Association of preoperative low circulating basophil counts with the prognostic factor in gastric cancer

doi:10.21203/rs.3.rs-5011542/v1

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Research Article

Association of preoperative low circulating basophil counts with the prognostic factor in gastric cancer

https://doi.org/10.21203/rs.3.rs-5011542/v1

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Purpose

Basophils play a crucial role in immunoglobulin E-mediated allergic reactions and parasitic infections. Recently, a low basophil count was reported to be a poor prognostic indicator in patients with malignant tumors. This study aimed to investigate the cut-off value to evaluate the clinicopathological and prognostic significance of the basophil count in patients with gastric cancer.

Methods

This study enrolled 1192 consecutive gastric cancer surgically treated between 2001 and 2020. The cut-off values were fixed at 26/µl based on the receiver of characteristics curves for overall survival, and 606 patients were classified as the low basophil group. The clinicopathological and prognostic significance of the low basophil count was assessed by univariate and multivariate analyses

Results

Elderly age (p = 0.009), high C-reactive protein level (p < 0.001), and low neutrophil count (p < 0.001), are independently associated with low basophil count. The low basophil group demonstrated a significantly worse overall survival than the high basophil group (p = 0.005). Although there was no significant difference in stage I, the low basophil group demonstrated poor overall survival in stage II/III/IV. The low basophil count was an independent risk factor for poor overall survival (p = 0.042).

Conclusion

Low basophil count was significantly associated with elderly age, high C-reactive protein level, and low neutrophil count (< 26/µl). And, low basophil count was an independent poor prognostic factor in patients with gastric cancer. Thus, preoperative circulating basophil count assessment may be useful for predicting the postoperative survival of patients with gastric cancer.

Gastric cancer

Basophil count

Prognosis

Gastric cancer is the fourth and third leading cause of death globally and in Japan, accounting for approximately 800,000 and 40,000 deaths annually, respectively [1, 2].

Several studies reported the association between neutrophils, lymphocytes, and C-reactive protein (CRP) in gastric cancer [3–5]. A high neutrophil-to-lymphocyte ratio [6, 7], high CRP level [3, 8], and low lymphocyte count are considered poor prognostic factors [4], and an association between these factors and tumor growth and progression has been indicated. However, the fraction of basophils is very small; thus, only one study [9] reported on the clinicopathological significance of basophils in patients with gastric cancer. Basophil is a type of granulocyte and accounts for < 1% of white blood cells in peripheral blood. Basophil is involved in allergic diseases and parasitic infections by regulating immunoglobulin E -mediated reactions and type 2 immune responses through various mediators, including histamine, leukotriene C4, and interleukin-4 and − 13 [10].

Clinicopathological significance of circulating basophils in esophageal cancer [11], gastric cancer [9], and colorectal cancer [12–14] have been reported in gastrointestinal cancer. These previous studies revealed that low circulating basophil count was associated with poor prognosis other than gastric cancer. These reports analyzed mixed populations, including both surgical and non-surgical cases, and only one report focused on surgical cases [11]. Wu C et al. discussed that the high basophil count around the tumor cells was associated with poor prognosis in advanced and/or recurrent gastric cancer [9]. Such tendency was not similar in esophageal cancer [11] and colorectal cancer [12–14]. No studies analyzed the association between circulating basophil count and prognosis only focused on surgically treated gastric cancer.

Therefore, this study analyzed the clinicopathological and prognostic significance of preoperative circulating basophil count in patients with surgically treated gastric cancer to establish the cut-off value of basophil count as a derivation cohort.

Study population

A total of 1514 patients with primary gastric cancer underwent surgery at Toho University Omori Medical Center from January 2001 to December 2020. This retrospective study enrolled 1192 consecutive patients (811 males and 381 females with a median age of 68 years; range, 32–96 years) after excluding patients who received preoperative chemotherapy, those who had residual gastric cancer, and double cancer (Fig. 1). The cut-off value was determined to classify circulating basophil count as low group and high group based on receiving operating characteristic curves, and then clinicopathological factors and overall prognosis were compared between these two groups. All patients were followed up until the end of December 2020 or death. The median follow-up period was 48 (range: 0–60) months. The Ethics Committee of Toho University Omori Medical Center (#M23174 21320 21039 20200 20196 19056 18002) approved this study, conducted under the Declaration of Helsinki. Informed consent was obtained in the form of opt-out on the web-site. Those who rejected were excluded.

