Clinical and endoscopic characteristics of colorectal sessile serrated lesion with dysplasia: a single-center cross-sectional comparative study

Introduction

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide, and the incidence and mortality rate of CRC continue to rise (1,2). According to the latest statistics of the National Cancer Center, CRC accounts for 9.9% of newly reported malignant tumor cases. As shown in the global cancer statistics in 2022, the total incidence rate of CRC in China was 41.9/100,000, ranking second among malignant tumors, with 340,257 cases for males and 251,975 cases for females. By contrast, the mortality rate was 21.9/100,000, ranking the fifth, with 177,921 males and 131,193 females having died because of CRC (2,3). It was estimated that China had 592,232 prevalent CRC cases occurred in 2022, accounting for 30.7% of all prevalent CRC cases worldwide, constituting a large burden on society (4).

Currently, it is accepted that the oncogenic pathway of CRC includes the classical adenoma-carcinoma pathway, inflammatory-cancer pathway, de novo pathway, and the serrated pathway, among which the adenoma-carcinoma pathway is the most common, explaining approximately 80% of CRC (5). In recent years, an increasing volume of evidence has demonstrated that a subset of lesions also harbor malignant potential and can progress to cancer through the alternative serrated neoplasia pathway rather than following the traditional adenoma-carcinoma sequence (6-9). Serrated lesions are characterized by the serrated shape of the crypt epithelium with or without dysplasia (7). According to the latest classification of World Health Organization (WHO) in 2019, serrated lesions are classified into hyperplastic polyp (HP), sessile serrated lesion (SSL), SSL with dysplasia (SSL-D), traditional serrated adenoma (TSA), serrated adenoma, and unclassified (10). The latest WHO classification separately divides SSL-D into one category, on the basis of facts that it takes an average of 15 years for SSL to develop to CRC, whereas it takes SSL-D as little as 2 years (11,12).

Serving as a precancerous lesion of CRC, SSL is a colorectal lesion for which malignant potential originates from the serrated pathway, primarily leading to microsatellite instable-high (MSI-H) CRC, which demonstrates the rapid tumor growth (13,14). It has been claimed that some serrated lesions may rapidly evolve into invasive carcinoma (11). Furthermore, some studies have reported that submucosal invasive carcinoma caused by SSL shows greater potential for lymph invasion and lymph node metastasis than conventional carcinoma caused by tubulovillous adenomas (15). Owing to the fact that SSL is mainly flat and occurs in the proximal colon, errors in its detection and diagnosis are not uncommon (14).

In this study, we comparatively discuss the influence of the endoscopic and pathological features as well as the associated factors of SSL and SSL-D on the development of dysplasia, in order to provide a framework for screening high-risk patients and lower the missed diagnosis and misdiagnosis rates. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2024-901/rc).

Methods

Study design

This retrospective clinical study collected data from patients hospitalized between January 2019 and December 2024. Patients meeting the following inclusion criteria were pathologically confirmed as having SSL after colonoscopy in our hospital: age ≥18 years old, well-prepared bowel, the lens reaches the ileocecum, and the observed pathological diagnostic criteria were from the 2019 WHO classification (5^th edition). The exclusion criteria were as follows: malignancy or inflammatory bowel disease (IBD), acute gastrointestinal bleeding, poor bowel preparation, and incomplete clinical and endoscopic data. The laboratory examination and pathological characteristics of lesions were analyzed for the purpose of determining the endoscopic characteristics of colorectal SSL-D and related factors. Baseline clinicopathological characteristics and endoscopic findings were collected through Medecon software (Medecon Healthcare, Buckinghamshire, England) in the Affiliated Drum Tower Hospital of Nanjing University, Medical School. Comparative analyses of SSL and SSL-D patients on general data [age, gender, body mass index (BMI), etc.], underlying diseases (hypertension, diabetes), blood biochemical indicators [total cholesterol (TC), total triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), apolipoprotein A (APOA), apolipoprotein B (APOB)], endoscopy (size, location, shape, etc.), and pathological characteristics were conducted. All of the endoscopic findings were conducted by experienced endoscopists who had completed more than 3,000 colonoscopy procedures. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by institutional ethics board of the Affiliated Drum Tower Hospital of Nanjing University Medical Ethics Committee (No. 2025-0325-02) and individual consent for this retrospective analysis was waived.

Endoscopic data

Bowel preparation

patients fasted for 12 hours before the electronic colonoscopy, and they were required to drink 1,000 mL of warm water within 1 hour at the same time of day, in which polyethylene glycol electrolyte powder (1 package) was dissolved. Then, when it was 4 hours before the electronic colonoscopy, they were required to drink the same solution twice (2 packages) within 2 hours, additionally using dimethyl silicone oil defoaming agent to empty the bowel. This process ensured that all solid stool was passed, and visual field within the intestinal lumen were clear.

