Supplementary Material for: A Consensus-Developed Morphological Re-Evaluation of 196 High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms and Its Clinical Correlations

High-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are classified according to morphology as well-differentiated neuroendocrine tumours (NETs) G3 or poorly differentiated neuroendocrine carcinomas (NECs). Little data exist concerning which morphological criteria this subdivision should be based on. Uncertainty exists if the NEC group should be further subdivided according to proliferation rate. Clinical data on NET G3 and NEC with a lower Ki-67 range are limited. A total of 213 patients with high-grade GEP-NEN (Ki-67 >20%) were included from the Nordic NEC Registries. Four experienced NET pathologists re-evaluated the cases to develop the best morphological criteria to separate NET G3 from NEC, assuming longer survival in NET G3. Organoid growth pattern, capillary network in direct contact to tumour cells, and absence of desmoplastic stroma were found to best separate NET G3 from NEC. Of 196 patients with metastatic disease, NET G3 was found in 12.3%, NEC with a Ki-67 <55% (NEC < 55) in 29.6%, and NEC with a Ki-67 ≥55% (NEC ≥ 55) in 56.6%. Only in 1.5%, the morphology was ambiguous. Of 164 patients receiving first-line chemotherapy, 88% received platinum/etoposide treatment. Response rate was higher for NEC ≥ 55 (44%) than that of NEC < 55 (25%) and NET G3 (24%) (p = 0.025 and p = 0.026). Median progression-free survival was 5 months for all groups. Median overall survival was 33 months for NET G3 compared to 11 months for both NEC < 55 and NEC ≥ 55 (p = 0.004 and 0.003). Specific morphological criteria can separate NET G3 from NECs and show prognostic significance. High-grade GEP-NEN patients stratified by morphology and proliferation rate demonstrate significant differences in response to chemotherapy and survival.

高级别胃肠胰神经内分泌肿瘤（high-grade gastroenteropancreatic neuroendocrine neoplasms, GEP-NENs）按照形态学可分为高分化神经内分泌肿瘤（well-differentiated neuroendocrine tumours, NETs）G3与低分化神经内分泌癌（poorly differentiated neuroendocrine carcinomas, NECs）。目前针对该亚型划分所依据的形态学标准，相关研究数据仍较为匮乏；此外，针对是否应依据增殖率对神经内分泌癌组进行进一步亚型划分，目前仍存在争议。针对Ki-67指数较低的NET G3与NEC患者，相关临床数据十分有限。本研究从北欧神经内分泌癌登记库（Nordic NEC Registries）中纳入了213例高级别GEP-NEN患者，其Ki-67指数均＞20%。4名经验丰富的神经内分泌肿瘤病理学家对所有病例进行了重新评估，旨在明确区分NET G3与NEC的最优形态学标准，研究假设NET G3患者的生存周期更长。研究发现，类器官样生长模式（organoid growth pattern）、与肿瘤细胞直接接触的毛细血管网（capillary network）以及无促纤维增生性间质（desmoplastic stroma）这三项特征，可最优区分NET G3与NEC。在196例存在远处转移的患者中，NET G3占比12.3%，Ki-67＜55%的NEC（NEC＜55）占比29.6%，Ki-67≥55%的NEC（NEC≥55）占比56.6%；仅1.5%的病例形态学特征难以明确归类。在164例接受一线化疗的患者中，88%采用了铂类/依托泊苷（platinum/etoposide）联合方案。NEC≥55组的客观缓解率（44%）显著高于NEC＜55组（25%）与NET G3组（24%）（p=0.025、p=0.026）。三组患者的中位无进展生存期（progression-free survival）均为5个月。NET G3组的中位总生存期（overall survival）为33个月，而NEC＜55组与NEC≥55组均为11个月，组间差异具有统计学意义（p=0.004、p=0.003）。明确的形态学特征可有效区分NET G3与NEC，且具有预后评估价值。依据形态学与增殖率对高级别GEP-NEN患者进行分层后，其化疗应答效果与生存结局均存在显著差异。