Colorectal carcinoma incidence and association of preoperative carcinoembryonic antigen levels with staging and histological types in the Malabar region; A cross-sectional study

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the fourth leading cause of cancer death globally, with steadily increasing mortality rates [1-3]. At the same time, CRC is third in terms of recognition/diagnosis (6.1%) and second in terms of mortality (9.2%). It is estimated that by 2035, the total number of deaths from rectal and colon cancer will increase by 60% and 71.5%, respectively [4-6].

As the incidence of CRC, it is the seventh most common cancer in India and the fourth most common in Kerala [7,8]. It is more common in developed countries than in developing countries. Even though the incidence in India is low, Kerala has shown an increase in incidence in recent times. Worldwide the prevalence of colorectal carcinoma is closely associated with the consumption of red meat and especially processed meat products. Therefore, there is a need to study the risk factors of colorectal cancer in Kerala, especially in the Malabar region, as there is a high intake of meat products in the region. Our institution is the largest tertiary care center for the four districts of the Malabar region. And the food habits of the people here are different from other parts, the food of Malabar being famous all over the world.

Lifestyle changes, including high-fat diet, lack of exercise and mental stress, have led to an increase in CRC cases. Radical surgery still remains the best therapeutic option for CRC patients [9,10]. Tumor biomarkers are widely used in the diagnosis, postoperative follow-up of tumor recurrence, prognosis and curative therapy of CRC cases [11-13].

Serum CEA is a universally used tumor marker for colorectal malignancies. Even so, the significance of pre-and post-operative CEA levels is still controversial [14]. The study by Hotta et al. reported that the pre- and post-operative CEA ratio is the prognostic predictor after surgery in stage III rectal cancer [15].

CRC tumor is evaluated by TNM staging for treatment purpose. There are different histological variants of CRC, as in any form of cancer. Forms such as adenocarcinoma (including well-differentiated, moderately differentiated

Bibin James & Edathikudi Manjush and poorly differentiated tumors), signet ring tumors, mucinous tumors, etc. have been described.

Elevated preoperative CEA levels correlate with older age, circumferential tumors, large colon tumors, liver metastases, and high-stage tumors.

The objective of our study is to analyze the incidence of colorectal carcinoma in adults in Malabar region and also to find out the relationship between serum CEA with different histological tumor variants and its TNM staging.

Materials and Methods

Study design This is a descriptive cross-sectional analysis of prospectively collected data from a single general surgery department. 168 patients operated on for colorectal adenocarcinoma over 1 year and 6 months at the Department of General Surgery, Government Medical College, Kozhikode.

Ethics statement Ethics committee approval was received for this study from the ethics committee of the Government Medical College, Kozhikode, India. Written informed consent was obtained from patients participating in this study.

Study Population Adult patients over 30 years who are diagnosed with colorectal carcinoma and operated on from the Department of General Surgery. All patients over 30 years of age newly diagnosed with colorectal carcinoma were also included in the study.

Exclusion criteria were patient age below 30 years, patients with other synchronous malignancies, patient with history of other malignancies or recurrences, patient with pre-malignant lesions, and patients with family history of colorectal carcinoma or premalignant lesions.

Sample size calculation The number of enrolled patients was calculated using the formula [8,16]:

N = Z2P (1-P)/d2 Where N = minimum required sample size Z = value of 1.96 for 95% confidence interval P = highest prevalence of pregnancy induced-hypertension in India (10.3%). d = absolute precision of 5% or 0.05. N= 168.

Study variables Independent variables such as demographics and dependent variables such as tumor site, presenting complaints, histopathology, serum CEA levels, and metastases were measured.

Statistics The Statistical Package for Social Sciences software version 20.0 was used for data analysis (SPSS Inc. Chicago, IL, USA). The chi-square test was used to analyze the significance between categorical variables. The dependent variables were analyzed by the t-test. Spearman correlation analysis was performed to explain this relationship. A p value < 0.05 was considered as a statistically significant result.

Results

In the present study, data from 168 patients diagnosed with colorectal cancer over an 18-month period were evaluated.

