A new combined criterion to better predict malignant lesions in patients with pancreatic cystic neoplasms

Introduction

The detection rate of pancreatic cysts has increased dramatically owing to the universal use of cross-sectional imaging modalities^1,2. Pancreatic cystic neoplasms (PCNs) account for approximately 10%–15% of all pancreatic cystic lesions^1,3 and approximately 1% of all pancreatic neoplasms³. PCNs include three distinct common tumor types: serous cystic neoplasm (SCN), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm (MCN)^4,5. IPMN and MCN are believed to potentially lead to pancreatic ductal adenocarcinoma, whereas SCN is almost always benign^4,6,7.

Some PCNs undergo malignant transformation, and detection thus provides an opportunity to surgically cure or prevent pancreatic adenocarcinoma⁸. In current clinical practice, evaluation of the benign or malignant status of PCNs remains a major challenge. Surgery is recommended for all suitable patients with suspected PCNs^9,10. However, it is important to consider that pancreatic surgery is risky, and the possibility of major postsurgical complications (as well as of long-term impairment of pancreatic function) is non-negligible^11,12. The risk of over-treatment (unnecessary pancreatectomy) should be balanced carefully with the risk of under-treatment (missing the opportunity to cure a potentially curable malignant or premalignant lesion)⁴. The differentiation of a potentially malignant cystic neoplasm from other benign neoplasms prior to surgery plays an important role in treatment planning^13,14. Use of a combined diagnostic method is recommended not only for preoperative diagnosis, to reduce the performance of unnecessary surgery in patients with observable progress, but also to prevent surgical delay when appropriate⁹.

Unfortunately, based on current guidelines, diagnosis and management of PCNs is a clinical challenge¹⁵. Preoperative diagnosis of pancreatic cysts is largely reliant on radiographic and clinical features and lacks both consistency and sensitivity¹⁶, particularly for non-symptomatic cystic neoplasms of the pancreas. In many cases, PCNs have characteristic morphological imaging features that can inform diagnosis¹⁷. However, it is often difficult to accurately differentiate these lesions due to morphological overlaps in imaging between benign and malignant forms¹⁸. For example, up to one-fifth of pancreatic cystic lesions resected for malignancy, even in high-volume medical research centers, were confirmed to be benign on final pathology¹⁹. Misdiagnosis often leads to unnecessary surgeries with associated complications^4,17. As accurate differentiation among types of pancreatic cysts remains impossible with abdominal imaging, considerable effort has been made toward development of improved combinational diagnostic methods.

A variety of diagnostic imaging modalities are routinely used, such as contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI), contrast-enhanced ultrasound (CEUS), and endoscopic ultrasonography (EUS) with cystic fluid aspiration¹⁶. Recently, studies have reported similar diagnostic accuracy among CT, MRI, and CEUS in the characterization of pancreatic cystic masses^20–23. Radiologic features, including the size, density, and location of the lesion; wall characteristics such as septations; nodules; and calcification, have been suggested as potential categorization criteria for the lesions²⁴. However, the ideal test has not yet been identified^20,25.

The serum tumor markers carbohydrate antigen19-9 (CA19-9) and carcinoembryonic antigen (CEA) have both been shown to be relatively adequate diagnostic and prognostic predictors for malignant PCNs²⁶. However, CA19-9 appears to be a better predictor of malignancy. These markers assist in the identification of potentially malignant PCNs that require resection. Host inflammatory responses to types of cancers have been indicated to be correlated with tumor progression^27,28. Neutrophil-to-lymphocyte ratio (NLR) is a simple and convenient index of systemic inflammation. Elevated pretreatment NLR was identified as an independent prognostic factor correlated with poor prognosis in patients with several types of malignancy^29,30. Studies have reported that elevated NLR correlates with poor prognosis in patients with pancreatic cancer undergoing curative resection and bypass surgery^31,32. However, the relationship between NLR and the pathological characteristics of PCNs has not been sufficiently elucidated. The purpose of this study was to examine whether a combination of NLR with other factors could better predict malignancy of PCNs.

Patients and methods

Results

Correlation between clinical characteristics and PCN malignancy

According to pathology results, the patients were divided into benign and malignant groups. Sex could not be considered a predictor of malignancy in the patients with PCNs. Tumor location between body or tail of the pancreas and older age were significantly associated with malignancy (P=0.005, P=0.002, respectively) (Table 1). Symptoms at admission were recorded more often in the malignant group (31/41; 75.6%) (P=0.009). Preoperative serum CA19-9, CA242, and CEA levels were closely associated with PCN malignancy (P<0.001,P<0.001, andP=0.010, respectively) (Table 1).

Representative pathology and images of both benign and malignant lesions are shown in Figure 1. Patients with malignant PCNs had a higher probability of exhibiting enhanced solid components on CT images (P<0.001) (Table 1). It is unsurprising that the presence of an enhanced solid component is strongly associated with malignant PCNs.

