Diagnostic value of platelet‐lymphocyte ratio and hemoglobin‐platelet ratio in patients with rectal cancer

Abstract Background This study aimed to investigate the diagnostic value of platelet‐lymphocyte ratio (PLR) and hemoglobin‐platelet ratio (HPR) combined or not with carcinoembryonic antigen (CEA) in rectal cancer. Methods We recruited 235 patients pathologically diagnosed with rectal cancer, 113 patients with benign rectal diseases, and 229 healthy control patients in this retrospective analysis. Then, the correlation between PLR, HPR, and clinicopathological findings was analyzed. Receiver operating characteristic (ROC) curve was used to assess the diagnostic value of PLR and HPR combined or not with CEA in rectal cancer patients. Results The levels of PLR, HPR, and CEA were higher in rectal cancer patients than those in the subjects with benign rectal diseases (P < .001) and the healthy controls (P < .001). Platelet‐lymphocyte ratio and HPR were associated with lymph node metastasis and tumor stage, rather than serosa invasion, distant metastasis, or tumor size. PLR or HPR combined with CEA produced larger area under curve (AUC) (AUCPLR+CEA = 0.75, 95% CI = 0.70‐0.79, AUCHPR+CEA = 0.76, 95% CI = 0.71‐0.80) than PLR (P < .0001), HPR (P < .0001), or CEA (P = .024) alone. Conclusion Our results suggest that PLR or HPR combined with CEA can increase diagnostic efficacy and may be a useful diagnostic marker for patients with rectal cancer.

diagnosis can improve the survival rate of patients with CRC. The 5-year survival rate of early CRC was more than 90.0%, while that of metastatic CRC was only 14.0%. 4 Rectal cancer accounts for 30.7% of all CRC cases and the incidence of rectal cancer increases with age. 2,5 Therefore, early screening and diagnosis is an indubitable way to prevent and treat rectal cancer. The identification of a reliable biomarker that can diagnose rectal cancer early is imperative.
Inflammation plays an extremely important role in the process of tumorigenesis and development. Both local and systemic inflammatory reactions can stimulate the immune microenvironment and contribute to the occurrence and development of cancer cells. 6 Inflammatory response markers include neutrophil, lymphocyte, platelet, albumin, and so on. Platelet can stimulate the growth of tumor cells by aggregating and degranulating in tumor microvessels. Tumor-related inflammatory mediators can also stimulate platelet elevation. 7 Lymphocyte is an important component of anti-tumor immunity. It can distinguish and kill tumor cells or release a series of cytokines to activate anti-tumor immunity. 8,9 Being an indicator to reflect the balance between systemic inflammatory response and immune system function that confirmed by several retrospective studies. Platelet-lymphocyte ratio (PLR) was associated with the diagnosis and prognosis of several malignant tumors, such as gastric cancer, 10 colorectal cancer, 11 and pancreatic cancer. 12 On the other hand, the diagnostic and prognostic role of hemoglobin level has not been clearly defined yet. One study reported that low hemoglobin levels were proposed as parts of a prognostic model regarding cancer-specific survival in different cancerous diseases. 13 Hematological parameters as indicator to reflect the balance between systemic inflammatory response and immune system function were confirmed by several retrospective studies.
Rectal cancer is a high malignancy with insidious onset and lack of specific symptoms in the early stage. Early screening and diagnosis play an important role in reducing the mortality of rectal cancer. Fecal occult blood test (FOBT) is economical, non-invasive, and widely used screening important method, while the results are susceptible to the influence of diet and drugs, and it can be detected only when the pathological tissue is bleeding. 14 Carcinoembryonic antigen (CEA) is a widely used tumor marker, and most malignancies usually have a high concentration of CEA serum. Due to insufficient sensitivity and low organ specificity, CEA cannot be used alone as a cancer screening biomarker. Recent studies have shown that markers of systemic inflammation could be useful biomarkers for the diagnosis of many cancers. As far as we know, there were several retrospective analyses that investigated the relationship between PLR, neutrophil-lymphocyte ratio (NLR), and albumin-globulin ratio (AGR) in the prognosis of rectal cancer. 11,15,16 But rarely have studies assessed the diagnosis role of these hematological parameters in rectal cancer. Therefore, we intend to investigate the role of PLR, hemoglobin-platelet ratio (HPR), and CEA, which were used alone or in combination, in early screenings and diagnoses of rectal cancer.

