Challenges and Opportunities in Cronkhite-Canada Syndrome Research: A Bibliometric Analysis Based on the Web of Science Core Collection

Introduction

Cronkhite-Canada syndrome (CCS) is a rare gastrointestinal polyposis syndrome first described by Cronkhite and Canada in 1955 [1]. It is characterized by diffuse gastrointestinal polyposis, severe metabolic disorders, and ectodermal changes, such as alopecia, skin pigmentation, and onychotrophia [2–5]. This syndrome is also known as polyposis-pigmentation-alopecia-onychotrophia syndrome [6]. The estimated prevalence of CCS is 3.7 per million, with more than 500 cases reported worldwide by 2014, predominantly in Japan [7–9]. A nationwide survey in Japan revealed that the average onset age for CCS is 63.5 years (range 31–86 years), with a male-to-female ratio of 1.84: 1 [7]. CCS has a poor prognosis and a high mortality rate. Without timely and effective treatment, severe malnutrition, electrolyte imbalance, intussusception, pulmonary embolism, gastrointestinal bleeding, opportunistic infections, and cancer can lead to death [10]. CCS has historically been associated with a poor prognosis, with earlier reports describing a 5-year mortality rate of approximately 50% to 60% [10,11]. However, with improvements in nutritional support, endoscopic surveillance, and immunosuppressive therapy, more recent studies have suggested substantially improved long-term outcomes, with reported long-term survival rates reaching approximately 85% to 95%. [12]

The pathogenesis of CCS remains unclear. Many studies suggest that it is closely associated with immune dysregulation, possibly involving an autoimmune background [13–15]. Genetic mutations, Helicobacter pylori infection, and physiological and psychological stress can also contribute to CCS development [7,16–18]. Current treatment strategies mainly include corticosteroids, nutritional support, 5-aminosalicylic acid, antitumour necrosis factor-α drugs, immunomodulators, and H. pylori eradication [2,7,18,19]. Corticosteroids are considered the primary treatment; however, there is no unified standard for dosage, and relapses and adverse effects are common.

Several narrative reviews and case-based summaries have described the clinical manifestations, pathological characteristics, potential pathogenesis, and treatment strategies of CCS over the past decades [3,4,19]. These studies have provided important clinical insights; however, due to the rarity of CCS and the predominance of case reports and small case series, the overall publication patterns, collaboration structure, and evolution of research topics across time have not been quantitatively mapped.

Bibliometric analyses serve to quantify the impact of individual research findings, track the development of discipline-specific literature, and evaluate trends in scientific research and information metrics [20]. Bibliometric analyses are also capable of assessing the quantity and progression of scientific outputs among nations in key biomedical domains. This capability is particularly advantageous for emerging disciplines whose contributions to the broader field of biomedical research have not yet been comprehensively assessed [21]. This study aims to integrate previous research on CCS through bibliometric methods, such as analyzing author and institution distributions, keyword co-occurrence, and clustering, to provide an understanding of research trends and development in CCS. Bibliometric and scientometric approaches have been increasingly applied in gastroenterology and rare-disease research to summarize global publication trends, identify influential contributors, and visualize evolving research hotspots [22]. Such analyses provide a complementary perspective to conventional narrative reviews by mapping collaboration networks and knowledge structures across time. However, bibliometric mapping has rarely been applied to CCS, leaving its long-term publication patterns and topic evolution insufficiently characterized. To our knowledge, this is one of the first Web of Science Core Collection (WoSCC)-based bibliometric and visualization studies to systematically summarize CCS research trends, major contributors, collaboration networks, and keyword evolution using CiteSpace and VOSviewer.

Material and Methods

Data Source and Retrieval Strategy

DATA SOURCE AND RETRIEVAL STRATEGY:

The WoSCC was selected as the sole database for this study due to its standardized and high-quality citation metadata, which is compatible with bibliometric analysis tools such as CiteSpace. WoSCC provides broad coverage of biomedical and clinical research and allows direct export of full records and cited references, thereby facilitating co-citation network construction and citation burst detection analyses.

