Depicting developing trend and core knowledge of Pigmented Villonodular Synovitis: a bibliometric and visualized analysis

doi:10.21203/rs.3.rs-1504334/v1

Background Pigmented Villonodular Synovitis（PVNS）is a subtype of Tenosynovial Giant Cell Tumor that can broadly affect the soft tissue inner layer of the joints and tendons. It has a high rate of invasiveness and recurrence, which means it has become a crucial issue. This study provides information on the present status, evolutionary path, worldwide trends, frontier research hotspots, and future research developmental trends in this field.

Methods Publications from 1971 to 2021 were retrieved from the Web of Science database and analyzed using a bibliometric methodology. VOSviewer software was utilized for analysis.

Results There is an increasing trend of relative research interests and the number of publications per year globally. The research institution with the highest documents and citations was Harvard University. The United States showed its dominant position in publication outputs, followed by China and Germany. Clin Orthop Relat Res and Skeletal Radiol have published the most papers in this field. The keywords can be divided into eight clusters: ‘mortality’, ‘surgical management’, ‘rehabilitation’, ‘osteoporosis’ and ‘epidemiology’.

Conclusions The publications about PVNS research would be remaining at a high level in the future based on the current global trends. The key focus of PVNS has been synovectomy, joint replacement, radiation therapy, and targeted therapy. Most patients can be controlled through simple surgery, and more research needs to be conducted for patients who need comprehensive treatment.

Pigmented Villonodular Synovitis

VOSviewer

Visualized analysis

PVNS

Pigmented Villonodular Synovitis (PVNS) is a benign lesion characterized by the growth of the villonodular synovium and the deposition of hemosiderin. It encompasses a wide spectrum of diseases and is divided into localized and diffuse variants.[1] Its symptoms usually last for several years before being diagnosed. In addition, it is more aggressive with a high recurrence rate compared to other major subtypes of tendon sheath giant cytomas (GCT-TS).[2] PVNS has been shown to have tumor components.[3] Chromosome 1p13 translocation is present in most PVNS cases and its end effect is overexpression of colony-stimulating factor 1 (CSF1).[4] And it can lead to the recruitment of CSF-1 receptor (CSF1R) inflammatory cells including giant cells, macrophages, and osteoclasts.[5]

The traditional gold standard for the treatment of PVNS is surgical excision and full-slip membrane excision of affected joints, whether using open or arthroscopic methods. However, even after surgery, the recurrence rate of PVNS is as high as 50%,[5] prompting researchers to explore other treatment options. Recently, the clarification of the CSF-1 pathway led to the study of a variety of systemic therapies, including monoclonal antibodies and tyrosine kinase inhibitors.[6] Up to now, surgery remains the most common treatment for PVNS, which is often aided by novel targeted drugs or other adjuvant therapy.[7] Due to the rarity of PVNS, prospective clinical trial studies on the efficacy and safety of different treatment regimens have not been able to be conducted on a large scale. Currently, most studies have reported cases, and their results may be influenced by factors such as disease type, location, treatment, and increased number of cases (through a combination of primary and recurrent cases), and therefore lack comparability.

The mechanisms and treatment options were still controversial, this study sought to capture the trends in PVNS research by use of bibliometric analysis, which is more easily allows visualization of publication trends as compared with systematic reviews. Bibliometric analysis is a feasible strategy to summarize and anticipate the research trends qualitatively and quantitatively by evaluating the studies of major authors, journals, institutes, and nations.[8] Additionally, it makes contributions to clinical policy-making and guideline development. This study specifically aimed to trace the evolution of PVNS in the literature with a specific focus on the frequency and connectivity of key terms, authors, journals, publication, institution, and country.

The Web of Science (WOS) Core Collection serves as the standard data set underpinning the journal impact metrics found in the Journal Citation Reports and the institutional performance metrics found in InCites, we selected it for this evaluation. The search strategy was as follows: ((TS= (“Pigmented Villonodular Synovitides”)) OR TS= (“Pigmented Villonodular Synovitis”)) OR TS= (“Diffuse Tenosynovial Giant Cell Tumor”) and the dates of the search were from 1971 to August 5, 2021, which resulted in a total of 1301 records. Information on all identified publications, including title, author, publication year, contributing nations, affiliations, journal, keywords, and abstract, was downloaded.

VOSviewer is a software tool for constructing and visualizing bibliometric networks.[9] These networks may for instance include journals, researchers, or individual publications, and they can be constructed based on citation, bibliographic coupling, co-citation, or co-authorship relations. The core idea of VOSviewer is "co-occurrence clustering", that is, the simultaneous occurrence of two things means that they are related. Based on the analysis unit and cluster visualization of co-occurrence clustering, the main functions of VOSviewer can be summarized as follows: Network visualization, Overlay visualization, and Density visualization.

