Abstract
Background/Aim: The platelet-to-lymphocyte ratio (PLR) has recently been suggested as a new predictor of the prognosis in several carcinoma types. However, the clinical impact remains controversial in patients with ampullary carcinoma. Thus, the aim of this study was to investigate other useful biomarkers for identifying poor prognosis in patients with ampullary carcinoma. Patients and Methods: Forty-one patients with ampullary carcinoma underwent pancreaticoduodenectomy (PD) with curative resection between April 2000 and April 2017. Various clinicopathological findings of the patients and their tumors were evaluated as potential prognostic factors which might enable better stratification of prognosis. Results: Platelet-to-lymphocyte ratio, as well as other markers, was found to be a prognostic factor in patients with ampullary carcinoma. The 2-year disease-free survival percentage was significantly higher in the group with low PLR than in the high PLR group (70.2% vs. 28.6%; p=0.005). Combinational analysis of the PLR and conventional TMs enabled us to stratify prognosis of the patients more clearly than by each marker alone. Conclusion: PLR was a useful prognostic factor for patients with ampullary cancer. The combination of preoperative PLR and conventional TMs markers may be powerful predictive factors for postoperative prognosis in patients with ampullary carcinoma following PD.
Ampullary carcinoma is extremely rare, accounting for approximately 0.2-0.5% of all gastrointestinal malignancies and approximately 6-17% of periampullary tumors (1-4). The most commonly recommended treatment is pancreaticoduodenectomy (PD), which has a reported resectability rate of 82.1% (1). Although ampullary carcinoma is considered to have a better prognosis [5-year survival rate of 30% to 60% (1, 5, 6)] than other peripancreatic head adenocarcinomas, some cases have a poor prognosis with early recurrence.
Several prognostic factors have been reported in ampullary carcinoma, including lymph node metastasis (1, 7-10), depth of tumor infiltration (2, 9), tumor stage (3, 10), involvement of resection margins (5), lymphatic vessel invasion (7), perineural invasion (8), and pancreaticobiliary subtype (4, 10, 11). However, accurate information for these factors are generally obtained postoperatively.
In recent years, biomarkers have been suggested as new prognostic factors in several cancer types. Of these, the lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) have been studied extensively and adopted as predictors of prognosis in other diseases (12-25). However, in ampullary carcinoma, the roles of these biomarkers remain controversial, as the presence of this disease is relatively rare and blood-based biomarkers may be affected by comorbidities, such as obstructive jaundice and cholangitis.
Based on this, we evaluated preoperative LMR, NLR, and PLR as prognostic factors for ampullary carcinoma in patients free of obstructive jaundice and cholangitis. Furthermore, in order to better stratify groups based on prognosis, we examined whether the combination of these blood-based biomarkers and conventional TMs would act as prognostic factors for ampullary carcinoma.
Patients and Methods
Patients. We examined 41 patients with ampullary carcinoma who underwent PD with curative resection at the First Department of Surgery at Yamanashi University, between April 2000 and April 2017.
Clinical characteristics, preoperative laboratory data, postoperative complications, and pathological examinations were collected from patient's electronic medical records. Preoperative data, including serum TMs carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9) and Duke pancreatic monoclonal antigen type 2 (DuPAN-2), were collected within 2 weeks of surgery. Additionally, total bilirubin, white blood cell (WBC) count, and C-reactive protein (CRP) values were confirmed to be within normal reference values, as these may have affected the LMR, NLR, and PLR. From these data, we calculated the LMR, NLR, and PLR. To supplement the perioperative data, a review of the surgical and anesthetic charts of each patient was carried out. Histopathological examination was performed after surgery. We used the TNM classification of Malignant Tumors Eighth Edition edited by the Union for International Cancer Control for determining the TNM stage (26). As cases with recurrence within 2 years have extremely poor prognosis, the patients were divided into two groups: i) Non-early recurrence group, patients without recurrence within 2 years (non-ER group); 2) early recurrence group, patients with recurrence within 2 years (ER group). Patient characteristics are shown in Table I.
Adjuvant treatment. The patients with T3/lymph node metastasis routinely received chemotherapy, except for those with renal dysfunction and three patients who did not agree to the treatment.
The main regimens were intravenous gemcitabine (1000 mg/m2) on days 1, 8, and 15 every 4 weeks (1 cycle) for up to six cycles, and intravenous gemcitabine (1000 mg/m2) plus cisplatin (25 mg/m2) on days 1 and 8 every 3 weeks (1 cycle) for up to eight cycles. Four patients chose orally administered S-1 (TS-1; Taiho Pharmaceutical, Tokyo, Japan), at 40 mg, 50 mg, or 60 mg based on body surface area, twice a day for 28 days followed by a 14-day rest (1 cycle) for up to four cycles after surgery, because frequent visits were difficult.
