Background: A growing body of evidence suggests that inflammatory response markers such as the neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) are associated with outcomes of various malignancies. However, no study has reported the prognostic value of NLR and LMR in patients with distal bile duct cancer (DBDC) to date. We investigated the prognostic significance of these inflammatory markers in patients with DBDC who underwent radical resection. Methods: The study included 40 patients diagnosed with DBDC who underwent pancreaticoduodenectomy at Narita Red Cross Hospital between January 2000 and December 2017. The cutoff values for these markers were determined by receiver operating characteristic curve analysis. Survival curves are estimated for each group in the study considered separately using the Kaplan-Meier method. The association between overall survival (OS) and the NLR, LMR, and other prognostic factors was investigated using log-rank test and multivariate Cox proportional hazards regression analysis. Results: Corresponding to the point with the maximum combined sensitivity and specificity on the ROC curve, the best cutoff value for NLR and LMR was determined to be 3.14 and 4.55, respectively. Most clinicopathological factors were not associated with the NLR and LMR based on these cutoff values. However, serum albumin levels were associated with both the NLR and LMR (P = 0.011 and P = 0.023, respectively), and serum carbohydrate antigen 19-9 (CA 19-9) levels were also associated with the LMR (P = 0.030). Univariate analysis showed that a high NLR (P < 0.001), low LMR (P = 0.002), hypoalbuminemia (P = 0.004), high serum CA 19-9 levels (P = 0.008), and lymph node metastasis (P = 0.033) were significantly associated with poor survival rates. Multivariate analysis showed that a high NLR (hazard ratio 5.799, 95% confidence interval 1.188–28.32, P = 0.030) and a low LMR (hazard ratio 4.837, 95% confidence interval 1.826–2.331, P = 0.025) were independent prognostic factors for OS. Conclusion: Both NLR and LMR may serve as significant independent preoperative prognostic indicators of disease in patients with DBDC who undergo radical resection.
Keywords: NLR; LMR; Distal bile duct cancer; Prognostic maker
Bile duct cancer is rare and represents a diverse anatomical location. Distal bile duct cancer (DBDC) originates from extrahepatic bile ducts just distal to the cystic duct and proximal to the duodenal ampulla. This malignancy accounts for approximately 20–30% of all bile duct cancers [[
The neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) are well-known systemic inflammatory response markers; several studies have reported that NLR and LMR are important prognostic factors in various cancers [[
In this single-center study, we investigated the association between these biomarkers and survival in patients with DBDC who underwent pancreaticoduodenectomy.
This study included 40 patients diagnosed with DBDC who were treated with pancreaticoduodenectomy at Narita Red Cross Hospital between January 2000 and December 2017. Preoperative diagnosis of DBDC was based on imaging studies, including computed tomography, magnetic resonance imaging, and endoscopic retrograde cholangiopancreatography. The distal bile duct was confined to the area between the origin of the cystic duct and the duodenal ampulla. The American Joint Committee on Cancer (7th edition, 2009) staging system was used to stage the cancer [[
The NLR was calculated by dividing the total neutrophil count (obtained from peripheral blood samples) by the total lymphocyte count, and the LMR was calculated as the ratio of the total number of lymphocytes divided by the total number of monocytes. All blood samples were obtained during routine preoperative evaluation of patients scheduled for elective surgery. Receiver operating characteristic (ROC) curves were plotted to verify the accuracy of these biomarkers as prognostic indicators of overall survival (OS). We selected cutoff values for NLR, LMR, and tumor markers based on ROC curve analysis to predict 5-year survival. Furthermore, using the modified Glasgow Prognostic Score, the cutoff values for low serum albumin and high C-reactive protein (CRP) levels were calculated as 3.5 g/dL and 0.5 mg/dL, respectively [[
Survival curves are estimated for each group in a study considered separately using the Kaplan-Meier method. The association between the aforementioned prognostic indicators and OS rates was investigated using the log-rank test and Cox proportional hazards regression analysis. The preoperative indicators observed to be statistically significant (P < 0.05) in univariate analysis were subjected to multivariate Cox proportional hazards regression analysis. A P value < 0.05 was considered statistically significant. All statistical analyses were performed using the JMP Pro software, version 13.2.0 (SAS Institute Inc., Cary, NC).
