74例胃肠道间质瘤临床病理与生物学行为评价

目的　探讨在胃肠道间质瘤(GIST)的病理诊断和预后分析上采用一种简单实用且重复性好的病理学“标准”,以利于GIST的日常病理诊断和生物学行为评价及指导治疗,并对Fletcher等推荐的GIST生物学行为评价表进行评估。方法　85例消化道间叶组织肿瘤,复习其病理形态学并应用CD117、CD34、平滑肌肌动蛋白(SMA)、结蛋白、S 100等进行免疫组织化学标记,结合 31例随访资料进行分析。结果　85例消化道间叶组织肿瘤中,GIST74例,平滑肌瘤和交界性平滑肌瘤 8例(食管),平滑肌肉瘤 1例(直肠 ),神经鞘瘤 1例 (胃 ),恶性纤维组织细胞瘤 1例 (肠系膜 )。74例GIST中,发生在胃和小肠的分别为 34例和 30例,占 86. 5%,食管 3例,胃肠道外(肠系膜、网膜、后腹膜)7例。年龄 23~80岁,平均 52 5岁, 40岁以上者占 85%,男性 45例,女性 29例。镜下观察:梭型细胞型 48例,上皮样细胞型 10例,混合细胞型 16例。瘤细胞呈长、短梭形和圆形,胞质丰富弱嗜酸性,排列呈旋涡状、栅栏状或弥漫巢状。免疫组织化学: 85例消化道间叶组织肿瘤波形蛋白均阳性,其中 74例表达CD117,诊断为GIST,表达形式有弥漫胞膜 /胞质强阳性、散在阳性、胞质点状着色等,其中 54例同时表达CD34 (阳性率 72. 9% ), 25例表达SMA, 5例表达结蛋白, 5例表达S 100蛋白。在 85例     

胃肠道间质瘤156例临床病理学特征与预后的分析

目的探讨胃肠道问质瘤（GIST）的生物学行为,分析临床病理特征对于GIST患者生存率的影响,同时检测c—kit基因11号外显子的突变,试图发现对GIST预后判断有意义的指标。方法收集解放军总医院病理科156例发生于胃与小肠的GIST,总结临床病理特征包括年龄、临床分期、肿瘤直径、核分裂象计数、坏死、风险分级等,并进行统计学分析。套式PCR扩增c—kit基因11号外显子,变性高效液相色谱法筛查,并进行DNA直接测序检测突变。结果胃GIST83例,平均年龄55．4岁,62例获得随访,17例复发或转移,5年生存率为66．5％±17．1％。小肠GIST73例,平均年龄50．6岁,43例获得随访,22例发生复发或转移,5年生存率为61．8％4-18．3％。对于胃GIST患者,年龄小于50岁（P=0．046）,临床分期晚（P=0．0001）,肿瘤直径大（P=0．0001）,核分裂象计数多（P=0．0001）,肿瘤组织出现坏死（P=0．0001）和风险分级高（P=0．004）提示生存率低。COX风险比例模型发现临床分期晚（P=0．001）、肿瘤直径大（P=0．001）、核分裂象计数多（P=0．002）、风险分级高（P=0．018）与患者预后差相关。在小肠GIST中,肿瘤组织坏死（P=0．036）、临床分期晚（P=0．010）与患者生存率低相关,其中临床分期为独立的预后提示因子。c—kit基因11号外显子突变检测发现共25例患者存在突变,胃GIST的突变率为32．0％,主要发生于50岁以上患者,小肠GIST的突变率为22．5％,主要发生于40～49岁患者。结论根据临床病理特征可以对GIST患者的预后进行判断,其中胃GIST患者可以根据临床分期、肿瘤直径、核分裂象计数、风险分级来判断预后,小肠GIST患者可依据临床分期及肿瘤组织坏死来判断预后。小肠GIST比胃GIST更易复发或转移。胃与小肠GIST基因的突变可能与患者的年龄相关。     

