HCC had been ranked as the 2nd leading cause of cancer death in Taiwan for several years . Most oncologists try to get a good survival due to the improvement of care program in the world  . Pretreatment imaging and assessment remain the main methods used to evaluate prognosis in liver cancer patients after treatments   . The relationship of the prognosis of HCC patients and inflammation was noted in recent decade   .
Inflammation is an important component of tumor progression which had been mentioned for decades. It is well known that major liver cancer develops during inflammatory reaction of hepatitis B or C virus infection  . Tumor micro-environment regulated by inflammatory cells clearly plays a basic role in the neoplastic process, stimulation of proliferation and migration and survival   . The inflammatory reaction usually responds to tumors persistence. Tumor cells produce various cytokines and chemokines that attract leukocytes. The inflammatory component of a developing neoplasm may include a diverse leukocyte population such as neutrophils, macrophages, and lymphocytes  .
Platelets can release granules containing a variety of contents that can both inhibit and stimulate plasmatic coagulation, angiogenesis immune-surveillance, or neoplasm growth through the releasing growth factors such as platelet derived growth factor, platelet factor IV and thrombospondin  . Therefore, platelets can play important roles in tumor pathophysiology, including immune escape in hematogenous tumor spread and leading to tumor cell adhesion, invasion and tumor progression. In the previous reports, good or poor predictor of survival with neutrophil-lymphocyte ratio (NLR) or platelet-lymphocyte ratio (PLR) was demonstrated in some solid tumors such as liver, colo-rectum, breast, lung, and cervical cancers     . The prognostic potential of a novel inflammation-based system, the combination of the NLR and PLR, for predicting the survival time of 287 patients with HCC who had an elevated NLR (>2.58) and an elevated PLR (>131.78) were allocated an important prognostic score . In addition to clinical grading scales of HCC, NLR or PLR could be used for demonstrating that patients with HCC have a significantly high risk of progressive disease following initial treatments  . Therefore, we try to study the roll of NLR and PLR scales in the predictor of prognosis of HCC patients.
2. Patients and Methods
There were a total of 653 HCC patients registered in Cancer Registry Center of our hospital from 2010 to 2014. Among them, 525 patients with complete data were enrolled in this study and there were 371 (70.7%) male and 154 (29.3%) female. All patients were confirmed diagnosis based on the cancer treatment guideline from our Cancer Registration Center. There were 131 (24.9%) and 394 (75.1%) patients initially underwent surgical and non-surgical treatments in our series. The non-surgical treatment included trans-arterial chemo-embolization (TACE), hepatic artery chemo-infusion (HAI), percutanous ethanol injection (PEI) or radio-frequency ablation (RFA) based on our hospital treatment guideline. The clinical features include patient’s basic profiles, and neutophil, lymphocyte and platelet count in the peripheral blood at the time of diagnosis. The optimal cut-off from normal range of leukocyte, neutrophil & lymphocyte, and platelet were 4000 - 10,000/dl, 43% - 71% & 16.7% - 43.4%, and 150,000 - 440,000/dl respectively, the scale of NLR and PLR were derived from the lower normal range and higher normal range in cell number for neutrophil, lymphocyte and platelet. The 3 scales of NLR and PLR were ≤1.62, 1.63 - 2.57, ≥2.58 and ≤224, 225 - 253, ≥254 respectively. The 1-, 3-, and 5-year survival rates were analyzed.
These results are presented as mean ± SD and Kaplan-Meier analysis for their survival rates. Statistical analysis was performed with an unpaired Student’s t-test after ANOVA for more than the other two groups in liver cancer patients. The P-values less than 0.05 were considered to be significant.
1) General profiles of the patients of three scales of NLR
Three scales of NLR of HCC patients and their basic profiles were listed in Table 1. Relatively poor survival was found to be in the scale of higher NLR. Higher NLR was found mostly in the male (248, 74.5%) and TMN stage III and IV with a significant difference (P < 0.01). Surgical treatment was underwent more in the patients of low NLR (n = 26, 36.6% vs n = 299, 79.9%, P < 0.002).
