Abstract Objectives Tenosynovial giant-cell tumour or pigmented villonodular synovitis is an aggressive synovial proliferative disease, with the knee joint being the most commonly affected joint. The mainstay of therapy is surgical resection. The aim of this study was to evaluate the main patient characteristics, treatment and outcomes in a large single-centre retrospective study, focusing on meticulous aggressive open surgical procedures. Methods From 1996 through 2014, 122 surgical interventions were performed in 105 patients. All patients underwent open synovectomy and when the knee joint was affected, combined anterior and posterior synovectomy. Radiotherapy was applied in 2 patients, radiosynoviorthesis in 27 patients. Results In histopathology, the diffuse type was seen in 66 (54%) lesions. Two patients were lost during follow-up. At a median follow-up time of 71 months (range: 13–238), 22 (18%) lesions recurred within a median of 18 months, >90% in the first 3 years. Out of those 22 recurrences, 9 (11%) were seen in primary disease and 13 (34%) were a second recurrence. After renewed resection, 6 (5%) out of the 120 resections had persistent tumour at the end of follow-up. Based on the number of patients with complete follow-up (n = 103), this represents 5.8%. Conclusion In diffuse-type pigmented villonodular synovitis, total synovectomy might be difficult to achieve. As shown in our results and also in the literature, meticulous open resection, especially in difficult to approach areas such as the popliteal space, reduces local recurrence rates. External beam radiation is an option in prevention of otherwise non-operable local recurrences or in non-operable disease. tenosynovial giant-cell tumour, PVS, surgery, recurrence, prognostic factors Rheumatology key messages Pigmented villonodular synovitis has a high risk of recurrence after synovectomy in the first 3 years. Patients with already recurring lesions of pigmented villonodular synovitis are especially at risk for further recurrence. Meticulous surgical resection reduces local recurrence rate in pigmented villonodular synovitis to less than 10%. Introduction Tenosynovial giant-cell tumour, historically known as pigmented villonodular synovitis (PVS), is a benign but aggressive synovial proliferative lesion. It was first described by Chassaignac  and termed PVS by Jaffe et al. . PVS is rare with an annual incidence of about 1.8 patients/million and with a peak in the third or fourth decade of life . The knee joint is the most commonly affected, followed by the hip and ankle joints . In tenosynovial tissue, a proliferation of synoviocytes attracts inflammatory cells such as histiocytes and hemosiderin-laden macrophages . We now distinguish the localized (nodular)—where brownish, villous and nodular tissue is seen, sometimes invading the adjacent bone—from the diffuse type . The aetiology of the lesion is still unknown but neoplastic clones found in PVS often express colony-stimulating factor 1 (CSF1) and frequently have a t(1; 2) translocation . Malignant transformation is reported in very few cases . Clinical presentation is nonspecific with symptoms such as swelling, pain and joint locking caused by nodular lesions . The mainstay of therapy is surgical resection either with marginal excision in localized disease or with total synovectomy in diffusely involved joints or tendon sheaths. There is still controversy whether this should be done by aggressive open synovectomy or by an arthroscopic approach, if feasible [10, 11]. Conventional radiotherapy as well as radiosynoviorthesis might also affect the rate of local recurrence (LR) or even cure the disease . In recent years, systemic antibody treatment with PLX3397, a selective CSF1 receptor inhibitor, has shown some favourable results . The aim of our study was to evaluate the main patient characteristics, treatment and outcomes in a large single-centre retrospective study, focusing on meticulous aggressive open surgical procedures. Methods Patient characteristics From 1996 through 2014, 105 consecutive patients with PVS were treated at our institution and a total of 122 surgical interventions were performed. All lesions had a diagnosis of PVS based on histological features and immunohistochemistry. In most cases, MRI was used to preoperatively define the size and localization of the tumour. The median age of the 58 male and 47 female patients was 42 years (range: 12–82) showing two peaks at 20–30 and 40–50 years, respectively. The affected anatomical region was the knee joint in 58 patients, the feet in 16, the hand in 11, the ankle joint in 9, the hip joint in 4, the elbow joint and soft tissue at the lower calf with 2 each, and sacral joints, soft tissue of the upper calf and shoulder with 1 each. Pain (54%), swelling (40%), joint effusion (12%) and knee locking (3%) were the typical symptoms. The median duration of symptoms until diagnosis was 8 months (range: 0–428). For detection of recurrent lesions, sequential MRI had been used. Forty of the 122 resected lesions were already recurrences after previous surgical resections. Treatment characteristics All patients underwent open synovectomy and in some cases, an additional arthroscopy was performed for diagnostic reasons. At the knee, a combined anterior and posterior synovectomy in diffuse PVS or mini open resections in nodular diseases were performed. In large lesions (e.g. involvement of all parts of the hind and middle foot), a two-stage resection was performed. Adjuvant