Circulating basophil count and pathological factors

We analyzed circulating basophil count through routine blood tests within 7 days preoperatively. The tumor, node, and metastasis stage [15] were determined by pathological diagnosis using resected specimens. Correlation between basophil count and clinicopathological factors, such as age, gender, tumor depth, lymph node metastasis, distant metastasis, liver metastasis, CRP, lymphocyte count, and neutrophil count, were evaluated. Tumor depth was classified into the T1T2 (M, SM) and T3T4 (MP, SS, SE, SI) groups. Lymph node, distant, and liver metastases were classified as negative or positive.

Statistical analysis

The cut-off value of basophil count was set at 26/µl based on receiving operating characteristic curves for overall survival (Fig. 2a). Univariate and multivariate analyses were performed to evaluate the clinicopathological and prognostic significance of low basophil count. The p-value was calculated using Fisher’s exact test for univariate analysis. Overall survival probabilities were calculated using the product limit method of Kaplan–Meier, considering overall deaths and the log-rank test was utilized to analyze the survival differences between the groups. The multivariate analysis calculated the odds ratio, 95% confidence interval, and p-value using a logistic regression analysis. EZR was used for all statistical analyses [16]. Two-sided p-values of < 0.05 indicated statistical significance.

The median basophil count of 1192 patients was 27/µl (0–368/µl). We fixed the cut-off value of the basophil count as 26/µl based on the receiving operating characteristic analysis(Fig. 2a). We classified 586 (49.2%) patients into the high basophil group and 606 (50.8%) patients into the low basophil group using the cut-off value (Fig. 2b).

Clinicopathological significance of low basophil count

Univariate analysis identified elderly age (p < 0.001), high CRP (p < 0.001), low lymphocyte count (p = 0.002), and low neutrophil count (p = 0.002) to be significantly associated with low basophil count (Table 1). Multivariate analysis determined elderly age (p = 0.009), high CRP (p < 0.001), and low neutrophil count (p < 0.001) to be significantly associated with low basophil count (Table 2).

Prognostic significance of low basophil count on overall survival

Univariate analysis of all patients revealed a significantly worse prognosis of the low basophil group than that of the high basophil group (p = 0.005, Fig. 3). The prognosis of both groups was almost similar, comparing the prognosis of both groups according to the stage, in stage I. However, the low basophil group demonstrated a worse prognosis than the high basophil group in stage II/III/IV (Fig. 4).

Univariate and multivariate analyses of the prognostic effect of low basophil count on overall survival

Univariate analysis revealed that elderly age (p < 0.001), T3T4 invasion depth (p < 0.001), lymph node metastasis (p < 0.001), distant metastasis (p < 0.001), liver metastasis (p < 0.001), high CRP (p < 0.001), low lymphocytes (p < 0.001), low neutrophils (p < 0.001), and low basophil count (p = 0.005) were significantly associated with poor overall survival. Multivariate analysis determined elderly age (p = 0.001), T3T4 invasion depth (p < 0.001), lymph node metastasis (p < 0.001), high CRP (p < 0.001), low lymphocyte count (p = 0.039), high neutrophil count (p = 0.028), and low basophil count (p = 0.042) as independent risk factors for poor overall survival (Table 3).

No study indicated the cut-off value of circulating basophil count in gastric cancer; thus, this study aimed to establish an appropriate cut-off value (< 26/µl) as the derivation cohort. We assessed the clinicopathological significance of preoperative circulating basophil count in surgically treated gastric cancer. Additionally, we revealed that low basophil count was associated with tumor progression. The low basophil count was an independent risk factor for poor overall survival. This study is the first to reveal an association between preoperative circulating basophil count and prognosis in surgically treated gastric cancer.

Other similar studies, indicated cut-off values for circulating basophil count at 25/µl (area under the curve = 0.669) in colorectal cancer [13] and 20/µl (area under the curve = 0.7208) in unresectable gastric cancer [9] based on receiver operating characteristic curves. This value was similar to the cut-off value set in our present study, so the cut-off value might be reasonable.

