Abstract
Background/Aim: Immunosuppressive and nutritional treatments have improved the prognosis of Cronkhite-Canada syndrome (CCS). CCS-associated polyps are benign and categorized into hamartomatous, inflammatory, hyperplastic, and adenomatous polyps; however, the development of gastrointestinal cancer is considered the most significant prognostic factor for CCS. Although the adenoma-carcinoma sequence and inflammation-associated carcinogenesis are two major pathways for the development of colorectal cancers (CRCs), it remains largely unknown which pathway plays critical roles in the development of CRCs in CCS. Inflammation-associated carcinogenesis might be involved in the development of CRCs associated with CCS because CCS-associated polyps are characterized by submucosal infiltration of immune cells. Given the fact that proinflammatory cytokines including interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α underlie the pathogenesis of inflammation-associated carcinogenesis, we examined the involvement of proinflammatory cytokines in the transformation of CCS-associated polyps into CRCs.
Patients and Methods: Three cases of CCS were enrolled: two cases with concurrent CRCs and a single case without CRC. mRNA was isolated from non-cancerous CCS-associated polyps and subjected to reverse transcription quantitative polymerase chain reaction to determine expression of proinflammatory cytokines. Colonic biopsy samples were isolated from non-tumor portions of patients with colonic adenoma to determine mRNA expression of proinflammatory cytokines in healthy colonic mucosa.
Results: Higher mRNA expression of IL-6, but not IL-1β or TNF-α, in non-cancerous CCS-associated polyps was observed in two patients with CCS and concurrent CRCs as compared with four healthy colonic mucosal samples and a patient with CCS without CRC.
Conclusion: IL-6-mediated inflammation-associated carcinogenesis might be involved in the transformation of CCS-associated polyps into CRC.
Introduction
Cronkhite-Canada syndrome (CCS) is a rare disorder characterized by multiple polyps of the gastrointestinal (GI) tract and ectodermal abnormalities, including skin pigmentation, nail atrophy, and hair loss (1, 2). Multiple polyps with a reddish and erythematous appearance are observed in the gastric and colonic mucosa of patients with CCS (1, 2). Pathologically, CCS polyps are classified into four types: hamartomatous, inflammatory, hyperplastic, and adenomatous (1, 2). On microscopic examination, CCS-associated polyps are accompanied by infiltration of immune cells into the submucosa (1-3). Furthermore, the intervening mucosa between polyps is edematous, and patients with CCS experience severe diarrhea due to protein loss from the GI mucosa (1, 2).
Treatment with prednisolone (PSL) combined with nutritional support improves CCS prognosis. CCS polyps are benign; however, early and advanced cancers of the GI tract often develop in patients with CCS (1-5). Cancer development is currently regarded as the biggest concern and determines the prognosis of patients with CCS (1, 2). However, the molecular mechanisms underlying the development of cancers originating from CCS-associated polyps remain poorly understood. Interleukin-1 beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α) are prototypical inflammatory cytokines (6, 7). Given the increased accumulation of immune cells in the submucosa, the production of IL-1β, IL-6, and TNF-α is likely involved in the immunopathogenesis of CCS. Several case reports suggesting the involvement of TNF-α are available in PSL-resistant patients with CCS (8, 9). The adenoma-carcinoma sequence and inflammation-associated carcinogenesis are major pathways for the development of GI cancer; however, the involvement of proinflammatory cytokines in inflammation-associated carcinogenesis has not been clarified in CCS (10, 11). In this study, we recruited three cases of CCS: two cases of concurrent colorectal cancers (CRCs) and a single case without CRC. Here, we show that enhanced mRNA expression of IL-6, but not IL-1β or TNF-α, in non-cancerous CCS polyps is associated with concurrent occurrence of CRC.
Patients and Methods
Three patients with CCS were enrolled in this study. Non-cancerous lesions were detected in case 1, whereas the concurrent occurrence of CRC was observed in cases 2 and 3. The clinicopathological findings are summarized in Table I.
Clinical characteristics and colonic mRNA cytokine expression of patients with Cronkhite-Canada syndrome.