Publications related to CCS were retrieved from WoSCC on 21 June 2025 to minimize bias introduced by continuous database updates. The time interval for eligible publications was defined as from January 1, 1995, to June 21, 2025. A 2-step search strategy was applied to enhance retrieval transparency and sensitivity, consisting of a primary disease-name search and a supplementary symptom-based search.

PRIMARY DISEASE-NAME STRATEGY:

The primary query explicitly centered on CCS as the key concept: TS=(“Cronkhite-Canada syndrome” OR “Cronkhite Canada syndrome”).

SUPPLEMENTARY SYMPTOM-BASED STRATEGY AND JUSTIFICATION:

Because CCS is a rare disorder that is mainly reported as case reports or small case series, some publications – particularly earlier reports – may not consistently include the term “Cronkhite-Canada syndrome” in the indexed title, abstract, or author keywords. Therefore, a supplementary query was conducted using the characteristic constellation of diffuse gastrointestinal polyposis and ectodermal abnormalities: TS=(“gastrointestinal polyposis” AND (alopecia OR hyperpigmentation OR onychodystrophy OR nail dystrophy)).

FALSE-POSITIVE SCREENING AND ELIGIBILITY CONFIRMATION:

Records retrieved by the supplementary strategy were independently screened by 2 reviewers. Publications were included only when CCS was explicitly confirmed as the diagnosis based on the title, abstract, or full text (when accessible). Records related to other gastrointestinal polyposis syndromes or unrelated conditions were excluded. Discrepancies were resolved through discussion until consensus was reached. The inclusion criteria were as follows: (1) publications indexed in WoSCC; (2) topic related to CCS; (3) English language; and (4) document types restricted to articles and reviews. The exclusion criteria were as follows: (1) conference abstracts, editorials, letters, meeting reports, or notes; (2) non–English-language publications; (3) records unrelated to CCS; and (4) duplicate records.

A total of 642 records were initially retrieved. After excluding conference abstracts, editorials, non–English-language publications, and records unrelated to CCS, 256 eligible papers were included for subsequent bibliometric analyses (Figure 1). All included records were exported from WoSCC as “full record and cited references” for analysis and visualization using CiteSpace and VOSviewer.

DATA PROCESSING:

All the valid data retrieved from WoSCC were imported into CiteSpace (6.2. R6), VOSviewer (1.6.20), and Microsoft Excel 2019 to generate visual graphs from which quantitative and qualitative analyses were performed. Microsoft Office Excel 2019 was employed to analyze the trends in the number of articles published. CiteSpace was used to analyze the country and institution network maps, co-citation clustering and time-line maps, and keyword burst detection [20,23]. CiteSpace’s burst detection function was used to identify emerging keywords from titles, abstracts, descriptors, and bibliographic identifiers, allowing us to capture the evolution of research trends over time [24]. VOSviewer (1.6.20) was used to visualize the network of authors and keywords [25].

BIBLIOMETRIC ANALYSIS PARAMETERS:

Bibliometric visualization and network analyses were performed using CiteSpace (version 6.2.R6, 64-bit) and VOSviewer (version 1.6.20) [20,25,26]. In CiteSpace, the time span was set to 1995–2025, with a slice length of 1 year per slice. The node selection criteria were configured as g-index (k=25), with parameters LRF=3.0, L/N=10, LBY=5, and e=1.0. Network pruning was conducted using Pathfinder to simplify network structures, while preserving key links.

CiteSpace was used to generate country/region and institution collaboration networks, reference co-citation clustering and timeline visualizations, and keyword burst detection. Key network metrics, including betweenness centrality (as implemented in CiteSpace), network density, and burst strength, were obtained from CiteSpace outputs. Betweenness centrality was used to indicate the bridging role of nodes in collaboration and co-citation networks, while burst strength reflected a rapid increase in citation or keyword frequency over a specific time period.

