An immunohistochemical and clinicopathological study of gastrointestinal stromal tumors

Immunohistochemical and clinicopathological features of 58 gastrointestinal stromal tumors (GIST) were studied. One occurred in the esophagus, 41 in the stomach, nine in the small intestine, and seven in the large intestine. By using indirect immunoperoxidase staining for Cajal cell markers (c-kit protein and CD34), smooth muscle markers (alpha-smooth muscle actin, desmin, heavy caldesmon and calponin) and Schwann cell markers (S-100 protein and Leu 7), GIST were classified into five groups, such as Cajal cell type (n = 9), myogenic type (n = 5), Schwann cell type (n = 2), mixed cell type (n = 40) and undifferentiated type (n = 2). c-kit Protein (42/58; 72%) and CD34 (45/58; 78%) were commonly and diffusely expressed in GIST. Novel smooth muscle markers, caldesmon (29/58; 50%) and calponin (18/58; 31%), were useful in detecting myogenic characters of GIST. S-100 protein was expressed in 16 (28%) tumors, two of which were also reactive with Leu 7 (CD57). Three small bowel tumors with skeinoid fibers expressed the Cajal cell markers, and were categorizable in GIST. Clinicopathological analyses using aggressive (n = 21) and non-aggressive (n = 21) GIST indicated that the malignant potential was correlated with the intestinal location, large tumor size, high cellularity, necrosis, solid (non-interlacing bundled) pattern of growth, negativity of c-kit protein and/or CD34, high mitotic count, and high MIB-1 labeling.     

Comparative ultrastructural analysis and KIT/PDGFRA genotype in 125 gastrointestinal stromal tumors

GISTs are the most common mesenchymal neoplasms of the digestive tract and are thought to originate from or differentiate toward the interstitial cell of Cajal lineage. Almost all GISTs express KIT protein and the majority show activating mutations in either KIT or PDGFRA proto-oncogenes. Ultrastructurally, these tumors have been shown to have either a smooth muscle, neuronal, dual, or null phenotype. The objective of this study was to investigate the relationship between ultrastructural features and genotype in a large series of 125 histologically confirmed and CD117 positive GISTs. PCR analysis for the presence of KIT exon 9, 11, 13, and 17 and PDGFRA exon 12 and 18 mutations was performed. There were 62 (50%) tumors located in the stomach and 45 (36%) in the small bowel. Overall, KIT mutations were detected in 93 (75%) patients: 86 (69%) in exon 11, and 7 (6%) in exon 9. A PDGFRA mutation was detected in 7 (6%) cases and 25 (19%) cases had no mutation. Ultrastructurally, skeinoid fibers were seen in 55 (44%) cases and were more common in small bowel than stomach GISTs, and occurred in only in 1 of 16 patients with an ITD (KIT) exon 11 or PDGFRA mutation. Focal actin microfilaments were identified in 82 (65%) cases and did not correlate with location or mutation type. Rare neurosecretory-type granules (NS-G) were seen in 34 (27%) of cases, but were seen in most of the cells in only 5 (4%) cases. GISTs showing both NS-G and microtubules were associated with KIT exon 11 genotype and spindle cell morphology. PDGFRA mutated cases were associated with gastric location, predominantly epithelioid morphology and lacked NS-G.     

A ganglion‐rich gastrointestinal stromal tumor: A case report

We report a case of an extremely rare type of duodenal gastrointestinal stromal tumor (GIST) that included neuronal components. Although gastrointestinal autonomic nerve tumors (GANTs), a subtype of GISTs, exhibit ultrastructural features of the nerve plexus, neuronal cells have not been observed within GANTs or GISTs. GISTs originate from interstitial cells of Cajal (ICCs), which are markedly different from the progenitor cells of neural elements and neural‐crest‐derived stem cells. This may explain why GISTs typically lack neuronal elements. It remains unclear that the neuronal components of this tumor are neoplastic or hyperplastic, but proliferation and survival of ICCs have recently been reported to be closely related to neurons. Although we could not find the KIT, PDGFR, and BRAF mutation as far as we examined, it may have had a rare mutation in NF1, a fusion of EVT6‐NTRK3, or an as‐yet‐unknown KIT mutation that affected neurogenesis. Further investigation of related genetic mutations and accumulation of data from other similar cases is needed.     

