The results of this study demonstrated an association between elevated HbA1c, age and the presence of pancreatic cysts on initial surveillance imaging in HRIs.
The presence of IPMNs and pancreatic intraepithelial neoplasia (PanINs) indicates a risk of ductal cancer not only in the lesion itself but within the entire pancreas . A majority of patients with cysts in our study had sub-centimeter branch duct IPMNs, which is consistent with prior reports in HRIs . Pancreatic cancer surveillance programs have shown that up to 34% of HRIs ages 50–59 have pancreatic lesions, and this proportion increased to 54% in those ages 60–69 . The majority of these lesions are small (< 1 cm) branch duct IPMNs or PanINs, and are more commonly detected in HRIs than in the general population. Our study supports these data, demonstrating that pancreatic cysts are more commonly identified in older HRIs.
Prior studies have reported an association between older age and increased HbA1c levels in nondiabetic populations (HbA1c < 5.7%) . While our analyses do not argue against an association between increasing HbA1c and age, we focused on individuals at increased risk of pancreatic cancer. We have additionally sought to focus on whether impaired glucose metabolism, evidenced here by HbA1c levels above the prediabetic cutoff, are associated with the presence of pancreatic cysts in a unique cohort of individuals at high-risk of developing pancreatic cancer.
In HRIs, neoplastic progression has been described to occur more commonly in germline mutation carriers and individuals with multifocal cysts . In our study, 22 (29.7%) patients had multifocal cysts and 24 (32.4%) carried P/LP germline variants associated with pancreatic cancer. Mean surveillance in this study was 2.6 years. Therefore, our analyses focused on initial surveillance imaging studies; with a longer surveillance period, we will be able to determine if these factors and HbA1c levels predict neoplastic progression.
Tobacco is a known independent risk factor for pancreatic cancer . A recent study of HRIs has described an association between increased age and smoking history with the development of pre-malignant lesions or early pancreatic adenocarcinoma . Similar to their study, we found that increased age is associated with the development of cysts; however, we did not find that smoking was associated with precursor lesions such as IPMNs and PanINs. However, it is possible that among patients that smoke, pack-year tobacco exposure differed between the European and US-based studies. Further studies on the impact of tobacco exposure in HRIs are needed.
Two major causes of diabetes are pancreatic beta cell dysfunction and peripheral insulin resistance. However, type 3c diabetes is another form of diabetes caused by a variety of pancreatic diseases with varying mechanisms of hyperglycemia . Up to 80% of individuals with pancreatic cancer have evidence of impaired glycemic metabolism, and a diagnosis of new-onset diabetes has been associated with up to an 8-fold increased risk of pancreatic cancer [15, 25]. Elevations in fasting blood glucose may be apparent up to 36 months prior to a diagnosis of pancreatic cancer . Recent reports suggested that FPC kindreds have a similar abnormalities in their glycemic profile prior to the diagnosis of pancreatic cancer compared to those with sporadic pancreatic cancer . In this study, one patient with multifocal cysts went on to progress to adenocarcinoma associated with hyperglycemia. Our study provides additional support for further evaluation of glycemic profiles in HRIs to improve risk stratification .
Models to distinguish between pancreatic cancer-induced hyperglycemia and the prediabetes of type 2 diabetes mellitus have found that variables typically associated with increased risk of type 2 diabetes, including elevated BMI, hypercholesterolemia and hypertriglyceridemia, were associated with lower pancreatic adenocarcinoma risk . Others have noted that new-onset diabetes prior to pancreatic cancer development is associated with paradoxical weight loss . Multiple analyses have also demonstrated that obesity is associated with the development of pancreatic cancer [29,30,31]. In our study, we were not able to draw conclusions between BMI and cyst development in HRIs since the majority (86%) of our patients were found to be healthy or overweight. Future studies should address longitudinal changes in BMI and glycemic profiles in HRIs.
Other studies have evaluated the association between treatment for diabetes and overall survival in patients with pancreatic adenocarcinoma . For example, one study found that metformin, a biguanide oral hypoglycemic commonly used as first-line therapy in patients with diabetes, is associated with increased survival in patients with pancreatic cancer . Since only four of our subjects were found to be in the diabetic range (HbA1c ≥ 6.5%), we were unable to evaluate the impact of diabetes treatment in HRIs.
There are a number of strengths and limitations to this study. Although we assessed the presence of pancreatic cysts in HRIs, the presence of cysts does not suggest that these lesions will eventually progress into cancer. Additionally, as this study was retrospective in nature, we were not able to collect HbA1c and BMI values at the exact date of surveillance imaging. Patients were only included if they had HbA1c testing within one year of a clinical visit. However, one strength of this approach is that HbA1c data did not alter clinical decisions and prompt earlier investigations. We were not able to conduct a subgroup analysis in patients with worrisome features due to the small number of patients that fell into this category. Additionally, we do not have any information regarding differentiation of IPMN subtypes except for one patient who had a surgical resection. Since this study was conducted only in patients with a high risk of developing pancreatic cancer, the results are not generalizable to the general population.
At this time, HRIs with cysts in the setting of elevated HbA1c should continue surveillance under published guidelines [4, 18]. In newly established guidelines, there was expert consensus around the need for glucose testing (fasting glucose or HbA1c) to detect new-onset diabetes in HRIs. Additionally, there was consensus that the new emergence of diabetes in HRIs should prompt additional investigation . Further prospective surveillance data are required to evaluate risk factors for neoplastic progression in HRIs with cysts and elevated HbA1c.