Management of Pigmented Villonodular Synovitis (PVNS): an Orthopedic Surgeon’s Perspective

Abstract

Purpose of Review

Pigmented villonodular synovitis (PVNS) or tenosynovial giant cell tumor (TGCT) encompasses a wide spectrum of disease and is divided into localized and diffuse variants. Surgical resection remains the principal treatment for nearly all localized type disease and most diffuse type. Recent mechanistic understanding of the disease led to drug discovery that has opened new avenues for patients with recalcitrant disease. In this manuscript, we review the current treatment options for TGCT, presenting outcomes from traditional surgical approaches as well as those from nonsurgical approaches.

Recent Findings

Arthroscopic and/or open surgery remains the mainstay of treatment for TGCT for the vast majority of patients. While radiosynoviorthesis and external beam radiation have been used for recalcitrant disease, recent understanding of the colony stimulating factor 1 receptor (CSF1R) pathway and its paracrine and autocrine role in TGCT has led to the development of targeted inhibitors. Their optimal role and efficacy are unclear due to limited number of high-quality studies and contradictory results; however, recent and ongoing studies suggest there may be a role for their use, especially in diffuse and/or refractory disease.

Summary

Surgery remains the most common treatment for TGCT, however, there may be an increasing role for adjuvant therapies, including the new targeted agents. Weighing the side effects of these treatments against the symptomatic benefit on a patient-by-patient basis in this benign disease remains critical.

This is a preview of subscription content, log in to check access.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    de Saint Aubain Somerhausen N, van de Rijn M. Tenosynovial giant cell tumour, diffuse type. In: Fletcher CDM, Bridge JA, Hogendoorn P, Mertens F, editors. WHO Classification of Tumours of Soft Tissue and Bone, vol. 5. 4th ed: International Agency for Research on Cancer (IARC); 2013. p. 100–3.

  2. 2.

    Staals EL, Ferrari S, Donati DM, Palmerini E. Diffuse-type tenosynovial giant cell tumour: current treatment concepts and future perspectives. Eur J Cancer. 2016;63:34–40.

    Article  Google Scholar 

  3. 3.

    • Mastboom MJL, Verspoor FGM, Verschoor AJ, et al. Higher incidence rates than previously known in tenosynovial giant cell tumors. Acta Orthop. 2017;88:688–94 Prior to this study, there was limited epidemiologic data regarding TGCTs. This study found that the incidence of TGCT was higher than thought, affects more females than males, and recurrence is common.

    Article  Google Scholar 

  4. 4.

    Cupp JS, Miller MA, Montgomery KD, Nielsen TO, O’Connell JX, Huntsman D, et al. Translocation and expression of CSF1 in pigmented villonodular synovitis, tenosynovial giant cell tumor, rheumatoid arthritis and other reactive synovitides. Am J Surg Pathol. 2007;31:970–6.

    Article  Google Scholar 

  5. 5.

    West RB, Rubin BP, Miller MA, Subramanian S, Kaygusuz G, Montgomery K, et al. A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells. Proc Natl Acad Sci U S A. 2006;103:690–5.

    CAS  Article  Google Scholar 

  6. 6.

    Staals EL, Ferrari S, Donati DM, Palmerini E. Diffuse-type tenosynovial giant cell tumour: current treatment concepts and future perspectives. Eur J Cancer. 2016;63:34–40.

    Article  Google Scholar 

  7. 7.

    Mollon B, Lee A, Busse JW, et al. The effect of surgical synovectomy and radiotherapy on the rate of recurrence of pigmented villonodular synovitis of the knee: an individual patient meta-analysis. Bone Joint J. 2015;97-b:550–7.

    CAS  Article  Google Scholar 

  8. 8.

    NCCN. NCCN clinical practice guidelines in oncology: soft tissue sarcoma - version 3. 2019. Available at: https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf. Accessed 12/9/2019, 2019.

  9. 9.

    van der Heijden L, Gibbons CL, Dijkstra PD, et al. The management of diffuse-type giant cell tumour (pigmented villonodular synovitis) and giant cell tumour of tendon sheath (nodular tenosynovitis). J Bone Joint Surg (Br). 2012;94:882–8.