VOSviewer was used to visualize author collaboration networks and keyword co-occurrence networks and to provide complementary clustering views based on co-occurrence patterns.

Cluster labels were assigned based on the most representative high-frequency terms within each cluster, and overlap among clusters was allowed due to shared keywords across research themes.

FIGURE GENERATION AND PROVENANCE:

All figures in this study were generated by the authors using the bibliometric software CiteSpace (version 6.2.R6, 64-bit) and VOSviewer (version 1.6.20) based on records retrieved from the WoSCC. No figures were adapted from previously published sources.

Results

PUBLICATION VOLUME AND TRENDS:

Based on the publication year information extracted from WoSCC and summarized in Microsoft Excel 2019, the annual publication trend of CCS-related literature was analyzed. The overall publication volume related to CCS exhibited a fluctuating upward trend (Figure 2). A total of 256 articles published between 1995 and 2025 were included in this review. Initially, the annual publication volume remained low, and most studies were case reports or small-scale investigations. However, since 2005, a clear increase in publication volume was observed, with the number of papers gradually rising over a 17-year period. While there were fluctuations in publication rates annually, the overall upward trend was unmistakable and significant. An apparent decrease in publication output was observed after 2023; however, publication counts for 2025 may be underestimated because the data were retrieved in June 2025 and thus do not represent a complete calendar year. Therefore, short-term fluctuations in publication counts should be interpreted with caution.

COUNTRY/REGION AND INSTITUTIONAL ANALYSIS:

A collaborative network of countries/regions was constructed using CiteSpace to visualize the global distribution and cooperation patterns of CCS research. In the network map, node size reflects publication output, link thickness indicates collaboration strength, and node colors represent different publication years. In CiteSpace, betweenness centrality reflects the importance of each node in the network, whereas burst indicates periods of rapid growth in research activity [24,27].

The collaboration network of countries/regions includes 35 nodes and 30 connections, with a network density of 0.0252, indicating that 35 countries/regions contributed to research in this field. Figure 3 and Table 1 visually depict the collaborative relationships between countries and regions. The analysis revealed that the United States had the highest publication output (66 papers) and a centrality of 0.32, making it not only the primary contributor but also the key hub for international collaboration in CCS research. China followed with 55 publications, showing a significant burst of research activity since 2020. Japan, with the highest number of CCS cases, ranked third, with 51 publications. However, Japan showed a centrality of 0.05. Other countries, including Germany (13 papers), France (9 papers), and Australia (7 papers), have contributed significantly to CCS research.

Analyzing institutions and their collaboration networks helps us better understand the core research forces in this field and their collaboration characteristics. As shown in Table 1, the Mayo Clinic, with 14 publications, ranks first globally and is a leading institution in CCS research. Peking Union Medical College, Chinese Academy of Medical Sciences, ranked second with 12 publications, followed by Capital Medical University from China, with 6 publications in third place. The University of California system and Johns Hopkins University follow closely behind. Figure 4 shows the collaboration between institutions in CCS-related research. The knowledge map includes 261 institutions and 388 connections. All institutions have a centrality of less than 0.1, indicating a lack of strong central institutions and no core nodes occupying a bridge position in the network. In terms of collaboration, the University of California system has a higher degree of cooperation, whereas high-output institutions such as the Mayo Clinic and Peking Union Medical College show relatively lower cooperation, suggesting relatively limited inter-institutional collaboration. Overall, high-yield institutions collaborated mainly with domestic partners, and international cooperation appeared relatively limited. The most common collaborating institutions were large teaching hospitals or affiliated medical schools.

