OL Oncology Letters 1792-1074 1792-1082 D.A. Spandidos 10.3892/ol.2025.15148 OL-30-2-15148 Articles Prognostic impact of syndecan-1 expression and serum concentration in colorectal cancer TawadaKakeru 1 2 * HayashiHirokatsu 1 3 * EndoMasahide 1 3 HoraguchiTakeshi 1 3 YokoiRyoma 1 3 MatsumotoKeita 1 3 KunoMasashi 1 3 FukadaMasahiro 1 3 AsaiRyuichi 1 3 SatoYuta 1 3 YasufukuItaru 1 3 TajimaJesse Yu 1 3 TanakaYoshihiro 1 3 TakahashiTakao 1 4 MatsuhashiNobuhisa 1 3 TomitaHiroyuki 5 6 Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan Department of Surgery, Takayama Red Cross Hospital, Takayama, Gifu 506-0025, Japan Department of Gastroenterological Surgery, Gifu University Hospital, Gifu, Gifu 501-1194, Japan Department of Surgery, Seino Kosei Hospital, Gifu Seino Medical Center, Ibi, Gifu 501-0532, Japan Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan Center for One Medicine Innovative Translational Research, Gifu University Institute for Advanced Study, Gifu, Gifu 501-1193, Japan Correspondence to: Professor Nobuhisa Matsuhashi, Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Gifu 501-1194, Japan, E-mail: nobuhisa517@hotmail.com Dr Hiroyuki Tomita, Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Gifu 501-1194, Japan, E-mail: tomita.hiroyuki.y6@f.gifu-u.ac.jp

Contributed equally

 082025 19062025 30 2 402 22032025 07052025 Copyright: © 2025 Tawada et al. 2025 This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Syndecan-1 (SDC1), a transmembrane heparan sulfate proteoglycan that serves an important role in promoting tumorigenesis and metastasis, has been suggested as a potential biomarker for malignancy and as a therapeutic target. However, its role remains controversial because of its varying functions depending on carcinoma type and location. Elevated serum SDC1 levels after surgery have previously been associated with favorable disease-free survival (DFS). The present study aimed to clarify the role of SDC1 in resectable colorectal cancer (CRC) by evaluating its expression in tumor tissue, correlation with serum SDC1 levels and association with prognosis. In total, 46 patients who underwent radical surgery between July and December 2019 at Gifu University Hospital (Gifu, Japan) were included. The association between SDC1 expression in tumor tissues, assessed using immunohistochemical staining, and DFS was analyzed. Tumor tissue was compartmentalized into the membrane, cytoplasm and stroma. Staining intensity and percentage of positive cells were scored and categorized into two groups based on quartiles (Qs). The Q3-Q4 SDC1 staining scores for the membrane, cytoplasm and stroma were 30 (65.2%), 26 (56.6%) and 23 (50.0%) patients, respectively. Low SDC1 expression in all compartments was associated with advanced tumor stage (P=0.017, P=0.008 and P=0.035). In addition, low membranous SDC1 expression was associated with shorter DFS (P=0.013) and was an independent risk factor for recurrence (hazard ratio: 7.00, 95% confidence interval: 1.24–39.62, P=0.028). No significant correlation was observed between membranous SDC1 expression and serum SDC1 levels. The current study demonstrated that low membranous SDC1 expression may be an independent risk factor for recurrence and could serve as a prognostic biomarker for CRC. Furthermore, serum SDC1 levels may not depend solely on expression in tumor cells and are possibly influenced by multiple factors, including the tumor microenvironment and release from other tissues.

 syndecan-1 CRC prognosis heparan sulfate proteoglycan biomarkers immunohistochemistry tumor microenvironment JSPS KAKENHI JP20K0758723 (HT) JP23H03326 (HT) JST FOREST Program JPMJFR220W (HT) This study was supported by JSPS KAKENHI [grant nos. JP20K0758723 (HT) and JP23H03326 (HT)] and the JST FOREST Program [grant no. JPMJFR220W (HT)]. Introduction

Colorectal cancer (CRC) is the third most common cancer worldwide, accounting for almost 10% of all cancers (1). Although molecular targeted therapy and immune checkpoint inhibitors have improved clinical outcomes (2), CRC remains the second leading cause of cancer-related deaths. The development of biomarkers for the early and accurate evaluation of tumor grade is crucial for more efficient treatment strategies (3).