The number of death was 262 (78.7%) in the higher NLR ≥ 2.58 with poor prognosis compared to other scales as shown in Table 1 & Table 2. The survival curves demonstrated poorer prognosis of HCC patients in Figure 1. The mean survival times were 44.3 ± 3.2, 40.4 ± 2.6, and 24.1 ± 1.4 months for the scales of the NLR ≤ 1.62, 1.63 - 2.57, and ≥2.58 respectively. The 5-year survival rates were 33.9%, 33.7%, and 16.7% respectively (P < 0.001). If NLR was more than 2.58, the 5-year survival rate was shorter than that of the other two groups (P = 0.001).
2) General profiles of the patients of three scales of PLR
Basic profiles of three scales of PLR of liver cancer patients were listed in Table 3. Relative poor survival was found in the scale of higher PLR. Higher PLR ≥ 254 were found mostly in the male (62, 69.7%) and TMN stage III and IV (n = 68, 77.3%) with a significant difference (P < 0.01). Surgical treatment was performed in the patients of PLR ≤ 224 (n = 113, 26.6%) and PLR ≥ 254 (n = 15, 16.9%) without significant difference (P = 0.153).
Table 1. Basic profiles of patients divided by three scales of NLR.
*P ≤ 0.05.
Table 2. Survival rate based on the scale of N/L ratio of liver cancer.
*P < 0.001.
Table 3. Basic profiles of patients divided by three scales of PLR.
*P ≤ 0.05.
In the period of 5 years follow-up study, the number of death was 80 (89.9%) patients in the scale of PLR ≥ 254 with poorer prognosis compared to other scales as shown in Table 3 & Table 4. The survival curves demonstrated poorer prognosis of HCC patients with PLR ≥ 254 shown in Figure 2. The mean survival times were 34.1 ± 1.4, 29.3 ± 8.1, and 14.2 ± 2.1 months for the groups of the PLR ≤ 224, 225 - 253, and ≥254 respectively. The 5-year survival rates were 25.5%, 36.4%, and 7.7% for the groups of the PLR ≤ 224, 225 - 253, and
Figure 1. Survival cure of liver cancer patients based on the scale of N/L ratio and high ratio had a poor prognosis (χ2 = 43.4, P ≤ 0.001).
Figure 2. Survival cure of liver cancer patients based on the scale of P/L ratio and high ratio had a poor prognosis (χ2 = 51.5, P ≤ 0.001).
Table 4. Survival rate based on the scale of P/L ratio of liver cancer
Clinical features and molecular pathology of HCC are the main determinants of current treatment strategies and prognosis factors. The relationship between the inflammatory cells and cancer has been demonstrated by accumulating studies . The counts of peripheral inflammatory cells, including neutrophil, lymphocyte and platelet, have demonstrated the strong link between the inflammatory system and prognosis in cancer patients  . In particular, NLR and PLR have recently been reported to be prognostic factors in several types of solid cancers     .
Early in the neoplastic process, these inflammatory cells are powerful tumor promoters, facilitating genomic instability and promoting angiogenesis. The inflammatory cells produced chemokines and cytokines that influenced the whole tumor mass, regulating the growth, migration and differentiation of all cell types in the tumor micro-environment  . In addition, these inflammatory cells will release growth factors, promoting angiogenesis and lymphangiogenesis, stimulating DNA damage, remodelling the extra-cellular metaprotease to facilitate invasion, coating tumour cells to make available receptors for disseminating cells via lymphatics and capillaries, and evading host defense mechanisms. In fact, excess inflammatory cells in the tumor microenvironment which harbor risk for developing cancer or are indicators of prognosis in a fully developed malignancy   .
The role of neutrophils in cancer usually reflects a state of host inflammation, which is a hallmark of cancer. They can participate in different stages of the oncogenic process including tumor initiation, growth, proliferation or metastasis   . In patients with solid cancers, neutrophils expand both locally at the tumor microenvironment and systemically, the expansion of neutrophil is generally associated with poor prognosis because neutrophils are key regulators of intra-luminal survival of cancer cell line and extravasation through their cross-talk with host cells and disseminating cancer cells . Lymphocyte is a non-specific but commonly used as a marker of host immunity  . Liver cancer cells could evade the immune surveillance via modulating the key immune cells such as lymphocytes by alpha feto-protein  which will affect the prognosis of cancer patients. In recent years, numerous evidences had demonstrated that the lymphocyte count is an independent prognostic marker in various cancers, such as liver, breast, colorectal, lung and others cancers     . Besides, lymphocyte count and lymphocyte-white blood cell ratio were also associated with overall survival in advanced cancer patients reported by Zhao . Taken together, these results suggested that a low level of lymphocytes may reflect a poor health status and poor prognosis in advanced cancer patients.