Quantity of global publications

From 1971 to 5 August 2021, 1301 articles related to PVNS were included in the WOS Core database 2021. As shown in Fig. 1, the annual publications and citations show that the number of publications and references generally increased from 1971 to 2021, and most of the articles were published after 2000 (920,70.7%). The number of citations increased significantly since 2010. The world distribution map of the PVNS study is shown in Fig. 2. The shade of color reflects the density of the articles. The United States ranked first with 366, followed by 112 articles by China, followed by Germany, Japan, and the United Kingdom. A total of 68 countries and regions have published relevant articles

Analysis of global publications

Journals

Both Clin Orthop Relat Res (IF = 4.176) and Skeletal Radiol (IF = 2.199) published 53 articles related to PVNS and ranked first. Arthroscopy (IF = 4.772) came second with 44 publications. Figure 3 shows the top ten journals with the most publications related to PVNS.

Research orientation

The top 10 study directions associated with PVNS are shown in Table 1. So far, the main areas of research are Orthopedics (481), Surgery (335), and Radiology Nuclear Medicine Medical Imaging (268), and Rheumatology (133).

Table 1

The top 10 research orientations and the number of publications in each orientation
Research Areas	Record Count
Orthopedics	481
Surgery	335
Radiology Nuclear Medicine Medical Imaging	268
Rheumatology	133
Pathology	120
Oncology	111
Sport Sciences	106
General Internal Medicine	67
Neurosciences Neurology	58
Research Experimental Medicine	36

Authors

Figure 4 lists the top ten authors with the largest number of published papers. Ranked first, Van De Sande MAJ published 13 papers at the University Medical Center in Leiden, the Netherlands. And there are 12 papers from Blay JY at the LeonBelal Center in Lyon, France. Three of the ten highly productive authors are at the University of Leiden Medical Center in the Netherlands. We also included all the authors in the analysis, irrespective of their relative contribution (first author, corresponding author or co-author).

Institution output

As shown by Table 2, Harvard University published the most papers with 110, followed by University of California System (53) and then by Mayo Clinic (38).

Table 2

The top 10 affiliations and the number of records in each affiliation
Affiliations	Record Count
Harvard University	110
University of California System	53
Mayo Clinic	38
Leiden University	36
University of London	33
University of Texas System	19
Stanford University	19
Cornell University	18
Unicanccer	18
University of Pennsylvania	18
University of Toronto	18
Assistance Publique Hopitaux Paris Aphp	17
Pennsylvania Commonwealth System of Higher Education Pcshe	17
United States Department of Defense	17
Radboud University Nijmegen		16

Document Types

As shown in Appendix Fig. 3, Articles represented the vast majority (73%) and Review represented 10%, followed by Meeting Abstracts (6%), Editorial (3%), Notes (3%), Letters (3%) and Proceedings Papers.

Visualized analysis

In the network map developed by VOSviewer, the different nodes represent different elements, namely the different authors in this figure.8. The size of the nodes reflects the number of published articles. Links between nodes represent associations that include co-authors or co-occurrence, while the colors of nodes/lines reflect different clusters or years. Link intensities are expressed as the total link strength (TLS).

In Fig. 5, a total of 538 authors were identified and analyzed, and at least two papers were published. The five largest authors of TLS are: Stachiotti S (TLS = 58), Gelderblom H (TLS = 52), Palmerini E (TLS = 44), Staals EL (TLS = 43), Maki RG (TLS = 40).

As shown by Fig. 6, different colors represent different clusters. Screen out the Minimum number of occurrences of a keyword = 5. Of the 2476 keywords, 244 meet the threshold. The 244 keywords could be divided into approximately 7 study clusters: ‘mortality’, ‘surgical management’, ‘rehabilitation’, ‘osteoporosis’ and ‘epidemiology’.

The red cluster represents the keywords related to PVNS. Frequent keywords were Pigmented villonodular synovitis, tendon sheath, expression and tenosynovial giant cell tumor. Green clustering represents keywords related to the differential diagnosis of tumors. The frequent keyword was bone. Blue clustering represents the keywords related to imaging diagnosis. The frequent keywords were diagnosis, MRI and synovitis. Yellow clustering represents keywords related to the joints. The frequent keyword was arthroscopy. Purple clustering represents the keywords related to disease treatment. Frequent keywords were synovectomy, diffuse, recurrence and radiotherapy. Light blue clusters represent keywords related to osteology. Orange clustering represents keywords related to the knee.