Syndecan-1 (SDC1) is a transmembrane heparan sulfate proteoglycan that is mostly present in epithelial cells. It is involved in various biological processes, such as growth, differentiation, cell proliferation, cell adhesion, migration, invasion, and angiogenesis (4). Consequently, SDC1 is also involved in inflammatory and infectious diseases, including tumorigenesis (5). During malignant transformation of normal cells, SDC1 is shed from the epithelial cell membrane and released into the stromal and cytoplasmic compartments. The shedding of SDC1 promotes oncogene and growth factor signaling, inhibits cancer cell apoptosis, and promotes angiogenesis (6–8). Consequently, decreased SDC1 expression on the cell membranous, stromal, and cytoplasmic compartments are poor prognostic factors in various cancers; thus, SDC1 has been reported as a potential biomarker for prognosis evaluation (9).

In CRC, decreased or absent SDC1 expression on cancer cell membranes compared to normal cell membranes has been observed, and this reduction correlates with tumor progression (10). In metastatic colorectal cancer, high serum SDC1 levels have also been reported to be associated with chemotherapy resistance and decreased progression-free survival and overall survival (OS) (11,12). In contrast, stromal SDC1 expression has been reported to be associated with good prognosis (13). SDC1 has also been reported to inhibit tumor progression depending on the tumor type, location of activation, or regulatory mechanism (5). Despite previous research, the association between SDC1 expression and prognosis in CRC remains controversial.

We have previously reported dynamic changes in serum SDC1 levels from preoperative to postoperative CRC and their prognostic impact (14) and conducted SDC1 staining on tumor tissues. This study aimed to evaluate the association between SDC1 expression in tumor tissues and prognosis as well as its association with serum SDC1 levels to assess its usefulness as a prognostic biomarker.

 Materials and methods <sec> <title>Study populations

Consecutive patients who underwent radical surgery for CRC between July and December 2019 were identified from a prospectively maintained institutional database at the Department of Gastrointestinal Surgery, Gifu University Hospital (Gifu, Japan). Patients whose surgical specimens were pathologically diagnosed with CRC were included, and those with a history of cancer, synchronous double cancer, familial adenomatous polyposis or hereditary non-polyposis CRC, or inflammatory bowel disease were excluded. This study was conducted in accordance with the World Medical Association Declaration of Helsinki and approved by the Ethics Committee of Gifu University (approval nos. 2019-074 and 2021-C162). All patients provided written informed consent.

 Measurement of serum SDC1 levels

As previously reported (14), blood was collected preoperatively and 7 days after surgery. The blood samples were centrifuged at 4°C and 2,000 × g and were frozen at −80°C. The samples were thawed, and SDC1 levels were measured using an enzyme-linked immunosorbent assay (Diaclone, Besançon, France).

 Immunohistochemical staining of tissue and SDC1 scoring

Immunostaining was performed on formalin-fixed, paraffin-embedded colorectal tumors. Paraffin blocks were cut into 3-µm-thick sections, deparaffinized with xylene, and rehydrated thorough graded ethanol into distilled water. Deparaffinized sections were subjected to autoclave boiling in 5X Tris-EDTA buffer solution (pH 9.0) for 10 min at 110°C as an antigen retrieval procedure, followed by cooling down for 2 h at room temperature. After washing with phosphate-buffered saline (PBS), the sections were incubated with 3% H2O2 diluted in methanol for 10 min and blocked with 2% normal bovine serum for 40 min at room temperature. The sections were incubated with rabbit anti-SDC1 antibody (dilution 1:8,000, clone EPR6459, cat. ab128936; Abcam, Cambridge, UK) overnight at 4°C as the primary antibody and washed with PBS. Subsequently, the sections were incubated with the Histofine Simple Stain MAX-PO (R) kit (no dilution required; cat. 424132; Nichirei Biosciences Inc., Tokyo, Japan), which contains peroxidase-labeled polymer-conjugated goat anti-rabbit IgG Fab' fragments, for 30 min at room temperature as the secondary antibody and washed with PBS.