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1

(A) A 69-year-old asymptomatic woman with pancreatic body-tail cyst incidentally found by routine examination. (1) Computed tomography (CT) scan shows 8 cm cyst at body-tail of pancreas. (2) Axial contrast-enhanced CT image in portal venous phase demonstrates a large nonenhancing mass in pancreas (arrow). (3) Serous cystic neoplasm (SCN) confirmed by pathology (IHC staining, 20 x). (B) A 48-year-old woman with upper abdominal pain. (1) Computed tomography (CT) scan shows 7 cm cyst at body-tail of pancreas. (2) Axial contrast-enhanced CT image in portal venous phase demonstrates a large enhancing mass in pancreas (arrow). (3) Invasive mucinous cystic neoplasm (MCN) confirmed by pathology (IHC staining, 20 x).

To determine whether NLR prior to surgery was predictive of malignant potential, we compared the preoperative NLR in 124 patients with benign PCNs with that in 41 patients with malignant PCNs. The NLR of patients with benign PCNs (1.87±0.84) was significantly lower than that of patients with malignant PCNs (2.81±2.14, P=0.009). Furthermore, we compared peripheral blood NLR in patients with benign PCNs, malignant PCNs, PNET, PDAC, and IgG4-related sclerosing pancreatitis, with that in healthy controls (Figure 2). The NLR in patients with malignant PCNs was similar to that in patients with PDAC (P=0.640), and was significantly higher than that in patients diagnosed with PNET (1.90 ± 0.69, P=0.013) or in healthy donors (1.40 ± 0.48; P<0.001). NLR in patients with malignant PCNs and PDAC was higher than that in healthy volunteers, indicating that the increase in NLR might be caused by tumor microenvironment.

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2

Distribution of NLR in 603 patients with various types of pancreatic disease is shown. NLR values are compared among these groups. Healthy volunteers (n=330), PDAC: pancreatic ductal adenocarcinoma (n=49), PNET: pancreatic neuroendocrine tumor (n=44), IgG4: IgG4-related sclerosing pancreatitis (n=15), benign PCNs in the study (n=124), malignant PCNs in the study (n=41). *P<0.05, **P<0.01.

Independent factors predicting malignancy in PCNs

The optimal cut-off value of NLR for predicting malignant PCNs was 1.976 (AUC=0.673, Figure 3). Patients were divided into a low NLR group (NLR≤1.976; n=96) and a high NLR group (NLR >1.976; n=69). To evaluate the utility of NLR prior to surgery in identifying patients with malignancy, logistic regression analysis was performed with clinical parameters including NLR (Table 2). Univariate analysis showed that high NLR (>1.976), older age (>56 years), high CA19-9 (≥39 U/mL), high CEA (≥5 ng/dL), high CA242 (≥12 U/mL), presence of enhanced solid component, and tumor location in the body or tail of pancreas were all significantly associated with malignancy. Multivariate analysis revealed that high CA19-9 (≥39 U/mL), presence of enhanced solid component, and high NLR were independent predictors of PCN malignancy.

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3

Optimal NLR value for predicting malignant PCNs. Receiver operating characteristic (ROC) curve analysis for determining NLR cut-off value predictive of malignant PCNs is shown. Curved line shows ROC curve. AUC: area under the curve, COV: cut-off value.

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2

Univariate and multivariate analysis for predicting malignancy in PCNs

Clinical utility of NLR and the new combined criterion

Next, we aimed to identify whether NLR could be a supportive index to predict malignancy of PCNs when combined with other conventional indicators. The distribution of NLR value, serum CA19-9 level, presence of enhanced solid component, and the presence of PCN malignancy is shown in Figure 4. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for predicting PCN malignancy were evaluated with the combined criterion of NLR>1.976, abnormal serum CA19-9 level, and presence of enhanced solid component. The sensitivity, specificity, PPV, NPV, and accuracy of the new diagnostic criterion for predicting PCN malignancy are shown inTable 3, in comparison with each conventional indicator of PCN malignancy. Furthermore, the sensitivity, specificity, PPV, and NPV predicted by the new criterion were 68.8%, 93.2%, 80.5%, and 87.9%, respectively. The new criterion demonstrated both a high PPV of 80.5% and a high NPV of 87.9%. Thus, a higher accuracy (86.1%) in identifying malignancy could be obtained with the new diagnostic criterion.

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4

High NLR level is associated with the presence of malignant PCNs. Distributions of NLR level and serum CA19-9 level, presence of enhanced solid component, and presence of malignant lesions in patients with PCNs (n=165) are shown. Each bar chart shows the patient's NLR value, and lower heat map shows if patient meets the criterion. Red arrow shows the high NLR group (>1.976).

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3

The sensitivity, specificity, positive predictive value (PPV), negative predictive values (NPV) and accuracy for predicting PCNs malignancy of NLR, CA19-9, presence of enhanced solid component and combined criterion are all shown

Discussion

PCNs are now more frequently discovered with the increased use of abdominal CT imaging³³. Some of these neoplasms undergo malignant transformation^8,34. Therefore, considering the current efficacy of pancreatic resection, it is not surprising that the number of operations for PCNs has increased. Pancreatic resection can remove symptomatic, malignant, or potentially malignant lesions. However, some cystic lesions are benign or slow growing, and their potential for malignant transformation remains unclear³³. Recent studies have shown that only one-fifth of the resected asymptomatic pancreatic cysts are malignant³⁵. Surgeons require a rapid and accurate assessment of the risk benefit ratio of observation versus resection of these neoplasms in individual patients.

