Simple SummarySmoking, chronic obstructive pulmonary disease and obstructive sleep apnea have been recognized as risk factors for the development of cancer. We aimed to analyze the association between patients’ respiratory background and various pancreatic pathologies in patients that underwent a curative-intent resection of the pancreatic head. Using retrospective data from a prospectively maintained database sourced from a high-volume single center, smoking was identified to be strongly associated with pancreatic cancer and inflammatory pancreatic masses. A gender-specific association was found in males between chronic obstructive pulmonary disease and intraductal papillary mucinous neoplasms (IPMNs). In females, an association was found between obstructive sleep apnea and IPMNs. Given these multiple associations between hypercapnic and hypoxic respiratory diseases and premalignant and malignant pancreatic lesions, we propose that the pancreatic respiratory microenvironment may play a role in the incidence of certain pancreatic lesions.AbstractBackground: The purpose of this study was to examine the relationship between various respiratory conditions, including hypercapnic respiratory disease, and a multitude of resected pancreatic lesions. Methods: This retrospective case-control study queried a prospectively maintained database of patients who underwent pancreaticoduodenectomy between January 2015 and October 2021. Patient data, including smoking history, medical history, and pathology reports, were recorded. Patients with no smoking history and no concomitant respiratory conditions were designated as the control group. Results: A total of 723 patients with complete clinical and pathological data were identified. Male current smokers showed increased rates of PDAC (OR 2.33, 95% CI 1.07–5.08,p= 0.039). Male patients with COPD had a markedly increased association with IPMN (OR 3.02, CI 1.08–8.41,p= 0.039), while females with obstructive sleep apnea had a four-fold increase in risk of IPMN compared to women in the control group (OR 3.89, CI 1.46–10.37,p= 0.009). Surprisingly, female patients with asthma had a decreased incidence of pancreatic and periampullary adenocarcinoma (OR 0.36, 95% CI 0.18–0.71.p< 0.01). Conclusion: This large cohort study reveals possible links between respiratory pathologies and various pancreatic mass-forming lesions.