Gastrointestinal stromal tumours (GISTs): a clinicopathological and molecular study of 66 cases

AIMS: Predicting the clinical behaviour of gastrointestinal stromal tumours (GISTs) is difficult and criteria delineating benign from malignant cases are not firmly established. The aims of this study were to define the clinicopathological and molecular features of 66 GISTs, and to determine whether any specific parameters were associated with patient outcome. METHODS: Archival cases of GIST from two major teaching hospitals in Western Australia were studied. Inclusion criteria for the study were: (1) appropriate morphology, (2) CD117 positivity, (3) adequacy of pathological material for study, and (4) exclusion of other tumour types on the basis of immunophenotypic and/or ultrastructural features. Expression of CD117, CD34, S100 protein, keratin (using broad spectrum MNF116), alpha-smooth muscle actin (SMA) was determined by immunohistochemistry. PCR and single strand conformation polymorphism (PCR-SSCP) analysis were used to screen for mutations in exons 11 and 9 of c-kit. RESULTS: There were equal numbers of males and females with a mean age at diagnosis of 60 years, followed up for a mean of 54 months. Thirteen patients (21%) had died of GIST by the end of the study. Tumours were mostly located in the stomach (67%) and small intestine (SI; 25%). The cell types were pure spindle (68%), pure epithelioid (12%) and mixed epithelioid/spindle (20%). c-kit mutations were found in 69% of GISTs, with the large majority (91%) occurring in exon 11. Size > or = 10 cm, tumour necrosis and pure epithelioid cell morphology each were the only factors significantly associated with adverse survival (p=0.038, and p=0.047 and p=0.028, respectively). Mitotic activity > or = 5/50 HPF showed a definite trend association with adverse survival, but unlike some other studies, did not achieve statistical significance (p=0.067). c-kit mutations were more frequent in small intestinal GISTs (p=0.05) and in those with pure spindle cell morphology (p=0.023) but were not associated with patient outcome. CONCLUSION: In this study, size > or = 10cm, necrosis and/or pure epithelioid cell morphology correlated significantly with adverse survival. Mitotic activity showed a strong association with survival but this did not reach statistical significance. c-kit mutations occurred mainly in GISTs of the SI, and in purely spindle cell tumours. While the mutation status did not associate with patient outcome in this series, this remains a controversial issue, and further studies are needed to assess whether the type of mutation affects response to tyrosine kinase inhibitor therapy in metastatic GISTs. CD117 staining of any mesenchymal lesion of the gastrointestinal tract should be mandatory for accurate classification. PCR-SSCP analysis is a fast, sensitive and relatively inexpensive method of analysing c-kit mutations, which may be important prognostically and also of therapeutic relevance in the assessment of new tyrosine kinase inhibitor therapies.     

Gastrointestinal stromal tumors in children and young adults: a clinicopathologic and molecular genetic study of 22 Korean cases

Studies on gastrointestinal stromal tumors (GISTs) in young patients are limited due to their rarity, and none have been conducted in Asian populations. GISTs from patients under the age of 30 were retrospectively reviewed and were analyzed for clinicopathologic features, immunohistochemistry for SDHB (succinate dehydrogenase subunit B), and mutations for exon 9, 11, 13, and 17 of KIT gene and exon 12, 14, and 18 of PDGFRA gene. We found two pediatric (<18 years old) and 20 young adult (18–30 years old) GIST cases. Pediatric GISTs occurred in two girls, both as solitary masses with epithelioid histology in the stomach. Both GISTs were wild type for KIT and PDGFRA genes, were negative for SDHB, and there was no recurrence during follow‐up. Of the 20 GISTs in young adults, 12 (60%) were from extra‐gastric locations (six duodenum, five jejunum, and one esophagus), and 16 (80%) showed a spindle cell morphology. Mutations of KIT or PDGFRA genes were identified in 14 (78%) of the 18 cases. One patient with multiple gastric GISTs with perigastric lymph node metastases at presentation developed multiple distant metastases and died of the disease 7.3 years after diagnosis. Of the 19 R0‐resected young adult patients, one patient with small intestinal GIST harboring KIT exon 11 deletion mutation developed recurrence and showed partial responses for imatinib. In summary, compared with pediatric GIST cases, young adult GISTs are heterogeneous and share the characteristics of both pediatric and adult GISTs. When a mesenchymal tumor is clinically suspected in the small intestine of young adults, a GIST should be included in the differential diagnoses. Further mutation studies and extensive treatments are recommended for these cases.     