The mean age was 59.6 years (range 33 to 85 years). The male: female ratio was 54.8:45.2. Most of the patients were in the age group of 50-70 years which measured 55.4% followed by 23.8% in 70-90 years and 20.8% in 30- 50 years respectively.

The presenting complaints and dietary habits of the colorectal patients were described in Table 1. The histology, CEA levels and staging of the colorectal patients were detailed in Table 2 frequency percentage Presenting complaints Bleeding PR 92 54.8 Abdominal pain 32 19.0 Constipation 2 1.2 Low 6 3.6 LOA 1 0.6 Obstruction 22 13.1 Altered bowel habits 3 1.8 Anemia 2 1.2 Incidental 2 1.2 Mass P/A 1 0.6 Religion Hindu 85 50.6 Muslim 77 45.8 Christian 6 3.6 Food habits Veg 14 8.3 Non veg 152 90.5 Total 166 98.8 Site of lesion

Ascending colon 9 5.4 Transverse colon 8 4.8 Descending colon 11 6.5 Sigmoid 27 16.1 Rectosigmoid 23 13.7 Rectum 79 47.0 Caecum 11 6.5 When CEA levels were evaluated with tumor differentiation degrees, and found no statistically significant correlation was identified between the patients with CEA levels of ≤5 ng/mL and those with >5 ng/mL (p>0.05) (Table 3).

frequency percentage Histology Adenocarcinoma well differentiated 72 42.9 moderately differentiated 57 33.9 poorly differentiated 13 7.7 Mucinous adenocarcinoma 17 10.1 Lymphoma 1 0.6 Net 2 1.2 CEA levels <5 113 67.3 >5 54 32.1 TNM Staging Stage 1 4 2.4 Stage 2 79 47.0 Stage 3 74 44.0 Stage 4 11 6.5 When CEA levels were evaluated with tumor different stages of colorectal carcinoma, and found statistically significant correlation was identified between the patients with preoperative CEA levels (p<0.05) (Table 4) (Figure 1). The p value < 0.05 shows that there was a significant relationship between CEA levels and disease stage. Histology CEA levels Adenocarcinoma well differentiated

Moderately differentiated Poorly differentiated

Mucinous adenocarcinoma Lymphoma NET <5 39 40 12 13 1 2 36.4% 37.4% 11.2% 12.1% 0.9% 1.9% <5 32 17 1 4 0 0 59.3% 31.5% 1.9% 7.4% 0.0% 0.0% Chi-Square Test Value df Asymptotic significance

(2-sided) Pearson Chi-Square 10.762a 5 0.056 Likelihood Ratio 12.612 5 0.027 Linear-by-Linear Association 8.070 1 0.005 Number of Valid Cases 161 a5 cells (41.7%) have expected count less than 5. The minimum expected count is 0.34 CEA levels Staging

Stage 1 Stage 2 Stage 3 Stage 4 <5 4 68 38 3 3.5% 60.2% 33.6% 2.7% >5 0 11 36 7 0.0% 20.4% 66.7% 13.0% Chi-Square Tests Value df Asymptotic Significance (2-sided) Pearson Chi-Square 29.635a 3 .000 Likelihood Ratio 31.695 3 .000 Linear-by-Linear Association 28.550 1 .000 N of Valid Cases 167 a3 cells (37.5%) have expected count less than 5. The minimum expected count is 1.29.

Bibin James & Edathikudi Manjush

Discussion

In this study, most patients are in the age group of 50 to 70 years and the mean age of presentation is 59.6 years. There is a slight preponderance among male patients with colorectal carcinoma. 54.8% are male and the rest are female. According to Patil et al. study men were 65%, and according to Dakubo et al. study men were 53.5% [17,18].

The most common presenting complaint in this study is bleeding per rectum (54.8%), followed by abdominal pain (19.0%). Rectal bleeding (57%) was noticed as the most common presentation in Patil et al. study, followed by abdominal pain (44%). Dakubo et al. observed that 51.1% had rectal bleeding as presenting symptoms, followed by abdominal mass [17,18].

