The diagnosis and clinical management strategies of them still remains controversial currently because of the absence of factors that predict malignancy clearly [23]. Tumor biomarkers, such as CEA and CA19-9, were also used to predict the malignancy [5]. Our study demonstrated a reverse association between HDL-c and IPMN. Low HDL-c in malignant IPMN were significantly higher than non- malignant IPMNs. Multivariable logistic analysis further showed that low HDL-c was associated with occurrence of malignant IPMN. In addition, the combination of mural nodule and low HDL-c showed higher performance than mural nodule alone or combination of mural nodule plus cyst size in predicting malignant BD-IPMNs. Low HDL-c may be a potential biomarkers for malignant IPMNs.
An inverse relationship between serum total cholesterol levels and cancer risk has been reported [24–26]. Moreover, the associations between HDL-c and cancer risk, disease free survival (DFS) or overall survival (OS) have been reported in many malignancies [11, 16–22, 27]. Low HDL-C levels were associated with high TNM stage and occurrence of distant metastasis [28]. It is noteworthy that, in several studies, the HDL-c had shown the reverse correlation with the gastrointestinal cancer. The randomized controlled intervention studies showed [21] that the inverse associations of HDL-c with pancreatic cancer were not materially affected by other lipids, and the inverse association was unchanged after exclusion of the first 3 years of follow-up. Michalaki et.al [22] reported that serum HDL concentration was significantly lower in pancreatic cancer patients than in the controls. Serum apolipoprotein A-II, transthyretin, and apolipoprotein A-I were also decreased at least 2-fold in pancreatic cancer compared with the control group [29].HDL-c levels were inversely associated with the risk of developing liver cancer [17], and pre-operative HDL-c levels was associated with the risk of cancer recurrence [18]. Patients in the lowest quintile of HDL-c (< 30 mg/dL) had a 11.6-fold higher risk of gallbladder cancer and a 16.8-fold higher risk of bile duct cancer, relative to the reference group [20]. Moreover, alteration for HDL levels may be a therapeutic strategy for cancer [30]. However, the association between HDL-c and malignant IPMNs has not been clarified.
Interestingly, our data showed that low serum HDL-c was an independent risk factor for malignancy in IPMN both in training population and validation population even after adjustment for confounding factors. In addition, the diagnostic performance of mural nodule plus MPD diameter and low HDL-c was similar with mural nodule plus MPD diameter and CA19-9. Management of BD-IPMNs remains challenging[31]. Few biomarkers have been used to identify malignancy in BD-IPMNs. Our data showed that low serum HDL-c improved the diagnostic performance of mural nodule in predicting malignant BD IPMN. The AUC was increased from 0.71 to 0.81. Interestingly, we also observed a reverse association between low HDL-c (< 0.8 mmol/L) and grade 3 pancreatic neuroendocrine neoplasms (PNENs) (n = 197, OR = 2.37, 95%CI: 1.001–5.62, data not shown). These data further support that low HDL-c is associated with malignant pancreatic diseases. However, conflicting evidence was also reported between HDL and cancer incidence or mortality because this association may be tumor-type-dependent [30]. Anyway, there is increasing evidence that supports this association [30].
The possible mechanism of HDL on cancer development or progression has not been totally clarified. HDL-associated proteins may have antioxidant, anti-inflammatory, anti-angiogenesis, and immunomodulatory activities which can result in anti-tumorigenesis effects [27]. In addition, cancer cells expressed high level of scavenger receptor type B-I (SR-BI) which can promote lipid internalization and lipoprotein consumption by cancer cells [31]. Meanwhile, a large amount of cholesterol is demanded in cancer cells because of the formation of new membranes [31]. Consequently, low levels of circulating HDL-c occurred.
Our study has several limitations. First, the sample size was relatively small, especially for number of malignant IPMNs or carcinoma in BD-IPMNs. Second, it would be better to perform a longitudinal study to show the baseline serum HDL-c and developing malignant IPMNs. Third, whether low HDL-c level is a consequential or causal factor in malignant IPMNs need further exploration. Fourth, some confounding factors were not considered, such as lifestyle and diet habits. Finally, HDL-associated proteins and enzymes were not easily affected by covariates. We did not observed the association between malignant IPMNs and them. Our study is an exploration.
In conclusion, our data shows that low HDL-c is associated with malignant IPMNs. Low HDL-c may be a potential biomarker for identifying malignant IPMNs. Moreover, HDL-c may improve the predictive ability of malignancy in BD-IPMNs. Prospective study is needed to evaluate the role of HDL-c in malignancy of IPMNs.