Gastrointestinal stromal tumours (GISTs) negative for KIT (CD117 antigen) immunoreactivity
Gastrointestinal stromal tumours (GISTs) negative for KIT (CD117 antigen) immunoreactivity
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DOI：
10.1002/path.1546
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发表时间：
2004-04-01
影响因子：
7.3
通讯作者：
Sciot, R
中科院分区：
文献类型：
--
作者：
Debiec-Rychter, M;Wasag, B;Sciot, R
胃肠道间质瘤(GIST)目前被定义为表达KIT受体酪氨酸激酶的胃肠道间充质肿瘤。然而，符合GIST临床和形态标准的一小部分肿瘤缺乏试剂盒表达。到目前为止，这些肿瘤的生物学特征很少被提及。本研究描述了7例胃肠道间质瘤，这些肿瘤具有典型的GIST的临床病理特征，但免疫组织化学检测CD117表达缺失。肿瘤起源于胃(n=5)、十二指肠(n=1)和结肠(n=1)，在组织学上表现为上皮样(n=3)、梭形和上皮样混合(n=2)或间变/梭形细胞型(n=2)。CD34和α-平滑肌肌动蛋白(α-SMA)分别在4个和3个肿瘤中呈阳性表达。对两例患者进行了染色体分析，均显示14、22和1p染色体丢失，这是GIST的特征。双色间期荧光原位杂交(FISH)分析，利用染色体1p、14和22的特异性探针，在其余5个肿瘤标本中显示了类似的细胞遗传学特征。对所有病例进行KIT基因第9、11、13、17外显子突变分析，PDGFRA基因第12、18外显子突变分析。所有肿瘤均未显示KIT突变异构体。3例肿瘤存在PDGFRA外显子18激活突变，2例为Asp--&Gt；Val(842)错义替换，1例为DIM842-844氨基酸缺失。免疫印迹法检测KIT和PKCtheta(Cajal间质细胞和GIST间质细胞激活蛋白)的表达。三种肿瘤均不表达KIT，而所有标本均表达PKCtheta蛋白。这些发现表明，有一组KIT阴性的GIST表现出与KIT阳性肿瘤相同的形态、细胞遗传学和分子特征。虽然在其中一些肿瘤中存在基因内PDGFRA激活突变，但其他肿瘤的致癌事件仍不清楚。版权所有(C)2004年大不列颠和爱尔兰病理学会。作者：John Wiley Sons，Ltd.
Gastrointestinal stromal tumours (GISTs) are currently defined as mesenchymal tumours of the gastrointestinal tract that express KIT receptor tyrosine kinase. However, a small subgroup of tumours that fulfil the clinical and morphological criteria for GISTs lack KIT expression. So far, the biological features of these tumours have rarely been addressed. The present study describes seven gastrointestinal stromal neoplasms that presented clinicopathological features typical of GISTs but showed absence of CD117 expression as detected by immunohistochemistry. The tumours originated from the stomach (n = 5), duodenum (n = 1), and colon (n = 1), showing histologically either predominantly epithelioid (n = 3), mixed spindled and epithelioid (n = 2), or anaplastic/spindle cell (n = 2) type features. CD34 and alpha-smooth muscle actin (alpha-SMA) positivity was present in four and three tumours, respectively. Chromosomal analysis was performed in two cases, both showing losses of chromosomes 14, 22, and 1p, which is the characteristic feature of GISTs. Dual-colour interphase fluorescence in situ hybridization (FISH) analysis, utilizing chromosome 1p-, 14-, and 22-specific probes, revealed a similar cytogenetic profile in the remaining five tumour specimens. Mutational analysis of exons 9, 11, 13, and 17 of KIT, and exons 12 and 18 of PDGFRA was performed in all cases by denaturing high-pressure liquid chromatography (DHPLC) pre-screening, followed by direct sequencing. None of the tumours showed KIT mutant isoforms. Three tumours harboured PDGFRA exon 18 activating mutations; two were Asp --> Val(842) missense substitutions and one was a DIM842-844 amino acid deletion. KIT and PKCtheta (protein activated in interstitial cells of Cajal and GISTs) expression was determined by western immunoblotting of the total cell lysates from three tumour biopsies. None of these three tumours expressed KIT, while all specimens showed expression of PKCtheta protein. These findings indicate that there is a subgroup of KIT-negative GISTs that exhibit the same morphological, cytogenetic, and molecular features as KIT-positive tumours. While intragenic PDGFRA activating mutations are present in some of these tumours, the oncogenic events underlying the pathogenesis of the others remain unknown. Copyright (C) 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley Sons, Ltd.