Pancreatic cystic neoplasms (PCNs) are a group of tumors characterized by cystic lesions formed by pancreatic duct epithelial cells or acinar hyperplasia and retention of pancreatic secretions (1). The latest “European guidelines” suggest that PCN detection rates in the general population range from 2% to 45% (2), and the incidence rate of patients aged 70 years or above reaches 10% (3). PCNs mainly include three clinical subtypes as follows: intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), and serous cystic neoplasms (SCNs). Among them, SCNs has no malignant potential and rarely requires surgical treatment. MCNs may deteriorate and are potential malignant tumors that can show a series of biological behavior processes of different degrees of dysplasia and finally to invasive cancer (1). Moreover, due to the differences in biological behavior and the degree of benignity and malignancy between different subtypes, overtreatment or untimely diagnosis and treatment can easily occur, which makes the diagnosis and treatment of PCNs a difficult problem in the clinic. Therefore, there is an urgent need for an accurate preoperative assessment of the benign and malignant degree of PCNs to facilitate subsequent rational clinical treatment. Pathological diagnosis is the gold standard for identifying the nature of PCNs, but it is an invasive operation that causes unnecessary damage to the patient, resulting in certain limitations in clinical application (4).

Numerous studies have shown that laboratory examination is becoming increasingly important to help diagnose PCNs and to distinguish between benign and malignant PCNs. Inflammation plays a key role in the occurrence and progression of tumors. The systemic inflammatory response acts on the occurrence and development of malignant tumors by releasing cytokines and other inflammatory mediators (5–7). Some inflammatory markers based on circulating blood cells can be used as a simple and convenient way to measure the systemic inflammatory response and as independent predictors of survival in a variety of malignancies, including pancreatic cancer (8–10). Recently, there has been much evidence that inflammatory indices, such as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), also play an important role in predicting benign and malignant PCNs (11–13). Tumor markers can reflect the ability of tumor proliferation and metastasis to a certain extent. Studies in recent years have shown that cyst fluid carcinoembryonic antigen (CEA) and cyst fluid carbohydrate antigen 199 (CA199) in PCNs provide great accuracy in distinguishing mucinous and non-mucinous PCNs (14), while the identification value of CEA and CA199 in blood needs to be further studied. The purpose of the present study was to investigate the application value of CEA, CA199, and various inflammatory indicators in the blood in the differential diagnosis of SCNs and MCNs.

SCNs and MCNs have different biological characteristics. SCNs are usually benign with only 1% to 3% malignant potential (16), and they can be followed up (17), while MCNs have malignant potential, and surgical resection is recommended after adequate diagnosis (18, 19). Therefore, correctly distinguishing SCNs from MCNs is of great significance for appropriate treatment. Although there are many better methods for preoperative identification of SCNs and MCNs, such as contrast-enhanced endoscopic ultrasonography (20), endoscopic ultrasound-guided fine-needle aspiration of pancreatic cysts (21), and lesion punctures with fluid aspiration followed by through-the-needle biopsies (22), these methods are either invasive or expensive. Therefore, there is an urgent need to find non-invasive, convenient, and inexpensive tests for differential diagnosis.

In this study, the baseline data of the included patients indicated that there were more female patients with SCNs and MCNs than male patients, and the lesions were mostly located in the body or tail of the pancreas, which is consistent with previous research reports (23). At present, many studies have shown that cyst fluid CEA has a good diagnostic effect in differentiating SCNs and MCNs, while blood CEA has a poor diagnostic effect (24). Similarly, the results of the present study also showed that there was no significant difference in serum CEA levels between the SCN group and the MCN group. In contrast, serum CA199 showed good discrimination efficiency. In the present study, the ROC curve was generated, which demonstrated that when serum CA199 was higher than 31.315 U/ml, the occurrence of MCNs was indicated with a sensitivity and specificity of 0.4773 and 0.9143, respectively. The serum tumor marker, CA199 (a tumor-related carbohydrate protein), plays an important role in the diagnosis, treatment, and postoperative follow-up of pancreatic cancer. Increasing evidence indicates that serum CA199 levels play an important role in differentiating the benign and malignant properties of PCNs (25–27). Postlewait et al. (28) analyzed the preoperative blood CA199 level of 349 cases of MCNs and found that the median CA199 level in the malignant group was 210 U/ml; in the nonmalignant group, the median CA199 level was only 15 U/ml (p = 0.001), suggesting that the elevated level of serum CA199 indicated malignant MCNs, which was consistent with the results of the present study.