radiotherapy was applied in 2 patients and radiosynoviorthesis in 27 cases at the knee following a standardized protocol 6–8 weeks after surgery: under sterile conditions, 185 MBq (5 mCi) of 90Y-colloid was administered, after the intraarticular position of the needle tip was ensured by an injection of radiopaque contrast under fluoroscopy. Follow-up evaluation and statistical analysis All but two patients could be contacted for this study. No patient had deceased. MRI was the standard imaging modality for follow-up, starting 3 months after surgery, followed by every 3 months in the first year, every 6 months in the second year and then yearly for 5 years. However, not all patients adhered strictly to that schedule. Recurrence was defined either as a progressive lesion with the typical appearance of PVS in MRI or by conclusive histopathology from repeat excisions. The time to recurrence was calculated from the date of surgery to the date of the first imaging study with a recurrence (as diagnosed by imaging directly or by later histopathology). The study was approved by the Ethics Committee of the Faculty of Medicine, Ludwig-Maximilians-University Munich (P 17-889). Written consent was obtained from all patients. For statistical analysis, the recurrence-free survival was calculated according to the Kaplan-Meier method. Significance analysis was performed using the Log-Rank test or the Chi-square test. The data analysis software used was MedCalc, MedCalc Software, Ostend, Belgium. Results Diffuse PVS was seen in 66 (54%) lesions. Two patients could not be contacted, leaving 120 resections in 103 patients for follow-up. At a median follow-up time of 71 months post-surgery (range: 13–238), 98 of the 120 resected patients showed no evidence of LR. Twenty-two lesions recurred within a median of 18 months (range: 3–75) after surgery (Fig. 1). Of those 22 recurrences, 9 (11%) were seen in primary disease whereas 13 (34%) were in already recurring cases (Fig. 2). Our LR rate was 18% in total. Fig. 1 View largeDownload slide Local recurrence-free survival in 120 surgical resections of PVS PVS: pigmented villonodular synovitis. Fig. 1 View largeDownload slide Local recurrence-free survival in 120 surgical resections of PVS PVS: pigmented villonodular synovitis. Fig. 2 View largeDownload slide The impact of recurrent disease on local recurrence-free survival (P = 0.0009) Fig. 2 View largeDownload slide The impact of recurrent disease on local recurrence-free survival (P = 0.0009) Including all locations, there was no statistically significant difference between LR in diffuse and nodular forms with regards to recurrence. At the knee, 8 of 36 (22%) diffuse and 3 of 28 (11%) nodular lesions recurred (not significant). Out of 29 patients who came to our department with LR after having had the index surgery at other institutions, 10 recurred again. Seven out of those 10 patients had further surgery with one LR treated in a third surgery, which then again led to LR. Out of nine patients with LR after initial resection at our institution, seven had additional surgery, one recurred again and is disease-free after a third surgery. In total, 6 out of 120 resection patients (5%) had persistent tumour at the latest follow-up. Based on the number of patients with complete follow-up (n = 103) this represents 5.8%. Regarding radiotherapy, none of the two patients showed recurrent disease. In 27 patients with adjuvant radiosynoviorthesis, 7 (32%) recurred. Six surgical complications were encountered in total: one necrosis of the femoral condyle after total synovectomy of the knee and repeated radiosynoviorthesis/radiosynovectomy; one peroneal nerve palsy with total recovery; one deep infection; one instability of the collateral ligament at the knee; and two wound revisions due to haematomas. Discussion As described in literature, PVS shows a predilection for young adults. In our large series, we found a previously undescribed double-peak distribution, with the first peak between 20 and 30 and the second between 40 and 50 years of age. Beyond these two peaks, we also saw very young or much older patients with PVS. The latter group had in some cases PVS diagnosed by coincidence in the context of an arthroplasty procedure and in consequence received additional synovectomy. There was no statistically significant sex difference in our series, but we observed a tendency towards males, which is in contrast to most previsously published studies . The duration of symptoms prior to diagnosis was also independent of sex. Our study does not focus on the diagnosis of PVS. MRI is a well-established standard and was used for primary diagnosis and in follow-up [14, 15]. Surgery remains the mainstay of therapy, but there is no generally accepted standard as to what type of surgical procedure should be preferred. Primarily with knee joint PVS, but also when the hip is affected, arthroscopic and open synovectomy are competing treatment modalities. In a survey including 173 patients from 10 centres in Germany and Austria, the rate of LR was very much dependent on the number of cases treated . Institutions with <20 cases per year had an LR of 56%, those with greater numbers ranged between 15 and 37%. In a large meta-analysis including 630 patients with PVS of the knee, in diffuse disease with open synovectomy or the combination of open and arthroscopic synovectomy and adjuvant external beam radiotherapy or radiosynoviorthesis in open and combined surgery, lower rates of LR (24 