Introduction

Colorectal cancer is the third most common cancer worldwide. Although mortality rates due to colon cancer have decreased after 1990, it is still the third most common cause of mortality.^1,2 The widespread use of screening tests, primarily colonoscopy, removal of detected premalignant polyps, and the effective and widespread use of neoadjuvant chemoradiotherapy protocols for local advanced-stage tumors have played important roles in the reduction of mortality rates.³ Distant metastasis is detected at the time of diagnosis in 20% of colorectal cancers, and average life expectancy in stage 4 colorectal cancers ranges from 6 to 8 months even under the best palliative treatment.⁴

Studies conducted since Rudolph Virchow defined the relationship between inflammation and cancer in the 19^th century have demonstrated the extensive and significant impact of inflammation on tumor development, progression, and response to treatment.⁵ Moreover, many cancers develop from a background of infection, chronic irritation, and inflammation.⁶ Although many biochemical parameters have been investigated in terms of their clinical effect on colorectal cancer, the routine clinical use of these tests has been limited by their high cost, a lack of standardization, and unsuitability for widespread use.⁷

Platelet and lymphocyte values, which are among the most commonly analyzed parameters in peripheral blood, are inexpensive to measure and are suitable for routine use, and are therefore the most commonly investigated inflammation markers. The platelet-to-lymphocyte ratio (PLR) has been associated with poor prognosis in many cancers, including colorectal cancer.^6,8,9 Previous studies have focused on changes in PLR at different stages of colon cancer and its effect on prognosis, response to chemotherapy, and recurrence time.^{4,5,6,7,8,9,10}

In this study, we aimed to determine the utility of PLR at time of admission in predicting hepatic metastasis and lymph node positivity in patients who have undergone colorectal surgery.

Materials and Methods

After receiving approval from the Kafkas University Faculty of Medicine, Local Ethics Committee (Approval number: 80576354-050-99/87, date: 11.01.2017), we retrospectively reviewed the medical records of patients who were diagnosed with colorectal cancer and operated after being admitted to the general surgery and emergency departments of our hospitals between March 2010 and September 2016 with complaints of abdominal pain, gas, inability to defecate, and blood in stool. The patients’ age, sex, medical history, preoperative PRL determined at time of admission, intraoperative findings, and data from postoperative histopathological reports regarding tumor, lymph node involvement, and metastasis [tumor-node-metastasis (TNM) staging] were recorded from their records. The PLR was measured from the complete blood count. The Beckman Coulter R Gen-S System® (Beckman Coulter Diagnostic System Laboratories, Inc., Texas, USA) device was used for hematological analysis. Patients were grouped based on those with hepatic metastasis (group 1a) and those without (group 1b) and as those with lymph node positivity (group 2a) and those without (group 2b).

Thirty-five patients were excluded from the study because they had a hematologic disease or active infection within the past week, their records were not accessible, or they had a history of blood transfusion within the last 10 days.

Statistical Analysis

SPSS version 22 for Windows (Chicago, Illinois, USA) software package was used for statistical analyses. Distribution normality of continuous variables was determined using the Kolmogorov-Smirnov test. Descriptive statistics were reported as continuous variables, mean ± standard deviation, or median or range, depending on the context and relevance. Categorical variables were expressed as case numbers and ratios. Differences between groups were compared using student’s t-test for mean values and the Mann-Whitney U test for median values. Pearson’s chi-square test was used for categorical variables. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were compared using ROC curve analysis. P values <0.05 were accepted as statistically significant.

Results

The male/female ratio among the 152 patients included in the study was 1.53. Tumors were most commonly located in the rectosigmoid region of the colon (73.7%). Eight patients had a family history of colorectal cancer and 66 patients had a history of comorbid disease. Pulmonary embolism, anastomotic leakage, and early mortality due to comorbid diseases were observed in 8 patients (5.3%) in the postoperative 30-day period. In 31 patients, a mass lesion consistent with liver metastasis was detected intraoperatively, metastasectomy was performed, and the mass was confirmed as adenocarcinoma in histopathologic examination. The demographic characteristics of the patients are given in Tables 1 and 2.

The groups were homogenous in terms of both sex and age distribution (p=0.357 and p=0.240, respectively) (Table 3). Tumor location was not associated with liver metastasis (p=0.596).

Mean PLR value was significantly higher in the group with metastasis (232.4; range, 79.4-837.5) than in the nonmetastatic group (159.7; range, 57.4-289.3) (p<0.001). The PLR distribution graph for the two groups is shown in Figure 1.

When the common effect of age, sex, and comorbid diseases was examined, it was found that the PLR value was significantly higher in patients with liver metastasis independent of these three parameters (p<0.001).

Based on the 194.7 cut-off value determined using the ROC curve, PLR was found to have 74.2% sensitivity, 72.7% specificity, 91.7% NPV, and 41.1% PPV in predicting liver metastasis (Figure 2).

Mean PLR value was significantly higher in the group exhibiting lymph node positivity (p<0.001) (Figure 3).

Based on the 163.95 cut-off value determined using the ROC curve, PLR had 56.8% sensitivity, 56.3% specificity, 53.3% NPV, and 59.7% PPV in predicting lymph node positivity (Figure 4).