AUTHOR CONTRIBUTION AND COLLABORATION:

An author co-authorship network was generated using VOSviewer to visualize author productivity and collaboration patterns in CCS research (Figure 5), which revealed that 688 authors contributed to CCS-related research. Ji Li published the most articles, with 9 papers, followed by Shuang Liu, with 6 papers. Both authors are from the Peking Union Medical College and have led CCS research in recent years. Among authors from Europe and the United States, Lisa Boardman (3 papers), Lodewijk AA Brosens (3 papers), and HC Wolfsen (3 papers) have been particularly active in CCS research.

KEYWORD CO-OCCURRENCE ANALYSIS:

Keyword co-occurrence analysis was performed using VOSviewer to identify research hotspots and thematic clusters in CCS-related publications. As a concise expression and advanced summary of academic research, keyword co-occurrence is a commonly used method in bibliometrics to reveal the research focus within a field [22]. It can reflect the academic ideas, themes, and content of specific studies. By analyzing keywords, the research hotspots and directions in the field are clarified. A visual analysis of keyword co-occurrence was conducted via VOSviewer, and the network shown in Figure 6 was constructed. The frequency and centrality of keywords are key indicators of their relevance and importance in the literature. High-frequency keywords in CCS research include “Cronkhite-Canada syndrome”, “gastrointestinal polyposis”, “colon cancer”, “juvenile polyposis”, “clinical characteristics”, “alopecia”, “adenomatous polyposis”, “Peutz-Jeghers syndrome”, and “hamartomatous polyposis”. These keywords represent the clinical features, differential diagnoses, and prognoses (Table 2). The keyword clustering analysis grouped related terms into 13 clusters, with each cluster reflecting a research theme (Figure 7). On the basis of the interactions and variations among each cluster, as well as the most frequent keywords associated with each cluster over time, a timeline view was further generated (Figure 8). The keywords were clustered into 13 categories, numbered from 0 to 12, with most clusters overlapping with each other. Combined with timeline analysis, in addition to disease ontology (#1), clusters including “disease ontology” (#1) and “pathogenesis” (#2) showed substantial temporal continuity. Notably, “case reports” (#0) represents a publication type rather than a mechanistic research topic. Over time, the keyword timeline analysis indicated sustained attention to hamartomatous polyps, differentiation from other polyp types, and cancer-related topics in CCS research.

BURST DETECTION OF KEYWORDS:

Burst detection, a feature of CiteSpace, highlights emerging trends in CCS research by identifying keywords that experience sudden surges in frequency (Figure 9). The initial emergence of “Cronkhite-Canada syndrome” (1995–1996) marked widespread recognition of the disease. Other notable bursts included “Muir-Torre syndrome” (1998) and “Peutz-Jeghers syndrome” (2008–2010), which indicated growing recognition of the genetic basis of CCS, and “mutations” (2010–2011), reflecting an increasing focus on genetic mechanisms. Research focused on clinical phenotypes and complications from 2015 to 2016, with “diagnosis” and “gastrointestinal polyposis” emerging as key topics. Recent bursts, such as “cyclosporine” (2020–2021), indicated increased research attention to immunosuppressive treatments in recent years, whereas “therapy” and “remission” (2020–2022) indicated increasing attention to long-term disease management in CCS research. In 2022 to 2025, “case reports” emerged as the most significant burst keyword, underscoring the importance of case accumulation in rare disease research.

Discussion

GENERAL INFORMATION:

In this study, we conducted a WoSCC-based bibliometric analysis of CCS-related publications, resulting in the selection of 256 papers published between 1995 and 2025. The relatively low publication output in the early period may be attributable to the rarity of CCS and the limited awareness of this disease, with most publications consisting of case reports or small case series.

Analysis of the annual publication volume revealed a significant increase in CCS publications after 2005, which may be associated with broader advances in biomedical research capacity and the increasing availability of molecular and translational techniques for rare-disease investigations. The peak in publications after 2015 also overlapped with the rapid development of multiomics approaches (eg, genomics and transcriptomics) [6], microbiome studies [28], and organoid technologies [29], which facilitated a deeper exploration of CCS etiology (eg, gut microbiota and immune pathways). Technological advancements in biotechnology may have contributed to the increasing attention to mechanistic studies in CCS research. The slowed growth observed after 2023 may be influenced by multiple factors, such as variability in publication cycles for rare diseases, potential database indexing and updating effects, and external disruptions (eg, pandemic-related delays), in addition to challenges in assembling large CCS cohorts and biospecimens for mechanistic research.

