Risk Factors of Submucosal Invasion in Early Colorectal Cancer

doi:10.21203/rs.3.rs-2478420/v1

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Risk Factors of Submucosal Invasion in Early Colorectal Cancer

https://doi.org/10.21203/rs.3.rs-2478420/v1

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Aim

This study aimed to explore the risk factors of submucosal invasion in early colorectal cancer (ECC), so as to provide more accurate treatment strategies for ECC patients.

Methods

We retrospectively enrolled patients with ECC who received endoscopic or surgical treatment at the First Affiliated Hospital of Wannan Medical College, from January 2017 to December 2021. Univariate analysis and multivariate Logistic regression analysis were used to explore the risk factors of submucosal invasion in ECC. We used a receiver operating characteristic (ROC) curve to estimate the predictive value of independent risk factors for the risk of submucosal invasion in ECC.

Results

A total of 109 ECC patients were enrolled, among them, 46 cases (42.20%) with infiltration depth of submucosa were classified as the study group, and the remaining 63 cases without submucosal invasion were classified as the control group. Univariate analysis showed that age ≥ 65 years old, lesion diameter > 1cm, differentiation degree, lesion surface accompanied by erosion or ulceration, redness and bleeding tendency were associated with submucosal invasion of ECC (P < 0.05). Multivariate Logistic regression analysis showed that the moderate or poor differentiation (β = 4.158, odds ratio [OR] = 63.960, 95% confidence interval [CI]:15.149-270.038, P < 0.001), bleeding tendency (β = 2.828, OR = 16.914, 95%CI:1.728-165.553, P = 0.015) were independent risk factors for submucosal invasion with ECC. The area under the ROC curve (AUC) of differentiation degree was 0.871 (95%CI: 0.797–0.945, P < 0.001), the AUC of bleeding tendency was 0.582 (95%CI: 0.471–0.693, P = 0.145), and the AUC of the combined measurements was 0.906 (95%CI: 0.845–0.967, P < 0.001).

Conclusion

Moderate or poor differentiation and bleeding tendency are independent risk factors for submucosal invasion with ECC. The accuracy of combined measurements is higher than that of single measuremnet. Patients with ECC meeting the above conditions should be adequately evaluated before surgery, so as to provide more accurate treatment strategies.

Early colorectal cancer

Submucosal invasion

Risk factor

Colorectal cancer (CRC) is a very common malignant tumor of the digestive system, characterized by high malignancy degree and poor prognosis.The Japanese Society for Cancer of the Colon and Rectum [1] and the Vienna classification criteria [2] classify high-grade intraepithelial neoplasia (HGIN) and colorectal cancers whose invasion depth does not exceed submucosa as early colorectal cancer (ECC). The 5-year survival rate of patients with ECC can reach 90%, while this rate in advanced CRC is less than 10% [3]. Therefore, the early diagnosis and treatment of ECC plays an important role in the diagnosis and treatment of CRC, and the depth of infiltration of ECC is significantly related to its treatment strategy and prognosis. Currently, endoscopic treatments, including endoscopic submucosal dissection and endoscopic mucosal resection, is the preferred treatment in ECC. Compared with surgery, it has the advantages of lower treatment cost, smaller trauma scope, fewer complications and faster recovery [4]. However, when the invasion depth of ECC reaches the submucosa, there is about 10% risk of lymph node metastasis (LNM). Endoscopic surgery cannot meet the demand of lymph node dissection, so surgical radical resection is preferred [5]. The deeper the invasion depth of ECC, the higher the probability of LNM. When the invasion depth exceeds 1 mm submucosal, the histological manifestations of the lesions are significantly changed compared with those without invasion, and the risks of lymph invasion, venous invasion and malignant tumor budding are significantly increased [6].

Therefore, it is very important to accurately determine whether submucosal invasion occurs preoperatively in ECC, so as to provide more accurate treatment strategies for patients with ECC. To date, some studies have shown that some clinicopathological features may be related to the submucosal infiltration of ECC. For example, Wei ZC et al. suggested that the occurrence of submucosal invasion by ECC is related to the degree of tumor differentiation and histological typing [7], and Li P et al. suggested that the nature and depth of invasion of ECC may be initially predicted using developmental morphotyping [8]. But the results are controversial. Thus, we retrospectively enrolled patients with ECC who received endoscopic or surgical treatment to explore the risk factors for the submucosal infiltration of ECC.