胃肠道间质瘤合并消化道癌20例临床病理分析

目的 探讨20例胃肠道间质瘤(gastrointestinal stromal tumor,GIST)合并消化道癌的临床病理特征.方法 回顾性研究165例GIST,对其中20例合并发生消化道癌的病例进行临床病理特征分析并行免疫组化CD117、DOG1等染色.结果 GIST合并发生消化道癌的病例占所有收集GIST病例的12.1%.20例患者中16例男性、4例女性(P＜0.05),年龄44～79岁,平均64.3岁(P＜0.05).19例GIST发生于胃(95.0%),1例发生于食管(5.0%),其中3例为消化道癌根治术中探查发现,其余均为术后病检偶然发现,直径0.4～4.5 cm,平均1.0 cm(P＜0.01).肿瘤细胞均为梭形细胞型,生物学危险度分级为极低危险度18例(90.0%)和低危险度2例(10.0%),免疫标记肿瘤细胞CD117阳性16例(80.0%),DOG1阳性19例(95.0%),其中DOG1阳性、CD117阴性4例(20.0%),CD117阳性、DOG1阴性1例(5.0%).合并发生的消化道癌中胃腺癌10例(50.0%),食管鳞癌9例(45.0%),1例为直肠腺癌(5.0%),肿瘤TNM分期0期1例(5.0%),Ⅰ期3例(15.0%),Ⅱ期7例(35.0%),Ⅲ期9例(45.0%).结论 GIST合并消化道癌并不少见.本病好发于老年男性,其中GIST多发生于胃且生物学危险度低,合并的消化道癌多为胃癌和食管癌.组织学主要为梭形细胞型,危险度分级较低.临床和病理均应重视本病的诊断,特别是在术中探查及术后随访过程中应注意与消化道癌的转移性癌结节鉴别.DOG1能帮助鉴别诊断其他胃肠道间叶源性肿瘤.     

原发性子宫外子宫内膜间质肉瘤5例临床病理分析

目的 探讨原发性子宫外子宫内膜间质肉瘤(extrauterine endometrial stromal sarcoma,EESS)的临床病理特征、免疫表型、生物学行为及诊疗进展.方法 收集5例EESS的临床病理资料,并进行免疫组化检测及预后随访.结果 5例患者病理诊断均为低级别EESS,其中1例发生于腹腔、网膜及肠系...     

钙化性纤维性肿瘤的临床病理学分析

目的探讨钙化性纤维性肿瘤(calcifying fibrous tumor,CVF)的临床病理学特征、免疫表型和鉴别诊断。方法回顾性分析7例CFT的临床资料、病理学形态和免疫组化标记结果。结果患者中1例为少年,6例均为成年人,年龄14—50岁,平均37岁。5例临床表现为局部缓慢性生长的无痛性肿块,2例为术中偶然发现。肿瘤分别位于腹腔／盆腔(3例)、颈部(2例)、左腹股沟(1例)和左小腿(1例)。眼观：肿块境界清楚,卵圆形或结节状,质地坚韧。镜检：肿瘤由大量胶原化的纤维结缔组织组成,其间夹杂少量梭形细胞。特征性形态学表现为在胶原化的纤维组织间可见散在的钙化灶或砂砾小体,间质内伴有多少不等的淋巴细胞和浆细胞浸润灶,部分病例中可见生发中心形成。免疫组化标记显示,梭形细胞主要表达vimentin,不表达CD34、S-100蛋白、actin、desmin、h-caldesmon和ALK1等标记。随访6例,均无复发。结论CFT是一种不同于炎性肌纤维母细胞瘤的良性纤维母细胞性肿瘤。CFT不仅好发于儿童和青少年,也可发生于成年人。组织学上应与伴有钙化的纤维母细胞／肌纤维母细胞性病变相鉴别。     