Visual analysis of countries and institutions revealed a triad of dominant research hubs, namely, the United States, China, and Japan, forming the core forces in CCS research. However, collaboration among these 3 countries is characterized by an “island phenomenon”. The United States, despite being the central hub (centrality=0.32), predominantly collaborates with English-speaking countries (Australia and the United Kingdom) and has weak cooperation with China and Japan. Although China ranks second in publication output (burst=11.60), its international collaboration remains shallow (centrality=0.16). Japan, which reports more than 50% of global CCS cases, has the lowest centrality (0.05), indicating strong isolation in its CCS research. High-output institutions such as the Mayo Clinic and Peking Union Medical College primarily conduct single-center studies, with cross-border collaborations largely limited to case report exchanges, lacking in-depth cooperation in mechanistic research. The relatively limited international collaboration observed in institutional networks may be influenced by the low incidence of CCS and the difficulty of assembling multicenter cohorts, highlighting the potential value of cross-border cooperation and standardized data-sharing frameworks.

Given the rarity of CCS and the limited international collaboration observed, leveraging rare-disease research networks and registry-based collaborations may facilitate standardized data sharing and prospective multicenter studies to support future mechanistic and clinical research.

RESEARCH HOTSPOTS AND FRONTIERS:

Keywords indicate the main research themes and hotspots in a particular scientific field. On the basis of keyword clustering analysis, timeline analysis, and burst keyword detection, CCS research can be divided into 3 stages, as follows.

The first stage (1995–2010) focused on disease definition and a basic understanding of the disease. During this period, research focused primarily on clinical symptoms, particularly the manifestations of polyps, and explored their association with hereditary polyposis syndromes, thereby broadening our understanding of the disease.

The second stage (2010–2020) was marked by mechanistic exploration and prognostic analysis. With advancements in biotechnology, the emergence of “mutations” as a burst keyword signaled a shift in the research focus toward genetic mechanisms, and studies on the pathogenesis of CCS deepened [30]. Additionally, as case reports have accumulated, there has been a clear emphasis on the prognosis of CCS. The increasing risk of malignancy has prompted increased research on polyp characteristics and pathology during the latter part of this phase [31,32]. Consistent with the bibliometric signals, CCS-related studies have increasingly discussed polyp pathology and malignancy-related issues, indicating sustained concern regarding cancer surveillance and long-term outcomes.

The third stage (2020–2025) involves evolving therapeutic strategies and precision management of the disease. During this period, the exploration of pathogenesis led to the emergence of keywords such as “cyclosporine”, “therapy”, and “remission”, signifying significant progress in disease treatment [33,34]. The focus of research has gradually shifted toward achieving long-term remission, improving quality of life, and facilitating social reintegration. An increasing number of case reports with significant treatment outcomes has contributed to the accumulation of data in this field. It should be noted that burst keywords reflect a rapid increase in research attention rather than the overall frequency of clinical use. In addition to cyclosporine, azathioprine has been increasingly reported as a steroid-sparing immunomodulator, including a recent case series from Peking Union Medical College Hospital [35]. Additionally, the emergence of “endoscopic surveillance” as a burst keyword highlights the growing importance of endoscopic monitoring in long-term disease management, with sustained attention to precision management and long-term remission [36,37].

Recent studies from Peking Union Medical College have reported cohort-based investigations using multiomics approaches (eg, genomics and transcriptomics) and have explored treatment outcomes such as corticosteroids and immunosuppressants [6,35], suggesting increasing interest in mechanistic exploration and clinical management of CCS.