Study subjects

We enrolled patients with ECC who received endoscopic or surgical treatment at the First Affiliated Hospital of Wannan Medical College, from January 2017 to December 2021. The inclusion criteria were: (1) postoperative pathological findings were CRC or HGIN; (2) pathological results showed that the depth of lesion invasion did not exceed that of the submucosa. The exclusion criteria were as followed: (1) patients’ information is incomplete; (2) patients had a history of inflammatory bowel disease, advanced CRC, or non-primary lesions involving the colorectum due to malignant tumors elsewhere; (3) no colonoscopy was performed before surgery, or the colonoscopy results were incomplete; (4) postoperative pathological report was incomplete.

Data Collection

Lesions that reached submucosa were included in the study group, while those that did not reach submucosa (including HGIN and mucosal invasion) were included in the control group. The following data were collected: (1) general information of patients: gender, age, hemoglobin level, tumor markers (CA199, CA125, CEA) level, smoking history, drinking history, combined with cholecystitis or gallstones; (2) pathological information: lesion diameter, degree of differentiation, depth of invasion, lymphatic or vascular invasion; (3) endoscopic characteristics of lesions: location, developmental morphotyping, redness on the surface of the lesion, bleeding tendency, erosion or ulceration, central depression.

Data analysis

We used SPSS 26.0 to analyze the collected data. Normally distributed measures in univariate analysis were tested by Z-test and presented as mean ± standard deviation. The counting data were analyzed by x² test and expressed as number (percentage) of cases. Binary logistic regression was used in multivariate analysis to calculate odds ratios and beta-coefficients. The predictive value of independent risk factors for the risk of submucosal invasion was analyzed using ROC curves. In this study, two-sided tests were used, and P < 0.05 indicated statistically significant differences.

Patient characteristics

A total of 109 ECC patients were included in the study. A number of 46 patients were included in the study group, including 23 (50.00%) males and 23 (50.00%) females with a mean age of 62.65 ± 10.88 years. In the control group, there were 63 cases, including 41 males (65.08%) and 22 females (34.92%), with a mean age of 59.89 ± 10.50 years.

Risk Factors Associated With Submucosal Invasion In Ecc

The clinicopathological characteristics of the two groups were compared, as detailed in Table 1. The results of univariate analysis showed that the significant differences were that submucosal invasion occurred more often in the patients with years ≥ 65 years (P = 0.006), lesion diameter > 1 cm (P = 0.004), moderate or poor differentiation (P < 0.001), lesion surface erosion or ulceration (P = 0.036), redness (P = 0.002) and bleeding tendency (P = 0.005).

There was no difference in patients with gender (P = 0.114), hemoglobin levels (P = 0.230), tumor marker levels (P = 0.421, 0.335, 0.167), smoking history (P = 0.771), drinking history (P = 0.882), and combined cholecystitis or gallstones (P = 0.407), lesion location (P = 0.086), developmental morphotyping (P = 0.090), and central depression (P = 0.822).

Multivariate Analysis Of Specific Risk Factors For Submucosal Invasion In Ecc

As shown in Table 2, the results of multivariate analysis showed that moderate or poor differentiation and bleeding tendency were independent risk factors for ECC invading into the submucosa (P < 0.05). The lower the degree of tumor differentiation, the higher the risk of submucosal invasion. The risk of submucosal invasion was 63.960 fold higher in lessions with moderate or poor differentiation when compared with well differentiated lesions (β = 4.158, OR = 63.960, 95%CI: 15.149-270.038, P < 0.001). Lesions with bleeding tendency had an 16.914-fold higher risk of submucosal invasion than those without (β = 2.828, OR = 16.914, 95%CI:1.728-165.553, P = 0.015). However, patients’ age, lesion diameter, redness on the lesion surface, and erosion or ulceration were not independent risk factors for submucosal invasion (P > 0.05).

