Zhang L, Chen YP, Ji M, Ying LQ, Huang CC, Zhou JY, Liu L. Inflammation-related markers and prognosis of alpha-fetoprotein producing gastric cancer. World J Gastrointest Oncol 2024; 16(9): 3875-3886 [DOI: 10.4251/wjgo.v16.i9.3875]
Corresponding Author of This Article
Lin Liu, MD, Chief Physician, Department of Oncology, Zhongda Hospital, Medical School of Southeast University, No. 87 Dingjiaqiao, Nanjing 210009, Jiangsu Province, China. 101012478@seu.edu.cn
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Retrospective Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Lu Zhang, Yan-Ping Chen, Min Ji, Le-Qian Ying, Chun-Chun Huang, Jing-Yi Zhou, Lin Liu, Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, Jiangsu Province, China
Author contributions: Liu L designed and directed the study; Zhang L wrote the manuscript draft; Liu L and Chen YP critically reviewed the manuscript; Zhang L, Ji M, Ying LQ, Huang CC and Zhou JY collected the original data; All authors reviewed the manuscript.
Institutional review board statement: This study design was approved by the ethics board of Zhongda Hospital of Southeast University, No. 2019ZDSYLL067-P01.
Informed consent statement: Informed consent of the patients could be waived because it was retrospective, and all information was anonymous.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The data that support the findings of this study are available upon reasonable request at 101012478@seu.edu.cn.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Lin Liu, MD, Chief Physician, Department of Oncology, Zhongda Hospital, Medical School of Southeast University, No. 87 Dingjiaqiao, Nanjing 210009, Jiangsu Province, China. 101012478@seu.edu.cn
Received: May 4, 2024 Revised: June 20, 2024 Accepted: July 15, 2024 Published online: September 15, 2024 Processing time: 128 Days and 4.6 Hours
Abstract
BACKGROUND
Inflammation-related markers including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI) and prognostic nutritional index (PNI) could reflect tumor immune microenvironment and predict prognosis of cancers. However, it had not been explored in alpha-fetoprotein (AFP) producing gastric cancer (GC).
AIM
To determine the predictive value of inflammation-related peripheral blood markers including as NLR, PLR, MLR, SII, SIRI and PNI in the prognosis of AFP- producing GC (AFPGC). Besides, this study would also compare the differences in tumor immune microenvironment, clinical characteristics and prognosis between AFPGC and AFP- GC patients to improve the understanding of this disease.
METHODS
573 patients enrolled were retrospectively studied. They were divided into AFP+ group (AFP ≥ 20 ng/mL) and AFP- group (AFP < 20 ng/mL), comparing the levels of NLR/PLR/MLR/SII/SIRI/PNI and prognosis. In AFP+ group, the impact of NLR/PLR/MLR/SII/SIRI/PNI and their dynamic changes on prognosis were further explored.
RESULTS
Compared with AFP- patients, AFP+ patients had higher NLR/PLR/MLR/SII/SIRI and lower PNI levels and poorer overall survival (OS). In the AFP+ group, mortality was significantly lower in the lower NLR/PLR/MLR/SII/SIRI group and higher PNI group. Moreover, the dynamic increase (NLR/PLR/MLR/SII/SIRI) or decrease (PNI) was associated with the rise of mortality within 1 year of follow-up.
CONCLUSION
Compared with AFP- patients, the level of inflammation-related peripheral blood markers significantly increased in AFP+ patients, which was correlated with OS of AFP+ patients. Also, the gradual increase of SII and SIRI was associated with the risk of death within one year in AFP+ patients. AFPGC should be considered as a separate type and distinguished from AFP- GC because of the difference in tumor immune microenvironment. It requires basic experiments and large clinical samples in the future.
Core Tip: Compared with alpha-fetoprotein (AFP)- patients, the level of inflammation-related peripheral blood markers significantly increased in AFP+ patients, which was correlated with overall survival of AFP+ patients. AFP- producing gastric cancer (AFPGC) should be considered as a separate type and distinguished from AFP- gastric cancer because of the difference in tumor immune microenviroment. It might have different response rates in immunotherapy, which provided basis for selection of immunotherapy for AFPGC.