Patient follow-up. TM analysis was examined monthly, and computed tomography was performed every 3 months. Recurrence was diagnosed based on imaging findings or continuous rise of TMs.
Statistical analysis. TMs were classified as within or beyond the reference value, and biomarkers were expressed as the mean ± standard deviation. Patient characteristics and preoperative/intraoperative data between the two groups were compared using chi-squared test, Fisher's exact test, and Mann–Whitney U-test. The cutoff values for clinical characteristics were determined using receiver operating characteristics (ROC) curve analysis. The recommended cutoff values for the characteristics were defined using the most prominent point on the ROC curve. Disease-free survival (DFS) was calculated as the time from the date of surgery to the date of first recurrence. Overall survival (OS) was calculated as the time from the date of surgery to the date of death from any cause or last follow-up. DFS and OS were estimated using the Kaplan–Meier method. Significance was defined as a p<0.05. The statistical analyses were performed using SPSS version 23.0 software (IBM, Armonk, NY, USA).
Characteristics of patients according to recurrence within 2 years.
Results
Patient characteristics. Table I shows the comparison between the non-ER group and the ER group. Preoperative PLR was significantly higher in the ER group, although there was no significant difference in other preoperative blood markers, such as LMR and NLR. With the exception of PLR, T-stage and lymph node metastasis were found to be significant prognostic factors in this cohort. However, there was no significant difference in sex, age, intraoperative findings, and presence or absence of postoperative pancreatic fistula between groups with and without recurrence and nonrecurrent groups. TMs tended to be higher in the early recurrence group, but there was no significant difference between the two groups.
Receiver operating characteristics curve analysis curve for recurrence within 2 years. The optimal cut-off value was for the platelet-to-lymphocyte ratio was 211.7, with an area under the curve of 0.744.
Comparison between the low PLR group and the high PLR group. According to the ROC curve analysis, the optimal cutoff value was 211.7 (Figure 1). Based on the cutoff value, patients were classified into a low PLR group (PLR ≤211.7) and a high PLR group (PLR >211.7), and clinicopathological findings were compared. There were no significant differences in sex, intraoperative findings, and presence or absence of postoperative pancreatic fistula. However, the high PLR group had significantly more advanced tumors (p=0.002) and tended to have a slightly greater lymph node metastasis than the low PLR group, although not significant (p=0.130). The recurrence rate was significantly higher in the high PLR group (p=0.010; Table II).
Impact of the combination of preoperative PLR and TMs as a prognostic factor. In the low PLR group, the 1-year and 2-year DFS were 81.5% and 70.2%, respectively, and those in the high PLR group were 57.1% and 28.6%, respectively. There was a significant difference between the two groups (p=0.005; Figure 2A).
One-year and 2-year DFS in those with TMs falling within the reference values (low TM group) were 85.7% and 71.1% respectively, and for those with TMs above the reference value (high TM group) were 60.0% and 40.0%, respectively (p=0.043; Figure 2B).
Patient characteristics and relationship of recurrence within 2 years according to platelet-to-lymphocyte ratio (PLR).
Further prognostic analysis was performed by dividing all patients into the three following groups according to preoperative PLR and TMs: Group 1: Patients with both low PLR and low TMs (n=14); group 2: patients with either high PLR or high TMs (n=20); and group 3: patients with both high PLR and high TMs (n=7). One-year DFS was 92.3%, 71.4%, and 42.9%, respectively, and 2-year DFS was 84.6%, 52.4%, and 14.3%, respectively (p=0.003; Figure 3). Out of all the groups, group 3 showed the worst prognosis. Notably, in group 3, six out of seven cases had recurrent tumors within 2 years (85.7%), and the remaining patient also had recurrent tumors 27 months after surgery.
Discussion
Various inflammatory markers, including LMR, NLR, and PLR, have been identified and evaluated as prognostic factors for several gastrointestinal malignancies, including esophageal squamous cell carcinoma (12, 13), adenocarcinoma of the esophagogastric junction (14), gastric cancer (15, 16), colorectal cancer (17, 18), perihilar cholangiocarcinoma (19), and pancreatic cancer (20-25). These are clinically common hematological markers for evaluating the inflammatory response in patients with carcinoma because they are relatively easy to examine prior to surgery and have no adverse effects on treatment. However, in patients with ampullary carcinoma, the usefulness of these markers is still controversial, as obstructive jaundice or cholangitis may affect the peripheral blood. Therefore, we evaluated biomarkers when total bilirubin, WBC count, and CRP were within the normal reference values, indicating that patients were not affected by jaundice or cholangitis.
The 2-year disease-free survival (DFS) rates according to platelet-to-lymphocyte ratio (PLR) (A) and aberrant levels of tumor markers (TMs) (B). Those with a low PLR (p=0.005), and those with low TM levels (p=0.043) had significantly better DFS.
