Patterns of Recurrence after Resection for Pancreatic Neuroendocrine Tumors: Who, When, and Where?

Abstract

Background/Aims: Pancreatic neuroendocrine tumors (pan-NENs) represent an increasingly common indication for pancreatic resection, but there are few data regarding possible recurrence after surgery. The aim of the study was to describe the frequency, timing, and patterns of recurrence after resection for pan-NENs with consequent implications for postoperative follow-up. Methods: We performed a retrospective analysis of pan-NENs resected between 1990 and 2015 at The Pancreas Institute, University of Verona Hospital Trust. Predictors of recurrence were assessed. Survival analysis was conducted using the Kaplan-Meier and conditional survival (CS) methods. Results: The cohort consisted of 487 patients with a median follow-up of 71 months. Recurrence developed in 12.3%: 54 (11.1%) liver metastases, 11 (2.3%) local recurrence, 10 (2.1%) nodal recurrence, and 8 (1.6%) metastases in other organs. Thirty-one (6.4%) died due to disease recurrence. Size > 21 mm, G3 grade, nodal metastasis, and vascular infiltration were independent predictors of overall recurrence. Recurrence occurred either during the first year of follow-up (n = 9), or after 10 years (n = 4). CS analysis revealed that nonfunctioning G1 pan-NEN ≤20 mm without nodal metastasis or vascular invasion had a negligible risk of developing recurrence. In the present series, after 5 years of follow-up without developing recurrence, tumor recurrence occurred only in the form of liver metastases. Conclusions: Recurrence of pan-NENs is rare and is predicted by tumor size, nodal metastasis, grading, and vascular invasion. Patients with G1 pan-NEN without nodal metastasis and vascular invasion may be considered cured by surgery. After 5 years without recurrence, follow-up should focus on excluding the development of liver metastases.

Surgical Management of Neuroendocrine Tumours of the Pancreas

“…Despite a 5-year survival rate for resected patient is around 90%, recurrence rate is 12-25% at five years and late recurrence were described (up to 70% at 15 years) [117][118][119][120][121]. Follow-up requires a close monitoring with physical examination, biology (essentially for F-pNETS) and cross-sectional imaging (CT/MRI), 3-6 monthly for NF-pNETs and 6-12 monthly for F-pNETs every year for three years, every 1-2 years thereafter, and until 10 years post-pancreatectomy.…”

Clinical and Molecular Risk Factors for Recurrence Following Radical Surgery of Well-Differentiated Pancreatic Neuroendocrine Tumors

“…Among patients undergoing surgery, commonly reported sites of recurrence are the liver, pancreas remnant, and lymph nodes (14,17). Less frequently, other sites including lungs, bone, kidney, and peritoneum are involved (Figure 1).…”

“…Liver involvement is the most frequent accounting for 50-83% of cases of recurrence. Data on the rate of pancreatic local recurrence and lymph nodes remains heterogeneous, ranging widely among surgical series, from 12-23% to 1-16%, respectively (14,16,17). While liver recurrence is associated with biological characteristics of the tumor and more specifically with a more aggressive phenotype, pancreatic local recurrence seems to be related to the presence of microscopical residual disease left on the surgical margins and therefore related to surgical procedure (14,16).…”

“…• Tumor grade ↑ -The most significant prognostic factor for disease relapse -Risk of recurrence increased from G1 to G2 and to G3 neoplasms -The Ki67 value contributes to differentiate prognosis among G2 neoplasms (4,9,14,17,25,26) • • mTOR ↑ -Associated with higher Ki67 and reduced survival in G2 neoplasms (87) adjacent organs. The model performance was evaluated with a c-index, with 0.71 achieved in the test cohort.…”

“…Retrospective studies ( 9 , 14 ) report a median time to recurrence of 35–37 months from surgery, but several cases recurred up to 10 years, advocating long follow-up ( 9 , 14 ). Within the first 5 years after surgery, recurrence occurs at any site and might involve the liver, the remnant pancreas, lymph nodes, and other sites as lungs and bone, whereas late recurrences seem to affect mainly the liver ( 14 , 17 ). However, prospective studies based on homogeneous and accurate preoperative diagnostic workup, to avoid stage underestimation at diagnosis, are needed to clarify those findings.…”