Case 1. A 76-year-old man presented with melena and underwent esophagogastroduodenoscopy (EGD) and colonoscopy (CS) approximately five years ago. Diffuse brownish pigmentation was observed on the face during the physical examination. EGD revealed multiple polyps and lesions distributed from the gastric fundus to the duodenal bulb (Figure 1A). Multiple erythematous polyps were detected throughout the colon (Figure 1A). Pathological examinations using biopsy samples obtained from the gastric and colonic polyps revealed hamartomatous polyps and infiltration of immune cells into the submucosa (Figure 1B). Skin pigmentation and characteristic endoscopic and pathological findings supported the diagnosis of CCS (1, 2). The patient did not wish to undergo treatment with PSL; thus, we carefully repeated the EGD and CS from the time point of the initial diagnosis every six months. To date, cancerous lesions have not been detected on repeat EGD and CS.
Endoscopic and pathological findings in patients with Cronkhite–Canada syndrome (CCS) with or without colorectal cancers. (A, B) Endoscopic (A) and pathological images (B) of the gastric (top panel) and colonic (bottom panel) mucosa of patients with CCS. Multiple polyps with reddish or erythematosus appearance are observed in the gastric (A, top panel) and colonic mucosa (A, bottom panel). Pathological examinations verified the hamartomatous polyps and submucosal accumulation of immune cells (B, stomach; top panel, colon; bottom panel, scale bar; 250 μm). (C) Endoscopic (1st row) and pathological (2nd row) images of advanced colorectal cancers in case 2 and case 3. Type 1 and Type 3 advanced cancers were detected in cases 2 and 3, respectively. Scale bar: 250 μm.
Case 2. A 74-year-old man was referred to our hospital after experiencing repeated episodes of diarrhea and vomiting, accompanied by loss of appetite and body weight. Blood tests revealed massive hypoproteinemia (3.7 g/dl) and hypoalbuminemia (1.7 g/dl). EGD revealed numerous edematous and reddish polypoid lesions distributed from the fundus to the antrum (Figure 1A). In parallel with the EGD findings, multiple erythematous polyps were observed in the transverse, descending, and sigmoid colon and rectum (Figure 1A). We could not observe the mucosa of the ascending colon or cecum because the hepatic flexure was occupied by type 1 advanced cancer and the scope could not pass through the ascending colon (Figure 1C). Pathological examinations using biopsy samples obtained from the gastric and colonic polyps revealed hamartomatous polyps and accumulation of immune cells in the submucosa (Figure 1B). The patient was diagnosed with CCS based on characteristic endoscopic and pathological findings in addition to protein-losing enteropathy (1, 2).
Tubular adenocarcinoma was detected in the type 1 advanced cancer on pathological examination (Figure 1C), and the patient underwent open right hemicolectomy with ileostomy formation. Despite extensive nutritional support, including total parenteral nutrition, the patient experienced repeated episodes of aspiration pneumonia. Therefore, we could not start the treatment with PSL. The patient died approximately six months after surgery because of malnutrition and kidney failure. The patient was finally diagnosed as having CCS with concurrent CRC.
Case 3. We previously reported alterations in the expression of colonic cytokines of this case before and after PSL treatment (3). A 66-year-old man presented with alopecia, skin pigmentation, and nail atrophy. The patient also complained of diarrhea. EGD revealed numerous reddish polypoid lesions with adjacent edematous mucosa in the gastric body and antrum (Figure 1A). Multiple elevated and erythematous lesions were observed throughout the colon and rectum on CS (Figure 1A). Formation of hamartomatous polyps and infiltration of inflammatory cells into the submucosa was observed in pathological examinations of biopsy specimens obtained from gastric and colonic polyps (Figure 1B). These endoscopic and pathological findings, together with the presence of ectodermal abnormalities, were consistent with those of CCS.
Treatment with PSL (30 mg/day) with a tapering schedule of 5 mg every four weeks led to the regression of CCS-associated polyps in both the stomach and colon after three months of therapy. However, regression of the polyps enabled the detection of type 3 advanced cancer in the rectosigmoid region (Figure 1C). A rectal biopsy confirmed a well-differentiated adenocarcinoma (Figure 1C). The patient subsequently underwent a lower anterior resection, and the postoperative course was uneventful. Given the presence of advanced, not early-stage CRC, the patient likely had a concurrent occurrence of CRC at the initial diagnosis of CCS.
Reverse transcription quantitative polymerase chain reaction (RT-qPCR). RT-qPCR was conducted using colonic biopsy specimens as previously described (12-15). mRNA was isolated from non-cancerous inflammatory polyps of three patients with CCS. The biopsy sites used for mRNA expression analysis are shown in Table I. Non-tumor portions of the colonic mucosa from four patients with colon adenoma were used to determine mRNA expression in healthy colonic mucosa. SYBR Green-based qPCR was conducted using a LightCycler 480 system (Roche, Tokyo, Japan), and cytokine expression was normalized using ACTB as the reference gene. PCR primers for the target genes were purchased from Qiagen (Valencia, CA, USA). Ethical approval to perform this study was granted by the Review Board of the Kindai University Faculty of Medicine.
