Association between Preoperative Leukocytosis and Pathological Features of Colorectal Cancers

Colorectal cancer is one of the most common cancers among societies, highly affected by lifestyle. A number of risk factors for colorectal cancer have been recognized such as lack of physical activity, obesity, low use of vegetables and fruits, and smoking [1-6]. Prognostic factors are indicators affecting the overall results of treatment whereas predictive factors are those affecting the response to intervention or any specific treatment [7-8]. Using predictive factors, especially for high risk patients such as those with cancer which require more attention and precise treatments, was considered for appropriate treatment approaches with fewer side effects for patients [9-10]. Changes in blood parameters including anemia, leukopenia, leukocytosis, and thrombocytosis in most malignancies have been well studied and considered as a part of paraneoplastic syndromes. Abstract


Introduction
Colorectal cancer is one of the most common cancers among societies, highly affected by lifestyle. A number of risk factors for colorectal cancer have been recognized such as lack of physical activity, obesity, low use of vegetables and fruits, and smoking [1][2][3][4][5][6]. Prognostic factors are indicators affecting the overall results of treatment whereas predictive factors are those affecting the response to intervention or any specific treatment [7][8]. Using predictive factors, especially for high risk patients such as those with cancer which require more attention and precise treatments, was considered for appropriate treatment approaches with fewer side effects for patients [9][10]. Changes in blood parameters including anemia, leukopenia, leukocytosis, and thrombocytosis in most malignancies have been well studied and considered as a part of paraneoplastic syndromes.
Paraneoplastic syndromes include non-metastatic systematic manifestations which observe in many malignancies and have negative alter on the prognosis. These non-metastatic manifestations almost always occur in all malignancies, but their patterns in each cancer are different [11]. Many of patients who have abnormality in hematology profile even before the diagnosis is established. Other paraneoplastic syndroms develop during treatment course and related with the progression or regression of the tumor [12][13][14]. Among paraneoplastic syndromes, leukocytosis (mainly granulocytosis) is more prevalent in non-hematologic malignancies. About 10 percent of patients with non-hematologic malignancies have leukocytosis. This percentage is higher in tumors of lung, head and neck, pancreas, brain, and melanoma. reaction which observes with the increased presence of mature neutrophils and some other related forms [15]. Based on recent studies suggest that using hematology profiles including leukocyte count has been considered as prognostic factors in some cancers [16][17][18][19][20]. Hematology profile test is cheap, easy to use, and available in all surgery centers. Particularly during the hospitalization of patients, is suitable to use it [21][22]. In this study, we report the association between preoperative leukocytosis and pathological features of colorectal cancers based on data from the 2017 to 2019 in Sina hospital, Tehran, Iran. The purpose of this study is to investigate prognostic value of leukocytosis before surgery in colorectal cancers.

Materials and Methods
This is a cross-sectional study included patients with colorectal cancers who were treated in Sina hospital affiliated to Tehran University of Medical Sciences from 2017 to 2019. Inclusion criteria for the study were patients with colorectal cancer (confirmed by pathology result) that underwent surgery with curative goal. Exclusion criteria were the incomplete medical record files, loss of patients during follow up, and patients with abscess, obstruction, and patients who had neoadjuvant chemoradiation's side effects. Recorded variables for each patient were age, sex, tumor location and pathologic characteristic of the tumor after resection (depth of invasion, lymph node status, lymphovascular invasion, perineural invasion, tumor differentiation grade). Laboratory findings were assessed such as Carcinoembryonic antigen (CEA) and complete blood cell count (CBC) by Electrochemiluminescence assay and blood cell analyzer (Sysmex KX21), respectively. Based on the amount of leukocyte (higher or lower than 10000/µl), patients were divided into two groups of leukocytosis and non-leukocytosis, respectively. Other factors including tumor stage, its degree, its anatomical location as well as CEA levels were compared between two groups.
Statistical analysis of the results was performed by using SPSS-16 software (SPSS Inc, Chicago, Illinois, USA). Descriptive and statistical analysis was done. Results were presented as mean ± standard deviation (SD) for quantitative variables and were summarized by absolute frequencies and percentages for categorical variables. The association between the variables and leukocytosis was examined using by Chi-square test. All statistical tests were 2-sided and P-value less than 0.05 were considered significant.
There was no statistically significant difference in lymphovascular and perineural invasion between the two groups (P-value>0.05). There was no statistically significant difference in tumor staging and presence of metastasis between the two groups (P-value>0.05).
There was statistically significant difference in grade of the differentiation tumor between two groups (P-value<0.05). Leukocytosis has been seen in 6.7% of well differentiated tumors, in 35.1% of moderately differentiated tumors and in 81.8% of poorly differentiated tumors. Chi-square test had shown statistically significant correlation between the differentiation of tumor and the existence of leukocytosis (p<0.001).
Other important finding of the current study was the correlation between leukocytosis and location of the tumor. Data analysis showed that the percentage of tumors accompanied with leukocytosis in right colon cancer and transverse was 60%, in left colon was 22.2% and in rectum was 14.3%. Chi-square test have shown that presence of leukocytosis had a significant decrease from right colon towards rectum (p<0.005) (Tables 1). There was no statistically significant mean between other hematologic findings and CEA level with our variables (Tables 2).