In the current study, rectum is the most common site of the lesion (47%), followed by sigmoid (16.1%). The study by Dakubo et al. also showed that the rectum was the main site of lesion, consisting of 46.8% cases. Similar results were observed in the study of Patil et al. (with rectum 49%).

In the current study, 90.5% of the study population consumes non-vegetarian diet. Similarly, studies show that vegetarian diets are associated with an overall lower incidence of colorectal cancer. Thus, vegetarians, pescetarians and 1 day/week meat eaters showed a non-significantly decreased risk of colorectal cancer compared to 6-7 day/week meat consumers, mainly due to differences in dietary pattern other than meat intake [19-21].

However, the relationship of vegetarian or non-vegetarian dietary patterns to colorectal cancer risk is not well established [22-24].

In the present study of all histological variants, well-differentiated adenocarcinoma was observed in most cases and represents 44.4%, followed by moderately differentiated adenocarcinoma. Whereas the study by Dakubo et al. showed that 62.5% is well differentiated and 25.6% is moderately differentiated adenocarcinoma [18].

CEA is a structural protein that regulates promoter functions in intracellular adhesion and aggregation. As a result, it is considered that CEA plays an important role in tumour invasion and metastasis. Filiz et al. reported in a study (published in 2009) performed on 151 colorectal cancer patients that 58.8% of patients had normal preoperative CEA levels [25].

The relationship between patients' CEA levels and the degree of differentiation of CRC was also investigated in other studies. CEA levels were high in tumors that were well and moderately differentiated, while they were low in tumors that were poorly and slightly differentiated [26-28].

This condition was thought to be caused by low CEA levels in patients with undifferentiated or poorly differentiated tumors at an advanced stage. When CEA levels and differentiation degrees of tumors were compared in the aforementioned study, it was discovered that tumour differentiation was mild or undifferentiated in patients with CEA levels > 5ng/mL, but generally well or moderate in cases with CEA levels < 5ng/mL. The observation, however, was not statistically significant [29,30].

Huh et al., investigated the correlation between CEA levels and TNM staging in 474 patients with colorectal cancer. Patients were divided into two groups according to CEA levels of above or below 5 ng/mL. In addition, only patients with non-metastatic colorectal cancer were included in the study. As result of the study, a statistically significant correlation between CEA levels and TNM staging of patients was established [31].

CEA levels were high in 32.1% of the study population in our study. Study by Topdagi et al. noted higher CEA levels in 47.8% of subjects [32].

In the current study, the association of CEA levels with different stages of colorectal carcinoma was investigated and association tested with chi-square test, which results in P value < 0.05, showing that there is significant association with stages of cancer and preoperative CEA levels.

In the study by Topdagi et al. it was observed that cases with CEA ≤ 5 ng/mL were majorly in Stage III, whereas those with CEA >5 ng/mL were predominantly in Stage IV. TNM stage, tumor sizes, and differentiation levels were defined, but no statistically significant relationship between these parameters and CEA levels was found.

In our study, an association was tested between the histologic variants and its association with CEA values, and chi-square test showed p>0.05, thus suggesting no significant association.

According to study of Topdagi et al., when CEA levels were evaluated with tumor differentiation degrees, no statistically significant correlation was identified between the patients with CEA ≤5 ng/mL and those with CEA >5 ng/mL (p>0.05) [32].

Conclusions

Colorectal cancer worldwide is associated with consumption of red meat and smoked products. In this study, we investigated various aspects of colorectal carcinoma, including epidemiology and relationship with dietary habits, as well as preoperative carcinoembryonic antigen (CEA) levels in relation to histological variants and TNM staging.

Most of the patients (90.2%) were non vegetarians. The most common presentation among the study population was rectal bleeding followed by abdominal pain, with rectum as the most common site of the cancer. Eating habits have a significant role in colorectal carcinoma; also, high preoperative CEA levels may suggest a possible advanced stage of the disease.

In conclusion, colorectal cancer is a malignancy in which more studies should be performed, as there appears to be a statistical association between CEA levels and TNM stages.