and 14%) as compared with arthroscopic synovectomy (38%) could be shown. In the localized lesions, there was no difference between the subgroups (LR 6–8%) . This reflects our own experience with a LR at the knee of 22% in diffuse and 11% in localized forms, and either open or combined open and arthroscopic procedures. It is worth mentioning that the rate of joint stiffness was higher (11%) after open surgery as compared with arthroscopic (2%). A careful physical rehabilitation program therefore seems important especially after open synovectomies. These results are in contrast to another large meta-analysis on the same subject including 1019 patients . In localized disease, LR was 7–9% for both methods whereas in the diffuse form, arthroscopic surgery did better (16%) than open surgery (23%). Complications are described in 0% of arthroscopic resections and 19% of open synovectomy. However, in that study radiotherapy in either form was not a selection criterion. The largest analysis with 214 PVS cases at the knee was performed in the UK  with the chosen treatment being nearly exclusively open synovectomy. In this series, LR was 48% in diffuse forms and 9% in localized disease. The authors did not discuss this specifically, but these surprisingly poor results in diffuse forms might be due to the fact that six different surgeons had performed those cases over several years. The number of recurrent cases at presentation (12%) in the UK study offers no adequate explanation for those results (this study 29/105, 28%). So as clearly shown by Bruns et al. , experience and meticulous surgery is most important in aggressive diffuse lesions. During follow-up, one-third of LR were within the first year, another third in the second and <10% after 3 years. Therefore, follow-up MRIs every 6 months during the first 3 years should be able to detect >90% of all LR. LR has a good chance of cure by additional surgery. LR in recurring lesions was in total 34%, but eventually, 94% of the patients were free of tumour. Radiotherapy is a valid option in patients with diffuse disease that cannot be treated by means of surgery. Park et al.  reported LR rates in 4 of 23 patients (17%) treated with 12–34 Gy of external beam radiation with PVS of the knee. But in all of these patients, either arthroscopic or open synovectomy was performed prior to radiation. An LR of 0% after arthroscopic resection and radiotherapy with 20–30 Gy in 26 patients was reported by Li et al. . Adjuvant radiosynoviorthesis/radiosynovectomy with Yttrium-90 is also used in many patients especially at the knee, and this was also the case in our study. There are reports of favourable outcomes but there is no clear indication for this method of treatment [18, 19]. New approaches with an antibody-mediated inhibition of the CSF1 receptor-kinase in a dose escalation study on 41 patients showed stable disease in eight cases and one partial response. The subsequent treatment study in 23 patients showed 12 patients with stable disease and 7 with a partial response . Conclusions PVS is a rare aggressive lesion affecting most often the knee but also any other synovial tissue. In localized disease, marginal resection shows favourable results whereas in diffuse forms, total synovectomy might be difficult to achieve. As shown in our own results as well as in the literature, meticulous resection especially in difficult to approach areas like the popliteal space reduces LR rates. Adjuvant external beam radiation is an option in prevention of otherwise non-operable LRs or in non-operable disease. In follow-up, two-thirds of LR were diagnosed during the first 2 years, and <10% after 3 years. A follow-up MRI every 6 months during the first 3 years should be able to detect >90% of all LR. Acknowledgements Each author has contributed significantly to, and is willing to take public responsibility for, this study: its design, data acquisition and analysis and interpretation of data. All authors have been actively involved in the drafting and critical revision of the manuscript. C.F.C.: student doing his thesis on PVS, contacted the patients and collected the data, involved in drafting and revising of the manuscript. R.T.: nuclear medicine, did the radiosynoviorthesis, involved in drafting and revising of the manuscript. A.K.: surgeon, involved in drafting and revising of the manuscript. A.B.-M.: radiologist, involved in drafting and revising of the manuscript. T.K.: pathologist, involved in drafting and revising of the manuscript. F.R.: reviewing the radiotherapy and deciding which patient to treat or not to treat, involved in drafting and revising of the manuscript. C.B.: surgeon, involved in drafting and revising of the manuscript. V.J.: surgeon, involved in drafting and revising of the manuscript. H.R.D.: corresponding author, developed the study concept, did the final data analysis and provided the major clinical input in writing and revising of the manuscript. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. References 1 Chassaignac M. Cancer de la gaine des tendons. Gaz Hop Civ Milit 1852; 25: 185– 6. 2 Jaffe HL, Lichtenstein L, Suro CJ. Pigmented villonodular synovitis, bursitis and tenosynovitis. 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Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: firstname.lastname@example.org This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
Rheumatology – Oxford University Press
Published: May 16, 2018
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