Procedures

the colonoscope firstly entered the terminal of ileum, and then the microscope was inserted for microscopic observation of the colon. The size of colon polyps was measured upon detection, and their number, location, and morphology were recorded. The size of the polyps was measured according to the open diameter size of the biopsy clamp (5 mm) or by measuring the maximum diameter of the resection specimen. The site of polyps was divided into proximal colon (cecum, ascending colon, liver curvature, transverse colon, spleen curvature) and distal colon (descending colon, sigmoid colon, and rectum). The morphology of the polyps was classified according to the Paris classification in 2005, which divides polyps into protruded lesions (type I) and superficial lesions (type II), type I lesions are up to 2.5 mm (standard for closed biopsy forceps), pedunculated (0–Ip), or sessile (0–Is); type II lesions are divided into slightly elevated (0–IIa), flat (0–IIb), or depressed (0–IIc) in detail (16).

Pathological analysis

All cases were appropriately collected, then the specimens were fixed by formaldehyde solution, embedded in paraffin, and a pathological histology examination was performed. The pathological results were decided by the pathologist of our hospital, referring to the diagnostic criteria of the 2019 WHO classification (5^th edition). The typical histological features of SSL include horizontal growth along the muscularis mucosae, dilation of the crypt base (basal third of the crypt) such that it is wider than the luminal opening, serrations extending into the crypt base, and asymmetrical proliferation. A lesion with at least one clearly distorted crypt was diagnosed as the SSL (14). SSL-D referred to those SSL with abrupt transition to dysplasia, with the dysplasia component characterized by the existence of crypt architecture with cytological atypia. Endoscopic morphological findings, such as large or small nodules on the surface and partial protrusion of SSL were taken to indicate SSL-D (17).

Relevant definitions

Blood biochemical parameters

TG (normal value 0.52–1.56 mmol/L); TC (normal value 2.8–4.14 mmol/L), LDL (normal value 1.55–2.59 mmol/L), HDL (normal value 0.88–1.76 mmol/L), APOA (normal value 1.2–1.6 mmol/L), APOB (normal value 0.8–1.2 mmol/L).

Single lesion

a single SSL detected in a participant was regarded as a single lesion in SSL; when there was only one SSL-D, and no SSL was detected in a case, this was regarded as single lesion in SSL-D.

Statistical analysis

Statistical analysis was performed with the software SPSS 27.0 (IBM Corp., Armonk, NY, USA) and a P value <0.05 was considered statistically significant. The quantitative parameters of the sample were described using means, percentages, and standard deviations, expressed as the mean ± standard deviation (x¯±s). The t-test was used to compare the mean between the quantitative data, whereas the Chi-squared test or Fisher’s exact probability method was used for comparing the counting data. The test level a=0.05, and P<0.05 were deemed statistically significant.

Results

General demographic data of patients with colorectal SSL

A total of 454 participants with a male-to-female ratio of 0.91:1 were enrolled in this study. Their age ranged from 25 to 92 years, with a mean of 58.43±13.94 years, with a predominance of participants aged 51–70 years (Table 1 and Figure 1).

Figure 1 Age and gender distribution of patients with SSL. Totally 454 subjects were collected in this study, including 216 males (47.58%) and 238 females (52.42%). Group aged 51–70 years represented largest proportion, whereas patients ≤50 years are also prominent (26.21%). SSL, sessile serrated lesion.

There were 397 SSL patients with a mean age of 57.93±14.28 years [196 male and 201 female (50.63%) with a ratio of 0.98:1]. Respectively, there were 57 SSL-D patients (12.56%) with mean age of 61.87±10.74 years, 20 males and 37 females (64.91%), with a male-to-female ratio of 0.54:1. Notably, there were significant differences between the SSL and SSL-D groups in the gender distribution (P=0.044), whereby females seemed to be more susceptible to SSL-D. There were significantly more cases with hypertension in the SSL-D group than there were in the SSL group (17.13% vs. 33.33%, P=0.004), yet the proportion of the combined diabetes mellitus indicated no significant difference. No significant difference was discovered in BMI values between the two groups (P=0.71). The results are summarized in Table 2.