Baseline patient characteristics are described in Table 1. The median age was 70 years (range 48–77 years), and 33 patients (82%) were men. Histopathological examination revealed well, moderately, and poorly differentiated cancers in 8 (20%), 30 (77%), and 2 patients (3%), respectively. T1, T2, T3, and T4 stage cancers were observed in 4 (10%), 6 (15%), 29 (73%), and 1 patient (3%), respectively. Lymph node metastasis was detected in 19 patients (48%), and 29 patients (73%) underwent R0 resection. The median NLR and LMR values were 1.98 (interquartile range [IQR] 1.37–2.54) and 4.75 (IQR 2.93–5.84), respectively.
Demographic and clinicopathological features
Variables Total ( Age (year) Mean ± SD 70 (66–77) Gender Male 33 (82%) Female 7 (18%) Differentiation Well 8 (20%) Moderately 30 (77%) Poorly 2 (3%) T classification T1 4 (10%) T2 6 (15%) T3 29 (73%) T4 1 (3%) N classification N (+) 19 (48%) N (−) 21 (52%) Resection margin R0 29 (73%) R1 8 (20%) R2 3 (8%) alb (g/dL) Mean ± SD 3.7 (3.3–3.9) CRP (mg/dL) Mean ± SD 0.27 (0.1–1.3) CEA (ng/mL) Mean ± SD 2.6 (1.9–4.0) CA19-9 (U/mL) Mean ± SD 53.9 (10.1–173.5) WBC (/mm3) Mean ± SD 5800 (4200–7000) Hb (g/dL) Mean ± SD 11.6 (10.5–13.1) plt (104/mm3) Mean ± SD 22.2 (19.4–26.7) NLR Mean ± SD 1.98 (1.37–2.54) LMR Mean ± SD 4.75 (2.93–5.84)
The area under the curve (AUC) for NLR calculated from the ROC curve was 0.640 (95% confidence interval [CI] 0.450–0.850). Corresponding to the point with the maximum combined sensitivity and specificity on the ROC curve, the best cutoff value for NLR was 3.14. Based on this cutoff value, 9 patients (28%) were assigned to the high NLR group. The cutoff value of LMR was determined to be 4.55, and 11 patients (28%) were assigned to the high LMR group. The AUC for LMR was 0.640 (95% CI 0.450–0.850) (Fig. 1). Cutoff values for serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) were determined to be 2.4 ng/mL and 60.2 U/mL, respectively. Eleven patients (34%) were classified into the high CEA and 12 patients (38%) into the high CA 19-9 group.
Graph: Fig. 1 Receiver operating characteristic (ROC) curve analysis for 5 years survival to set cutoff values for neutrophil-to-lymphocyte ratio (NLR) and lymphocyte -to-monocyte ratio (LMR). The cutoff value for NLR and LMR were 3.14 and 4.55, respectively. The area under the curve (AUC) for NLR and LMR was 0.624 and 0.699, respectively
We validated the association of the clinicopathological factors between these groups (Table 2). Our analysis showed that most clinicopathological factors were not associated with the NLR and LMR. However, serum albumin levels were associated with both the NLR and LMR (P = 0.011 and P = 0.023, respectively), and serum CA 19-9 levels were also associated with the LMR (P = 0.030). Additionally, the collinearity between NLR and LMR was relatively small (Pearson's correlation coefficient = 0.156).
