Preoperative lymphocyte‐to‐monocyte ratio is useful for stratifying the prognosis of hepatocellular carcinoma patients with a low Cancer of the Liver Italian Program score undergoing curative resection

Abstract Background and Aim Although the Cancer of the Liver Italian Program (CLIP) score is useful for prognostication of patients with hepatocellular carcinoma (HCC), a previous study has reported that the CLIP score was unable to stratify the postoperative outcomes of HCC patients in whom the score was low (0‐1). Recent studies have reported that the preoperative lymphocyte‐to‐monocyte ratio (LMR) is useful for prognostication of patients with various cancer. Methods We reviewed 329 HCC patients with a low CLIP score (0‐1) undergoing curative resection. This study had the approval of the Institutional Review Board (28068). Multivariate analyses were carried out to detect clinical factors correlating with overall survival (OS). Kaplan‐Meier analysis and the log‐rank test were used for comparison of OS. Results Multivariate analysis showed that LMR (<4.35/≥4.35) was significantly associated with OS (hazard ratio [HR], 2.022; 95% CI, 1.141‐3.583; P = 0.016) as well as portal vein invasion (HR, 2.410; 95%CI, 1.258‐4.618; P = 0.008). Kaplan‐Meier analysis and the log‐rank test showed a significant difference in OS and relapse‐free survival between patients with high LMR and those with low LMR. Conclusion Preoperative LMR is useful for stratifying the prognosis of HCC patients with a low CLIP score (0‐1) undergoing curative resection.


| INTRODUC TI ON
Prognosis of hepatocellular carcinoma (HCC) patients may not be fully predictable on the basis of tumor-node-metastasis (TNM) stage alone. However, the Child-Pugh classification, which represents liver functional reserve, is able to stratify the prognosis of such patients. 1 In order to provide better prognosis of HCC patients, the Cancer of the Liver Italian Program (CLIP) score, the Japan Integrated Staging (JIS) score and the Tokyo score were established as an integrated prognostic system for HCC patients, combining tumor progression with liver functional reserve. [2][3][4] Previous studies have reported that the JIS score seems to be a better predictor for prognosis of patients undergoing liver resection in comparison with the CLIP score and the Tokyo score. 5,6 Recently, a large population study (n = 3182) showed that the CLIP score is the best prognostic system for HCC in comparison with several prognostic systems including the JIS score and the Tokyo score, because the CLIP score had the highest homogeneity in patients with the same stage. 7 This study showed that the CLIP score attracted attention as the best predictor of HCC patients. However, the CLIP score inadequately estimates outcome after curative resection for HCC, because it includes HCC patients with distant metastasis (3.2%, 14/435), Child-Pugh classification C (15.9%, 69/435), and non-surgical treatment (90.8%, 395/435). 2 Although a previous study has reported that the CLIP score is useful for prognostication of HCC patients receiving non-surgical treatment, 8 it is inferior to other prognostic systems for prognostication of HCC patients undergoing surgery. 5 In our previous study, most HCC patients (74.0%, 222/300) undergoing liver resection had a low CLIP score (0-1). 9 Additionally, because CLIP score was not good at stratifying the postoperative outcome of such patients, CLIP score was inferior to hepatic Glasgow Prognostic Score in prognostication of HCC patients undergoing liver resection. 9 In order to apply the CLIP score to prognostication of HCC patients undergoing curative resection, further investigation is required to stratify the prognosis of those with a low CLIP score.
Recent studies have shown that the lymphocyte-to-monocyte ratio (LMR) is useful for prognostication of patients with various types of cancer. 10,11 LMR includes lymphocytes and monocytes, which play a crucial role in the immune system. As tumor infiltrating lymphocytes are well known to exert an antitumor effect by inhibiting the proliferation of tumor cell, decreased lymphocyte count might indicate a weak antitumor reaction and poor clinical outcome. 12 In contrast, monocytes are white blood cells that can further differentiate into a range of tissue macrophages and dendritic cells. 13 Monocytes promote tumorigenesis through local immune suppression 14 and, in addition, can differentiate into tumor-associated macrophages (TAM), which promote tumor growth, angiogenesis, invasion, and metastasis. 15 Thus, in cancer patients, peripheral blood lymphopenia and an increased monocyte count are associated with poor prognosis.
In patients with HCC, several studies have reported that the LMR is significantly associated with surgical outcome after curative resection. [16][17][18] As a low LMR was associated with tumor size, vascular invasion and tumor staging, it could be a good predictor of post-surgical outcome in HCC patients. [16][17][18] Therefore, LMR might be able to stratify the prognosis of HCC patients with a low CLIP score undergoing curative resection. In the present study, we investigated whether the LMR was able to stratify the prognosis of HCC patients with a low CLIP score.
F I G U R E 1 Receiver operating characteristic (ROC) curve shows the optimal cut-off value for the lymphocyteto-monocyte ratio (LMR). Arrow shows the most prominent point on the ROC curve. AUROC curve of the LMR for overall survival is 0.559 Three hundred and twenty-nine patients who underwent initial   and curative resection between April 2005 and December 2015 at our department were retrospectively reviewed. All operative procedures had been carried out by the same surgical team at Second Department of Surgery, Dokkyo Medical University Hospital. All patients in the present study had a preoperative low CLIP score (0-1). Patients who underwent non-curative surgery, surgery for HCC recurrence, or combined resection of other organs were excluded. There were no patients who had infectious disease, chemotherapy or irradiation therapy before surgery for HCC.