Table 1

Comparison of clinicopathological characteristics between ECC patients groups [x±, ,n(%)]
Variables	Study group (n = 46)	Control group (n = 63)	x²/Z	P-value
Gender			2.494	0.114
male	23(50.00)	41(65.08)
female	23(50.00)	22(34.92)
Age(years)			7.623	0.006
<65	20(43.48)	44(69.84)
≥ 65	26(56.52)	19(30.16)
Hemoglobin(g/L)	122.28 ± 18.61	126.17 ± 16.20	1.163	0.230
Tumor markers
CA199(U/ml)	9.80 ± 11.02	11.69 ± 12.79	0.806	0.421
CA125(U/ml)	13.66 ± 10.37	11.75 ± 6.62	-1.169	0.335
CEA(ng/ml)	3.14 ± 2.69	2.55 ± 1.77	-1.384	0.167
Smoking history	5(10.87)	8(12.70)	0.085	0.771
Drinking history	4(8.70)	6(9.52)	0.022	0.882
Cholecystitis or gallstones	14(30.43)	24(38.10)	0.687	0.407
Diameter(cm)			8.365	0.004
≤ 1cm	6(13.04)	24(38.10)
>1cm	40(87.96)	39(61.90)
Location			2.956	0.086
Rectum and sigmoid	28(60.87)	48(76.19)
Left and right colon	18(39.13)	15(23.81)
Differentiation			59.490	<0.001
Well	6(13.04)	55(87.30)
Moderate or poor	40(86.96)	8(12.70)
Developmental morphotyping			2.879	0.090
Elevated type	42(91.30)	50(79.37)
Superficial type	4(8.70)	13(20.63)
Erosion or ulceration	9(19.57)	4(6.35)	4.421	0.036
Redness	26(56.52)	17(26.98)	9.711	0.002
Bleeding tendency	9(19.57)	2(3.17)	7.872	0.005
Central depression	1(2.17)	1(1.59)	0.051	0.822

Table 2

Multifactor Logistic Regression Analysis of ECC invasion in Submucosa
Risk factors	OR	95%CI	β	S E	Wald	P-value
Age(years)
< 65	1.000
≥ 65	2.039	0.538–7.729	0.712	0.680	1.098	0.295
Diameter(cm)
≤ 1	1.000
> 1	3.094	0.703–13.609	1.130	0.756	2.234	0.135
Differentiation
Well	1.000
Moderate or poor	63.960	15.149-270.038	4.158	0.735	32.019	<0.001
Erosion or ulceration
No	1.000
Yes	1.188	0.182–7.754	0.172	0.957	0.032	0.858
Redness
No	1.000
Yes	2.118	0.569–7.889	0.750	0.671	1.251	0.263
Bleeding tendency
No	1.000
Yes	16.914	1.728-165.553	2.828	1.164	5.904	0.015

Predictive Value Of Independent Risk Factors For The Submucosal Invasion In Ecc

The predictive value of the independent risk factors for the occurrence of submucosal invasion of ECC was calculated using the ROC curve. As shown in Fig. 1 and Table 3, the area under the ROC curve (AUC) of the differentiation degree and bleeding tendency were calculated, which showed that AUC of differentiation degree was 0.871 (95% CI: 0.797–0.945, P < 0.001) and the sensitivity and specifcity of differentiation degree were 86.96% and 87.30%, respectively. For bleeding tendency, AUC was 0.582 (95% CI: 0.471–0.693, P = 0.145), and the sensitivity and specifcity of bleeding tendency were 19.57% and 96.83%, respectively. The AUC of the combined measurements of differentiation degree and bleeding tendency in predicting ECC was 0.906 (95% CI: 0.845–0.967, P < 0.001), which was larger than that predicted by the degree of differentiation or bleeding tendency independently. The Youden index of the combined measurements was 0.776, with a cut-off value of 0.331, and the sensitivity and specifcity of the combined measurements were 93.48% and 84.13%, respectively.

Table 3

Reference values under the ROC curve for each independent risk factor
Risk factors	AUC	95%CI	P-value	Youden index	Cut-off value	Sensitivity(%)	Specificity (%)
Differentiation	0.871	0.797–0.945	<0.001	0.743	0.466	86.96	87.30
Bleeding tendency	0.582	0.471–0.693	0.145	0.164	0.598	19.57	96.83
Combined diagnosis	0.906	0.845–0.967	<0.001	0.776	0.331	93.48	84.13

CRC is one of the most common malignant tumors in the world today. According to the global cancer data reported by the International Agency for Research on Cancer of World Health Organization in 2020, CRC is now the third most common cancer in the world with the second highest mortality rate and a continuous rising trend compared with the past. CRC is a serious threat to human life and health [9]. The onset of CRC is insidious and usually progresses in a “polyp- adenoma-carcinoma” mode. It takes about 10–20 years to develop from normal mucosa to advanced malignant tumor [10]. The five-year survival rate of advanced CRC is significantly lower than that of early-stage CRC, which puts forward higher requirements for the diagnosis and treatment of ECC. It is important to accurately determine whether the tumor has submucosal infiltration.