Citation: Zhang L, Chen YP, Ji M, Ying LQ, Huang CC, Zhou JY, Liu L. Inflammation-related markers and prognosis of alpha-fetoprotein producing gastric cancer. World J Gastrointest Oncol 2024; 16(9): 3875-3886
Alpha-fetoprotein producing gastric cancer (AFPGC) is a special subtype of gastric cancer (GC) that was first described in 1970 based on alpha-fetoprotein (AFP) positive serum and pathological specimens[1]. Currently, most academics hold that AFP immunohistochemistry is not essential for the diagnosis of AFPGC[2]. Studies had shown that compared with common GC, AFPGC is more aggressive, with higher liver metastasis rate and a worse prognosis, therefore, AFPGC should be considered as a unique type and distinguished from common GC[3-5]. However, the molecular characteristics of AFPGC have not been clearly defined, which severely limits the understanding and treatment of the disease and treatment options, resulting in a lack of effective biomarkers to predict the prognosis of patients with AFPGC. Although an increasing number of studies has used multiple inflammation-related markers that reflect peripheral immune microenvironment to predict the prognosis of tumor patients[6-8], so far, there are no studies investigating the relationship between inflammation-related peripheral blood markers and prognosis of AFPGC. Also, previous studies have focused on exploring the differences in clinicopathological features between AFPGC and AFP- GC rather than the tumor immune microenvironment. This study sought to determine the predictive value of inflammation-related peripheral blood markers including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI) and prognostic nutritional index (PNI) in the prognosis of AFPGC. Furthermore, the differences in tumor immune microenvironment, clinical characteristics and prognosis between AFPGC and AFP- GC patients were compared to improve understanding of this disease.
MATERIALS AND METHODS
Patients
From October 13, 2013 to March 31, 2022, 573 patients were retrospectively screened and included in this study based on the inclusion and exclusion criteria. Serum AFP ≥ 20 ng/mL before treatment of patients was defined as AFP+ while serum AFP < 20 ng/mL was defined as AFP-. Treatment involved surgery including radical surgery, palliative surgery, and endoscopic surgery, as well as radiotherapy, immunotherapy and other treatments related to the primary disease. The study was conducted in accordance with the ethical guidelines of the 1995 Declaration of Helsinki and was approved by the Ethics Committee of Zhongda Hospital Affiliated to Southeast University. Because this study was retrospective and all information was anonymous, the requirement for informed consent from patients was waived.
Collection of clinical data
The results of routine blood, liver function and serum AFP tests were retrospectively collected for all patients before treatment within 1 week before treatment. NLR, PLR, MLR, SII, SIRI and PNI were calculated using the following formulas: NLR = neutrophil count/lymphocyte count, PLR = platelet count/lymphocyte count, MLR = monocyte count/lymphocyte count, SII = neutrophil count × platelet count/lymphocyte count, SIRI = neutrophil count × monocyte count/lymphocyte count, PNI = albumin value + 5 × lymphocyte count.
Data on clinical characteristics and overall survival (OS) of AFP+ and AFP- groups, respectively were collected. For patients with liver metastasis, the time interval between the occurrence of liver metastasis and the first diagnosis was recorded. Liver metastasis occurring within 6 months after diagnosis of GC was defined as simultaneous liver metastasis, while liver metastasis occurring 6 months after diagnosis of GC was defined as heterochronous liver metastasis[9]. For the AFP+ group, NLR, PLR, MLR, SII, and SIRI were repeatedly measured within 1 year follow-up after diagnosis until death, with repeated measurements irregularly spaced over time. Follow-up started on the date of diagnosis and ended on September 30, 2022. Enrolled cases were followed up for prognosis by telephone, outpatient review, or hospitalization information. OS was defined as the time from the date of diagnosis to the time of death in months, and the time of the last follow-up visit was recorded if death had not occurred.
Statistical analysis
All data were analyzed with SPSS 26.0 software and EmpowerStats software (www.empowerstats.com, version 4.1). Student’s t-test and Mann-Whitney U-test were employed for continuous variables with normal and non-normal distribution, respectively. Categorical variables were reported as percentages, and rates were compared via χ2 test or corrected χ2 test or Fisher’s precision probability test. Survival analysis was performed by the Kaplan-Meier method, and the log-rank test was performed to identify differences between groups.
For the AFP+ group, the cut-off values of inflammatory indicators were obtained according to receiver operating characteristic (ROC) curves. The relationships between changes in inflammatory markers and the risk of death in AFP+ patients were analyzed by restricted cubic spline (RCS). The generalized additive mixed model (GAMM) was also used to study the relationships between dynamic changes in inflammatory indicators and death in AFP+ patients. GAMM was particularly suitable for assessing the results of repeated measurements when the interval between repeated measurements was irregular and a part of the data was missing[10,11]. All results were for two-sided tests, with P < 0.05 considered to indicate statistical significant. The flow chart of the study design was shown in Figure 1.
Figure 1 The flowchart of the study.
AFP: Alpha-fetoprotein; GC: Gastric cancer; PNI: Prognostic nutritional index; ROC: Receiver operating characteristic; SII: Systemic immune-inflammation index; SIRI: Systemic inflammation response index.