Serous cystadenomas, which are often located in the body or tail of the pancreas, occur most commonly in middle-aged women. In contrast, IPMN occurs more frequently in the pancreatic head in elderly male patients, and mucinous cystadenomas occur mostly in elderly females^34,36. In our results, sex could not be considered a predictor of malignant PCN. Patients with benign MCN have a median age of 50 years, whereas patients with mucinous cyst adenocarcinoma have a median age of 65 years³. Other studies reported that patients with malignant cysts were older than patients with benign cysts, with statistical significance^16,37. This observation is consistent with our findings that age is correlated with malignant cystic pancreatic neoplasms.

Medical consensus suggests 3 cm as the cut-off value for resection of asymptomatic lesions⁸. On the other hand, large numbers of studies have reported that cyst size had little correlation with pathological malignant traits³⁵. Sarr et al.³⁸ reported no difference in the mean size between benign mucinous cystadenoma and mucinous cystadenocarcinoma. Lee et al.³⁹ found that 19% (31/166) of cystic pancreatic tumors <3 cm proved to be malignant. In the present study, lesion size was also not predictive of malignant cysts. However, we found that tumor location was a predictive factor of malignant PCNs. Lesions located in the body or tail of the pancreas were more likely to be malignant.

Owing to the morphological overlap in imaging, and poor inter-observer consensus in relation to the standards between benign and malignant PCNs, CT images allow correct characterization of only 25%–60% of cystic pancreatic masses⁴⁰. Numerous researchers have reported that the presence of solid component inside the cyst on imaging is a significant predictor of malignancy⁴⁰. In the present study also, the most significant radiological finding correlated with malignancy was the presence of enhanced solid component. Moreover, the presence of enhanced solid component was found to be an independent predictor in multivariate analysis.

In clinical practice, CA19-9 and CEA are two of the important biomarkers for patients with pancreatic malignant diseases⁴¹. Serum CA19-9 level is elevated in more than three quarters of patients with pancreatic ductal adenocarcinoma⁴². These biomarkers were found to be correlated with the presence of malignancy. An increased level of CA19-9 was found to be specifically correlated with malignant PCNs. Thus, CA19-9 is considered to be a vital test for all patients, a finding consistent with the results of other series⁸. However, although the specificity of serum CA19-9 is high, its sensitivity has been shown to be very low⁴². Some researchers have suggested that endoscopic ultrasound with fine-needle aspiration (EUS-FNA) and cystic fluid analysis hold promise in identifying lesions with malignant potential⁴³. EUS is not always accessible, however, particularly in rural areas where the equipment for distinguishing malignant lesions from benign PCNs is not available⁴⁴. Limitations to the access of EUS indicate that clinicians must rely on other noninvasive techniques to assess the risk of PCN.

Various investigations of NLR have been performed in various types of cancer, considering its role in the prediction of cancer development^29,45. A strong connection between neutrophil infiltration and malignant progression has been described by inflammatory mediators released by peripheral blood cells, which play a vital role in the intersection between neoplastic and inflammatory cells⁴⁶. Recently, it was reported that tumorigenesis in the pancreas correlates with distinct intra- and peri-tumoral inflammation⁴⁷. Thus, despite its non-specificity, increased NLR might be indicative of increased inflammatory activation in PCN-derived malignancies. The present study demonstrated that NLR is significantly higher in patients diagnosed with malignant PCNs than in those with benign lesions. As there was a remarkable difference in NLR value between healthy volunteers and patients with malignant PCNs, NLR might be important for monitoring malignant progression of PCNs. Intriguingly, in our study, we found that the cut-off value of NLR >1.976 was an independent predictor for the malignant potential of PCNs. Other studies selected different cut-off values of NLR^48,49, but these findings all indicate that high NLR is a supportive predictor of malignancy in PCNs.

The conventional guidelines for the diagnosis of malignancy of PCNs were unsatisfactory and complex, owing to the variety of predictors and their ambiguity. Preoperative prediction of malignancy often depends on the surgeon’s experience or other important factors that are difficult to clearly ascertain and have low PPV and NPV⁵⁰. The new combined criterion is a quantitative standard that is more accurate, practical, and convenient for all surgeons. Therefore, we recommend the diagnosis of malignancy of PCNs on the basis of CA19-9, NLR, and CT imaging.

In conclusion, we defined a new combined criterion to predict malignancy in patients with PCNs. The combined accuracy for predicting malignant PCNs was superior to that of any one of the abovementioned three standards. This criterion is superior to current practice in the identification of patients with malignant lesions in PCNs. It is important to distinguish benign from malignant lesions to select individuals who would benefit from early surgery.