The number of new CRC cases and deaths in China is also increasing compared with the past, among which the morbidity and mortality of males are higher than that of females. In addition, the morbidity and mortality of CRC tend to increase with the increase of age, with a gentle growth rate before the age of 40, a gradual growth rate after 40, and a peak growth rate after the age of 65 [11]. In our study, there were 64 (58.71%) male and 45 (41.28%) female ECC patients. The incidence of male patients was higher than that of female patients, which was consistent with the epidemiological characteristics of CRC. However, no correlation between gender and submucosal infiltration of ECC was found (P > 0.05). A total of 26 patients (56.52%) aged ≥ 65 years in the study group were significantly higher than 19 patients (30.16%) in the control group, the difference was statistically significant (P = 0.006), indicating that age at ECC was associated with submucosal invation.

Tumor markers are substances produced by the body or tumor cells themselves in the process of tumorigenesis and development, and tumors labeled with CEA, CA199, CA125 are commonly used to screen ECC and evaluate prognosis [12]. CEA is a carcinoembryonic antigen, which is often used to predict the recurrence and prognosis of CRC. Some studies have shown that serum CEA level has predictive significance for CRC staging, and the positive rate of serum CEA (> 5ng/ml) in patients with middle and advanced CRC is significantly higher than that in patients with ECC [13]. With the deeper the rectal cancer invasion, the higher the serum CEA level [14]. CA199 is an oligosaccharide tumor-associated antigens, and its expression level changes are related to the size, depth of invasion, and metastasis of CRC. Its sensitivity for CRC screening alone is not high, and it is often used in combination with CEA for diagnosis and as an independent prognostic marker for CRC [15]. CA125 is a class of macromolecular glycoproteins, and studies have found that its expression level is positively correlated with the TNM stage of CRC, but the correlation strength is less than CEA and CA199 [16]. In this study, no correlation was found between CEA, CA199 and CA125 and the submucosal invasion of ECC (P > 0.05), that is, these three tumor markers had no significant reference significance for the submucosal invasion of ECC. Some scholars have found that the expression levels of CA242 and CA724 are related to the depth of CRC infiltration [17–18], but this study has not carried out research on them due to limited research conditions.

Some studies found that cholecystitis is closely related to the poor long-term prognosis in patients with CRC. Compared with non-CRC patients, the survival time of CRC patients with cholecystitis is significantly reduced, and the higher the TNM stage, the shorter the survival time [19]. In addition, gallstones are also associated with the incidence of CRC, which may be attributed to the disorder of bile acid metabolism caused by cholecystitis or gallstones [20]. Secondary bile acids can promote the formation of reactive oxygen radicals, further damage cellular DNA, reduce apoptosis, increase mutations, and promote the transformation of normal cells into cancer cells [21]. However, this study has not found any association between the the combination of cholecystitis or gallstones and the submucosal infiltration of ECC (P > 0.05).

In this study, no correlation was found between the location of ECC lesions and the invasion of submucosa (P > 0.05), but among the 109 cases included in the study, 76 cases (69.72%) occurred in the rectum or sigmoid colon, accounting for significantly higher proportion than 33 cases (30.28%) located in other locations, which was consistent with the epidemiological results of CRC prone sites. About half of CRCs occurs in the rectum, followed by the sigmoid colon. The reason is related to the anatomical structure of the rectum, where harmful and carcinogenic substances carried in feces accumulate, causing inflammatory reactions such as intestinal mucosal congestion and edema under the influence of intestinal flora, thus inducing the occurrence and development of CRC [22].

It has not been concluded whether the diameter of ECC lesions is related to the occurrence of submucosal infiltration. Some studies have shown that when the diameter of ECC lesions is less than 1cm, the probability of infiltration of the submucosa is less than 1% [23]. When the lesion diameter was greater than 1.5 cm, the tumor had a higher probability of LNM [24], whereas ECC has a chance of LNM only when there was submucosal invasion. Some studies have also found that there is no correlation between the diameter of ECC lesions and submucosal invasion [7]. In this study, 40 cases (87.96%) with lesion diameter > 1 cm in the study group accounted for significantly higher than 39 cases (61.90%) in the control group, the difference was statistically significant (p = 0.004), indicating that lesion diameter > 1cm in ECC was associated with the occurrence of submucosal infiltration in ECC.

