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胰腺神经内分泌肿瘤的形态学变异:临床病理分析和预后分层。

Morphologic Variants of Pancreatic Neuroendocrine Tumors: Clinicopathologic Analysis and Prognostic Stratification.

机构信息

Department of Pathology, (Previously) Emory University Hospital, (Currently) Northwestern University, Chicago, IL, USA.

Department of Statistics, Northwestern University, Chicago, IL, USA.

出版信息

Endocr Pathol. 2020 Sep;31(3):239-253. doi: 10.1007/s12022-020-09628-z.

Abstract

Better prognostication/stratification of pancreatic neuroendocrine tumors (PanNETs) is needed. In this detailed morpheomic study of 163 resected PanNETs, 11 unusual variants, some of which were not previously recognized, and others scarcely documented in the literature, were identified, and their pathologic characteristics were further analyzed. By behavior and clinicopathologic associations, these variants could be grouped into three prognostically different categories. I. More aggressive (20%). Included in this group were the variants that in average showed higher grade and stage and adverse outcome including oncocytic, plasmacytoid, lipid-rich and previously unrecognized hepatoid variants, which often had a more diffuse/broad-band growth pattern, with some also displaying discohesiveness. They were characterized by abundant cytoplasm and often had prominent nucleoli (as seen in metabolically active cells), thus the provisional name "metabolic cell phenotype." Because of their diversion from classical neuroendocrine cytomorphology, these variants created challenges on original diagnostic workup, particularly hepatoid examples, which revealed Arginase 1/Hep Par-1 expression in 50%. II. Less aggressive (10%). These cases either showed signs of maturation, including nested growth, paraganglioid pattern (which was previously unrecognized), and organoid PanNETs such as "ductulo-insular" growth, or showed symplastic/degenerative changes, and despite their paradoxically disconcerting histology, were more benevolent in behavior. III. Undetermined. There were other variants including mammary tubulolobular-like, pseudoglandular, peliotic, and sclerotic PanNETs, which although diagnostically challenging, their biologic significance could not be determined because of rarity or heterogeneous characteristics. Prognostic associations: Features that were significantly different in the more aggressive group than the less aggressive group were median size (5.0 vs 1.6 cm, p < 0.001), percentage of pT3+T4 cases (72% vs 12%, p < 0.001), Ki67 index (5.3% vs 2.3%, p = 0.001), % G2 and G3 cases (77% vs 27%, p < 0.001), and rate of lymph node and distant metastasis (96% vs 27%, p < 0.001). In stepwise logistic regression model using the 3 established prognosticators of T stage, size, and grade along with morphology, only aggressive-morphology (metabolic cell phenotype) was found to be associated with metastatic behavior with an odds ratio of 5.9 with 95% confidence interval (C.I.) 1.688 to 22.945 and p value 0.007. In conclusion, PanNETs display various morphologic patterns that are not only challenging and important diagnostically but appear to have biologic significance. Tumors with more diffuse growth of cells with nucleoli and abundant cytoplasm and/or discohesion (oncocytic, hepatoid, lipid-rich, plasmacytoid PanNETs), provisionally termed "metabolic cell phenotype," show aggressive characteristics and are an independent determinant of adverse outcome and thus may require closer post-surgical follow-up, whereas variants with more degenerative or mature features (ductuloinsular, pleomorphic, paraganglioma-like) appear to be more benevolent despite their more atypical and worrisome morphology.

摘要

需要更好地预测/分层胰腺神经内分泌肿瘤 (PanNETs)。在这项对 163 例切除的 PanNETs 的详细形态学研究中,发现了 11 种不寻常的变体,其中一些以前未被识别,另一些在文献中几乎没有记录,并进一步分析了它们的病理特征。根据行为和临床病理关联,这些变体可以分为三组具有不同预后的类别。I. 更具侵袭性 (20%)。包括在该组中的是平均显示更高等级和分期以及不良结局的变体,包括嗜酸细胞、浆细胞样、富含脂质和以前未被识别的肝细胞样变体,它们通常具有更弥漫/宽带状的生长模式,其中一些也表现出脱黏附性。它们的特征是丰富的细胞质,通常具有明显的核仁(如在代谢活跃的细胞中所见),因此暂定名为“代谢细胞表型”。由于它们偏离了经典的神经内分泌细胞形态学,这些变体在最初的诊断工作中带来了挑战,特别是肝细胞样变体,其中 50% 的病例显示 Arg 酶 1/肝 Par-1 表达。II. 侵袭性较低 (10%)。这些病例要么表现出成熟的迹象,包括巢状生长、副节瘤样模式(以前未被识别)和器官样 PanNETs,如“导管-胰岛样”生长,要么表现出合胞体/退行性变化,尽管它们的组织学令人不安,但在行为上更为仁慈。III. 不确定。还有其他变体,包括乳腺小管状小叶样、假腺状、海绵状和硬化性 PanNETs,尽管在诊断上具有挑战性,但由于其罕见或异质性特征,其生物学意义无法确定。预后关联:在侵袭性较强的组与侵袭性较弱的组之间存在显著差异的特征包括中位大小(5.0 对 1.6cm,p<0.001)、pT3+T4 病例的百分比(72%对 12%,p<0.001)、Ki67 指数(5.3%对 2.3%,p=0.001)、%G2 和 G3 病例(77%对 27%,p<0.001)和淋巴结和远处转移率(96%对 27%,p<0.001)。在使用 T 分期、大小和分级的 3 个既定预后指标以及形态学的逐步逻辑回归模型中,只有侵袭性形态(代谢细胞表型)与转移行为相关,优势比为 5.9,95%置信区间(CI)为 1.688 至 22.945,p 值为 0.007。总之,PanNETs 表现出各种形态模式,不仅具有挑战性和重要的诊断意义,而且似乎具有生物学意义。具有核仁丰富细胞质和/或脱黏附性的细胞弥漫性生长的肿瘤(嗜酸细胞、肝细胞样、富含脂质、浆细胞样 PanNETs),暂命名为“代谢细胞表型”,表现出侵袭性特征,是不良结局的独立决定因素,因此可能需要更密切的术后随访,而具有退行性或更成熟特征的变体(导管-胰岛样、多形性、副节瘤样)尽管其形态更不典型和令人担忧,但似乎更为仁慈。

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