Immunoreaction was visualized using 3,3′-diaminobenzidine tetrahydrochloride (cat. D5637; Sigma-Aldrich, St. Louis, MO, USA). Sections were counterstained with hematoxylin. SDC1 immunoreactivity was classified as membranous, cytoplasmic, or stromal. Staining intensity was defined as follows: 0, no staining; 1, weak; 2, moderate; 3, strong (Fig. 1). The percentage of cells stained was as follows: 0, no staining; 1, 1–25%; 2, 26–50%; 3, 51–75%; 4, 76–100%. The immunohistochemical (IHC) score was calculated by multiplying the staining intensities and percentages rated on a score of 0–12 (15). The IHC scores were categorized into quartiles (Qs) based on the median score: Q1-Q2 (negative/low) and Q3-Q4 (medium/high). Staining was evaluated independently and in a blinded manner by two individuals, including a pathologist.

 Outcome measures and statistical analyses

The preoperative variables included age, sex, body mass index, and tumor markers (carcinoembryonic antigen and carbohydrate antigen 19-9). The pathological variables included SDC1 score, grade, pathological T (pT) and N (pN) stage according to the 8th edition of the Union for International Cancer Control's tumor-node-metastasis classification and lymphovascular invasion (16).

The primary endpoint was disease-free survival (DFS), which was defined as the interval from the date of surgery to the date of recurrence, death, or most recent follow-up. DFS was compared among membranous, cytoplasmic, and stromal SDC1 scores, and histopathological risk factors for recurrence were investigated. To further reveal the association between SDC1 staining and serum SDC1 levels, the correlation between the SDC1 staining score and preoperative and postoperative serum SDC1 levels was evaluated.

All statistical analyses were performed using EZR version 1.68 (Easy R; Saitama Medical Center, Jichi Medical University, Saitama, Japan). Categorical variables were summarized as numbers (percentages) and analyzed using the Pearson χ2 test or Fisher's exact test. The Pearson χ2 test was applied when the expected frequency in each cell was 5 or more, whereas Fisher's exact test was used when any expected frequency was less than 5. Continuous variables are expressed as median (interquartile range) and were compared using the Mann-Whitney U test. DFS was calculated using the Kaplan-Meier method and compared using the log-rank test. Preoperative and histopathological factors (log-rank test, P<0.05) were entered into a multivariable Cox proportional hazards model. Firth-penalized Cox proportional hazards model was applied to address small sample bias, thereby identifying the independent predictors of recurrence. The results were expressed as hazard ratios and 95% confidence intervals. The correlation between the different SDC1 scores and serum SDC1 levels was tested using Spearman's correlation analysis after outliers were excluded using the Smirnov-Grubbs test (α=0.05). All tests were two-sided, and P<0.05 was considered to indicate a statistically significant difference.

 Results <sec> <title>Clinical and pathological characteristics

During the study period, 48 patients underwent radical surgery; however, two patients were excluded due to difficult IHC staining, leaving 46 patients in the final cohort. The clinicopathological characteristics are summarized in Table I. The median age was 70 (61–74) years, and the male-to-female ratio was 1:1. Of the 46 patients, 31 (67.4%) had CRC or rectosigmoid cancer, and 15 (32.6%) had rectal cancer. Tumor invasion deeper than T3, lymph node metastasis, and vascular invasion were observed in 28 (60.9%), 18 (39.1%), and 33 (71.7%) patients, respectively. Recurrence was observed in 11 patients (23.9%), and 6 patients (13.0%) died.