| Patients
Subjects with rectal cancer, benign rectal diseases, and healthy con- No statistical differences were found in gender or age among the three groups. This study was approved by the ethics committee of the First Affiliated Hospital of Guangxi Medical University, China.

| Data collection
All data were collected from the hospital's electronic medical records for the first test results of laboratory. Whole blood cell parameters were tested by the Beckmann 780 (Beckman Coulter). The collected data included total number of white blood cells (WBC), platelet values, absolute value of neutrophil, an absolute value of lymphocyte and hemoglobin. The concentration of serum CEA was detected with the Roche E6000 analyzer (Roche Diagnostics). Platelet -lymphocyte ratio was calculated as platelet/lymphocyte count. HPR was calculated as hemoglobin/total number of platelets.

| Statistical analysis
Normality test was performed using the Kolmogorov-Smirnov test.
Abnormal data were represented as the median with interquartile ranges. A Mann-Whitney U test was used to assess the statistical differences between the two groups, and a chi-square test was

| Clinical characteristics among different groups
The patient-related parameters and baseline hematological parameters are shown in Table 1. No significant differences existed in age or gender among the rectal cancer, benign rectal diseases, and healthy control groups. Compared to the benign rectal diseases and healthy control groups, rectal cancer patients had a higher level of WBC, platelet and lower hemoglobin, lymphocyte. The concentration of CEA in the rectal cancer group was significantly higher than that in groups of benign rectal diseases (P < .001) and healthy control (P < .001). As shown in Table 1 and Figure 1, the median of PLR in the rectal cancer group was significantly higher than that in the benign rectal diseases(P < .001) or healthy control (P < .001) groups, while there were no statistical differences in PLR between the benign rectal diseases and healthy control groups (P = .078). The median HPR levels in the two disease group were lower than that in the healthy control group (rectal cancer vs benign rectal diseases, P < .001; rectal cancer vs healthy controls, P < .001; benign rectal diseases vs healthy controls, P < .001).

| Correlation between PLR, HPR, CEA, and clinicopathological features in rectal cancer
As shown in Table 2, the median of HPR in male patients was higher than that in female patients (P < .001), while there were no statistical differences in PLR, CEA between male and female patients (P = .770 for PLR; P = .506 for CEA). PLR and HPR were both related to lymph node metastasis and tumor stage; however, they were not associated with serosa invasion, distant metastasis, or tumor size. A significant difference of CEA level was observed according to the

| Diagnostic efficacy of PLR, HPR, and CEA, alone or in combination to differentiate rectal cancer from benign rectal diseases
The diagnostic accuracy of PLR, HPR, and CEA for the prediction of histologic severity is shown in Table 3 and Figure 2.   21 A study by Emir also reported that patients with CRC had significantly higher PLR values than patients with colorectal polyps and healthy controls. 22 Platelet-lymphocyte ratio can also be used as a prognostic marker in CRC, with high PLR associated with decreased overall survival and progression-free survival. 11,23 Jia et al reported that PLR levels were higher in CRC patients and also indicated that PLR was predominantly related to the different stages of CRC development. 24 Our study also found that PLR was related to lymph node metastasis and tumor stage, coinciding with previous research conclusions.

| D ISCUSS I ON
Research has proven that anemia and thrombocytosis may occur in cancer patients. Growing tumors induce thrombocytosis by secretion of inflammatory cytokines, which may also cause bone marrow suppression and disorders of iron metabolism, resulting in tumor-induced anemia. 25,26 Low hemoglobin levels contribute to tumor hypoxia which is responsible for enhanced tumor growth; in addition, anemia can promote angiogenesis and genomic mutations in cells. 27 Serta et al 28  were not excluded which might affect the results. Therefore, prospective study design, larger sample size, and multi-center clinical study are demanded in future.
In conclusion, we found that PLR and HPR were significantly associated with rectal cancer and its lymph node metastasis, tumor stage. The combination of PLR or HPR with CEA can increase diagnostic efficacy and may be a useful diagnostic marker for distinguishing rectal cancer from benign rectal diseases.