The collinearity of clinicopathological factors between groups that divided by NLR and LMR
Factors NLR LMR NLR ≥ 3.14 NLR < 3.14 LMR ≥ 4.55 LMR < 4.55 Age (years) ≥ 65 5 26 0.503 19 12 0.135 < 65 2 7 3 6 Gender Male 6 27 0.645 17 16 0.297 Female 1 6 5 2 Differentiation well differentiated 0 8 0.181 3 5 0.237 others 7 25 19 13 T classification T1/2 2 8 0.572 6 4 0.503 T3/4 5 25 16 14 N classification N (−) 4 17 0.559 14 7 0.203 N (+) 3 16 8 11 Resection margin R0 6 23 0.364 17 12 0.347 R1 or R2 1 10 5 6 Albumin (g/dL) ≥ 3.5 1 23 17 7 < 3.5 6 10 5 11 CRP (mg/dL) ≥ 0.5 4 12 0.273 6 10 0.068 < 0.5 3 21 16 8 CEA (ng/mL) ≥ 2.5 4 17 0.559 12 9 0.512 < 2.5 3 16 10 9 CA19-9 (U/mL) ≥ 60.2 5 14 0.164 7 12 < 60.2 2 19 15 6
The comparison of Kaplan-Meier survival curves using the log-rank test revealed that the NLR and LMR were significantly associated with OS (Fig. 2). The median survival time of the high NLR group was 14.9 months and that of the low NLR group was 65.9 months (P < 0.001). The median survival time of the low LMR group was 27.0 months and that of the high LMR group was 82.2 months (P < 0.001).
Graph: Fig. 2 a Kaplan-Meier estimates of overall survival (OS) based on neutrophil-to-lymphocyte ratio (NLR) for patient with distal bile duct cancer (log-rank test P < 0.001). b Kaplan-Meier estimates of OS based on lymphocyte-to-monocyte ratio (LMR) for patient with distal bile duct cancer (log-rank test P < 0.001)
Cox proportional hazards regression analysis was also performed to investigate the association between OS and age, histopathological differentiation, serum albumin, CRP, CEA, and CA 19-9 levels, as well as the NLR and LMR. Univariate analysis showed that hypoalbuminemia (P = 0.004), lymph node metastasis (P = 0.033), a high NLR (P < 0.001), and low LMR (P = 0.002) were significantly associated with poor OS. Furthermore, only those preoperative factors that were observed to be statistically significant on univariate analysis were subjected to multivariate analysis using the Cox proportional hazards regression model. Multivariate analysis showed that only a high NLR (hazard ratio 6.133, 95% CI 1.453–25.90, P = 0.014) and low LMR (hazard ratio 3.16, 95% CI 1.024–9.751, P = 0.045) were independently associated with poor OS (Table 3).
Univariate and maltivariate analysis of the association between preoperative clinicopathological factors and overall survival in patients with distal bile duct cancer who underwent pancreaticoduodenectomy
Factors No. (%) Univariate analysis Multivariate analysis Hazard ratio 95% CI Hazard ratio 95% CI Age (years) ≥ 65 31 (82%) 0.508 0.2046–1.245 0.138 < 65 9 (22%) (Referent) Gender Male 33 (87%) 0.945 0.352–3.282 0.920 Female 7 (13%) (Referent) Differentiation Well differentiated 8 (20%) 1.243 0.416–3.716 0.697 Others 32 (80%) (Referent) T classification T1/2 10 (25%) (Referent) 0.6476–5.816 0.236 T3/4 30 (75%) 1.941 N classification N (−) 21 (53%) (Referent) 1.078–5.772 N (+) 19 (48%) 2.495 Resection margin R0 29 (73%) (Referent) 0.9687–5.581 R1 or R2 11 (27%) 2.325 Albumin (g/dL) ≥ 3.5 24 (60%) (Referent) 1.521–8.495 1.484 0.537–4.107 0.447 < 3.5 16 (40%) 3.595 CRP (mg/dL) ≥ 0.5 16 (40%) 1.220 0.5223–2.85 0.646 < 0.5 24 (60%) (Referent) CEA (ng/mL) ≥ 2.5 21 (53%) 1.665 0.7226–3.838 0.231 < 2.5 19 (48%) (Referent) CA19-9 (U/mL) ≥ 60.2 19 (48%) 3.165 1.345–7.449 2.614 0.978–6.993 0.056 < 60.2 21 (53%) (Referent) NLR ≥ 3.14 8 (20%) 11.810 3.296–42.32 6.133 1.453–25.900 < 3.14 32 (80%) (Referent) LMR ≥ 4.55 18 (45%) (Referent) 1.826–12.81 3.16 1.024–9.751 < 4.55 22 (55%) 4.837
In this cohort, 5 patients died of other diseases; stomach cancer: leukemia, acute myocardial infarction (1 patient each), and aspiration pneumonia (2 patients). The mean survival time of these 5 patients was relatively long (36.2 months), suggesting that the effect on survival was not significant. The comparison of Kaplan-Meier survival curves using the log-rank test showed that both NLR and LMR were significantly related to disease-free survival (P < 0.001 and P = 0.018, respectively).