NLR is calculated from existing routine blood examination for our patients. An elevated NLR is associated with worse outcomes in many solid tumors, both in early and advanced stage of cancer  . By using NLR acting as a biomarker, there is a potential for the identification of early responders and prognostic relevance associated with clinical outcome  . We should note that the excessive presence of inflammation and neutrophil which were an indirect risk and can be varied among cancer cell types has the worse impact on the outcome. In our series, three scales of NLR were ≤1.62, 1.63 - 2.57, and ≥2.58 for comparison in our HCC patients. Patients with lower baseline of NLR ≤ 1.62 were associated with better overall survival. In addition, in other reports, patients with baseline NLR < 5 had a better median survival of 20.7 months compared to a median overall survival of 7.9 months in patients with baseline NLR ≥ 5 specifically in advance cancer patients , Cancer patients of poor prognosis were reported if NLR ≥ 5 in patients with advanced solid tumors treated with PD-1/PD-L1 inhibitors reported by Ameratunga et al. . Concerning base line, there was a statistically significant association between baseline NLR ≥ 3.5 and immediate progression on 2-month follow-up imaging after TACE patients with progressive disease had a mean of NLR 4.10 compared to stable disease, partial, and complete response had a mean of 2.76, 2.72, and 2.48 respectively in their follow-up results . In our series, the mean survival times were 44.3 ± 3.2 and 24.1 ± 1.4 months if the NLR ≤ 1.62, and ≥2.58 (P < 0.001). Moreover, in another report by using the Cox proportional hazards model showed that NLR > 2.81 was significantly associated with poor overall survival and tumor recurrence in the total or subgroups of patients grading with Barcelona Clinic Liver Cancer (BCLC) stages . Taking together, it is true to demonstrate that a higher NLR resulted in a poorer prognosis reported in similar observations in liver cancer patients  . From above studies, the base line of NLR was variable due to their study population included patients in general or specific focus on a specific clinical stage of HCC patients.
It is clear that higher platelet level will result in poorer prognosis because platelet granules contain the greatest abundance of cancer-related factors including, adhesion molecules, growth factors, angiogenic factors, tissue metalloproteinases, chemokines, and immunologic molecules   . Even circulating tumor cells may encounter platelet-derived microparticles which may serve to activate the platelets and lead to metastasis  . This process is facilitated by adhesion of tumor emboli to the vascular endothelium as well as stimulation of immune cells cytokine and growth factor production among the cellular responses. Therefore, platelets are well suited to serve as facilitators in cancer progression and metastasis which will clearly affect the prognosis of cancer patients   . Increased platelet will create an elevated PLR which was associated with reduced overall survival in patients with advanced cancer  in addition to HCC  . Mean survival was shorter if PLR ≥ 254 in our series. It is an evidence that either higher NLR or PLR were significantly associated with lymph node metastasis, and poor overall survival in most studies   . Taken together, either increased neutrophil and platelet, or decreased lymphocyte will elevate either NLR or PLR. This can be a predictor for the poor prognosis of cancer patients by routine clinical tests. There are some limitations including the applying treatment methods in the patients who follow the treatment guide-line of our hospital cancer registry center. Therefore, there is still a work to be done before using NLR and PLR as validated prognostic markers in clinical settings.
In conclusion, the neutrophil, lymphocyte and platelet are players in cancer growth and have a potential role as predictors of survival in our HCC patients. NLR and PLR are easily obtained in our clinical practice and we should pay more attention to reach a lower ratio for getting a better survival in our patients where possible.
Authors want to express our sincere appreciation of research found supported from Yuan’s General Hospital (Research no. 20181107B).
Contribution of Authors
Study Design: Ker CG.
Data collection: Tong HI, Yang MY, Tseng IT, Chang DM, Chen HY, Ko CM, Chao CY.
Biostastic: Wang BW, Chen YF.
Interpretation and Manuscript: Ker CG.
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