Ampullary adenocarcinoma (AC) is a rare malignancy with an incidence of 0.73 cases/100,000 inhabitants, and only accounts for 0.2% of gastrointestinal tumors [1
]. It is suggested that AC is more frequent in male patients, with a wide age range of diagnoses [2
]. So far, surgical treatment, including the whipple procedure, is still the main curative strategy for AC patients. The 5-year survival rate of AC is lower than 45% in the resected patients, which indicates a heavy disease burden on patients with AC [3
In recent years, lipid metabolism in cancer has attracted a lot of attention [5
]. Lipids are hydrophobic molecules and consist of sterols, monoglycerides, diacylglycer-ides, triglycerides, phospholipids, and glycolipids. A number of lipids are originated from fatty acids (FAs), a diverse group of molecules including long hydrocarbon chains varying in length (number of carbon atoms) and saturation (number of double bonds) [6
]. As one of the most prominent metabolic alterations in cancer, dysregulation in lipid metabolism produces a vital impact on the energy acquisition, biological membrane formation, proliferation, survival, invasion, metastasis, and drug resistance of cancer cells [7
]. In daily clinical work, Serum lipids function as indicators to evaluate the status of patient lipid metabolism, including triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). Currently, several studies have determined that serum lipids aforementioned are significantly associated with the tumor progression and therapy in multiple cancer types, including lung cancer [10
], liver cancer [11
], breast cancer [12
], prostate cancer [13
], gastric cancer [14
] colorectal cancer [15
], and ovarian cancer [17
]. However, the exact impact of serum lipids on prognosis of AC patients is still unclear.
Given these considerations, the discussion on the influence of lipid metabolism on the AC patient survival can specify potential strategies for lipid metabolism, thus providing new insights for AC arrangement. As such, we conducted this study to determine the association between serum lipids and long-term prognosis (OS and RFS) of AC.
Lipid metabolism indicated by serum lipids (TC, TG, HDL-C, and LDL-C) is found to be involved in various important biological processes of cancer cells [20
], and the association between serum lipids and cancers has sparked debate in recent years [21
]. To the best of our knowledge, there is no study reported to have investigated the effects of serum lipids on the long-term prognosis of AC. In the present study, a high level of preoperative LDL-C was identified as a significant predictor for better RFS, which might produce a favorable impact on AC patients underwent curative surgical resection.
Previous studies and meta-analyses had investigated the roles of serum lipids (including TC, TG, HDL-C, and LDL-C) in the risk and prognosis of several cancer types. A significantly inverse association between high levels of serum lipids and risk of ovarian cancer [25
], colorectal cancer [23
], breast cancer [24
], lung cancer [26
], and non-hodgkin lymphoma [27
] was identified. Additionally, a systematic review and meta-analysis demonstrated that serum TC (HR = 0.82, 95% CI: 0.75–0.90) and HDL-C (HR = 0.63, 95% CI: 0.47–0.86) were protective factors for long-term prognosis in patients with cancer [28
]. As for LDL-C, previous studies revealed that patients with increased LDL-C seem to own a poor prognosis in lung cancer [29
] and ovarian cancer [17
], while a better prognosis was induced in gallbladder cancer [32
]. In the current study, multiple analyses mainly demonstrated that high levels of LDL-C and HDL-C were significantly associated with a better survival of AC patients (p
Compared with previous studies, evidence seems to support the favorable impact of high HDL-C and LDL-C levels on AC patients in this study. From the perspective of mechanism research, the role of HDL-C in cancer prognosis was potentially related to the mechanisms as following. Firstly, tumor-associated macrophages (TAMs) include M1-TAM and M2-TAM that inhibits and promotes the tumor growth, respectively. HDL-C has an immunomodulatory effect of converting M1-TAM to M2-TAM [33
]. In addition, HDL-C also induces multiple alterations at the cellular level, such as cholesterol exhaustion in TAM, thereby weakening the tumor promoting effect of TAM [34
]. Moreover, serum lipids are observed to enhance the anti-inflammatory effect of neutrophil, the activation of CD8+T cell, and the survival of CD4+T cell, and inhibit tumor progression by strengthening the anti-tumor immune response [35
]. Secondly, in inflammatory TME, HDL-C can suppress tubulogenesis and endothelial cell migration by downregulating the expression of VEGF, VEGFR2, and TNF-α, thereby inhibiting pathological angiogenesis [36
]. In hypoxic TME, HDL-C can also promote the phosphorylation of VEGFR2 to enhance angiogenesis through the p38 MAPK signaling pathway [37
]. Thirdly, in addition to anti-inflammatory and immune regulation, HDL-C also has antioxidant effects, which can maintain intracellular cholesterol homeostasis, regulate signal transduction and cell proliferation, thereby being a protective factor for cancer patients [38
Regarding LDL-C, several studies have concluded that it had an unfavorable impact on the prognosis for cancer patients because of its oxidant effects [30
], while views also exist that a low-level of LDL-C also tended to be associated with an increased cancer deaths [39
]. The cause for perspectives of the latter originated from the observation in early retrospective epidemiological studies, such as the one from the Seven Countries Study published by Pekkanen et al., which demonstrated a reverse association between LDL-C and incidence of cancer [40
]. Nevertheless, the early study from western society concerning this view had its limitations: the number of patients with low cholesterol levels was too limited to make the study balanced and comparable. Afterwards, a study based on the Chinese population was conducted by Chen et al. to investigate the same subject. They excluded patients dying in the first 3 years and the result demonstrated that patients with a lower cholesterol level had an increased incidence and mortality for liver cancer. In 2007, a larger scale study published by Iribarren et al. further completed a similar investigation. The cholesterol of 5941 men without history of coronary heart disease, stroke, cancer, and gastrointestinal-liver disease was prospectively tracked over 6 years. The risk factor adjusted all-cause mortality rate of those with lower cholesterol was demonstrated to increase by 30%. Meanwhile, the increased risk of mortality was analyzed to be induced by hematopoietic, esophageal, and prostate cancers and multiple non-cancer non-cardiovascular causes, particularly liver disease [41
]. Multiple trials also drew a conclusion that there was a significantly inverse relationship between incidence of cancer and the achieved LDL-C level of patients taking statins [42
]. This evidence functions as support for results of the present study. Additionally, LDL-C level was observed to be higher in AC patients without vascular invasion, suggesting that higher LDL-C level may reduce the risk of vascular invasion in our analysis, thereby accounting for the results as well.
There are also some limitations in this study that need to be taken into account. Firstly, this was a retrospective cohort study and therefore subject to various biases. Meanwhile, the sample size of this study was relatively small due to the rarity of AC. Secondly, except for major serum lipids including TC, TG, HDL-C, and LDL-C, several other alterations reflecting lipid metabolism were not included in the current study, such as Apo A1, Apo B, and Lp (a). The lack of these data may lead to a neglect of an opportunity to discover new insights. Thirdly, serum lipid levels were only tested preoperatively, so we were unable to further investigate the prognostic impact of changes in serum lipids dynamics. However, the strengths also should not be ignored that the present study was the first to discuss the impact of serum lipids on the prognosis of AC. In addition to the effects of serum lipids on the survival, we also compared the levels of serum lipids in different groups divided by various aggressive factors, and these differences may further suggest the reason for the impact of serum lipids on the prognosis of patients with AC. In addition, we controlled for the confounding factor of the application of lipid-lowering drugs, which makes our results more reliable. We hope this research can bring new insights in arrangement of AC patients to clinical workers.