A recent study on gastric adenocarcinoma defined early recurrence as recurrence within 2 years following surgery and concluded that, within the first 2 years, patients should be carefully monitored for distant metastasis (27-29). Therefore, this definition was also used in this study.
The patients were divided into three groups according to the platelet-to-lymphocyte ratio (PLR) and levels of tumor markers (TMs). Group 1: Both PLR and TMs were low; group 2: either high PLR or high TMs; group 3: high PLR and high TMs. DFS rates of groups 1, 2 and 3 at 1 year were 92.3%, 71.4% and 42.9%, respectively and 2 years were 84.6%, 52.4%, 14.3%, respectively (p<0.003).
The main finding of the study demonstrates that a preoperative PLR ≥211.7 is an independent predictor of poor postoperative DFS for patients with ampullary carcinoma undergoing radical PD treatment. Another important finding was that the T-stage was advanced in the group with high PLR compared with the low PLR group. However, there was no significant difference between groups in regard to lymph node metastasis. This result suggests that the preoperative PLR correlates in all patients with evidence of local invasion of the resected ampullary carcinoma; this finding is consistent with previous reports (30-32).
Another point of this study is that the combination of preoperative high PLR and high TMs exhibited superior prediction of poor prognosis for patients with resected ampullary carcinoma. In our study, out of the seven cases who had high levels of both PLR and TMs, six (85.7%) had recurrent tumors within 2 years. Several studies described that combination of PLR and CA19-9 is a prognostic factor in ampullary carcinoma (30, 31). However, these studies included patients who had jaundice, which would artificially increase the value of CA19-9. Furthermore, a low CA19-9 value can be a false-negative finding in patients with the Lewis blood-negative group phenotype. Therefore, it may be useful to evaluate CA19-9 along with other TMs.
Invasive tumor causes tissue damage adjacent to the tumor, which results in both a local and systemic chronic inflammatory response (10). Cancer-related inflammation increases regulatory T-cells and activating chemokines which causes the suppression of antitumor immunity. Transforming growth factor beta (TGFβ), interleukin (IL)-10, and other inhibitory cytokines secreted by inflammatory cells can depress lymphocyte function and reduce circulating lymphocyte counts (33). Conversely, thrombocytosis appears to be stimulated by cancer-related production of cytokines, mainly IL1, IL3, IL6, IL9, and granulocyte-macrophage colony stimulating factor (34, 35). These results suggest that PLR may reflect tumor-related host systemic immune responses. While the most suitable cutoff value of PLR is unknown, the values reported here are similar to those of previous report (32).
In ampullary cancer, the current study showed that the recurrence rate was approximately 35%, and median time to recurrence was 15.3 months in such patients (9). Several adjuvant chemotherapies (e.g. gemcitabine) have been attempted as treatments for patients with ampullary carcinoma, the efficacy of which is controversial (36-39). However, the efficacy of the neoadjuvant chemotherapy has been reported for many gastrointestinal cancer types (40-44). In ampullary carcinoma, the efficacy of neoadjuvant chemotherapy remains controversial (45, 46) but it may be considered as one of the therapeutic strategies for patients with poor prognosis. Furthermore, the stratification of patients based on the results of this investigation may be useful for determining the best treatment strategy in ampullary carcinoma. Aside from surgery, ampullary carcinoma still does not have established treatment recommendations. Thus, more aggressive multidisciplinary treatment for patients with ampullary carcinoma should be established, especially for patients at a high risk of poor prognosis; moreover, the results of this study may be useful for determining which patients will likely exhibit the poorest prognosis.
Conclusion
Measurement of the PLR has been shown to serve as a clinically accessible and useful biomarker for patient outcomes in patients with ampullary cancer, and the combination of high preoperative PLR and high TMs led to even greater predictive power regarding prognosis. In this investigation, patients with resected ampullary carcinoma with the combination of a high preoperative PLR and high TMs exhibited the poorest postoperative prognosis.
Footnotes
Authors' Contributions
Hiromichi Kawaida was actively involved in this study, especially in terms of statistical design. Seven surgeons (Hiromichi Kawaida, Naohiro Hosomura, Hidetake Amemiya, Hiroshi Kono, Jun Itakura, Hideki Fujii, and Daisuke Ichikawa) contributed to the concept and clinical design. Pathological examination of tissues was performed by Tadao Nakazawa. Acquisition of data was carried out by all physicians. Interpretation of data and drafting of the article was performed by Hiromichi Kawaida. Finally, this article was revised and approved by all 23 investigators. Thus, all 23 Authors actively participated in this study.
Conflicts of Interest
The Authors declare that they have no conflicts of interest in regard to this study.
Ethics Approval
This study was approved by the Ethics Committee of Faculty of Medicine, University of Yamanashi (H30108).
- Received October 25, 2019.
- Revision received November 4, 2019.
- Accepted November 5, 2019.
- Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