The intermediate filament protein synemin (SYNM) was found to be more widespread in CD117+ gastrointestinal stromal cell tumors (GIST) than the CD34 transmembrane phosphoglycoprotein: an immunohistochemical study

Interstitial cells of Cajal (ICC) are the pacemaker cells in the gastrointestinal system, initiating the rhythmic systematic contraction of smooth muscle to regulate peristalsis. Benign ICC are identified immunohistochemically by positive staining for CD117, c-kit tyrosine kinase receptor. CD117 expression is maintained during the malignant transformation of ICC into gastrointestinal stromal cell tumors (GIST). However, to date, no single reliable marker for GIST has been identified by immunohistochemical (IHC) staining, and correct diagnosis depends on IHC staining results using multiple markers. This study compared the reactivities of synemin (SYNM) intermediate filament protein and CD34, a known marker for stem cells, endothelial cells, and many GIST tumors, in 54 formalin-fixed, paraffin-embedded GIST, which were determined by this study to be CD117 positive. Double-immunofluorescence (IF) staining was also used to assess whether CD117 and SYNM were co-expressed by ICC. While 81.5% of the GIST were CD34⁺, 92.9% of these tumors were SYNM⁺. ICC were CD117⁺/SYNM⁺, whereas mast cells were CD117⁺/SYNM^?. Because the percentage of CD117⁺/SYNM⁺ GIST was higher than the percentage of 117⁺/CD34⁺ GIST, this study suggested that SYNM was a better marker than CD34 for GIST diagnosis. In addition, differential expression of SYNM and CD117 helped distinguish between ICC and mast cells.     

Gastrointestinal stromal tumors (GISTs): a review

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms in the gastrointestinal tract, which, over the last 10 years, have emerged from a poorly understood neoplasm to a well‐defined tumor entity exhibiting particular molecular abnormalities and for which promising novel treatment modalities have been developed. GISTs probably arise from the precursor cell of the interstitial cell of Cajal, express KIT tyrosine kinase in most of the cases and harbor mutations of importance for individualized treatment. The molecular targets for therapeutic interventions are not only of importance for the treatment of GIST patients but also useful for in the development of novel drug modalities and new strategies in basic cancer therapy.     

Interstitial cells of Cajal in health and disease. Part II: ICC and gastrointestinal stromal tumours

Mesenchymal tumours in the gastrointestinal tract have long been problematic in terms of diagnosis, prognosis and therapy, but recent advances in immunohistochemistry and related therapies have allowed more specific diagnosis. In particular, the recognition that both the interstitial cells of Cajal (ICC) and many gastrointestinal stromal tumours (GISTs) are positive for c-kit and CD34 and have other features similar to those of ICC has led to the use of imatinib, a novel small molecule therapy that blocks the CD117/c-kit tyrosine kinase receptor, which shows remarkable efficacy in treatment of malignant and metastatic GISTs as well as other malignancies.     

CD117、PDGFRA蛋白单独及联合DOG1检测在胃肠道间质瘤中的诊断价值

目的:探讨组织中CD117、PDGFRA两种蛋白表达在胃肠道间质瘤(gastrointestinal stromal tumors,GIST)中的诊断价值及联合DOG1蛋白检测的意义。方法:回顾性对99例GIST和25例非GIST肿瘤标本进行CD117、PDGFRA和DOG1蛋白表达进行检测并进行相关性分析。结果:GIST组CD117、PDGFRA和DOG1蛋白表达率分别为93.94%(93/99)、53.54%(53/99)和90.91%(90/99),非GIST组分别为4.00%(1/25)、4.00%(1/25)和12.00%(3/25),组间比较均有统计学意义(P<0.05);GIST组性别、年龄、肿瘤直径、肿瘤部位、组织学类型和危险度分级等临床病理参数与CD117、PDGFRA和DOG1蛋白表达无统计学意义(P>0.05);CD117、PDGFRA、DOG1、CD117和DOG1联合、PDGFRA和DOG1联合及三者联合判断GIST的敏感性分别为0.989、0.981、0.968、0.960、0.933和0.961,特异性分别为0.800、0.343、0.710、0.840、0.947和0.955,ROC曲线下面积(AUC)分别为0.945、0.748、0.895、0.895、0.840和0.975。结论:GIST中CD117、PDGFRA及DOG1蛋白表达在胃肠道间质瘤中的优势人群有待进一步研究;CD117、PDGFRA蛋白单独及联合DOG1检测可提高对GIST诊断的准确度。     