Recent studies have shown that not only the internal characteristics of tumor cells but also the host inflammatory response determine the occurrence and development of tumors (29). In patients with malignant tumors, host factors, such as weight loss, malnutrition, and systemic inflammatory response, are interrelated, and systemic inflammatory response can be used as a predictor of benign and malignant tumors (30). Some inflammatory indicators (NLR, PLR, and LMR) based on circulating blood cells can be used as a simple and convenient way to measure systemic inflammatory response and as an independent predictor of survival and prognosis in various malignant tumors, including pancreatic cancer (8–10). Recently, there has been much evidence that inflammatory indicators also play an important role in predicting benign and malignant PCNs (12, 13, 31). Our study discovered that LA had good discrimination efficiency between SCNs and MCNs with an AUC of 0.6765 and a diagnostic cutoff point of 65.45. Thus, LA values <65.45 indicate MCNs. Although the potential causal effects behind the association between LA and differential SCNs and MCNs are unclear, the following hypotheses can be proposed. The high density of tumor-infiltrating lymphocytes is closely related to the good prognosis of several cancers, indicating that the antitumor immune response is mainly mediated by lymphocytes (32). Serum ALB is produced by the liver and is known as one of the negative acute phase proteins in response to inflammation. In addition, low ALB concentrations also indicate malnutrition, which can negatively affect tumor immunity in the microenvironment. Given these findings, LA may reflect both the immune response, as represented by lymphocyte count, and nutritional status, as represented by serum albumin levels.

When the two risk factors mentioned above are present at the same time, it indicates a higher risk of MCNs. Surgical treatment and regional pancreatectomy according to imaging results can be considered. In addition, intraoperative frozen pathological results should be considered to prevent more extensive pancreatic parenchymal invasion. Therefore, the present study provides clinicians with a simple, effective, and non-invasive method to identify SCNs and MCNs, thereby facilitating the management and treatment of PCN patients.

The present study had several limitations. First, this study was a retrospective analysis. Only cases with PCNs clearly indicated by surgical pathology or EUS-FNA cytopathology were included, which may have led to selection bias. In addition, due to the limited sample size, we failed to analyze the differential value of these indicators in other types of PCNs, and the predictive efficacy of CA199 and LA still needs to be verified in future clinical work. Importantly, there are an increasing number of studies on PCNs that are exploring the risk factors for the preoperative prediction of malignant PCNs. For clinicians, comprehensive analysis of various risk factors before surgery and accurate balance between the risk of surgery and the risk of malignancy will bring maximum benefits to patients with PCNs.

In conclusion, as a non-invasive method, tumor markers and inflammatory indicators can complement each other, and joint detection can play an important role in distinguishing SCNs and MCNs. The present study found that serum CA199 and LA can be used independently in the differential diagnosis of SCNs and MCNs. It is worth noting that this is the first report that reveals the value of LA in identifying SCNs and MCNs. The new marker is easily evaluated by routine blood tests, which could provide an opportunity for further investigation.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethical approval/written informed consent was not required for the study of animals/human participants in accordance with the local legislation and institutional requirements.

HW and SC performed this study and wrote the manuscript as co-first authors; XS and ZL checked the statistics; PL and YoZ revised the manuscript; HX and YoZ designed this study and edited the manuscript. All authors contributed to the article and approved the submitted version.

This study was supported by the National Natural Science Foundation of China (No. 82060108) and the Youth Project of the Jiangxi Natural Science Foundation (20202BABL216007).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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