Comparison of laboratory blood lipid tests

This study also explored the discriminations in lipid metabolism, comparing the laboratory blood lipid tests between the SSL and SSL-D groups (Table 3). The SSL-D group had obviously higher readings than the SSL group in TC (4.53±1.18 vs. 3.70±1.31 mmol/L), TG (1.69±1.28 vs. 1.37±0.86 mmol/L), LDL (2.74±0.92 vs. 2.01±0.94 mmol/L), HDL (1.14±0.48 vs. 1.01±0.40 mmol/L), and APOB (0.87±0.33 vs. 0.77±0.23 mmol/L), for which the differences were statistically significant (Table 3). APOA level was comparable between the two groups (1.12±0.25 vs. 1.12±0.23 mmol/L, P>0.05). Therefore, the lipid indexes were higher in the SSL-D group.

Comparison of endoscopic features

A total of 482 SSLs were detected in the 454 enrolled patients, including 423 lesions without dysplasia (9 SSL detected in the SSL-D group were not included in the overall analysis in the SSL group) and 59 lesions with dysplasia. A total of 414 lesions in 397 participants were enrolled in the SSL group, including 14 cases with 2 lesions and 1 case with 4 lesions. There were a total 59 lesions in 57 cases in the SSL-D group, since 4 special cases (2 SSL and 1 SSL-D, 4 SSL and 1 SSL-D, 3 SSL and 2 SSL-D, and 2 SSL-D, respectively observed in each case) were included (Figure 2). The SSL-D and the SSL groups were significantly different in polyp size and mucosal color. Features ranging from ≥10 mm (86.44% vs. 57.00%, P<0.001), 0–IIa (55.93% vs. 41.55%, P=0.049), to kermesinus surface (22.03% vs. 7.49%, P<0.001) were more easily observed in SSL-D lesions, forming a crude SSL-D appearance. However, there was no significant difference between the two groups on the lesion site, since they both more readily locate in the proximal colon (67.80% vs. 77.05%, P=0.12), which aligns with previous studies (14) (Table 4).

Figure 2 Age distribution of SSL and SSL-D groups. Of the 454 cases included in the study, 397 were SSL, including 196 males (49.37%) and 201 females (50.63%) with a ratio of 0.98:1. Fifty-seven were SSL-D (12.55%), including 20 men (35.09%) and 37 women (64.91%), with a male-to-female ratio of 0.54:1. Patients older than 50 years shared the largest proportion in both groups. SSL, sessile serrated lesion; SSL-D, sessile serrated lesion with dysplasia.

Discussion

Not only does CRC serve as the most common gastrointestinal tract cancer, but it is one of the predominant causes of cancer-related death worldwide (2). Given that its incidence and mortality continue to rise, CRC places a heavy economic burden on society (1). In recent years, mounting evidence has corroborated that CRC can also develop through the serrated pathway, and 15–30% of CRC cases develop through serrated precursor lesions, which had previously been regarded as benign lesions (5,18). A series of interval CRC (occurring during the recommended surveillance intervals, usually 3–5 years) is considered to be germinated through the serrated pathway (19,20). Due to the fact that the SSL is typically flat and located in the proximal colon, it is easy to be missed in detection and diagnosis (21). Moreover, SSL-D are easily omitted or incompletely removed and ultimately develop into interval CRC, because the mucosal features of most SSL-D are so minute that they are easily covered by mucinous or stool debris (22). Thus, the detection of subtle mucosal features associated with dysplasia and careful endoscopy after mucus removal are noteworthy for the prevention of interval cancer.

Among 454 cases collected in this study, 414 cases of SSL were discussed with a mean age of 57.88±14.18 years and a male-to-female ratio of 0.97:1. Meanwhile, there were 57 cases of SSL-D (12.55%) with a mean age of 61.58±10.32 years, including 20 males and 37 females with a ratio of 0.54:1. Significant differences in gender distribution (P=0.044) were observed, which is consistent with previous studies, since SSL-D tends to affect more female patients (23,24). The mean age of the SSL-D cases was higher than that of SSL cases, but without significance; the majority of the previous papers reported that SSL-D diameters were larger than those of SSL, to a level of significance in some of those studies (25,26). In terms of combined disease history, the proportion of patients with hypertension in the SSL-D group was exceedingly higher than that in the SSL group (33.33% vs. 17.13%, P=0.004), whereas no significance was detected in patients with combined diabetes mellitus. The influence of arterial hypertension on SSL development is uncertain; on the one hand, anti-hypertensive medications angiotensin I-converting enzyme inhibitors and angiotensin II type-1 receptor blockers could decrease tumor-associated angiogenesis, though no remarkable CRC risk with these drugs was observed in meta-analysis (27), on the other hand, obesity and diabetes mellitus affect both blood pressure and cancers, and the association between them differ by sex. BMI values were relatively higher in both of the groups without significant difference, although BMI value was an independent risk factor for CRC (P>0.05) (28). On part of data associated with lipid metabolism, lipid indexes (TC, TG, LDL, HDL, APOA, and APOB) increased in both of the groups, with obviously significant differences in harmful TC and LDL (P<0.001). Adipose tissue can secrete a wide range of inflammatory cytokines related to lipid metabolism, which are thought to be pro-carcinogenic (29).