This paper reviews the research situation and development trend of PVNS included in WOS. The number of publications gradually increases each year. Major researchers, institutions, countries and their partnerships have been identified and important publications highly cited have been highlighted. Using the co-occurrence cluster analysis, the co-occurrence relationship network graph was constructed by analyzing the keywords found in related studies. Clin Orthop Relat Res and Skeletal Radiol contain the most publications on PVNS. Harvard University, University Of California System and Mayo Clinic, represent the top three institutions by publication number, with the most publications coming from the United States, China and Germany.

Through the analysis of word co-occurrence, four key points of PVNS were found: arthroscopic synovectomy, joint replacement, radiotherapy and targeted therapy.

Arthroscopic synovectomy

PVNS lesion synovial tissue is invasive and can destroy bone, so early surgical resection of diseased synovial tissue is of great significance. At present, synovectomy mainly includes open surgery and arthroscopic surgery. [11]Regardless of the surgical method, there is a possibility of recurrence. The longer the follow-up, the greater the likelihood of recurrence.[12]Different types of lesions have different recurrence rates. For localized pigmented villonodular synovitis (LPVNS), there was no significant difference in recurrence rates in open surgery or arthroscopic surgery, but arthroscopic surgery has fewer complications, so arthroscopic surgery is more recommended for the treatment of LPVNS.[13]For diffuse pigmented villonodular synovitis (DPVNS), Gu. et al. report that multidirectional arthroscopic surgery is superior to open surgery in terms of knee function recovery, and can shorten the length of hospital stay and reduce the amount of bleeding.[14]So arthroscopic surgery is preferred for arthroscopic synovectomy

Joint replacement

With the development of surgical techniques and material science, artificial joint replacement has been widely used in the treatment of various end-stage osteoarthropathy. Studies have shown that complete synovectomy combined with joint replacement to treat PVNS can expose the joint more fully and remove the lesion synovium more thoroughly. So the postoperative recurrence rate was lower than synovectomy alone.[15]Houdek et al. studied PVNS patients undergoing 48 total knee replacements (TKA), with a mean follow-up of 14 years, found a 10-year relapse-free survival of 88%.[16]

Casp et al. showed that PVNS patients in TKA had a higher rate of infection and stiffness when compared with the control group. Therefore, the long-term effects of joint replacement for PVNS require more data assessment. Joint replacements still require caution, which is usually reserved for older end-stage patients. Because the patient population of PVNS is about 40 years old, joint replacement is not the best choice unless the joints are very poor or the end-stage bone destruction is severe.

Radioactive therapy

Due to the invasive nature of PVNS, it is difficult to completely remove the lesion synovium when the lesion expands outside the joint or erodes the vascular nerve tract. This is an important cause of postoperative recurrence, and postoperative radiotherapy plays an auxiliary role in eradicating residual small lesions after surgery.[17]And surgery will aggravate irreversible damage to the bone and joints. Radioactive therapy is the most commonly used adjuvant modality, including External beam radiation therapy (EBRT) and Internal radiation synovectomy (RSO).

When analyzed according to different radiotherapy modalities, EBRT, OR = 0.16[95%CI (0.07,0.38)], P < 0.0001, indicating that the recurrence rate of combined EBRT after synovectomy is significantly lower than that of the surgical group alone. For internal radiation synovectomy, OR = 0.54[95%CI (0.25,1.14)], P = 0.10, no significant difference was seen. The results showed that it was feasible to reduce the recurrence rate in combination with EBRT, while no significant evidence was found with RSO.[19]

Radiation therapy can remove residual lesions after surgery, but it is also damage to the tissues around the knee joint, so radiation therapy may be accompanied by complications.[18]Among them, there are some recent conditions, such as joint swelling and transient bone marrow suppression, and there are also long-term, such as skin pigmentation, ischemic necrosis and cancerous degeneration of bone.

Targeted therapy

Small molecule and monoclonal antibody targeted therapies are being investigated as novel treatment methods for PVNS.[20]Based on the role of CSF-1 in the pathogenesis of PVNS, it is clear that CSF-1R inhibitors (tyrosine kinase inhibitors) can be used clinically as targeted therapeutic agents targeting the CSF-1/CSF-1R axis. The main targeted therapeutic agents are nilotinib, imatinib, ematuzumab, and pecidatinib.

Cassier et al use emmatuzumab to treat advanced DPVNS patients and follow-up for 12 months, which found a total efficiency of 86%.[10]Gelderblom et al treated nilotinib in 56 patients with advanced PVNS who could not be surgically and was controlled in 92.6% of patients.[21]A multicentre retrospective study of Verspoor et al was performed with imatinib in 62 patients with advanced or relapsed DPVNS patients. The result was found to be 31% overall efficient, and the 1 year after surgery and 5 years without progress Survival rates were 71% and 48% respectively.[22]Percidatinib is a more selective and more selective novel oral CSF-1R inhibitor. Giustini et al treated one patient with percidatinib, reducing its tumour volume by 48% and significantly improving both symptoms and function after 4 months.[23]Recently, a phase III clinical trial was treated with percidatinib in 61 patients with advanced PVNS. After 25 weeks, the total effective rate was 39% in the drug treatment group, while none in the placebo group was effective.[7]The results above all show that biologically targeted therapy has achieved some results and has good application prospects.

