the superior lateral recess (a). After incision of the tumour, macroscopic evidence of cartilage zones and central necrosis (b).
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TABLE 1. Overview of the localization, length of medical history, sex distribution, age, height, and concomitant intra-operative findings in patients with ALNS of the knee joint. Classification of the cartilage findings according to Outerbridge [15]
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The diagnosis of ALNS was confirmed histologically in all cases. Characteristically, flat synovial cover cells were found on the surface in the resected material [16]. The lesion itself was characterized by polygonal mononuclear cells and by the detection of giant cells with up to 20 nuclei. In addition, lipid and haemosiderin pigment deposits were observed (Fig. 7a
, b).

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Fig. 7 Histological picture of ALNS. (a) Image of the typical colourful picture with giant cells, foam cells, histiocytes and fibroblasts (haematoxylin and eosin x 40). (b) Image of iron deposition in ALNS localized in the superior recess (Fe staining x 20).
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In the follow-up examinations, all of the patients had clinically normal palpatory and mobility findings. All knees were stable. There were no signs of meniscal or patellofemoral disorders. At the follow-up, 16 patients had an excellent and two patients a good knee function in the Lysholm knee score. Three patients reported occasional pain during vigorous activities, but none of the patients had knee swelling or locking. No cases of recurrence were found in subsequent sonographic, radiological or MRT examinations. According to Ahlbäck's radiographic classification, seven patients had no signs of arthrosis, 10 patients had grade 1 arthrosis and one grade 2 arthrosis.
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Discussion
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The findings of 18 patients with ALNS of the knee joint were described in the present study. After a varying length of medical history, mild to moderate pain, recurrent joint swelling and functional impairments were typical. Acute locking of the joint, as described in the literature, was rare in our patient clientele [17, 18]. Our results show that the clinical symptoms were mostly caused by the concomitant findings, such as cartilage damage, meniscus and ligament lesions. Diagnosis of the tumour was rendered in only four cases on the basis of the clinical findings. Sonography, radiology [5, 19, 20] and MRT can detect the mass directly or indirectly. MRT has the highest sensitivity, although a reliable differential diagnosis compared with synovial chondromas or hemangiomas is not possible, even after gadolinium administration (contrast medium enhancement as a result of vascular proliferation) [21, 22]. Moreover, differentiation from post-operative scars can be difficult in the follow-up examination. The sensitivity and specificity of other examination techniques, such as laboratory diagnostics, arthrography (imaging of the mass), scintigraphy (increased enhancement), digital subtraction angiography (moderate vascularization, lack of vascular atypia, late phase with barely increased parenchymal perfusion) and CT (soft-tissue dense, smoothly differentiated tumour with a homogeneous internal structure), are lower. Confirmation of the diagnosis is always provided by histological examination after primary complete surgical resection of the substrate and the adjacent synovial membrane [9, 2326]. Complete tumour excision is essential in order to avoid persistence or recurrence of the symptoms. Open and arthroscopic techniques are of equivalent rank. Complete synovectomy, post-operative radiotherapy, or an additional radiosynovirothesis, as required for GVNS, are not necessary [10, 19, 24, 27].
Despite an average age of 34.9 yr, degenerative joint changes were found in all the patients. Alteration of the synovial membrane as a result of degenerative changes is a known phenomenon [26, 28, 29]. It is known from other studies that radiographic arthrosis at grades 1 and 2, as in our patients, does not significantly influence knee function [30, 31]. Whether or not the arthrotic changes advance and eventually become symptomatic can only be answered by longer follow-up.
Rao and Vigorita [9] also evaluated 14 patients with ALNS, and found nine with pathological radiological findings. Since concomitant degenerative and traumatic damage was found in all cases in the present patient clientele, it is in our opinion conceivable that the development of ALNS is caused by disordered differentiation of the mesenchymal synovial tissue after intra-articular damage. The varying reaction of the synovial membrane to these changes can be explained, as described for alloplastic materials, e.g. in relation to the size of the particles [32]. This supposition is consistent with the histological picture of ALNS, which is characterized by proliferation and fibroblastic growth of histiocytic mesenchymal cells. The foam cells and iron deposits mentioned are secondary changes. The cholesterol-loaded macrophages are not the major characteristic, neither are they permanently detectable [6, 14].
The classification of ALNS and GVNS as different forms of the same pathological process goes back as far as Jaffe et al. [1]. Rao and Vigorita [9] also postulated that, on the basis of the common histological characteristics of solitary nodular, multiple nodular and diffuse lesions, a common histiogenesis is probable. However, in light of the results of our study and taking into account the literature, it must be questioned whether there is a common pathogenesis. The follow-up examinations did not yield evidence of recurrence in any of the patients, which is consistent with the observations of other authors [2, 9, 23, 24].
In contrast to this, a recurrence rate of up to 46% is reported for GVNS [23], including the occurrence of malignant transformation [33] and the occurrence of metastases [34]. Moreover, in genetic investigations, a recurrent aberration on the short arm of chromosome 1 has been demonstrated [35]. Other authors found a trisomy 7 and 5 and a clonal rearrangement of chromosomes 1, 3, 15 in GVNS [36]. The trisomy of chromosome 7 represents a recurrent aberration [37], which is required for synovial chromosomal changes, since genetic changes also occur in ALNS and in normal synovial tissue [38].
A stimulation of growth via parathyroid hormone-related peptide (PTHrP) is conceivable. Receptors of this peptide, which primarily induces the production of osteoclastic cells from haematopoietic cells, have been demonstrated on the histiocytic stromal cells and the giant cells in villonodular synovitis [39].
Determinations of the cytochemical and functional phenotype also demonstrate the expression of all phenotypical characteristics of osteoclasts for the giant cells in GVNS, which explains the bone destruction [40, 41]. The cartilage destruction is in part related to the production of collagenase and stromelysin by the synovial cells in GVNS [40].
The characteristics of GVNS invasiveness [36], aneuploid DNA pattern [42], high recurrence rate [43], occurrence of chromosomal abnormalities [35, 37, 44], malignant transformation [33], and the detection of metastases [34], suggest that an independent entity is involved which is to be differentiated from ALNS. They should be clearly distinguished, in spite of their comparable histological appearance, due to the different therapeutic approach required. The results of our study support the thesis of a neoplastic nature of diffuse villonodular synovitis and a reactive granulomatous origin of ALNS. It remains unclear to what extent the degenerative changes are responsible for inducing the disordered differentiation of the synovial cells, or whether it was the existing structural damage that first led to treatment, as a result of the attendant pain, and thus led to the subsequent diagnosis.
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Acknowledgments
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The authors thank Mrs Manuela Wiechmann, for her assistance in preparing the manuscript.
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Notes
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3 Correspondence to: C. Perka, Klinik und Poliklinik für Orthopädie, Universitätsklinikum Charité, Humboldt-Universität zu Berlin, Schumannstraße 20/21, D-10117 Berlin, Germany. 
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Submitted 9 April 1999;
revised version accepted 21 September 1999.