 SDC1 expression and comparison of clinicopathological characteristics

The results of the IHC staining of the membranous, cytoplasmic, and stromal compartments are presented in quartiles (Table II). The median membranous score was 2, and 30 patients (65.2%) had medium/high scores (Q3-Q4). The median cytoplasmic and stromal scores were 2 and 3, respectively, and 26 (56.5%) and 23 (50.0%) patients had medium/high scores (Q3-Q4), respectively. Table III summarizes the comparison of clinicopathological characteristics between Q1-Q2 and Q3-Q4 for each compartment. In both compartments, the frequency of pT3-pT4 was significantly higher in Q1-Q2 than in Q3-Q4 (membrane, 87.5% vs. 46.7%, P=0.017; cytoplasm, 85.0% vs. 42.3%, P=0.008; stroma, 78.3% vs. 43.5%, P=0.035). Lymphovascular invasion was observed more frequently in the cytoplasmic compartments in Q1-Q2 than in Q3-Q4 (90.0% vs. 57.7%, P=0.037). The membranous SDC1 score showed a significant positive correlation with the cytoplasmic score (ρ=0.902, P<0.001). Similarly, significant positive correlations were observed between the membranous and stromal SDC1 scores (ρ=0.613, P<0.001) and between the cytoplasmic and stromal SDC1 scores (ρ=0.533, P=0.001; Fig. 2).

 Correlation between serum SDC1 levels and membranous SDC1 expression

One data point was removed because it significantly deviated from the distribution of postoperative serum SDC1 values, and serum SDC1 levels changed from before to after the operation. No significant correlation was observed between preoperative serum SDC1 levels and membranous SDC1 scores (ρ=−0.197, P=0.189; Fig. 3). Similarly, no significant correlation was observed between postoperative serum SDC1 levels and membranous SDC1 scores (ρ=0.138, P=0.361). The change in serum SDC1 levels from preoperative to postoperative showed no significant correlation with the membranous SDC1 scores (ρ=−0.056, P=0.714). The results were the same as those obtained before excluding the outlier (Fig. S1).

 Survival analysis

The median follow-up period for the DFS analysis was 42 months (interquartile range, 27–43 months), and 11 patients experienced recurrence. Comparisons of the DFS based on the SDC1 score for each compartment are shown in Fig. 4. The 3-year DFS rates were significantly different between Q1-Q2 and Q3-Q4 for membranous SDC1 scores (50.0% vs. 80.0%, P=0.013). A significant difference was also observed in the 3-year DFS rate between Q1-Q2 and Q3-Q4 for cytoplasmic SDC1 scores (65.0% vs. 80.0%, P=0.033). However, no significant difference was found in the 3-year DFS rate between Q1-Q2 and Q3-Q4 for stromal SDC1 scores (60.9% vs. 78.3%, P=0.106).

Log-rank tests were performed to identify the risk factors for recurrence. Univariate analyses showed that pathological grade, pT and pN stage, and lymphovascular invasion were significant risk factors for recurrence (Table SI). In the multivariable analysis, which included the SDC1 score for each compartment and variables identified as significant risk factors for recurrence in the univariate analyses, Q1-Q2 membranous SDC1 score was identified as an independent risk factor for recurrence (hazard ratio, 6.32; 95% confidence interval, 1.12–35.64; P=0.037; Table IV). The statistical significance of the Q1-Q2 membranous SDC1 score was retained in the Firth-penalized Cox proportional hazards model (hazard ratio, 4.78; 95% confidence interval, 1.15–26.35; P=0.031; Table SII).

 Discussion

This study investigated the association between SDC1 expression, as identified using IHC staining, and prognosis in CRC, as well as evaluated its correlation with serum SDC1 levels. Decreased or absent SDC1 expression in all compartments was associated with tumor depth, and decreased or absent membranous SDC1 expression was identified as an independent risk factor for recurrence. SDC1 expression was not associated with serum SDC1 levels.