Gastrointestinal stromal tumor of the digestive organs: a histopathologic study of 31 cases in a single Japanese institute

The author herein reports histopathologic features of 31 surgical cases of gastrointestinal stromal tumor (GIST) of the digestive organs. The 31 cases of GIST were diagnosed in our pathology laboratory. They consisted of 24 cases of gastric GIST, 1 case of hepatic GIST, 1 case of small intestinal GIST, 4 cases of colon GIST, and 1 case of rectal GIST. The age of the patients ranged from 56 year to 84 years with a mean of 71 years. Male to female ratio was 21:10. The presenting symptoms were gastrointestinal bleeding in 13 cases, abdominal pain and discomfort in 13 cases, and asymptomatic in 5 cases. Endoscopy and imaging modalities including US, CT and MRI were useful to detect the tumors in all cases, and biopsies confirmed the GIST diagnosis in 21 cases. The size of GIST ranged from 1 cm to 12 cm with a mean of 4.3 cm. Grossly, 23 cases were submucosal tumors, 6 serosa-side tumors, 1 solid tumor in the liver, and 1 rectal polyp. Histologically, 28 cases were of spindle cell type and 3 of epithelioid type. According to mitotic counts and tumor size, the malignant risk was very low in 4 cases, low in 14 cases, intermediate in 9 cases, and high in 4 cases. Immunohistochemically, all cases were positive for KIT and vimentin, 30 cases for CD34, and 4 cases for α-smooth muscle actin. None were positive for desmin and S100 protein. Ki-67 labeling ranged from 2% to 18%. P53 protein was negative in all cases. PDGFRA was positive in 20 cases among 24 cases examined. Genetic analysis using PCR-direct sequencing method was performed in 5 GISTs; all the 5 GISTs showed point mutations or deletions in KIT gene, but did not in PDGFRA gene. The 5 cases of GIST were positive for PDGFRA protein, suggesting that PDGFRA overexpression is not associated with PDGFRA gene mutations. Four of the 31 cases showed metastases. The chemotherapy was imatinib mesylate in 6 cases, and none in 25 cases. Four cases of high risk died of GIST, and 27 cases are alive now without tumors.     

Gastrointestinal stromal tumors (GIST)--a paradigm of successful targeted therapy of solid tumors

Gastrointestinal stromal tumors (GIST) have attracted basic scientists as well as clinicians in the last 10 years. The reason for this is explanation of the pathogenetic mechanism of tumor growth by activation of c-Kit protein, followed by a rationally designed suppressor, a drug named imatinib. It is the first successful therapy for solid tumors to date, although there are other ongoing studies of agents with targeted action on different molecules in different tumors. In 80% of patients there is a clinical benefit from imatinib trreatment. GIST shows great diversity in clinical presentation and some questions still remain, such as malignant potential and prognostic criteria in these tumors. Imatinib therapy demonstrates many favorable effects such as acceptable toxicity and relative mild side effects, excellent quality of life, good patient compliance, etc. There are ongoing trials of new agents designated for target molecules, which would hopefully show benefit after developing resistance to imatinib.     