In the keyword analysis, “case reports” occupy a significant position, and the continuing importance of case reports in CCS research cannot be overstated. Case reports remain a significant research focus, as they provide essential clinical data on this rare disease, allowing for the accumulation of critical knowledge. These reports are vital for developing a deeper understanding of the clinical manifestations, treatment responses, and long-term prognosis of the disease. However, relying solely on case reports limits the ability to draw definitive conclusions regarding the pathophysiology and therapeutic strategies of CCS. The integration of multiomics approaches, organoid technologies, and large-scale collaborative studies will be essential for advancing our understanding and enabling more robust, evidence-based therapeutic interventions.

Overall, the CCS literature remains largely clinically oriented, with many publications focusing on disease characterization and treatment experience, which is consistent with the rarity of CCS and the predominance of case-based evidence.

RESEARCH GAPS AND RECOMMENDATIONS FOR FUTURE WORK:

Currently, there is insufficient depth in mechanistic studies, and genetic research has emerged only briefly, without progressing to the discovery of actionable therapeutic targets. The clustering of pathogenesis research is small, and its connection to clinical clusters is weak, indicating a disconnect between basic research and clinical translation. Existing case data are dispersed across individual reports, and the lack of a standardized registration platform hampers research integration. Furthermore, the development of alternative models, such as organoids, remains underdeveloped, which is a significant limitation for mechanistic exploration.

There is also a lack of standardized diagnostic and treatment protocols [38]. Currently, there are no unified diagnostic standards or treatment consensuses [39,40]. Diagnosis is primarily based on clinical symptoms, endoscopic findings, and pathological results. Corticosteroids remain the mainstay of treatment; however, their use is inconsistent, leading to high recurrence rates and significant drug-related adverse effects [38,41]. The efficacy of immunosuppressants has been demonstrated only in small, single-center cohort studies, with insufficient evidence from evidence-based medicine.

LIMITATIONS:

Although bibliometric mapping provides a quantitative overview of research landscapes, several limitations of this study should be acknowledged. First, the literature data in this study were sourced solely from the WoSCC, which, while it offers standardized citation metadata suitable for bibliometric visualization, excluding other databases (eg, PubMed, Scopus, and Embase), it can result in incomplete coverage, particularly for rare-disease case reports, and may introduce selection bias in the observed publication and collaboration patterns.

Second, despite applying a 2-step search strategy with a supplementary symptom-based query, some CCS-related publications may still have been missed, particularly those that mentioned CCS without detailed ectodermal descriptors (eg, alopecia, hyperpigmentation, or nail dystrophy). This is especially possible if CCS was not explicitly stated in the indexed title, abstract, or author keywords. In addition, manual screening of symptom-based retrieval can introduce a degree of subjectivity, although it was performed independently by 2 reviewers to minimize false positives.

Third, bibliometric analysis primarily quantifies publication and citation patterns and does not directly evaluate the methodological quality or evidence level of individual studies. Also, bibliometric indicators reflect research attention rather than clinical efficacy. Given that CCS research is dominated by case reports and small case series, the present findings should be interpreted as an overview of research activity rather than a comparative assessment of clinical evidence strength.

Despite these limitations, our findings provide an overview of CCS-related publications indexed in WoSCC and may offer a useful reference for understanding publication patterns and research topic evolution in this field.

Conclusions

This study provides a WoSCC-based bibliometric analysis of CCS research, summarizing publication patterns, major contributors, and evolving research topics. Overall, CCS research has partially shifted from disease recognition to mechanistic exploration and clinical management; however, limited global collaboration and relatively insufficient mechanistic studies remain key challenges.

It should be noted that the present findings reflect trends in the indexed literature and bibliometric indicators, rather than direct advances in clinical outcomes or disease mechanisms. Future research may benefit from integrating multicenter case resources, strengthening international collaboration, and exploring emerging approaches such as multiomics and organoid-based modeling to support more evidence-based management strategies for CCS.