Peripheral blood cell count studies revealed low lymphocyte count [4] and high neutrophil count [17] as risk factors for poor prognosis in gastric cancer. Since basophils are negatively correlated with neutrophils, it is natural that low basophil counts are a poor prognostic factor. Our study revealed that low lymphocyte count, high neutrophil count, and low basophil count were independent poor prognostic factors. A significant correlation between low basophil, low lymphocyte, and neutrophil count was observed, which may reflect decreased hematopoietic function mainly due to aging. A significant correlation between low basophil count and high CRP level was observed because differentiation into neutrophils is prioritized during infiltration that causes high CRP levels, such as inflammation or infection.

The immunohistochemical analysis of previous reports revealed that a large number of basophils infiltrating the tumor was a poor prognostic factor in gastric cancer [9, 18]. Furthermore, it has been reported that there is a positive correlation between the infiltration of basophils into the tumor and the infiltration of M2 macrophages into the tumor in gastric cancer. Macrophages are known to promote tumor angiogenesis and distant metastasis [19, 20], suggesting that basophils may also be immunologically involved in the tumor microenvironment in gastric cancer. There are only limited reports on the relationship between the number of basophils in peripheral blood and the number of basophils infiltrating into the tumor, and it is not yet fully understood. Chronic urticaria is a typical disease in which the number of basophils in the peripheral blood decreases. In patients with chronic urticaria, the number of basophils in the peripheral blood decreases as basophils are recruited to the skin, which is the main site of inflammation. [21] Considering the biological response of patients with chronic urticaria, gastric cancer patients may also similarly decrease the number of circulating basophils due to an increase in the number of basophils infiltrating the tumor. Regarding the prognosis in unresectable gastric cancer who were treated with immunotherapy, the high basophil group demonstrated a worse prognosis than the low basophil group [9]. This contradicts our study results probably because the research participants were limited to recurrence and distant metastasis cases [9]. The prognosis of the high and low basophil count groups was very similar in stage I. This indicates that the low basophil counts did not have any effects on the other cause of death in stage I. The absence of a statistically significant difference in stage III/IV was due to the insufficient number of cases.

This study has some limitations. First, this is a retrospective single-center study. Second, this study did not investigate the patient’s history of immune diseases, vulnerabilities including bone marrow function, allergies, or use of immune-related drugs, including anti-allergy drugs and/or steroids. Third, this study included long periods of patients; thus, various adjuvant chemotherapy and systematic therapy after recurrence influenced the prognosis. The present study was a derivation cohort to fix the appropriate cut-off value of circulating basophil count. Further evaluation cohort is warranted to ensure the impact of circulating basophil count. Therefore, further multi-institutional studies are required to assess the effect of low circulating basophil counts on the survivals in patients with gastric cancer postoperatively.

In conclusion, low basophil count was significantly associated with high neutrophil count and high CRP level, but low basophil count was an independent poor prognostic factor in patients with gastric cancer. Thus, preoperative circulating basophil count assessment may be useful for predicting the postoperative survival of patients with gastric cancer.

Acknowledgments

The authors would like to thank MARUZEN-YUSHODO Co., Ltd. (https://kw.maruzen.co.jp/kousei-honyaku/) for the English language editing. We thank Seiko Otsuka for preparing the ethical　documents.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

Makiko Kawano, Hideaki Shimada, and Kimihiko Funahashi conceived and designed the current study. Makiko Kawano, Yoko Oshima, Fumiaki Shiratori, Takashi Suzuki, and Satoshi Yajima contributed to the acquisition of the patient’s clinicopathological data. Makiko Kawano and Yoko Oshima analyzed the patient data. Makiko Kawano and Hideaki Shimada drafted the manuscript. All authors read and approved the final manuscript.

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Faculty of Medicine, Toho University Omori Medical Center (Tokyo, Japan; #M23174 21320 21039 20200 20196 19056 18002).

Consent to participate

The participants were given the opportunity to decline to be enrolled in the study (opt-out).

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You are reading this latest preprint version

Association of preoperative low circulating basophil counts with the prognostic factor in gastric cancer

Status:

Version 1

Abstract

Purpose

Methods

Results

Conclusion

Figures

Introduction

Methods

Study population

Circulating basophil count and pathological factors

Statistical analysis

Results

Clinicopathological significance of low basophil count

Prognostic significance of low basophil count on overall survival

Univariate and multivariate analyses of the prognostic effect of low basophil count on overall survival

Discussion

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1