Tumor-associated Neutrophils and Malignant Progression in Intraductal Papillary Mucinous Neoplasms: An Opportunity for Identification of High-risk Disease.

Abstract

To evaluate the association of tumor-associated neutrophils (TANs) with malignant progression in intraductal papillary mucinous neoplasms (IPMNs) and to study the cyst fluid from these lesions for biomarkers of the inflammation-carcinogenesis association. There is a strong link between TANs and malignant progression. Inflammatory mediators released by these cells may be a measurable surrogate marker of this progression. We evaluated 78 resected IPMNs (2004-2013). Lesions were divided into the low-risk (low- and intermediate-grade dysplasia: n = 48) and high-risk (high-grade dysplasia and invasive carcinoma: n = 30) groups. TANs were assessed and categorized (negative, low, and high). A multiplexed assay was performed to evaluate 87 different cyst fluid proteins, including cyst fluid inflammatory markers (CFIMs), as possible surrogate markers for parenchymal inflammation. Significant positive correlation between grade of dysplasia and TANs was found. High levels of TANs were identified in 2%, 33%, and 89% of the lesions when stratified by grade of dysplasia into low/intermediate-grade dysplasia, high-grade dysplasia, and invasive carcinoma, respectively (P < 0.001). Higher grades of dysplasia were also found to have positive correlation with 29 of the measured proteins, of which 23 (79%) were CFIMs. Higher levels of TANs correlated with higher levels of 18 CFIMs, of which 16 (89%) were also found to be associated with higher grades of dysplasia. In this study, TANs were strongly associated with malignant progression in IPMNs. Measurement of CFIMs may be a surrogate marker for IPMN progression and allow for the identification of high-risk disease.