The cell surface is covered with a layer of carbohydrate-rich glycocalyx, which is bound to the cell through several backbone molecules, such as proteoglycans and glycoproteins. SDC1 bears diverse heparan sulfate chains capable of interacting with extracellular matrix compartments, growth factors, cytokines, chemokines, lipid metabolites, and morphogenetic factors (9,17). During malignant transformation of normal cells or acquisition of invasive and metastatic potential by cancer cells, epithelial cells undergo multiple organized molecular alterations, which lead to the development of mesenchymal characteristics and migratory phenotypes. At the time of epithelial-mesenchymal transition, transcriptional repression of epithelial markers and loss of SDC1 on the cell membrane occur (18). In normal colons, it has been reported that SDC1 is expressed around the columnar epithelial basement membrane and plasma cells and that SDC1 is reduced or absent in the majority of adenocarcinoma cells (10). Loss of SDC1 expression has been reported to be associated with histological differentiation, clinical stage, OS, and DFS (19–21). There are two possible mechanisms for the prognostic impact of reduced membranous SDC1 expression: i) disruption of cell-cell and cell-extracellular matrix adhesion causes proliferation and migration of cancer cells (22); ii) shedding of SDC1 forms a vascular endothelial growth factor (VEGF) complex that activates integrin and VEGF receptors, thereby promoting cancer cell proliferation (23,24). In the present study, reduced membranous SDC1 expression was associated with the pT and pN stage, pathological TNM stage, and DFS. Considering these findings, SDC1 expression on the membrane of cancer cells is a potential biomarker of poor prognosis in patients with CRC.

In cancer cells, SDC1 is expressed in the cytoplasmic and stromal compartments, whereas membranous SDC1 expression is either decreased or lost. In breast and prostate cancer, cytoplasmic SDC1 expression has been reported to be associated with tumor stage, lymph node metastasis, recurrence, and poor prognosis (25,26). Cytoplasmic SDC1 expression is considered to be the accumulation of SDC1 shed from the cell membrane; however, SDC1 expression in the cytoplasmic compartments remains unclear. Previous reports on cytoplasmic SDC1 expression in CRC have demonstrated that epithelial SDC1 expression, which consists of cytoplasmic and membranous expression, is associated with advanced tumor stage, with no association to prognosis (27). In a previous study, cytoplasmic SDC1 expression was not found to be associated with prognosis. Nevertheless, cytoplasmic SDC1 expression was strongly correlated with membranous SDC1 expression and was associated with early tumor stage. The discrepancies in previous studies may be partly explained by differences in the evaluation of staining scores.

Stromal SDC1 expression has also been described as a poor prognostic factor for breast, prostate, ovarian, and pancreatic cancer (25,28–30). In breast cancer, stromal SDC1 expression may reflect its expression in fibroblasts. Fibronectin levels are elevated in the presence of fibroblasts that express SDC1, which is considered to promote tumor adhesion and invasion (31). In contrast, stromal SDC1 expression in CRC is a good prognostic factor, and fibroblasts that express SDC1 have been suggested to be responsible for tumor suppression (13). In the present study, stromal SDC1 expression was not associated with prognosis but was significantly associated with early tumor stage. In contrast to a previous report by Yang et al (31), stromal SDC1 expression was positively correlated with membranous SDC1 expression, and differences in staining patterns may be involved in the role of fibroblasts with SDC1 expression. However, the mechanism and function of SDC1 expression in stromal fibroblasts remain unclear and require further investigation.

Serum SDC1 levels have been reported to be associated with progression-free survival, OS, and chemotherapy resistance in CRC with distant metastasis, suggesting that soluble SDC1, shed from the cell membrane, interacts with heparin-binding epidermal growth factor (EGF), enhancing and activating the EGF receptor and downstream signaling (11,12). In contrast to previous reports, our study showed that elevated serum SDC1 levels after surgery significantly improved DFS and may be an indicator of prognosis in stages II–III (14). Our study included patients with curatively resectable CRC, which may be one of the reasons why serum SDC1 levels were not associated with poor prognosis. Although serum SDC1 levels were elevated by SDC1 shedding from the tumor cell membrane, there was no correlation between perioperative serum SDC1 levels and membranous SDC1 expression, suggesting that some differences might exist in the origin of serum SDC1. In animal studies, chemokine-1 and chemokine-2 clearance was promoted after the administration of vascular endothelium-derived SDC1, which has a homeostatic function by regulating inflammatory factors to resolve inflammation (5). The glycocalyx function of the vascular endothelium has been suggested to vary depending on the medical condition (32), and postoperative elevation of serum SDC1 levels may reflect differences in glycocalyx function in maintaining homeostasis. The heparan sulfate chain of SDC1 contains sequences that promote and inhibit tumor growth (33); thus, the functions of SDC1 may differ depending on the carcinoma type, location, and regulatory mechanisms (5,27).