Changing trends of pigmentation villonodular synovitis and its research

Based on the latest findings, percidatinib has been approved by the US Food and Drug Administration for the treatment of PVNS patients with severe dysfunction and contraindications to surgery. Percidatinib and imatinib are also listed as class 1 and 2A recommended drugs by the latest guidelines of the US National Comprehensive Cancer Network for the systemic treatment of PVNS patients.[24]Patients with PVNS urgently need a drug that can replace surgery, reduce pain, and reduce relapse.[25]The results of existing studies suggest that CSF-1R inhibitors have anti-tumumor activity and acceptable toxicity in patients with inoperable advanced PVNS. However, more research is still needed to address the following issues: Adaptation, treatment dose, course of usage; the combination of treatment methods.

In cases where responses to conventional treatments are poor, bio-targeted treatments show encouraging prospects. However, there is still a long way to go to large-scale applications. Further basic research and clinical trials are needed to accumulate more experience.

The publications about PVNS research would be remaining at a high level in the future based on the current global trends. Most PVNS was caused by chromosomal translocation, with dual properties of inflammation and tumor. MRI is the most valuable method of imaging examination. Arthroscopic surgery is preferred for LPVNS, while the surgical method of DPVNS is combined with lesion location, severity, and operative experience. The long-term efficacy of joint replacement remains to be observed. Radiotherapy can reduce the recurrence rate, but its safety is still controversial. Targeted drugs for the CSF-1/ CSF-1R axis offer new therapeutic options. Most patients can be controlled through simple surgery, and more research needs to be conducted for patients who need comprehensive treatment.

Declarations of interest:

none

Funding

The Education Reform Foundation of Central South University (No. 2021JY188), National Natural Science Foundation of China (No. 81802208), and Natural Science Foundation of Hunan Province (No. 2021JJ40922) fund this study.

Ethical approval:

none

Informed consent

No informed consent was required for this study.

Acknowledgements

The authors appreciate Dr. Jinshen He offering constructive suggestions on data collection and revision of the paper.

Authors’ contribution

QC wrote the original manuscript and collected all the data. JF and SC assisted in the collection of all data and made suggestions for the manuscript. QC, JF, and SC participated in the conception and design of the original study. All authors read and approved the final manuscript.

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No competing interests reported.

14AppendixFigure1.tiff
Appendix Figure 1 Coauthorship analysis: Mapping of countries. (The minimum number of documents of a country = 2)
15AppendixFigure2.tif
Appendix Figure 2 A common graph of the major institutions.
16AppendixFigure3.jpg
Appendix Figure 3 Percentage pie chart for each article type

rank	Title	Authors	Publication Year	Total Citations	Average per Year
1	Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor	Tap et al.	2015	234	33.43
2	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	Cassier et al.	2015	196	28
3	A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells	West et al.	2006	260	16.25
4	From the archives of the AFIP - Pigmented villonodular synovitis: Radiologic-pathologic correlation	Murphey et al.	2008	185	13.21
5	Efficacy of imatinib mesylate for the treatment of locally advanced and/or metastatic tenosynovial giant cell tumor/pigmented villonodular synovitis	Cassier et al.	2012	128	12.8
6	Current systemic treatment options for tenosynovial giant cell tumor/pigmented villonodular synovitis: targeting the CSF1/CSF1R axis	Brahmi et al.	2016	61	10.17
7	The macrophage colony-stimulating factor 1 response signature in breast carcinoma	Beck et al.	2009	129	9.92
8	Evaluation and treatment of disorders of the infrapatellar fat pad	Dragoo et al.	2012	90	9
9	CSF-1R inhibitor development: current clinical status	Peyraud et al.	2017	45	9
10	Pigmented villonodular synovitis and tenosynovitis: a clinical epidemiologic study of 166 cases and literature review	Myers et al.	1980	372	8.86

Depicting developing trend and core knowledge of Pigmented Villonodular Synovitis: a bibliometric and visualized analysis

Status:

Version 1

Abstract

Figures

Introduction

Methods

Results

Quantity of global publications

Analysis of global publications

Journals

Research orientation

Authors

Institution output

Document Types

Top 10 most-cited articles average per year

Visualized analysis

Discussion

Arthroscopic synovectomy

Joint replacement

Radioactive therapy

Targeted therapy

Changing trends of pigmentation villonodular synovitis and its research

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1