Gastrointestinal stromal tumors: Clinicopathological study of Chinese cases

In the present study, we reviewed 73 Chinese cases of gastrointestinal stromal tumor (GIST), and analyzed factors in evaluating malignant potential, in particular focusing on Ki-67 index and p53 expression to determine whether these can be used as prognostic indicators in GIST. The p53 positive rate was 50.7% and it was significantly higher in malignant (25/35; 71.43%) than in benign cases (13/38; 34.21%). A Ki-67 labeling index of >10% was also significantly different between malignant (23/35; 65.71%) and benign cases (14/38; 36.84%). In the cases in which the patient died, 15/21 and 14/21 cases showed expression of p53 and Ki-67, respectively; both had a higher expression than in surviving cases. Comparing the cases positive for both Ki-67 and p53 with those positive for Ki-67 or p53 alone, and those negative for both Ki-67 and p53, the latter demonstrated the best prognosis. The study also indicated that the malignant potential of GIST is correlated with the mitotic index (> or =1/10 high-power fields; HPF), tumor size (> or =5 cm), high cellularity, tumor invasive growth, tumor location, tumor hemorrhage and tumor necrosis.     

165例胃肠道间质瘤中c-kit和PDGFRA基因突变的检测和临床诊断意义

目的探讨在中国较大样本的胃肠道问质瘤（GIST）中c-kit基因和PDGFRA基因的突变状况,为进一步的生物靶向治疗提供依据。方法用免疫组织化学EnVision法、聚合酶链反应（PCR）扩增和直接测序的方法,检测165例GIST c-kit基因9、11、13和17号外显子突变以及PDGFRA基因12和18号外显子突变。结果病理组织学诊断的165例GIST病例中有155例（94％）免疫组织化学显示CD117阳性。在CD117阳性的GIST中,c-kit基因总突变率为76．1％（118／155）：分别为11号外显子67．1％（104／155）、9号外显子7．1％（11／155）、13号外显子1．3％（2／155）和17号外显子0．6％（1／155）。绝大多数为杂合性突变,少数为纯合性突变。11号外显子的突变位点多集中在5’端的经典热点,其次为3’端的框内串联重复。后者主要以核分裂象少的老年女性胃部病例多见。9号外显子突变代表一类发生在年轻男性体积较大的小肠病变。13号外显子发现一处新的突变点L641P。PDGFRA基因突变见于50％（5／10）CD117阴性病例,均为18号外显子突变,包括常见的D842V点突变和一个框内843-846处IMHD缺失伴有S847T的新突变。PDGFRA基因突变多见于发生在后腹膜／网膜的具有高度侵袭危险性的病例。结论中国GIST病例大多数存在c-kit基因和PDGFRA基因的突变,且在基因突变类型和肿瘤原发部位问有非随机的联系。除了发现几个新的突变形式外,国人的GIST似乎和西方国家有些不同的突变特点。靶向治疗需要基因突变分型的启示和指导。     

Cystic well-differentiated neuroendocrine carcinoma (carcinoid tumor): a clinicopathologic and immunohistochemical study of two cases

Two cases of primary neuroendocrine carcinoma (carcinoid tumor) arising in the walls of a multilocular thymic cyst (MTC) are described. The patients were 2 men, ages 36 and 44 years. Clinically, the patients had chest pain, cough, and dyspnea. Radiographic evaluation demonstrated the presence of anterior mediastinal tumor in both patients, and complete surgical resection of the tumor mass was performed. The tumors measured approximately 6 and 8 cm in greatest dimension and were cystic with solid areas but did not show areas of necrosis or hemorrhage. Histologic examination revealed a cystic tumor with features similar to those previously described for MTCs. In addition, in the walls of the cystic structures, there was cellular proliferation arranged in a nesting growth pattern, similar to the more solid areas of the tumor. The tumor was characterized by a homogenous cellular proliferation with mild cellular atypia and no more than 2 mitotic figures per 10 high-power fields. Immunohistochemically, the tumor cells showed strong positive reactions for keratin and neuroendocrine markers, ie, chromogranin and synaptophysin. Both patients were alive after periods of 12 and 18 months.     