| Diagnosis of liver cirrhosis
Liver cirrhosis was pathologically diagnosed as stage f4 when bridging fibrosis was observed surrounding the regenerative nodules in the liver parenchyma of the resected specimen. 20

| Diagnosis of portal vein invasion and hepatic vein invasion
Portal vein invasion and hepatic vein invasion were diagnosed on the basis of the General Rules for the Clinical and Pathological Study of Primary Liver Cancer (Liver Cancer Study Group of Japan, 3rd English edition). 20

| Definition of CLIP score
The CLIP score is based on four items and ranges from 0 to 6.

| Definition of preoperative portal hypertension
When patients had detectable esophageal varices or splenomegaly and/or a platelet count below 10.0 × 10 4 /mm 3 , portal hypertension was diagnosed. 22

| Definition of TNM stage
In the present study, TNM Classification of Malignant Tumors, 8th edition, edited by the Union for International Cancer Control (UICC) was used for determining the TNM stage. 23

| Postoperative surveillance
Surveillance after surgery was carried out every 3 months. Serum AFP and PIVKA-II level were routinely monitored every 3 months after surgery. Computed tomography (CT) was done every 3 months or when the levels of tumor markers were above the normal range.
However, if 5 years had passed since surgery, CT interval was prolonged from 6 to 12 months, or CT was carried out when the levels of tumor markers were above the normal range.   Table 2. There were no significant differences between the two LMR groups in all categorical clinical characteristics.

| RE SULTS
Continuous clinicolaboratory characteristics of patients in the two LMR group are listed in Table 3. There were significant differences between the two LMR groups in the serum levels of albumin, ALT and CRP.   surgery (P < 0.001) (Figure 4). Results of chi-squared test showed that LMR was not significantly associated with recurrence pattern (intrahepatic/extrahepatic) and salvage surgery (yes/no) ( Table 6).

| D ISCUSS I ON
It has been reported previously that most patients who undergo curative liver resection for HCC have a low CLIP score (0-1) (73.4%, 433/599) 6 . In order to apply the CLIP score to prognostication after curative surgery for HCC, a score of 0 or 1 must stratify postoperative outcome. However, because the CLIP score is unable to stratify the postoperative outcome of HCC patients with a low score (0-1), 5 its performance for prognostication after curative surgery for HCC is poor. Our study showed that the LMR (<4. 35 nutritional status of cancer patients. 30 In fact, in cancer patients, malnutrition is significantly correlated with a low lymphocyte count, and this can have an adverse impact on prognosis. Because our study showed that patients with a low LMR had poorer nutritional status than those with a high LMR, nutritional intervention might improve the prognosis of such patients. 30,31 In fact, a previous study has shown that nutritional therapy can improve the outcome after surgery for HCC. 32 Therefore, further studies of the relationship between LMR and nutrition in HCC patients are warranted.
The LMR can significantly stratify postoperative outcome in HCC patients with a low CLIP score undergoing curative resection, and combination of the LMR with the CLIP score was able to predict the postoperative outcome after curative resection for HCC.
Although postoperative intervention is needed for patients with a low LMR to prevent HCC recurrence, there is no effective postoperative adjuvant chemotherapy for such patients. A recent study showed that sorafenib is not an effective intervention in the adjuvant setting for HCC patients following resection or ablation. 33 Among other postoperative adjuvant therapies for HCC patients, immunotherapy, interferon therapy and internal radiation therapy have been reported. [34][35][36] A meta-analysis has concluded that interferon therapy is effective for prevention of HCC recurrence after surgery. 37 However, patients rarely receive interferon therapy because it has various restrictions such as age (≤70 years), performance status (≤2), Child-Pugh score (≤7), platelet count (≥10.0 × 10 4 /mm 3 ) and WBC count (≥3.0 × 10 3 /mm 3 ). Additionally, interferon therapy is very costly. Because there is no appropriate indication for adjuvant therapy after surgery for HCC patients, early detection of recurrence through tight postoperative surveillance is necessary for HCC patients with a low CLIP score (0-1) and a low LMR (<4.35), in order to improve survival after surgery.
In conclusion, we have carried out a retrospective database analysis at a single institution to investigate the relationship between the LMR and outcome in HCC patients with a low CLIP score undergoing curative resection. Our results showed that LMR significantly stratified the postoperative survival of those patients who had a low CLIP score. Takayuki Shiraki https://orcid.org/0000-0003-2935-6708