RESULTS
Comparison of clinicopathological characteristics and prognosis between the AFP+ and AFP- groups
Based on the inclusion and exclusion criteria, a total of 573 eligible patients were finally enrolled into this study, comparising 75 AFP+ patients (13.1%) and 498 AFP- patients with (86.9%). The average levels of NLR (Z = -5.636, P < 0.001), PLR (Z = -5.327, P < 0.001), MLR (Z = -5.544, P < 0.001), SII (Z = -5.666, P < 0.001) and SIRI (Z = -5.885, P < 0.001) in the AFP+ group were significantly higher than that of AFP- group, while PNI (Z = -5.838, P < 0.001) was significantly lower than that of AFP- group. Moreover, there was also a large disparity between the two groups in terms of survival. The AFP+ group had 55 deaths and 3 lost cases over the follow-up period, with a median follow-up time of 27.7 months (95%CI: 6.663-48.847) and a median survival time of 7.5 months (95%CI: 5.165-9.835), while the AFP- group had 131 deaths and 18 lost cases, with a median follow-up time of 46.7 months (95%CI: 40.599-52.841), and the median survival time was not reached by the end of follow-up. The total loss of follow-up rate was 4.2% in both groups. By the end of follow-up, the OS rate (27.3% vs 76.4%, P < 0.001) and median survival time (7.5 months vs not reached, P < 0.001) of patients in the AFP+ group showed lower than those in the AFP- group (Figure 2A). The distribution of complete clinical characteristics in each group were shown in Supplementary Table 1.
Figure 2 Kaplan-Meier survival curves.
A: Kaplan-Meier survival curves for patients in the alpha-fetoprotein (AFP)+ and the AFP- groups. B: Kaplan-Meier survival curves in groups of different AFP levels. AFP: Alpha-fetoprotein.
AFP+ patients were divided into the high-AFP group (AFP ≥ 485 ng/mL), medium-AFP group (54 ≤ AFP < 485 ng/mL) and low-AFP group (20 ≤ AFP < 54 ng/mL), with 25 cases in each group. The results of Kaplan-Meier analysis indicated that there were significant differences in OS among the three groups (P = 0.04; Figure 2B).
Accuracy of each inflammatory indicator in the peripheral blood in predicting the prognosis of AFP+ patients
The area under the curve (AUC) for NLR, PLR, MLR, SII, SIRI, and PNI was obtained from the ROC curves, as shown in Supplementary Figure 1. Although the AUCs of the above indicators were different, pairwise comparison did not reveal any significant differences (P > 0.05). The differences in clinical characteristics between patients with high and low levels of each indicator were shown in Supplementary Tables 2 and 3. In terms of mortality, patients with low NLR/PLR/MLR/SII/SIRI had significantly lower mortality rates than those with high NLR/PLR/MLR/SII/SIRI (38.9% vs 88.9%; 45% vs 88.5%; 65.3% vs 100%; 50.0% vs 95.3%; 53.8% vs 89.1%; P ≤ 0.001), while the mortality rate in patients with low PNI was significantly higher than those in patients with high PNI group (91.1% vs 51.9%, P < 0.001).
Analysis of factors affecting the prognosis of AFP+ patients
Kaplan-Meier univariate analysis showed that patients in the AFP+ group who received conservative treatments as well as had lymph node metastasis and liver metastasis, tumor-node-metastasis (TNM) staging III-IV and the levels of NLR ≥ 2.7, PLR ≥ 156.31, MLR ≥ 0.46, SII ≥ 755.75, SIRI ≥ 1.36 and PNI < 42.18 had shorter OS (Figure 3). Considering that NLR, PLR, and MLR had an extremely strong correlation with SII and SIRI, only SII, SIRI, and PNI were included in the multivariate analysis. The above risk factors were included in Cox multivariate regression analysis, which revealed that liver metastasis, tumor stage, and SII and PNI levels were independent risk factors affecting OS in AFP+ patients (Table 1).
The cut-off values of NLR, PLR, MLR, SII, SIRI and PNI were 2.70, 156.31, 0.46, 755.75, 1.36 and 42.18, respectively.