212例胃肠间质瘤的临床病理特征及预后分析

目的探讨胃肠间质瘤（GIST）的临床特征和分子病理学特点,分析影响GIST预后的相关因素。方法回顾性分析2004年4月至2011年8月南方医院收治的212例GIST患者的临床病理和随访资料,应用生存分析比较不同因素对预后的影响。对接受甲磺酸伊马替尼治疗的53例患者,采用基质辅助激光解析/电离-飞行时间质谱方法检测KIT和PDGFRa基因相关位点的突变情况。结果单因素生存分析显示肿瘤大小、核分裂数、美国国立卫生研究所（NIH）危险度分级、转移、手术及甲磺酸伊马替尼影响GIST患者的生存率。多因素生存分析提示,NIH危险度分级和甲磺酸伊马替尼是影响预后的独立因素。53例GIST患者中,KIT基因突变39例（73.6%）,其中外显子11突变21例（53.8%）,外显子9突变13例（33.3%）。KIT外显子11突变形式主要为5’端第557-558密码子缺失最常见;外显子9突变均为插入串联重复。未检测到PDGFRa基因突变的病例。结论 NIH危险度分级和甲磺酸伊马替尼治疗与GIST患者的生存密切相关,基因突变检测对指导生物靶向治疗和预测其疗效具有重要意义。     

New issues in gastrointestinal stromal tumors of the stomach

Gastrointestinal stromal tumors (GISTs) constitute the majority of mesenchymal tumors of the gastrointestinal tract. The activating mutations in the receptor tyrosine kinases KIT and PDFRA are key molecular changes in the pathogenesis of these tumors and their recognition has led to the development of targeted therapies. Approximately 10% of GISTs, referred to as wild-type, lack such mutations and respond poorly to treatment with tyrosine kinase inhibitors. These GISTs are almost exclusive to the stomach and include primarily tumors that occur in children and tumors that are part of several tumor syndromes. Recent studies have shown that most wild-type GISTs are succinate dehydrogenase deficient. This review summarizes current advances in the molecular biology of GISTs and discusses the clinical and pathologic features associated with different genotypes.     

KIT 1530ins6 mutation defines a subset of predominantly malignant gastrointestinal stromal tumors of intestinal origin

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs express KIT and show gain-of-function KIT mutations. Most of these mutations affect the KIT juxtamembrane domain, but other KIT domains are mutated at a lower frequency. In this study, frequency of GCC TAT insertion mutation (1530ins6) in KIT exon 9 (extracellular domain) and its possible clinicopathologic significance was investigated. Screening of 520 GISTs identified 26 cases with 1530ins6 KIT mutation and confirmed the previously reported low frequency of this type of KIT mutation among GISTs of different locations. Of the 26 tumors with 1530ins6 KIT mutation studied, 21 originated from the small intestine, 1 from the colon, and 3 from the rectum. In 1 case, primary small intestinal versus colonic localization could not be clearly established because of intra-abdominal dissemination. No distinctive morphological features were identified for the cohort of tumors defined by 1530ins6 KIT mutations. Most of the tumors showed predominant spindle cell morphology, and a few cases had epithelioid or pleomorphic histological features. Following previously published criteria based on tumor size and mitotic rate, 22 of 26 (85%) tumors were classified as malignant or potentially malignant, and 4 (15%) were classified as probably benign. A malignant clinical course was documented in 18 of 19 tumors from the malignant category. The survival times of 11 patients who died of disseminated GISTs ranged from 1 month to 105 months (median survival time, 26 months). In contrast, 2 of 4 GISTs assigned as probably benign tumors with follow-up information had long disease-free survival. GISTs carrying 1530ins6 occur exclusively in the intestinal location, and a great majority of these tumors follow a malignant course.     

Gastrointestinal stromal tumours: an update

Recently, there has been intense interest in the study of gastrointestinal stromal tumour (GIST); one might call it a virtual GIST revolution. This is due largely to the realization that most GISTs express KIT and harbour activating c-KIT (KIT) or platelet-derived growth factor receptor-alpha (PDGFRA) receptor tyrosine kinase mutations that can be targeted by small molecule pharmacological inhibitors. Pathologists have benefited greatly from this revolution, mainly in the form of an improved ability to classify GISTs and, even more recently, in understanding the molecular underpinnings that underlie many fascinating clinical and pathological correlations. It is the purpose of this review to summarize recent developments in GIST classification and the molecular pathogenesis of GIST.     

Knock-in murine models of familial gastrointestinal stromal tumours

In recent years, gastrointestinal stromal tumour (GIST) has emerged from a poorly understood group of mesenchymal tumours to a distinct pathological entity that has become a leading model for new therapies targeting kinases. GIST pathogenesis is driven by receptor tyrosine kinase-activating mutations most often in KIT or PDGFRA that may be sporadic or result in familial GIST syndromes. In a recent issue of The Journal of Pathology (J Pathol 2008;214:302-311), Nakai and colleagues report that mutation of the previously un-modelled tyrosine kinase II domain of KIT generates a spectrum of features very similar to that in two human GIST families. Knock-in mouse models of GIST may prove extremely useful in pre-clinical evaluation of kinase-targeted compounds and of the mechanism of drug resistance, but intriguingly it now seems clearer that the distribution of GIST in mouse models and humans is different.     