Discussion
Several studies have been conducted on factors affecting the prognosis of colorectal cancers. In these studies, age, sex, location of the tumor, size of the tumor, differentiation degree of the tumor, cancer stage, and the symptoms of disease have been assessed as prognostic factors for colorectal cancer [23]. Several studies regarded hematologic indexes consist of leukocytosis as a predictive factor for prognosis and mortality of the patients which was recognized in majority of solid tumors [21][22]. In a study by Qiu et  year survival and disease free survival. Also, the patients with accompanying anemia and leukocytosis had more decreased survival than the patients with only leukocytosis [17]. The current study demonstrates that leukocytosis is related to the location of tumor and degree of tumor differentiation which associated with poor prognosis. In a study by Nakshabendi et al. was conducted on patients with colorectal cancer which showed WBC to Hbg ratio was high and considered as concurrency of anemia (Hbg<10gr/dl) and leukocytosis. The ratio was higher in patients with right colon cancer about 55% while in those with left colon cancer was about 10% which the difference was statistically significant. Such studies had shown that patients with right colon cancer were more prone to develop leukocytosis and anemia [19] which is similar to our findings. Qiu et al. study established that anemia and thrombocytosis before treatment were independent prognostic factors for patients'survival in advanced and lung cancers was assessed which showed only leukocytosis can be an independent prognostic factor in patients with cervix cancer [22]. Studies showed that patients with cervix cancer who had leukocytosis (WBC count>10,000/ml), had lower treatment success and survival comparing to those without leukocytosis. Moreover, these patients had a higher activity of immune system comparing to groups without leukocytosis. Leukocytosis before surgery along with other variables such as the stage of disease, tumor diameter, and histology grade of tumor are the main prognostic factors in the patients and can be used for determination of the patients with poor prognosis [11]. In a study by Banerjee et al. it had been shown that leukocytosis in prior treatment of anal cancer was associated with lower life expectancy and survival. It seems that hematologic indexes can be used as the potential prognostic factors. This study showed that leukocytosis in the patients related with decreased two-  Table 2. CEA Level Changes in two Groups stages of the disease. In addition, the synergistic effect of anemia and thrombocytosis decreased the survival of the patients more than each one alone [21]. Several studies compared leukocytosis, anemia, and thrombocytosis between patients with colorectal cancers and patients with benign colorectal lesions including benign colorectal polyps. These results showed hematologic indexes were significantly higher among patients with colorectal cancers, especially in advanced stages of the disease [23]. The current study by considering leukocytosis before surgery aimed to use this variable as a prognostic factor in the patients with colorectal cancer alongside with other variables. Our results show that the leukocytosis is related to the location and degree of tumor differentiation.
Right colon cancer has more prominent leukocytosis than the other site and poorly differentiated tumor has more leukocytosis than well and moderately differentiated tumor. Unfortunately, our study has some limitations including limited sample size and we couldn't differentiate WBCs because all samples hadn't differential count. Also, for the reason that large disparities exist between population in cancer incidence, sign, and survival, further studies in Iran with larger scale in several main surgery center is recommended.
In conclusion, based on current study, the location and differentiation degree of the tumor is associated with the existence or lack of leukocytosis. The existence of leukocytosis is highly associated with tumor in the right colon as well as poor differentiation degree of tumor. So, we can use CBC test as prognostic factor easily.