Konukiewitz Björn, Schlitter Anna Melissa, Jesinghaus Moritz, Pfister Dominik, Steiger Katja, Segler Angela, Agaimy Abbas, Sipos Bence, Zamboni Giuseppe, Weichert Wilko, Esposito Irene, Pfarr Nicole, Klöppel Günter
Institute of Pathology, Technical University of Munich, Munich, Germany.
Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Mod Pathol. 2017 Apr;30(4):587-598. doi: 10.1038/modpathol.2016.217. Epub 2017 Jan 6.
Somatostatin receptor 2A expression is a feature of well-differentiated neuroendocrine neoplasms and is important for their diagnosis and therapy. Little is known about somatostatin receptor 2A expression in poorly differentiated neuroendocrine neoplasms in relation to TP53 and RB1 status and how these features may contribute to the separation of well from poorly differentiated neuroendocrine neoplasms with a proliferation index above 20%. This study investigates the expression of somatostatin receptors, p53 and Rb1, and TP53 alterations in pancreatic and extrapancreatic well and poorly differentiated neuroendocrine neoplasms (Ki67-index >20%). Thirty-seven poorly differentiated neuroendocrine neoplasms of pancreatic (n=12) and extrapancreatic origin (n=25) as well as 10 well-differentiated neuroendocrine neoplasms of the pancreas (n=9) and rectum (n=1) with a Ki67-index >20% were immunostained for synaptophysin, chromogranin A, Ki67, CD56, p53, Rb1, ATRX, DAXX, progesterone receptor, somatostatin receptor 2A, somatostatin receptor 5, and cytokeratin 20, and sequenced for TP53, exons 5-9. Somatostatin receptor 2A was positive in 6/37 of poorly differentiated and in 8/10 of well-differentiated neuroendocrine neoplasms. One well-differentiated and two poorly differentiated neuroendocrine neoplasms expressed somatostatin receptor 5. Abnormal nuclear p53 and Rb1 staining was found in 29/37 and 22/37 poorly differentiated neuroendocrine neoplasms, respectively, whereas all well-differentiated neuroendocrine neoplasms showed normal p53 and Rb1 expression. TP53 gene alterations were restricted to poorly differentiated neuroendocrine neoplasms (24/34) and correlated well with p53 expression. All cases were progesterone receptor negative. Somatostatin receptor 2A expression is not limited to well-differentiated neuroendocrine neoplasms but also occurs in 16% of poorly differentiated neuroendocrine neoplasms from various sites. Most poorly differentiated neuroendocrine neoplasms are characterized by TP53 alterations and Rb1 loss, usually in the absence of somatostatin receptor 2A expression. In the pancreas, these criteria contribute to separate well-differentiated neuroendocrine neoplasms with a Ki67-index above 20% from poorly differentiated neuroendocrine neoplasms.
生长抑素受体2A表达是高分化神经内分泌肿瘤的一个特征，对其诊断和治疗具有重要意义。关于低分化神经内分泌肿瘤中生长抑素受体2A表达与TP53和RB1状态的关系，以及这些特征如何有助于区分增殖指数高于20%的高分化和低分化神经内分泌肿瘤，目前所知甚少。本研究调查了胰腺和胰腺外高分化及低分化神经内分泌肿瘤（Ki67指数>20%）中生长抑素受体、p53和Rb1的表达以及TP53改变情况。对37例胰腺（n = 12）和胰腺外起源（n = 25）的低分化神经内分泌肿瘤以及10例胰腺（n = 9）和直肠（n = 1）的高分化神经内分泌肿瘤（Ki67指数>20%）进行免疫染色，检测突触素、嗜铬粒蛋白A、Ki67、CD56、p53、Rb1、ATRX、DAXX孕激素受体、生长抑素受体2A、生长抑素受体5和细胞角蛋白20，并对TP53外显子5 - 9进行测序。生长抑素受体2A在37例低分化神经内分泌肿瘤中有6例呈阳性，在10例高分化神经内分泌肿瘤中有8例呈阳性。1例高分化和2例低分化神经内分泌肿瘤表达生长抑素受体5。在37例低分化神经内分泌肿瘤中，分别有29例和22例发现异常核p53和Rb1染色，而所有高分化神经内分泌肿瘤均显示p53和Rb1表达正常。TP53基因改变仅限于低分化神经内分泌肿瘤（24/34），且与p53表达密切相关。所有病例孕激素受体均为阴性。生长抑素受体2A表达不仅限于高分化神经内分泌肿瘤，在来自不同部位的低分化神经内分泌肿瘤中也有16%出现。大多数低分化神经内分泌肿瘤的特征是TP53改变和Rb1缺失，通常不存在生长抑素受体2A表达。在胰腺中，这些标准有助于区分Ki67指数高于20%的高分化神经内分泌肿瘤和低分化神经内分泌肿瘤。