Splenic inflammatory myofibroblastic tumor (inflammatory pseudotumor): a clinicopathologic and immunophenotypic study of 12 cases

CONTEXT: Inflammatory pseudotumor is an uncommon and enigmatic lesion. The spindle cells found in this tumor have features of myofibroblasts. Because of the indefinite relationship of these lesions with inflammatory fibrosarcoma and their indefinite biologic behavior, inflammatory pseudotumor is currently classified as inflammatory myofibroblastic tumor (IMT). To date, only case reports or small series have been published on these tumors, which are primary in the spleen. DESIGN: In this study, we describe the clinical, morphologic, and immunophenotypic findings of 12 cases of splenic IMT and examine their relationship to Epstein-Barr virus (EBV). RESULTS: The patients included 8 women and 3 men, ranging from 19 to 77 years of age (mean, 53 years; median, 60 years). Demographic data were unavailable for 1 patient. Patients generally presented with abdominal pain (n = 5) and fever (n = 4). Associated lesions included renal cell carcinoma (n = 2), colonic adenocarcinoma (n = 1), and cholecystitis (n = 1). All tumors were composed of a bland spindle cell proliferation in association with a variable mixed inflammatory component. There were 2 growth patterns, namely, a cellular spindle cell pattern and a hypocellular fibrous pattern. An immunohistochemical panel confirmed the myofibroblastic nature of the spindle cells. The spindle cells of 2 cases were immunoreactive for EBV latent membrane protein 1, whereas 6 of 10 cases were positive for EBV-encoded RNA using in situ hybridization. Follow-up was available for 8 patients; 6 were alive with no evidence of recurrence and 2 were dead of other causes. CONCLUSION: Splenic IMTs are uncommon lesions that can be distinguished from other conditions using a combination of clinical, histologic, and immunophenotypic findings. Epstein-Barr virus may play a role in the pathogenesis of splenic IMT, and there may be an association of splenic IMT with concomitant disease or malignancy. Most splenic IMTs have an excellent long-term prognosis.     

Myxoid solitary fibrous tumor: a clinicopathologic study of three cases

While focal myxoid areas are occasionally observed in solitary fibrous tumors, neoplasms of this type exhibiting extensive myxoid change are considered exceedingly uncommon. Due to their rarity, the biologic behavior of myxoid solitary fibrous tumor has not been determined. Three cases of myxoid solitary fibrous tumor are described in order to better characterize the clinical and pathologic features of this uncommon variant of solitary fibrous tumor. The tumors occurred in one man and two women, with ages of 37, 47, and 58 years, respectively. Sites of involvement included the retroperitoneum, pelvis, and soft tissue of the neck. Histologically, all cases were characterized predominantly by the presence of myxoid stroma comprising 70% to 100% of the tumor. The tumor cells were predominantly spindled in all cases, and arranged randomly, in loose fascicles, or in anastomosing strands imparting a microcystic/reticular appearance. The lesional cells had a bland cytologic appearance and low mitotic count. All tumors lacked necrosis and areas of increased cellularity. By immunohistochemistry, all cases were positive for CD34, CD99, and bcl-2, and negative for keratin, epithelial membrane antigen, desmin, actin, smooth muscle actin, and S-100 protein. To date, all cases have followed a benign course without evidence of recurrence or metastasis with a follow-up duration ranging from 50 to 87 months. The data suggest that myxoid solitary fibrous tumors are associated with an indolent clinical course and favorable prognosis.     

胸部原始神经外胚层瘤5例临床病理分析

目的 探讨胸部原始神经外胚层瘤(PNET)的临床病理特征、免疫学表型及其鉴别诊断。方法 对5例发生于胸部的PNET进行光镜观察和免疫组化研究。结果 5例PNET中4例为女性,1例男性,年龄12～52岁,平均27．0岁。肿瘤体积较大,平均直径11．4cm,无包膜或包膜不完整。镜下：肿瘤由小圆细胞构成,细胞胞质少,部分区域肿瘤细胞胞质透亮,可见Homer-Wwright菊形团和假菊形团。免疫表型：5例CD99(MIC2)、NSE阳性,4例synaptophysin阳性,3例vimentin阳性,2例S-100蛋白阳性。结论 胸部PNET是较少见的高度恶性软组织肿瘤,其诊断主要依据病理形态学特征及免疫组化标记。