Relationship between dynamic changes in SII and SIRI levels and risk of death in AFP+ patients
We regarded pre-treatment inflammatory indicators as continuous variables and used RCS for further analysis. The results showed (Figure 4A) that the risk of death in AFP+ patients gradually increased with the gradual increase in NLR/PLR/MLR/SII/SIRI levels and gradual decrease in PNI levels. Furthermore, we collected a total of 622 blood samples from 65 AFP+ patients, each with data for at least two inflammatory markers. PNI data could not be accurately collected because it was difficult to synchronously collect results for liver function tests and routine blood tests, therefore, only the other 5 indicators were studied. We found that all AFP+ patients who died within 1 year of diagnosis exhibited an overall significantly increasing trend of inflammatory indicator levels via the GAMMs, while an overall decreasing trend was observed for the inflammatory indicators of AFP+ patients who were still alive within 1 year. Besides, there was a significant interaction between death-survival status and follow-up time for SII and SIRI (Pinteraction < 0.05) rather than the other indicators (Figure 4B).
Figure 4 Analysis of the relationship between these inflammatory indicators as continuous variables and death.
A: Restricted cubic spline (RCS) of six inflammation-related peripheral blood markers. The orange numbers were the corresponding values of each inflammatory indicator when hazard ratio equaled 1; B: Generalized additive mixed model (GAMMs) of six inflammation-related peripheral blood markers in survival group and death group. The RCS and GAMMs corrected age, sex, tumor location, tumor size, differentiation, lymphatic metastasis, liver metastasis, extrhepatic metastasis, time of liver metastasis, tumor-node-metastasis stage, T stage, N stage, vascular invasion and nerve invasion. In figure B, “0”, “1” and “Pint” referred to “survival group”, “death group” and “Pinteraction”, respectively. AFP: Alpha-fetoprotein; GC: Gastric cancer; PNI: Prognostic nutritional index; ROC: Receiver operating characteristic; SII: Systemic immune-inflammation index; SIRI: Systemic inflammation response index.
DISCUSSION
AFPGC is a rare subtype of GC with a global incidence of 1.3% to 15.0%[12,13]. The definition of AFPGC varies among studies. Some studies defined AFPGC based on immunohistochemical results from histological examination[13,14], while other studies defined AFPGC based on serum AFP levels[2,15]. Currently, most scholars hold that immunohistochemistry of AFP is not indispensable for the diagnosis of AFPGC[2]. Our study defined AFPGC as serum AFP ≥ 20 ng/mL before treatment, in accordance with other studies[2,15,16]. Among the GC patients included in this study, patients with AFPGC accounted for 13.1%, which was higher than the results in previous studies in Asian countries (1.8%-7.1%)[3,17,18] and more consistent with the global incidence.
TNM staging is one of the main criteria used for treatment planning and prognostic assessment of patients with GC[19]. However, accurate and complete TNM staging is only available for post-surgical patients and patients with the same TNM staging have heterogeneous prognosis[20]. Most studies have reported the use of complex and expensive genetic tests to predict prognosis and treatment response of AFPGC[14,21,22], ignoring the simplest and most accessible blood routine and biochemical tests in clinic. Recently, an growing number of studies have revealed that tumor-related inflammation is crucial for the occurrence and development of tumors[23]. Immune and inflammatory cells are considered to be important components of the tumor microenvironment that contribute to the proliferation and activation of tumor cells, promote tumor angiogenesis, weaken the adaptive immune response, and alter the response to hormones and antitumor drugs[24]. As common immune and inflammatory cells in peripheral blood, neutrophils[25,26], platelets[27-29], lymphocytes[30], and monocytes[24,31,32] have also been increasingly investigated for their role in tumor development. Therefore, a variety of indicators had been identified to predict the prognosis and efficacy prediction of tumor patients such as NLR, PLR and MLR[7,33,34]. Compared with NLR, PLR and MLR, SII and SIRI, as a combination of several indicators, enabled more comprehensive, balanced and objective assessment of the relationship between cancer and inflammation[35,36], and had high prognostic utility for multiple tumors[37-39]. PNI, as a nutritional index, had also been increasingly reported in recent years to be correlated with the prognosis of various types of cancer[40,41], indicating that the systemic nutritional and immune status of tumor patients were associated with prognosis[42]. With the gradual rise of cancer immunotherapy in recent years, the use of immune checkpoint inhibitors (ICIs) has changed the treatment prospects of many patients with advanced malignancies. However, a large proportion of patients show no response to ICIs or poor efficacy, as well as major side effects. Therefore, it is urgent to find effective biomarkers to predict the efficacy of ICIs[43]. In contrast to current studies focusing on biomarkers such as microsatellite instability-high status and programmed cell death 1 ligand 1 expression[44,45], inflammation-related peripheral blood markers, which are important components of the immune microenvironment, offer good predictive ability[46,47], as well as easy and inexpensive detection. Our study found that the levels of these markers were significantly higher (NLR/PLR/MLR/SII/SIRI) or lower (PNI) in the AFP+ group compared with those in the AFP- group, and the probability of death in the AFP+ group also increased gradually as the inflammation-related indicators increased (NLR/PLR/MLR/SII/SIRI) or decreased (PNI). Although previous studies have shown[48,49] that inflammation-related peripheral blood indicators could predict the prognosis of GC patients, there was no further differentiation of patients with GC. Our findings indicated that AFPGC differed from AFP- GC in terms of the peripheral tumor immune microenvironment and might have different response rates in immunotherapy, which provided a basis for the selection of immunotherapy for AFPGC. Following the discovery, our study attempted to explore the differences in indicators that could better represent the peripheral immune microenvironment, such as T-lymphocyte subsets and cytokines between the two groups. However, we were unable to investigate these differences owing to the unavailability of sufficient data for statistical analysis. This gap can be addressed in future research.