Our study highlights that preoperative NLR and LMR values were independent predictors of OS in patients with DBDC who underwent pancreaticoduodenectomy. Several studies have reported that preoperative indicators, such as serum albumin and CRP levels, as well as widely recognized tumor markers (CEA and CA 19-9) may also serve as prognostic indicators of biliary tract cancer outcomes [[
The potential mechanisms by which inflammation contributes to cancer progression are as follows: neutrophils inhibit the host immune response to cancer by suppressing cytotoxic immune cells via the secretion of cytokines and chemokines [[
Patients with DBDC show poor survival despite treatment. Pancreaticoduodenectomy ensures radical resection of DBDC; however, this operation is one of the most invasive and complicated procedures among all gastrointestinal surgeries. DBDC is a highly invasive tumor, and involvement of surrounding organs can result in postoperative complications that reduce patients' quality of life or may even be fatal. Therefore, it is important to determine whether operation is necessary for individual patients. The results of the present study highlight the role of NLR and LMR as preoperative prognostic predictors in patients with DBDC. Therefore, in addition to surgery, therapeutic options such as neoadjuvant chemotherapy can be considered in these patients. The efficacy of preoperative and postoperative chemotherapy remains unclear in patients with DBDC [[
The limitations of this study include the following: (a) Owing to the rarity of DBDC, this study included a small number of patients. (b) The uncontrolled and retrospective design is a drawback of this study. Despite these limitations, our study is the first to prove that preoperative NLR and LMR serve as independent predictors of OS in patients with DBDC undergoing radical resection. Further accumulation of cases and future cohort studies are warranted to provide a deeper understanding of the mechanism through which a high NLR and low LMR serve as predictors of poor survival in patients with DBDC.
Both preoperative NLR and LMR were independently associated with survival in patients with DBDC who underwent radical resection. The NLR and LMR can be estimated preoperatively; therefore, these biomarkers can help surgeons in preoperative evaluation of patients.
The authors declare that they had no funding source for this study.
Not applicable
Yoji Miyahara carried out the collection and assembly of data and analysis and drafted the manuscript. Takashi Shida coordinated and helped to draft the manuscript. Yoshiaki Shimizu carried out the conception and design of the study. Masayuki Ohtsuka coordinated and approved the final manuscript. The authors read and approved the final manuscript.
The dataset supporting the conclusions of this article is included within the article.
This study was conducted in accordance with the guidelines of the 1975 Declaration of Helsinki. The need for informed patient consent was waived because of the retrospective nature of the study. All procedures used in this research were approved by the Ethical Committee of Japanese Red Cross Narita Hospital.
Not applicable
The authors declare that they had no funding source for this study.
• NLR
- Neutrophil-to-lymphocyte ratio
• LMR
- Lymphocyte-to-monocyte ratio
• DBDC
- Distal bile duct cancer
• ROC
- Receiver operating characteristic
• OS
- Overall survival
• CT
- Computed tomography
• MRI
- Magnetic resonance imaging
• ERCP
- Endoscopic retrograde cholangiopancreatography
• AJCC
- The American Joint Committee on Cancer
• EBD
- Endoscopic biliary drainage
• PTBD
- Percutaneous transhepatic biliary drainage
• mGPS
- Modified Glasgow Prognostic Score
• CRP
- C-reactive protein
• SD
- Standard deviation
• IQR
- Interquartile range
• AUC
- The area under the curve
• CI
- Confidence interval
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By Yoji Miyahara; Shida Takashi; Yoshiaki Shimizu and Masayuki Ohtsuka
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