This study has some limitations. First, this was a single-institution retrospective cohort study, which may have introduced selection bias. However, a strength of the study is that histopathological assessments were performed by a single pathologist (HT) throughout the study period, ensuring uniform evaluation. Second, the small sample size may have also caused bias. To reduce bias, we investigated the predictors for recurrence using Cox regression analysis with Firth's penalized method. The statistical significance of membranous SDC1 expression was maintained (Table SII). Although Firth's correction can reduce bias, it may not be suitable for all scenarios. Thus, the results should be interpreted with caution. Despite the limitations, our findings provide practical clinical data showing the association between SDC1 expression and outcomes in CRC.

In conclusion, decreased or absent membranous SDC1 expression was associated with tumor grade and was an independent risk factor for recurrence. Elevated serum SDC1 levels after surgery may reflect the homeostatic function of the vascular endothelium, suggesting its potential as a prognostic indicator.

 Supplementary Material Supporting Data Supporting Data Acknowledgments

Not applicable.

 Availability of data and materials

The data generated in the present study may be requested from the corresponding author.

 Authors' contributions

KT, HH, YS and HT conceived and designed the study. HH, TH, ME, RY, KM, MK, MF, RA, JYT, TT and NM collected the data. KT, IY and YT performed the analysis and interpretation of the data. KT drafted the manuscript. HH, TH, KM, MK, NM and HT revised the manuscript. HH and NM confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.

 Ethics approval and consent to participate

The present study was conducted in accordance with the World Medical Association Declaration of Helsinki and was approved by the Ethics Committee of Gifu University (approval nos. 2019-074 and 2021-C162). All patients provided written informed consent.

 Patient consent for publication

Written informed consent for publication was obtained from all participants prior to study enrollment.

 Competing interests

The authors declare that they have no competing financial interests.

 Abbreviations CRC

colorectal cancer

 DFS

disease-free survival

 EGF

epidermal growth factor

 OS

overall survival

 IHC

immunohistochemical

 PBS

phosphate-buffered saline

 pN

pathological N

 pT

pathological T

 Q

quartile

 VEGF

vascular endothelial growth factor

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Immunohistochemical staining intensities. Grading of immunohistochemical staining intensities was defined independently in the membranous, cytoplasmic, and stromal compartments. Magnification, ×200.

Figure 1. Immunohistochemical staining intensities. Grading of immunohistochemical staining intensities was defined independently in the membranous, cytoplasmic, and stromal compartments. Magnificatio...

Correlation between compartmental SDC1 scores. (A) Strong positive correlation between membranous and cytoplasmic SDC1 scores. (B) Positive correlation between membranous and stromal SDC1 scores. (C) Positive correlation between cytoplasmic and stromal SDC1 scores. Correlations were assessed using Spearman's rank correlation coefficient. SDC1, syndecan-1.

Figure 2. Correlation between compartmental SDC1 scores. (A) Strong positive correlation between membranous and cytoplasmic SDC1 scores. (B) Positive correlation between membranous and stromal SDC1 sc...

Correlation between membranous SDC1 scores and serum SDC1 levels after outliers were excluded using the Smirnov-Grubbs test. Membranous SDC1 score and (A) preoperative and (B) postoperative SDC1 levels. (C) Membranous SDC1 score and changes in serum SDC1 level from preoperative to postoperative. Correlations were assessed using Spearman's rank correlation coefficient. SDC1, syndecan-1.

