SURGERY VS. CONSERVATIVE MANAGEMENT IN ALL PANCREATIC NEUROENDOCRINE TUMORS <2CM IN US: AN NCDB ANALYSIS

Abstract
Background and Aims: Currently, most patients with branch duct intraductal papillary mucinous neoplasms (BD-IPMN) are offered indefinite surveillance, resulting in health care costs with questionable benefits regarding cancer prevention. This study sought to identify patients where the risk of cancer is equivalent to an age-matched population, thereby justifying discontinuation of surveillance.

Methods: International multicenter study involving presumed BD-IPMN without worrisome features (WF) or high-risk stigmata (HRS) at diagnosis who underwent surveillance. Clusters of individuals at risk for cancer development were defined according to cyst size and stability for at least 5 years, and age-matched controls were used for comparison using standardized incidence ratios (SIRs) for pancreatic cancer.

Results: Of 3844 patients with presumed BD-IPMN, 843 (22%) developed a WF or HRS after a median surveillance of 53 (IQR 53) months and 164 patients (4.3%) underwent surgery. Of the overall cohort, 1617 patients (42%) remained stable without developing WF or HRS for at least 5 years. In patients 75 years or older, the SIR was 2.23 (95%CI 0.45-6.52), and in patients 65 year or older with stable lesions below 15mm in diameter after 5 years, the SIR was 1.77 (95%CI 0.20-6.39).

Conclusions: The risk of developing pancreatic malignancy in presumed BD-IPMN without WF or HRS after 5 years of surveillance is comparable to that of the general population depending on cyst size and patient age. Surveillance discontinuation could be justified after 5 years of stability in patients older than 75 years with cysts < 30 mm, and in patients 65 years or older who have cysts ≤ 15 mm.

Surgical management of Pancreatic neuroendocrine tumors (PNETs) has long been debated. Current NCCN guidelines state that non-functioning PNETs >2 centimeters (cm) should undergo primary surgical removal. Tumors < 2cm in size can be observed carefully and surgery is not always indicated. Recent NCDB based analysis suggests that surgical intervention for tumors 1-2 cms is beneficial while observation remains an option for tumors <1cm. In this analysis we seek to understand the influence of surgery on survival for smaller PNETS (</=2 cms).

Methods
The NCDB was used to identify 15,017 patients diagnosed with PNETs from 2004-2018 with known tumor size, surgical status, and survival outcomes. Variables included in this analysis are race, sex, age, rurality, Charlson-Deyo score, grade, surgery status, stage, site, and size of tumor. Variables were summarized with descriptive statistics including counts, percentages, and compared using Chi^2 analysis. Univariate Survival analysis was demonstrated through Kaplan Meyer survival curve analysis. Survival data was fit to an exponential curve and 60-month mortality estimates were reported. Cox-proportional hazards were used to conduct both whole cohort and stratified multivariate analysis. Hazard ratios and confidence intervals (95%) are reported.

Results
Tumor Size was separated into three categories (<1cm, 1-2cm, ≥2 cm). 950 (6.3%) were <1cm, 3043 (20.3%) were 1-2cm, and 11024 (73.4%) were ≥2cm in size. Of the 15017 patients included, 9911(66.1%) underwent surgical resection. Rates of surgical resection across tumor sizes differed with <1cm 680 (71.81%), 1-2 cm 2414 (79.46%) and ≥2 cm 6817 (61.9%). Five-year mortality estimates across all tumor sizes show a significant decrease in mortality with surgical resection. Survival curves show that patients across all tumor sizes that underwent surgical resection had improved survival outcomes. Multivariate analysis showed that patients not undergoing surgical resection, while controlling for effect of tumor size, had worse survival (HR: 2.41). Patients with increased tumor size (≥ 2cm) had worse survival outcomes compared to both smaller tumor size groups; 1-2 cm (HR 1.59) <1cm (1.34) while controlling for surgical status. Stratified Analysis showed that patients not undergoing surgical resection had worse survival across all tumor sizes; >2cm (HR: 2.46) 1-2 cm (HR: 2.22) <1cm (HR: 2.36).

Discussion
Our analysis suggest that surgical intervention across all tumor sizes is beneficial for overall survival. When controlling for other compounding factors, patients that underwent surgical intervention demonstrated increased survival. This analysis suggests that surgical or other ablative interventions should be considered across all PNET presentations regardless of tumor size and that current guidelines for watchful observation are not consistent with emerging survival data.