Abstract

Primary appendiceal neoplasms (ANs) comprise a heterogeneous group of tumors. The pathology and classification of ANs have been controversial, and thus, a new classification of these neoplasms was published in the World Health Organization (WHO) classification of tumors (5th edition, 2019). However, immunohistochemistry (IHC) features of epithelial ANs are not explained in this edition and the limited data on the molecular pathology of these tumors shows inconsistent findings in various studies. It would be useful to identify biomarkers appropriate for each subtype to better aid in treatment selection. Therefore, we reviewed the literature to investigate what is known of the molecular pathology and IHC features of the most frequently diagnosed pathological subtypes of epithelial ANs based on the recent classification. The inconsistencies in research findings regarding the IHC features and molecular pathology of ANs could be due to differences in the number of samples and their collection and preparation as well as to the lack of a universally accepted classification system for these neoplasms. However, the literature shows that epithelial ANs typically stain positive for MUC2, CK20, and CDX2 and that the expression of SATB2 protein could be used as a biomarker for appendix tumor origin. Low-grade appendiceal mucinous neoplasms tend to have mutations in KRAS and GNAS but are usually wild-type for BRAF, APC, and P53. Conversely, appendiceal adenocarcinomas are frequently found with mutations in KRAS, GNAS, P53, PIK3CA, and APC, and have significant nuclear expression of β-catenin, loss of nuclear or nuclear and cytoplasmic expression of SMAD4, and loss of cytoplasmic membranous expression of E-cadherin. Goblet cell carcinomas (GCCs) typically stain positive for keratin and mucin markers and are frequently mutated in P53 and chromatin-modifier genes, but they tend to be wild-type for KRAS, GNAS, APC, and PIK3CA. The expression of CK7 and SATB2 proteins is usually negative in appendiceal neuroendocrine neoplasms and they lack the mutations in common cancer-associated genes including APC, BRAF, SMAD4, and PIK3C. The available data suggest that GCCs have distinct molecular and immunohistochemical features and that they have characteristics more in common with adenocarcinoma than classical neuroendocrine tumors. In addition, MSI does not seem to have a role in the pathogenesis of epithelial ANs because they are rarely detected in these tumors. Finally, hereditary predisposition may have a role in the development of ANs because heterozygous CTNNβ1, NOTCH1, and NOTCH4 germline mutations have recently been identified in low and high grades ANs.

摘要

原发性阑尾肿瘤 (AN) 包括一组异质性肿瘤。AN 的病理学和分类一直存在争议，因此，这些肿瘤的新分类发表在世界卫生组织 (WHO) 肿瘤分类（第 5 版，2019 年）中。然而，本版并未解释上皮性 AN 的免疫组织化学 (IHC) 特征，而且这些肿瘤的分子病理学数据有限，在各种研究中结果不一致。确定适合每个亚型的生物标志物以更好地帮助选择治疗方法将是有用的。因此，我们回顾了文献，以根据最近的分类研究已知的最常诊断的上皮性 AN 病理亚型的分子病理学和 IHC 特征。关于 AN 的 IHC 特征和分子病理学研究结果的不一致可能是由于样本数量及其收集和制备的差异，以及缺乏对这些肿瘤普遍接受的分类系统。然而，文献显示上皮 AN 通常对 MUC2、CK20 和 CDX2 染色呈阳性，SATB2 蛋白的表达可用作阑尾肿瘤起源的生物标志物。低级别阑尾粘液性肿瘤倾向于在 文献显示上皮 AN 通常对 MUC2、CK20 和 CDX2 染色呈阳性，SATB2 蛋白的表达可用作阑尾肿瘤起源的生物标志物。低级别阑尾粘液性肿瘤倾向于在 文献显示上皮 AN 通常对 MUC2、CK20 和 CDX2 染色呈阳性，SATB2 蛋白的表达可用作阑尾肿瘤起源的生物标志物。低级别阑尾粘液性肿瘤倾向于在KRAS和GNAS但通常是BRAF、APC和P53 的野生型。相反，阑尾腺癌经常发现KRAS、GNAS、P53、PIK3CA和APC突变，并具有显着的 β-catenin 核表达，SMAD4 核或核和细胞质表达缺失，以及 E 的细胞质膜表达缺失。 -钙粘蛋白。杯状细胞癌 (GCC) 通常对角蛋白和粘蛋白标记物染色呈阳性，并且经常在P53和染色质修饰基因中发生突变，但它们往往是KRAS 的野生型，GNAS、APC和PIK3CA。CK7 和SATB2 蛋白在阑尾神经内分泌肿瘤中的表达通常为阴性，并且它们缺乏常见癌症相关基因的突变，包括APC、BRAF、SMAD4和PIK3C。现有数据表明 GCC 具有独特的分子和免疫组织化学特征，并且与典型的神经内分泌肿瘤相比，它们与腺癌的特征更相似。此外，MSI 似乎在上皮性 AN 的发病机制中没有作用，因为它们在这些肿瘤中很少被检测到。最后，遗传易感性可能在 AN 的发展中起作用，因为杂合CTNNβ1最近在低级别和高级别 AN 中发现了、NOTCH1和NOTCH4种系突变。