Figure 3. Correlation between membranous SDC1 scores and serum SDC1 levels after outliers were excluded using the Smirnov–Grubbs test. Membranous SDC1 score and (A) preoperative and (B) postoperative ...

Comparison of DFS according to compartmental SDC1 scores. DFS according to (A) membranous, (B) cytoplasmic (C) and stromal SDC1 scores (Q1-Q2 vs. Q3-Q4). DFS, disease-free survival; SDC1, syndecan-1; Q, quartile.

Figure 4. Comparison of DFS according to compartmental SDC1 scores. DFS according to (A) membranous, (B) cytoplasmic (C) and stromal SDC1 scores (Q1–Q2 vs. Q3–Q4). DFS, disease–free survival; SDC1, sy...

Clinicopathological characteristics.

Characteristic Results
Age, years (IQR) 70 (61–74)
Sex, n (%)
  Male/Female 23 (50.0)/23 (50.0)
BMI, kg/m2 (IQR) 22.0 (19.6–24.5)
CEA, ng/ml (IQR) 3.0 (2.1–4.6)
CA19-9, units/ml (IQR) 10.0 (7.0–25.2)
Tumor location, n (%)
  Colon and rectosigmoid colon 31 (67.4)
Rectum 15 (32.6)
Histological differentiation, n (%)
  Well/moderate/por/muc 14 (30.4)/29 (63.0)/1 (2.2)/2 (4.4)
Pathological T stage, n (%)a
  T0/T1/T2/T3/T4 4 (8.7)/9 (19.6)/5 (10.9)/23 (50.0)/5 (10.9)
Pathological N stage, n (%)a
  N0/N1/N2 28 (60.9)/12 (16.1)/6 (13.0)
Pathological stage, n (%)a
  0/I/II/III 4 (8.7)/12 (26.1)/12 (26.1)/18 (39.1)
Lymphovascular invasion, n (%) 33 (71.7)
Recurrence, n (%) 11 (23.9)

IQR, interquartile range; BMI, body mass index; CEA, carcinoembryonic antigen; CA, carbohydrate antigen; por, poorly differentiated adenocarcinoma; muc, mucinous adenocarcinoma.

The 8th edition of the Union for International Cancer Control-Tumor Node Metastasis classification.

Immunohistochemistry of SDC1 scoring by Qs.

Cellular compartment Median (IQR) Q Corresponding IHC score Frequency Percent
Membranous 2 (1–6) Q1 0 8 17.4
Q2 1 8 17.4
Q3 2, 3, 4 15 32.6
Q4 6, 9 15 32.6
Cytoplasmic 2 (1–6) Q1 0 6 13.1
Q2 1 14 30.4
Q3 2, 3, 4 14 30.4
Q4 6, 9 12 26.1
Stromal 2.5 (2–6) Q1 0, 1 9 19.6
Q2 2 14 30.4
Q3 3, 4 6 13.0
Q4 6, 8, 9 17 37.0

SDC1, syndecan-1; IHC, immunohistochemical; IQR, interquartile range; Q, quartile.

Comparison of clinicopathological characteristics.