胃肠道小间质瘤的研究进展

胃肠道间质瘤(gastrointestinalstromaltumor,GIST)是胃肠道最常见的间叶性肿瘤,约占胃肠道间叶性肿瘤80%.根据肿瘤大小、核分裂像计数以及肿瘤发生的部位将胃肠道间质瘤分为极低、低、中等和高度危险性.体积<2cm的间质瘤,称为小间质瘤.不同危险度的间质瘤其临床表现、生物学行为、遗传学表现和预后明显不同,小间质瘤的临床表现及预后明显好于大间质瘤.C-Kit基因突变是胃肠道间质瘤发生发展的驱动基因,因大小间质瘤C-Kit基因突变相似,导致对C-Kit基因突变在胃肠道间质瘤中的作用引起争议.本文综述小间质瘤的流行病学、临床病理表现、分子遗传学、治疗与预后的研究进展.     

胃肠道间质瘤的临床病理特征及危险度分级的影响因素

目的:分析胃肠道间质瘤(gastrointestinal stromal tumors,GISTs)的临床病理特点,探讨GISTs的临床病理因素与危险度分级的相关性.方法:回顾性分析77例手术切除的原发性GISTs患者的临床病理资料,检测GISTs的临床病理因素与危险度分级的相关性.结果:肿瘤是否囊性变、有无坏死、是否合并其他肿瘤是对GISTs危险度分级有显著影响的变量(P＜0.05).结论:肿瘤是否囊性变及有无坏死可以作为判断GISTs危险度分级的重要参考指标.     

High expression of the RNA-binding protein RBPMS2 in gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract and are often associated with KIT or PDGFRA gene mutations. GIST cells might arise from the interstitial cells of Cajal (ICCs) or from a mesenchymal precursor that is common to ICCs and smooth muscle cells (SMCs). Here, we analyzed the mRNA and protein expression of RNA-Binding Protein with Multiple Splicing-2 (RBPMS2), an early marker of gastrointestinal SMC precursors, in human GISTs (n = 23) by in situ hybridization, quantitative RT-PCR analysis and immunohistochemistry. The mean RBPMS2 mRNA level in GISTs was 42-fold higher than in control gastrointestinal samples (p < 0.001). RBPMS2 expression was not correlated with KIT and PDGFRA expression levels, but was higher in GISTs harboring KIT mutations than in tumors with wild type KIT and PDGFRA or in GISTs with PDGFRA mutations that were characterized by the lowest RBPMS2 levels. Moreover, RBPMS2 levels were 64-fold higher in GIST samples with high risk of aggressive behavior than in adult control gastrointestinal samples and 6.2-fold higher in high risk than in low risk GIST specimens. RBPMS2 protein level was high in 87% of the studied GISTs independently of their histological classification. Finally, by inhibiting the KIT signaling pathway in GIST882 cells, we show that RBPMS2 expression is independent of KIT activation. In conclusion, RBPMS2 is up-regulated in GISTs compared to normal adult gastrointestinal tissues, indicating that RBPMS2 might represent a new diagnostic marker for GISTs and a potential target for cancer therapy.     

Gastrointestinal stromal tumors and KIT-positive mesenchymal cells in the omentum

Gastrointestinal stromal tumor (GIST) is currently considered to be derived from the interstitial cells of Cajal (ICC). To test the hypothesis that omental mesenchymal tumor is also a type of GIST, we evaluated the expression of specific molecules in GIST, and c-kit gene mutation in omental mesenchymal tumors, and we identified a possible counterpart of ICC in the omentum. Immunohistochemically, all of the omental mesenchymal tumors (n = 5) were positive for both KIT and CD34, and three of the five tumors were also positive for an embryonic form of smooth-muscle myosin heavy chain (SMemb). Polymerase chain reaction-single-strand conformational polymorphism analysis (PCR-SSCP) and direct sequencing revealed mutations in c-kit gene exon 11 in all five tumors. As for the ICC counterparts in the omentum, there were some KIT-positive mesenchymal cells resembling ICC at the surface of the omentum. Double fluorescence immunostaining, using anti-KIT polyclonal antibodies and monoclonal antibodies against other molecules, demonstrated that KIT-, CD34- and SMemb-positive cells were present just beneath the mesothelial cells of the omentum. These results show that omental mesenchymal tumor corresponds to GIST of the omentum, and that KIT-positive bipolar mesenchymal cells may be a counterpart of ICC in the gastrointestinal tract. Identification of a new type of KIT-positive mesenchymal cell in the omentum may lead to the discovery of a new physiological role for this organ.     

