Grade progression of well-differentiated pancreatic neuroendocrine tumors (panNETs) can occur over time, with G1/2 to G3 being the most clinically relevant form. Here, we conducted a retrospective cohort study of 66 patients with initially G1/2 panNET (median initial Ki67, 4.6%). Patients were followed up for a median 6.8 years and had a median of two metachronous tumor biopsies over their disease course. 34.8% of patients underwent any form of grade progression, including G1 to G2/3 and G2 to G3, while 24.2% demonstrated G1/2 to G3 grade progression. Over a median 2.3 years, G1/2 to G3 grade progressors experienced a median Ki67 change of +27.0% (range, +6.4 to +48.7%). Subsequent biopsies showing progression to G3 had a median Ki67 value of 31.0% (range, 21.0–60.0%) and were more often performed following suspicious clinical behavior (75.0%) rather than routinely at the time of scheduled procedure/surgery (25.0%). Similar to prior studies, G1/2 to G3 grade progressors had worse overall survival from the time of metastatic disease (median, 4.8 years vs not reached for stably G1/2 disease; P = 0.002). Heavier pretreatment and heterogeneity or lack of uptake on somatostatin receptor imaging was independently associated with progression to G3. In the largest study of metachronous panNET biopsies to date, our findings show that baseline biopsies suggesting G1/2 disease may not accurately reflect future disease status, highlighting the possible limitations of using archived tissue to stratify patients into trials and/or choose future therapy. Additional work is needed to better understand the impact of prior therapies on grade progression and how to identify which lesions to best follow up for repeat biopsy.
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