Results
Colonic mRNA expression of various cytokines was determined using RT-qPCR. These included mRNA expression of interferon alpha-4 (IFNA4), IL1B, IL6, IL10, and TNFA encoding IFN-α, IL-1β, IL-6, IL-10, and TNF-α, respectively. mRNA was isolated from biopsy samples obtained from CCS-associated and non-cancerous inflammatory polyps (Table I). Compared to the mRNA expression of cytokines in healthy colonic mucosa, that of IFNA4, IL1B, IL10, and TNFA was highly variable in CCS-associated noncancerous polyps from patients with concurrent CRC (Figure 2 and Table I). In contrast, the mRNA expression of IL6 was markedly higher in CCS-associated non-cancerous polyps from two patients (cases 2 and 3) with concurrent CRC than that in healthy colonic mucosa and a CCS-associated non-cancerous polyp from a patient (case 1) without concurrent CRC (Figure 2 and Table I). Thus, these mRNA expression analyses suggest that enhanced mRNA expression of IL6 in non-cancerous polyps is associated with the presence of concurrent cancer in patients with CCS.
mRNA expression of colonic cytokines in non-cancerous polyps of patients with Cronkhite–Canada syndrome (CCS) with or without colorectal cancers. mRNA was isolated from colonic biopsy samples obtained from non-cancerous CCS polyps. Three cases with CCS were enrolled; two cases with concurrent colorectal cancers and a single case without colorectal cancer. Four biopsy samples obtained from non-tumorous colonic mucosa of patients with colonic adenoma were used as controls. Each dot represents the value of an individual patient.
Discussion
CCS is a rare GI disease characterized by ectodermal abnormalities and polyposis of the entire GI tract (1, 2). CCS-associated polyps are classified into inflammatory, hyperplastic, hamartomatous, and adenomatous types in microscopic examinations (1, 2). The gastric and colonic mucosa of patients with CCS are covered with multiple polyps with a reddish or erythematous appearance on EGD and CS (1, 2). All three CCS patients enrolled in this study displayed ectodermal abnormalities (cases 1 and 3) or protein-losing enteropathy (case 2) in combination with multiple reddish or erythematous polyps on EGD and CS (cases 1-3). Additionally, pathological examinations using gastric and colonic biopsy specimens from the three cases verified hamartomatous polyps and infiltration of immune cells into the submucosa. Thus, all three patients met the diagnostic criteria for definite CCS. The prognosis of CCS has improved with treatment with PSL and nutritional support; however, the high incidence of GI tract cancer remains the most significant concern (2). A retrospective Japanese survey of 210 patients with CCS showed a considerably high incidence of GI tract cancers, including gastric cancer (9.1%) and CRC (19.5%). However, the molecular mechanisms underlying the development of cancer in CCS are poorly understood. In this study, we determined the mRNA expression profiles of colonic cytokines in non-cancerous CCS polyps. We discovered that IL6 mRNA levels were markedly higher in two patients with concurrent CRC than in a patient without concurrent CRC and healthy colonic mucosa samples. Therefore, the present study suggests that IL6 mRNA expression in non-cancerous CCS polyps is involved in CRC development in patients with CCS. However, we must be cautious regarding the association between IL6 mRNA expression in non-cancerous CCS polyps and concurrent CRC because the sample sizes of patients with CCS with or without CRC are considerably small to draw a definitive conclusion.
The mRNA expression of IFNA4, IL1B, IL10, and TNFA was highly variable in non-cancerous CCS polyps from two patients with CCS and concurrent CRC. In contrast, the mRNA expression of IL6 was markedly higher in non-cancerous CCS polyps from the two patients with CCS and concurrent CRC than in the patient with CCS without CRC and four healthy colonic mucosa samples. Given that IL-6 plays multifaceted roles in carcinogenesis (16), one might assume that increased expression of IL-6 promotes the transformation of adenomatous polyps into CRC. IL-6 induces cell cycle progression and cancer stem cell survival (16). However, previous studies addressing the role of IL-6 in the adenoma-carcinoma sequence have shown that the expression levels of colonic IL-6 are lower in CRC than in colorectal adenoma (17, 18). Additionally, we isolated mRNA samples from non-cancerous and hamartomatous polyps, but not from adenomatous polyps, in all three patients with CCS. Thus, IL-6 is unlikely to promote the development of CRC through a direct action on the adenoma-carcinoma sequence. In fact, we encountered a case of CCS with triple gastric cancers that arose directly from non-adenomatous polyps without the adenoma-carcinoma sequence (19). Whether IL-6 promotes the transformation of non-cancerous CCS polyps into CRC requires further analysis of its expression in hamartomatous, adenomatous, and cancerous CCS polyps in a large number of patients with CCS.