    Article  Google Scholar 

  10. 10.

    Dangoor A, Seddon B, Gerrand C, Grimer R, Whelan J, Judson I. UK guidelines for the management of soft tissue sarcomas. Clin Sarcoma Res. 2016;6:20.

    Article  Google Scholar 

  11. 11.

    Gu HF, Zhang SJ, Zhao C, Chen Y, Bi Q. A comparison of open and arthroscopic surgery for treatment of diffuse pigmented villonodular synovitis of the knee. Knee Surg Sports Traumatol Arthrosc. 2014;22:2830–6.

    Article  Google Scholar 

  12. 12.

    Colman MW, Ye J, Weiss KR, Goodman MA, McGough RL 3rd. Does combined open and arthroscopic synovectomy for diffuse PVNS of the knee improve recurrence rates? Clin Orthop Relat Res. 2013;471:883–90.

    Article  Google Scholar 

  13. 13.

    Palmerini E, Staals EL, Maki RG, Pengo S, Cioffi A, Gambarotti M, et al. Tenosynovial giant cell tumour/pigmented villonodular synovitis: outcome of 294 patients before the era of kinase inhibitors. Eur J Cancer. 2015;51:210–7.

    Article  Google Scholar 

  14. 14.

    •• Mastboom MJL, Staals EL, Verspoor FGM, et al. Surgical treatment of localized-type tenosynovial giant cell tumors of large joints: a study based on a multicenter-pooled database of 31 international sarcoma centers. J Bone Joint Surg Am. 2019;101:1309–18 This study examined outcomes after surgical treatment of localized TGCT. Investigators found that larger tumor size and initial surgical treatment with arthroscopy (versus open resection) were associated with recurrence after resection. Open resection was associated with relatively low complication rates and good functional outcomes, and thus led the authors to recommend an open approach and complete resecection over arthroscopy to minimize the risk of recurrence.

    CAS  Article  Google Scholar 

  15. 15.

    •• Mastboom MJL, Palmerini E, Verspoor FGM, et al. Surgical outcomes of patients with diffuse-type tenosynovial giant-cell tumours: an international, retrospective, cohort study. Lancet Oncol. 2019;20:877–86 This international, multi-center, retrospective cohort study assessed outcomes after surgical management of patients with diffuse-type TGCT. Surgical treatment was associated with recurrence in 44% of patients and 12% of patients had complications.

    Article  Google Scholar 

  16. 16.

    Georgiannos D, Boutsiadis A, Agathangelidis F, Papastergiou S, Karataglis D, Bisbinas I. Arthroscopically-assisted mini open partial synovectomy for the treatment of localized pigmented villonodular synovitis of the knee. A retrospective comparative study with long-term follow up. Int Orthop. 2017;41:925–30.

    Article  Google Scholar 

  17. 17.

    Cassier PA, Italiano A, Gomez-Roca CA, le Tourneau C, Toulmonde M, Cannarile MA, et al. CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study. Lancet Oncol. 2015;16:949–56.

    CAS  Article  Google Scholar 

  18. 18.

    Gelderblom H, Cropet C, Chevreau C, Boyle R, Tattersall M, Stacchiotti S, et al. Nilotinib in locally advanced pigmented villonodular synovitis: a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2018;19:639–48.

    CAS  Article  Google Scholar 

  19. 19.

    Tap WD, Wainberg ZA, Anthony SP, Ibrahim PN, Zhang C, Healey JH, et al. Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor. N Engl J Med. 2015;373:428–37.

    CAS  Article  Google Scholar 

  20. 20.

    •• Tap WD, Gelderblom H, Palmerini E, et al. Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial. Lancet. 2019;394:478–87 This study investigated the efficacy and safety of a CSF1R tyrosine kinase inhibitor, nilotinib in locally advanced and non-resectable TGCT. 92.6% of patients attained disease control after 10 weeks of treatment – though 96% had a treatment-related adverse event. No grade 4 or 5 adverse events were reported and the authors concluded that CSF1R tyrosine kinase inhibitors have anti-tumor activity, and manageable toxicity in patients with inoperable diesase.