胃肠道间质瘤的误诊因素分析及鉴别

目的:分析胃肠道间质瘤（GIST）的影像误诊因素及鉴别要点。 方法:搜集术前误诊为GIST患者11例,GIST患者术前未正确诊断2例作为此次研究的对象,对所有患者的影像资料进行回顾分析。13例患者均有手术病理,进行MSCT扫描,观察CT影像特征,分析误诊或未正确诊断GIST的影像学因素及鉴别价值。 结果:13例误诊患者中,2例为腹膜后神经鞘瘤、2例为低分化腺癌、2例为异位胰腺、1例为类癌、1例为平滑肌瘤、1例为未分化肉瘤、2例为转移性癌、另外2例小肠间质瘤术前未正确诊断。误诊与肿瘤发生部位、大小、血供来源、生长趋势、观察方法等因素有关。 结论:GIST有一定的影像特点,降低胃肠道间质瘤的误诊,三维重建-肿块准确定位是重中之重,其次应仔细观察肿块细微关键征象,注意肿块血供来源及生长趋势也是鉴别要点。     

Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Despite clinicopathological differences, GISTs share oncogenic KIT or platelet-derived growth factor-alpha ( PDGFRA ) mutations. Imatinib, KIT and PDGFRA inhibitor, has been successfully used in the treatment of metastatic GISTs. There are primary KIT or PDGFRA mutations diagnosed before imatinib treatment, linked to GIST pathogenesis, and secondary mutations detected during treatment, causing drug resistance. KIT exon 11 mutations are the most common. Gastric GISTs with exon 11 deletions are more aggressive than those with substitutions. KIT exon 11 mutants respond well to imatinib. Less common KIT exon 9 Ala502_Tyr503dup mutants occur predominantly in intestinal GISTs and are less sensitive to imatinib. An Asp842Val substitution in exon 18 is the most common PDGFRA mutation. GISTs with such mutation are resistant to imatinib. PDGFRA mutations are associated with gastric GISTs, epithelioid morphology and a less malignant course of disease. GISTs in neurofibromatosis 1, Carney triad and paediatric tumours generally lack KIT and PDGFRA mutations. Secondary KIT mutations affect exons 13–17. GISTs with secondary mutations in exon 13 and 14 are sensitive to sunitinib, another tyrosine kinase inhibitor. KIT and PDGFRA genotyping is important for GIST diagnosis and assessment of sensitivity to tyrosine kinase inhibitors.     

Immunohistopathological and molecular genetic features of a case in which gastrointestinal stromal tumor recurred five times

Gastrointestinal stromal tumor (GIST) is a distinct group of mesenchymal neoplasms recently shown to exhibit differentiation toward interstitial cells of Cajal. Although previous studies have shown that the clinical outcome of patients with GIST is associated with mitotic activity, the proliferation index determined by the Ki-67 labeling index, immunophenotype (CD34 and/or p53) and mutation in exon 11 of the c-kit, a definitive discrimination between benign and malignant GIST has not yet been established. We report a patient in whom malignant GIST in the abdomen recurred five times. In this case, the primary GIST and the five recurrent GIST were associated with c-kit immunoreactivity, but the mitotic index of the GIST tended to be increasingly higher with subsequent recurrences. Mutational analysis of the c-kit revealed that the primary and recurrent GIST were mutant-negative. These data indicated that 'morphologically appearing benign' tumors with lower proliferative parameters may also have the capacity of metastasis and recurrence.     

小胃肠间质瘤的临床病理学特征

目的探讨小胃肠间质瘤(small gastrointestinal stromal tumors,sGIST)的临床病理学特征。方法回顾性分析21例sGIST的临床病理学及免疫表型特征,对比分析非sGIST,并进行随访。结果 21例sGIST中女性7例,男性14例,中位年龄63岁,直径0.5~1.5 cm,主要发生于胃,全部为梭形细胞型,其中9例同时伴有胃肠道恶性肿瘤。与非sGIST相比,sGIST很少出现肿瘤内出血、坏死、黏膜侵犯、溃疡及核分裂,复发风险明显低于非sGIST;免疫组化标记p53、Ki-67及肿瘤内微血管密度(microvascular density,MVD)明显低于非sGIST,差异有统计学意义(P0.05)。结论 sGIST可与胃肠道恶性肿瘤同时伴发,免疫组化标记p53、Ki-67及MVD均低于非sGIST,其预后较好。