Based on the above results, we further investigated the inflammatory indicators and prognosis of AFP+ patients and found that NLR/PLR/MLR/SII/SIRI/PNI was predictive of the prognosis of these patients. However, there was no statistical difference in the AUC, which failed to identify the inflammatory index with the best predictive ability. Furthermore, although our study, like other studies[50], discovered that the OS of patients was negatively correlated with AFP level in the AFP+ group, no difference was found in the level of inflammatory indicators between different AFP levels. There are no similar articles in the field of AFPGC for reference, and it is also controversial whether AFP levels are related to inflammatory indicators in similar studies on hepatocellular carcinoma[51,52]. Studies with larger samples are necessary for clarification. Kaplan-Meier survival analysis showed that compared with patients with lower NLR/PLR/MLR/SII/SIRI or higher PNI, patients with higher NLR/PLR/MLR/SII/SIRI or lower PNI had worse OS. The analysis of independent risk factors affecting OS showed that patients with higher levels of SII, lower levels of PNI, more advanced tumor stage, and liver metastases and those who received conservative treatment had worse OS. Tumor stage and liver metastasis have been proven to be independent risk factors for prognosis in AFPGC patients in some other studies[3,13], however, to our knowledge, there are no studies on inflammation-related indicators and prognosis of AFPGC patients. More studies exploring this relationship are necessary.
In regarding inflammatory indicators as categorical variables, important information may be omitted and the results may be biased to an extent. Therefore, we regarded the above indicators as continuous variables for further analysis. Numerous studies have analyzed the relationship between NLR[53], PLR[54] and other indicators as continuous variables and tumor prognosis in other tumors, but no such study has been performed in an AFPGC patient cohort. In our study, RCS, which was commonly used to analyze nonlinear dose-response relationships showed a gradual increase in the risk of death in patients with increased NLR/PLR/MLR/SII/SIRI or decreased PNI, similar to the previous analysis of inflammatory markers as a categorical variable. Considering that inflammation-related peripheral blood markers were affected by the physiological and pathological state of the organism and a single time point might not be sufficiently reliable, resulting in deviation of the final results, we collected a total of 622 blood samples for unified analysis and found significant differences in the levels of inflammatory indicators between the survival and death groups. Furthermore, the levels of SII and SIRI were increasingly different with the passage of time. This finding suggested that early reduction of inflammatory markers might reduce the risk of short-term death in AFP+ patients. Unfortunately, we found that the death-survival interaction was not significant for NLR, PLR, and MLR levels, although it was significant for SII and SIRI. This might indicate that SIRI and SII, as composite indicators, could reflect the relationship between inflammatory indicators and prognosis of patients in a more comprehensive and balanced way than NLR, PLR and MLR.
However, there are inevitable limitations to this study. First, because of the low prevalence of AGPGC, our sample size was small. Moreover, the single-center retrospective design might lead to potential bias. Secondly, as the first study to analyze inflammation-related peripheral blood indicators and prognosis of patients with AFPGC, the references for cutoff values of inflammatory indicators are not yet available. In order to be able to use these indicators in clinic, more retrospective, and prospective studies are needed to validate the best cutoff values.
CONCLUSION
Compared with that in AFP- patients, the level of inflammation-related peripheral blood markers was significantly higher in AFP+ patients which was correlated with OS of AFP+ patients. Also, the gradual increase in SII and SIRI was associated with the risk of death within one year in AFP+ patients. AFPGC should be considered as a separate type of GC and distinguished from AFP-GC because of the difference in tumor immune microenviroment. Further laboratory research and studies with large clinical samples are recommended to understand AFPGC in detail.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Oncology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade C
Novelty: Grade B
Creativity or Innovation: Grade B
Scientific Significance: Grade B
P-Reviewer: Dilek ON S-Editor: Li L L-Editor: A P-Editor: Yuan YY
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