Chronic inflammation plays a crucial role in the development of CRC (11). Persistent colonic inflammation caused by inflammatory bowel diseases increases the risk of CRC via inflammation-associated carcinogenesis (11). Marked submucosal infiltration of immune cells is among the characteristic pathological findings of CCS polyps, suggesting that persistent inflammation underlies the pathogenesis of CCS (1, 2). Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a recently established autoimmune disorder characterized by multiple organ involvement and an elevated IgG4 antibody response (20). Notably, an increased accumulation of IgG4-expressing plasmacytes in the submucosa is observed in non-cancerous CCS polyps (21). It remains unknown whether CCS is a GI tract manifestation of IgG4-RD; however, IL-6 has been implicated in the pathogenesis of IgG4-RD (22, 23). These previous studies, together with the present study, suggest that increased IL-6 expression due to autoimmunity might drive the transformation of non-cancerous CCS polyps into CRC via inflammation-associated carcinogenesis, but not via the adenoma-carcinoma sequence.
IL-1β, IL-6, and TNF-α are prototypical inflammatory cytokines associated with innate immunity (6, 7). Pathogenic roles played by TNF-α have been implicated in patients with CCS resistant to PSL (8, 9). Additionally, a recent case study conducted by Liu et al. provides evidence that signaling pathways mediated by IL-1β and IL-6 are upregulated in non-cancerous CCS polyps as assessed by whole transcriptome sequencing analysis (24). Thus, IL-6, TNF-α, and IL-1β are likely to be involved in chronic inflammatory responses in CCS. PSL-induced remission of colonic CCS polyps was accompanied by reduced mRNA expression of IL1β, IL6, and TNFα in the colon (3). However, mRNA expression of IL1β and TNFα was highly variable in non-cancerous CCS polyps from the two patients bearing CRC, and no association between mRNA expression of IL1β and TNFα and concurrent CRC was observed in this study. It remains unknown why the mRNA expression of IL6 alone was considerably high in two patients with CCS and concurrent CRC despite the fact that IL-1β, IL-6, and TNF-α might drive CCS-associated chronic inflammation. IL-6 promotes carcinogenesis through the proliferation and survival of cancer cells (16). Thus, IL-6 may promote CRC development through its oncogenic and proinflammatory functions. Involvement of IL-1β, IL-6, and TNF-α in the carcinogenesis of CCS polyps requires further studies addressing the expression profiles of cytokines in a large number of patients with CCS.
Conclusion
Enhanced mRNA expression of IL6 in non-cancerous CCS polyps might be involved in the development of CCS-associated CRC. CCS-associated CRC determines prognosis; however, the detection of CRC in the colonic mucosa covered with numerous non-cancerous polyps is usually difficult. Elevated mRNA expression of IL6 in non-cancerous CCS polyps may predict the presence of CRC. Therefore, the present study suggests that careful and repeated CS is necessary for patients with CCS who exhibit high levels of colonic IL6 mRNA to detect CRC.
Acknowledgements
The Authors thank Ms. Yukiko Ueno for the secretarial support.
Footnotes
Authors’ Contributions
Conceptualization: D.F., H.H., T.W.; Methodology: D.F., H.H., Y.M., T.W.; Formal analysis and investigation: D.F., H.H., Y.M., Y.O., S.M., K.M., K.K., N.T., T.W.; Writing – original draft preparation: D.F., H.H., T.W.; Writing – review and editing: D.F., H.H., T.W.; Funding acquisition: T.W. ; Supervision: M.K.
Conflicts of Interest
The Authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this study.
Funding
This study was supported in part by Grants-in-Aid for Scientific Research, the Japan Society for the Promotion of Science (25K11288), and Kindai University Research Enhancement Grants (KD2405 and KD2505).
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
- Received January 28, 2026.
- Revision received February 23, 2026.
- Accepted February 24, 2026.
- Copyright © 2026 The Author(s). Published by the International Institute of Anticancer Research.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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