In this study, the incidence rate of SSL-D was 12.55%, which is similar to the results of previous studies (2–30%). The average size of SSL and SSL-D was 11 and 16 mm, respectively, whereas it was 9.5–15.0 and 14.3–20 mm, respectively, in the previous studies (25). There are manifold reasons for diversified incidence rate, for example, different sample size and inevitable selection bias in retrospective studies, the rapidly updated naming, classification, diagnosis, and overall recognition of SSL and SSL-D (18), as well as inter-observer variations among pathologists and endoscopists (24). When it comes to endoscopic and pathological performance of SSL-D, large size, 0–IIa morphology, and surface color were identified as conspicuous relations. In parallel with previous studies, SSL and SSL-D were more frequently located in the proximal colon (77.05% vs. 67.80%, P=0.12) (25). SSL-D tended to be larger: the majority of the SSL-D were bulky [lesions ≥10 mm comprised 86.44% (51/59)], small SSL-D comprised only 5.08% (3/59). Some previous researchers have reported that SSL-D are frequently <6 mm in size and located throughout the colon, whereas others have reported that SSL-D are significantly more associated with the distal colon, large size, polypoid morphology, surface-changes, and no mucus cap (25,30,31).

Surface changes similar to advanced adenomatous polyps were found in SSL with atypical hyperplasia/carcinoma. In this study, 0–IIa morphology and kermesinus surface were more prevalent in SSL-D, since it also takes on polypoid morphology, focal nodular elevation, depression, and reddish color, which are useful markers for identifying dysplasia or a carcinoma within an SSL (17,32). It has been reported that if SSL are covered by mucus caps, which usually leads to an irregular or vague margin, possibility of dysplasia existed in SSL may be low, since reduced mucus secretion may act as a symbolized change in the conversion of SSL to SSL-D (23). Similar results were observed in this study with significant difference (P=0.03), since only one case with mucus cap was found in the SSL-D group.

Endoscopic discrimination between SSL and SSL-D based on morphological features seemed difficult, and so did laboratory blood lipid tests clinically; however, size, color, and location of the lesions simply facilitated diagnosis.

There are some limitations in this study. As a single-center, retrospective, and cross-sectional study which considered the enrollment of inpatients only, with a relatively small sample size, selection bias was inevitable and causality cannot be inferred. Secondly, some SSL that belong to flat polyps of smaller size may be misdiagnosed endoscopically as HPs (14). Moreover, the possibility of inter-observer variation in identifying, classifying, and even naming serrated lesions among pathologists cannot be ignored. Ideally, all SSL and HPs should be reevaluated by subspecialty pathologists referring to the criteria of WHO in 2019 to diagnose SSL, yet it is too burdensome to be implemented in practice (33). Besides, in terms of endoscopic characteristics, this study only investigated the size, location, and morphology of SSL, paying little attention to the histological features (e.g., loss of MLH1 expression), boundary situation, and microvascular structure of the lesion (17). Meanwhile, magnifying endoscopic observations were not carried out in all the patients in view of this retrospective study, leading to the immature data of opening gland duct. In addition, we also observed that records about histological features are inadequate and undeveloped clinically, which is essential for SSL and SSL-D diagnosis. There have reached no consensus or criteria about related classification, characteristics, and diagnosis, since studies about SSL have only just begun to be conducted.

Conclusions

Females with SSL and a history of hypertension are more prone to have dysplasia, whereas endoscopic discrimination between SSL and SSL-D based on morphological features is vague. Lipid metabolism may play a role in the evolution of SSL to SSL-D. Further studies with an amplified sample size are warranted to validate our findings.

SSL and SSL-D tend to locate in the proximal colon, and SSL with large size, 0–IIa morphology, kermesinus surface, and no mucus cap is more likely to develop dysplasia. For SSL with the characteristics mentioned above, thorough removal and curtate follow-up time are recommended. SSL with or without dysplasia remains an undeveloped field, requiring more comprehensive exploration and criteria.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2024-901/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2024-901/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2024-901/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2024-901/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by institutional ethics board of the Affiliated Drum Tower Hospital of Nanjing University Medical Ethics Committee (No. 2025-0325-02) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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