Discussion

Liver metastases of colon cancer pose a major clinical problem.11 Because lymphatic drainage of the colon occurs primarily through the portal vein, the first locations of metastasis are the regional lymph nodes, liver, lung, and peritoneum, in that respective order.12 Treatment options for cases of colon cancer with liver metastasis include adjuvant chemotherapy protocols as well as surgical resection, local tumor ablation, radiofrequency ablation, regional intraarterial chemotherapy, chemoembolization, and radiotherapy. Of these methods, only surgery has been reported to prolong survival. For this reason, with recent advances in surgical techniques and technology, the criteria for operability have been expanded in cases with liver metastasis.11,13

In contrast to previous studies investigating the prognostic value of PLR in cancer, in the present study we also aimed to determine the utility of earliest preoperative PLR in predicting lymph node positivity and hepatic metastases confirmed by postoperative pathology reports in patients with colon cancer. The retrospective nature of our study and the relatively low number of patients are among the fundamental limitations of our study.

Platelets play an important role in hemostasis and thrombosis, and they also positively affect the growth, spread, and neovascularization processes of tumor cells. Platelets aggregated by the tumor lead to cancer-related thrombosis. Tumor growth is also induced by platelet-derived growth factor and tissue growth factor, which are mainly secreted from the platelets.5,14 In many studies, significant PLR elevation has been associated with poor prognosis in many types of cancer.14,15,16,17

The male/female ratio in our study showed a predominance of males, in accordance with the literature. Similarly, consistent with the literature, the rectosigmoid region was the colon segment most commonly affected.1 Eight patients had a family history of colorectal cancer and 66 patients had comorbid diseases. Pulmonary embolism, anastomotic leakage, and early mortality due to comorbid diseases were observed in 8 patients (5.3%) in the postoperative 30-day period. Liver metastasis was detected intraoperatively in 20.3% of the patients, in accordance with the literature.4

When sex and age distributions between groups were examined, both were observed to be homogeneous (p=0.357 and p=0.240). Reports in the literature indicate that mortality is 25% higher among males than females and that colorectal cancers are located more proximally in females.18

Our analysis of colon segment involvement showed that tumor location was not associated with liver metastasis (p=0.596). We did not encounter any findings on this subject in the literature.

Mean PLR value was significantly higher in the group with metastasis (232.4; range, 79.4-837.5) than in the nonmetastatic group (159.7; range, 57.4-289.3) (p<0.001). This finding is important because it shows that tumor load is related to PLR. In many studies in the literature, higher PLR values have been shown to be a marker of poor prognosis, especially in colorectal cancer. Hypercoagulability induced by cytokines secreted by malign solid tumors produces reactive thrombocytosis. Interleukin-6 in particular leads the transformation of megakaryocytes into platelets in the bone marrow. Other important factors include the increase of platelet-associated inflammatory reactions, decreased antitumor response due to relative scarcity of lymphocytes, and tumoral growth and spread induced by various epithelial and endothelial growth factors secreted by circulating active platelets.4,5,6,7,8,9,10

When the common effect of age, sex, and comorbid diseases was examined, it was found that PLR was significantly higher in patients with liver metastasis independent of these three parameters (p<0.001). The most important prognostic marker in colon cancer is cancer stage, and liver metastasis detected preoperatively corresponds to a more advanced stage. The average 5-year survival rate is 35-58%, even in resectable cases. In addition to prognostic studies, the increase in PLR was also found to be significantly higher in more advanced stages of colorectal cancer, significantly affecting the T aspect of TNM staging.9 In another study, it was reported that an increased PLR value after surgical therapy could be a statistically significant indicator of disease recurrence in stage 2 and 3 patients.7 Another use of PLR in colorectal cancers is to evaluate response to chemotherapy. In a study conducted with metastatic colorectal cancer patients, Wu et al.10 reported that normalization of PLR value is a marker of good prognosis in the assessment of response to chemotherapy.

There is only one study in the literature evaluating liver metastases of colorectal cancers and PLR. In that study, PLR was found to be a significant and independent factor indicating overall survival and disease-free survival in patients with colorectal cancer who underwent curative liver resection after neoadjuvant chemotherapy and only had liver metastasis. In addition, preoperative PLR value was found to be superior to neutrophil-to-lymphocyte ratio (NLR) as a negative indicator in these cases.19

In the present study, we also evaluated lymph node positivity and found that this parameter was able to predict involvement in patients with statistically high PLR values. However, the sensitivity and specificity levels were not as high as those for PLR in predicting liver metastasis. In our review of the literature, we did not find any studies in which PLR predicted lymph node involvement in colon cancer. However, Özgehan et al.20 examined the effect of NLR on tumor staging in colon cancer and reported that NLR was significantly high in patients with lymph node positivity. This is important in that it demonstrates the importance of PLR, which is another inflammatory marker like NLR.

In their study conducted in the northeastern Anatolia region of Turkey in 2015, Çakmur et al.21 reported that colorectal cancer patients were diagnosed late in Turkey, which is not consistent with the literature. They emphasized the importance of screening tests, especially in the context of preventive health services.21 Considering these data in light of our results, we believe that PLR can be used as an inexpensive, convenient, universal, and non-invasive marker to predict liver metastases in newly diagnosed cases of colorectal cancer.

Ethics

Ethics Committee Approval: The study was approved by the Kafkas University Local Ethics Committee (Approval number: 80576354-050-99/87, Date: 11.01.2017).

Informed Consent: The study was designed retrospectively, and consent form was obtained from all patients.

Peer-review: Internally peer-reviewed.

Authorship Contributions

Surgical and Medical Practices: T.A., A.C.Y., Concept: T.A., Design: T.A., Data Collection or Processing: T.A., A.C.Y., Analysis or Interpretation: T.A., A.C.Y., Literature Search: T.A., A.C.Y., Writing: T.A.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.