The degree of CRC differentiation is closely related to the depth of invasion. It is generally believed that the lower the degree of tumor differentiation, the higher the degree of malignancy and the deeper the depth of invasion. In this study, there were 40 cases (86.96%) of moderate or poor-differentiated lesions in the study group, which accounted for a significantly higher proportion than 8 cases (12.70%) in the control group. It was confirmed that there was a significant correlation between the degree of differentiation of ECC and the occurrence of submucosal infiltration (P < 0.001). Multivariate Logistic regression analysis showed that the risk of submucosal infiltration in moderately or poorly differentiated lesions was 63.960 times higher than that in highly differentiated lesions (β = 4.158, OR = 63.960, 95% CI:15.149-270.038, P < 0.001), which was an independent risk factor for submucosal invasion of ECC. However, most of the medium-differentiated and low-differentiated lesions in the study group included in this study were moderately differentiated. There may be two reasons for this difference, firstly it is related to environmental factors; Secondly, poorly differentiated CRC has a high degree of malignancy, and patients often choose to seek treatment in other hospitals. Therefore, more comprehensive studies are needed to clarify the relationship between poorly differentiated lesions and the depth of ECC infiltration.

According to the developmental morphology, ECC can be divided into elevated type and superficial type, and the latter can be further divided into flat and superficial depressed type, which can be used to initially predict the nature and depth of invasion of ECC [8]. Some studies have found that the lesions with flat and depressed type are more malignant and the risk of submucosal invasion is significantly higher than that of elevated-type lesions [25]. However, ECC lesions included in this study were mostly elevated type, which may be related to the superficial lesions being covert and not easily distinguished endoscopically. In addition, bleeding tendency, redness, and increased friability on the surface of the lesion are common endoscopic morphology of flat and depressed types [26]. Therefore, there are of certain reference value in judging the depth of ECC invasion. In this study, 26 patients (56.52%) had redness on the surface of lesions in the study group were significantly higher than 17 patients (26.98%) in the control group (P = 0.002). There were 9 patients (19.57%) had bleeding tendency on the lesion surface in the study group, which accounted for a higher proportion than 2 patients (3.17%) in the control group (P = 0.005). Some studies also found that ECC lesions with erosion or ulceration were more likely to occur in submucosal carcinoma [27]. In our study, 9 patients (19.57%) had erosion or ulceration on the surface of the lesion of the study group were significantly higher than 4 patient (6.35%) in the control group (P = 0.036). The results indicated that bleeding tendency, redness, and lesions surface with erosion or ulceration were associated with submucosal invasion of ECC, and multivariate analysis showed that bleeding tendency was also an independent risk factor for submucosal invasion of ECC (β = 2.828, OR = 16.914, 95%CI:1.728-165.553, P = 0.015).

This study also has some limitations. As a single-center retrospective study with limited sample size, multicenter and expanded sample size studies are needed in the future to verify the accuracy of the results.

In conclusion, the age of patients ≥ 65 years old, lesion diameter > 1cm, differentiation degree, lesion surface erosion or ulceration, redness and bleeding tendency were associated with the occurrence of submucosal invasion of ECC. The moderate or poor differentiation and bleeding tendency were independent risk factors for submucosal invasion of ECC. The combined diagnosis was more accurate than the independent diagnosis. Patients with ECC meeting the above conditions should be adequately evaluated before surgery, so as to provide more accurate treatment strategies and better judge the prognosis.

ECC Early colorectal cancer

CRC Colorectal cancer

ROC Receiver operating characteristic

OR Odds ratio

CI Confidence interval

AUC Area under the ROC curve

HGIN High-grade intraepithelial neoplasia

LNM Lymph node metastasis

Ethics approval and consent to participate

The experimental protocol was established, according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of The First Affiliated Hospital of Wannan Medical College. Written informed consent was obtained from all patients.

Consent for publication

Not applicable.

Availability of data and materials

All data generated or analysed during this study are included in this published article.

Competing interests

The authors declare that there is no conflict of interest.

Funding

This study was supported by the Key Research Project of Wannan Medical College (Nos. WK2022ZF03), and Wuhu City Science and Technology Project (No. 2021cg36, No. 2021cg45).

Authors' contributions

CH and LL conceived the study design and supervised the study. TW performed the statistical analysis and wrote the manuscript. CH and LL reviewed and revised the manuscript. All authors read and approved the final manuscript.

Acknowledgments

We thank all participants who participated in this study.

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No competing interests reported.

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Risk Factors of Submucosal Invasion in Early Colorectal Cancer

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Abstract

Aim

Methods

Results

Conclusion

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Background

Objects And Methods

Study subjects

Data Collection

Data analysis

Results

Patient characteristics

Risk Factors Associated With Submucosal Invasion In Ecc

Multivariate Analysis Of Specific Risk Factors For Submucosal Invasion In Ecc

Predictive Value Of Independent Risk Factors For The Submucosal Invasion In Ecc

Discussion

Conclusion

Abbreviations

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