Membranous SDC1 score Cytoplasmic SDC1 score Stromal SDC1 score
Characteristic Q1-2 (n=16) Q3-4 (n=30) P-value Q1-2 (n=20) Q3-4 (n=26) P-value Q1-2 (n=23) Q3-4 (n=23) P-value
Age, year 0.153 0.494 0.489
  <75 10 (63.5) 25 (83.3) 14 (70.0) 21 (80.8) 16 (69.6) 19 (82.6)
  ≥75 6 (37.5) 5 (16.7) 6 (50.0) 5 (19.2) 7 (30.4) 4 (17.4)
Sex 0.353 0.372 0.555
  Female 6 (37.5) 17 (56.7) 8 (40.0) 15 (57.7) 10 (43.5) 13 (56.5)
  Male 10 (63.5) 13 (43.3) 12 (60.0) 11 (42.3) 13 (56.5) 10 (43.5)
BMI, kg/m2 0.649 0.684 0.665
  >18.5 15 (93.8) 25 (83.3) 18 (90.0) 22 (84.6) 21 (91.3) 19 (82.6)
  ≤18.5 1 (6.2) 5 (16.7) 2 (10.0) 4 (15.4) 2 (8.7) 4 (17.4)
CEA, ng/ml 0.463 0.262 >0.999
  <5 14 (87.5) 23 (76.7) 18 (90.0) 19 (73.1) 19 (82.6) 18 (78.3)
  ≥5 2 (12.5) 7 (23.3) 2 (10.0) 7 (26.9) 4 (17.4) 5 (21.7)
CA19-9, units/ml 0.463 >0.999 0.459
  <37 14 (87.5) 23 (76.7) 16 (80.0) 21 (80.8) 20 (87.0) 17 (73.9)
  ≥37 2 (12.5) 7 (23.3) 4 (20.0) 5 (19.2) 3 (13.0) 6 (26.1)
Tumor location 0.852 >0.999 0.208
  Colon or RS 10 (63.5) 21 (70.0) 13 (65.0) 18 (69.2) 13 (56.5) 18 (78.3)
  Rectum 6 (37.5) 9 (30.0) 7 (35.0) 8 (30.8) 10 (43.5) 5 (21.7)
Histological differentiation 0.274 0.572 0.233
  Well-moderate 14 (87.5) 29 (96.7) 18 (90.0) 25 (96.2) 20 (87.0) 23 (100.0)
  Por or muc 2 (12.5) 1 (3.3) 2 (10.0) 1 (3.8) 3 (13.0) 0
Pathological T stagea 0.017b 0.008b 0.035b
  T1-2 2 (12.5) 16 (53.3) 3 (15.0) 15 (57.7) 5 (21.7) 13 (56.5)
  T3-4 14 (87.5) 14 (46.7) 17 (85.0) 11 (42.3) 18 (78.3) 10 (43.5)
Pathological N stagea 0.432 0.308 0.131
  N0 8 (50.0) 20 (66.7) 10 (50.0) 18 (69.2) 11 (47.8) 17 (73.9)
  N1-2 8 (50.0) 10 (33.3) 10 (50.0) 8 (30.8) 12 (52.2) 6 (26.1)
Pathological stagea 0.046b 0.031b 0.030b
  0-I 2 (12.5) 14 (46.7) 3 (15.0) 13 (50.0) 4 (17.4) 12 (52.2)
  II–III 14 (87.5) 16 (53.3) 17 (85.0) 13 (50.0) 19 (82.6) 11 (47.8)
Lymphovascular invasion 0.101 0.037b 0.208
  Absent 2 (12.5) 11 (36.7) 2 (10.0) 11 (42.3) 13 (56.5) 18 (78.3)
  Present 14 (87.5) 19 (63.3) 18 (90.0) 15 (57.7) 10 (43.5) 5 (21.7)

SDC1, syndecan-1; Q, quartile; BMI, body mass index; CEA, carcinoembryonic antigen; CA, carbohydrate antigen; RS, rectosigmoid colon; por, poorly differentiated adenocarcinoma; muc, mucinous adenocarcinoma.

The 8th edition of the Union for International Cancer Control-Tumor Node Metastasis classification.

Statistically significant.

Multivariable analysis of disease-free survival.

Variable HR 95% CI P-value
Membranous SDC1
  Q1-2 Reference
  Q3-4 0.158 0.03–0.89 0.037a
Cytoplasmic SDC1
  Q1-2 Reference
  Q3-4 0.195 0.02–1.57 0.124
Stromal SDC1
  Q1-2 Reference
  Q3-4 0.756 0.17–330 0.710

DFS, disease-free survival; HR, hazard ratio; CI, confidence interval; SDC1, syndecan-1; Q quartile. The multivariable analysis included the variables that were significantly associated with DFS in the univariate analysis (P<0.05), including histological differentiation, pT stage, pN stage, pathological stage, lympohvascular invasion.

Statistically significant.