    CAS  Article  Google Scholar 

  21. 21.

    •• Verspoor FGM, Mastboom MJL, Hannink G, et al. Long-term efficacy of imatinib mesylate in patients with advanced tenosynovial giant cell tumor. Sci Rep. 2019;9:14551 This international, multi-institutional, retrospective study aimed to assess the efficacy of imatinib mesylate in treating patients with advanced TGCT. They report one- and five-year progression-free survival of 71 and 48% respectively.

    CAS  Article  Google Scholar 

  22. 22.

    DSI: Turalio (pexidartinib), prescribing information. Available at: https://dsi.com/prescribing-information-portlet/getPIContent?productName=Turalio&inline=true. Accessed 12/9/2019, 2019.

  23. 23.

    Modder G. Radiosynoviorthesis (radiation Synovectomy). In: Biersack HJ, Freeman LM, editors. Clinical Nuclear Medicine. Berline, Heidelberg: Springer; 2007.

    Google Scholar 

  24. 24.

    • Durr HR, Capellen CF, Klein A, et al. The effects of radiosynoviorthesis in pigmented villonodular synovitis of the knee. Arch Orthop Trauma Surg. 2019;139:623–7 This study examined the local recurrence rates of TGCT after open surgical synovectomy with or without adjuvant radiosynoviorthosis. The authors report a 23% recurrence rate in the radiosynoviorthosis group and 27% recurrence rate in the control group. The investigators conclude that surgery remains the mainstay of therapy, however radiosynoviorthosis may help reduce recurrence rates after surgical resection.

    Article  Google Scholar 

  25. 25.

    • Gortzak Y, Vitenberg M, Frenkel Rutenberg T, et al. Inconclusive benefit of adjuvant 90yttrium hydroxyapatite to radiosynovectomy for diffuse-type tenosynovial giant-cell tumour of the knee. Bone Joint J. 2018;100-b:984–8 This research investigated the long-term outcomes of patients with diffuse-type TGCT treated with synovectomy with or without intra-articular injection of90Yttrium hydroxyapatite. There was no significant difference in outcome.

    CAS  Article  Google Scholar 

  26. 26.

    Mollon B, Lee A, Busse JW, et al. The effect of surgical synovectomy and radiotherapy on the rate of recurrence of pigmented villonodular synovitis of the knee: an individual patient meta-analysis. Bone Joint J. 2015;97-b:550–7.

    CAS  Article  Google Scholar 

  27. 27.

    Patel KH, Gikas PD, Pollock RC, Carrington RW, Cannon SR, Skinner JA, et al. Pigmented villonodular synovitis of the knee: a retrospective analysis of 214 cases at a UK tertiary referral centre. Knee. 2017;24:808–15.

    CAS  Article  Google Scholar 

  28. 28.

    Mollon B, Griffin AM, Ferguson PC, Wunder JS, Theodoropoulos J. Combined arthroscopic and open synovectomy for diffuse pigmented villonodular synovitis of the knee. Knee Surg Sports Traumatol Arthrosc. 2016;24:260–6.

    Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Nicholas M. Bernthal.

Ethics declarations

Conflict of Interest

Nicholas M. Bernthal has received research funding from the National Institutes of Health (NIH), and has received compensation from Zimmer Biomet, Daiichi Sankyo, and Onkos Surgical for service as a consultant. Chad R. Ishmael and Zachary D.C. Burke have no potential conflicts of interest to disclose.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Sarcomas

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bernthal, N.M., Ishmael, C.R. & Burke, Z.D.C. Management of Pigmented Villonodular Synovitis (PVNS): an Orthopedic Surgeon’s Perspective. Curr Oncol Rep 22, 63 (2020). https://doi.org/10.1007/s11912-020-00926-7

Download citation

Keywords

  • Pigmented villonodular synovitis (PVNS)
  • Tenosynovial giant cell tumor (TGCT)
  • Orthopedic surgery
  • Radiosynoviorthesis
  • External beam radiotherapy
  • Oncology