Supplementary Material for: High-Grade Progression Confers Poor Survival in Pancreatic Neuroendocrine Tumors

<b><i>Introduction:</i></b> Little is known about how pancreatic neuroendocrine tumors (PanNETs) evolve over time and if changes toward a more aggressive biology correlate with prognosis. The purpose of this study was to characterize changes in PanNET differentiation and proliferation over time and to correlate findings to overall survival (OS). <b><i>Patients and Methods:</i></b> In this retrospective cohort study, we screened 475 PanNET patients treated at Uppsala University Hospital, Sweden. Sporadic patients with baseline and follow-up tumor samples were included. Pathology reports and available tissue sections were reevaluated with regard to tumor histopathology and Ki-67 index. <b><i>Results:</i></b> Forty-six patients with 106 tumor samples (56 available for pathology reevaluation) were included. Median Ki-67 index at diagnosis was 7% (range 1–38%), grade 1 <i>n</i> = 8, grade 2 <i>n</i> = 36, and grade 3 <i>n</i> = 2. The median change in Ki-67 index (absolute value; follow-up – baseline) was +14% (range –11 to +80%). Increase in tumor grade occurred in 28 patients (63.6%), the majority from grade 1/2 to grade 3 (<i>n</i> = 24, 54.5%). The patients with a high-grade progression had a median OS of 50.2 months compared to 115.1 months in patients without such progression (hazard ratio 3.89, 95% CI 1.91–7.94, <i>p</i> &lt; 0.001). <b><i>Conclusions:</i></b> A longitudinal increase in Ki-67 index and increase in tumor grade were observed in a majority of PanNETs included in this study. We propose that increase in Ki-67 index and high-grade progression should be investigated further as important biomarkers in PanNET.

引言：目前学界对胰腺神经内分泌肿瘤（pancreatic neuroendocrine tumors, PanNETs）的随时间演化进程，以及其侵袭性生物学特征变化是否与预后相关，尚且缺乏足够认识。本研究旨在阐明PanNET随时间推移的分化与增殖特征变化，并将相关发现与总生存期（overall survival, OS）相联系。患者与方法：本项回顾性队列研究纳入瑞典乌普萨拉大学医院收治的475例PanNET患者，筛选其中具备基线及随访肿瘤样本的散发性病例。针对肿瘤组织病理学特征与Ki-67指数（Ki-67 index），我们对病理学报告及可获取的组织切片进行了重新评估。结果：最终纳入46例患者，共计106份肿瘤样本（其中56份可用于病理学重新评估）。确诊时Ki-67指数中位数为7%（范围1%~38%），其中G1级8例、G2级36例、G3级2例。Ki-67指数的变化中位数（绝对值，即随访值减基线值）为+14%（范围-11%~+80%）。28例（63.6%）患者出现肿瘤分级升高，其中多数为从G1/G2级进展至G3级（n=24，54.5%）。发生高级别进展的患者中位总生存期为50.2个月，未发生该进展的患者则为115.1个月（风险比3.89，95%置信区间1.91~7.94，P<0.001）。结论：本研究纳入的多数PanNET患者均出现了Ki-67指数的纵向升高及肿瘤分级升高。我们建议进一步研究Ki-67指数升高与高级别进展作为PanNET重要生物标志物的潜在价值。