胃基质肿瘤的诊治分析

目的 :探讨胃基质肿瘤 (GSTs)的诊断和治疗原则。方法 :回顾性分析手术治疗的 2 9例GSTs的临床资料。结果 :术前 2 1例通过胃镜或内镜超声检查及活检确诊。 2 7例患者均得到随访 ,良性GSTs无复发 ;11例恶性GSTs中 2例因复发而死亡 ,3例术后吻合口局部复发及 1例术后肝转移者予甲磺酸伊马替尼治疗 ,效果良好。结论 :GSTs术前诊断比较困难 ,常需手术确诊。良性GSTs手术治疗效果良好 。

上皮样胃基质肿瘤(成平滑肌瘤)

Stout于1962年对一组具有上皮样圆形细胞的胃非上皮肿瘤命名为成平滑肌瘤,部分有恶变,1969年世界卫生组织称之为上皮样平滑肌瘤.鉴于免疫组织化学和电镜检查未能找到平滑肌现象,最好将此类肿瘤称之为上皮样胃基质肿瘤,并有良恶性之分.Mayo临床中心于1960～1986年曾收治477例胃基质肿瘤病人,其中55例为上皮样胃基质肿瘤,分析其临床和病理特点.全组55例中,男37例,女18例,平均年龄63岁(13～88岁),常见的症状有消化不良和疼痛(35%)、黑粪(9%)、扪及腹块(7%).1例出现肠梗阻,15例无症状(27%).18例在胃外尚有22个肿瘤.53%肿瘤位于胃体,33%位于胄窦,14%位于胃底、贲门部.肿瘤可向腔内或胃壁外生长,6例侵犯邻近器官.40例作了钡餐检查,26例发现异常,其中13例胃壁内肿瘤,1例有脐样外观,另1例有粘膜溃疡.5例有腔内息肉,5例有外在压迹.17例做了胃镜检查,12例有异常发现.

胃癌患者血清VEGF和MMP-3检测的临床意义

运用ELISA法检测18例健康人、52例胃癌患者术前VEGF和MMP-3的含量。胃癌患者血清VEGF和MMP-3水平明显高于健康者,并与浸润深度、淋巴结转移、远处转移、临床分期密切相关(P<0.05);与患者年龄、性别、肿瘤分化程度无关(P>0.05)。健康者血清VEGF和MMP-3含量没有相关性(P>0.05),但在胃癌患者血清中两者存在明显相关性(P<0.05)。VEGF、MMP-3参与肿瘤的发生发展,与肿瘤的侵袭、转移密切相关,检测血清中VEGF、MMP-3的水平有助于胃癌的临床治疗和预后评估。

Small gastrointestinal stromal tumor concomitant with early gastric cancer:A case report

The term gastrointestinal stromal tumors （GISTs） is defined diagnostically as the main group of mesenchymal tumors with spindle or epithelioid cells arising from the wall of the gastrointestinal tract with immunohistochemical reactivity for CD117 antibody. Previous studies revealed that cells in GISTs express a growth factor receptor with tyrosine kinase activity （termed c-kit）, which is the product of the c-kit protooncogene. The most specific and practical diagnostic criteria for GISTs are： immunohistochemically determined c-kit （CD117） expression; mitotic score; and tumor size. A small GIST concomitant with early gastric cancer is rarely encountered clinically. Herein we have reported a case of a 1.1-cm GIST detected by esophagogastroduo denoscopy concomitant with a IIc type of early gastric cancer （signet ring cell type）. It was detected during a routine physical health examination. To our knowledge, this is the first report of a small GIST concomitant with a signet ring cell type of early gastric cancer.

DNA ploidy and c-Kitmutation in gastrointestinal stromal tumors

AIM: To investigate the prognostic significance of c-Kitgen emutation and DNA ploidy in gastointestinal stromal tumors (GISTs).METHODS: A total of 55 cases of GISTs were studied for the expression of c-Kit by immunohistochemistry, and the c-Kit gene mutations in exons 9, 11, 13, and 17 were detected by polymerase chain reaction-single strand confirmation polymarphism (PCR-SSCP) and denaturing high performance liquid chromatography (D-HPLC) techniques. DNA ploidy was determined by flow cytometry.RESULTS: Of the 55 cases of GISTs, 53 cases (96.4%) expressed c-Kit protein. The c-Kit gene mutations of exons 11 and 9 were found in 30 (54.5%) and 7 cases (12.7%),respectively. No mutations were found in exons 13 and 17.DNA aneuploidy was seen in 10 cases (18.2%). The c-Kit mutation positive GISTs were larger in size than the negative GISTs. The aneuploidy tumors were statistically associated with large size, high mitotic counts, high risk groups, high cellularity and severe nuclear atypia, and epithelioid type.There was a tendency that c-Kit mutations were more frequently found in aneuploidy GISTs.CONCLUSION: DNA aneuploidy and c-Kit mutations can be considered as prognostic factors in GISTs.

Synchronous occurrence of gastrointestinal stromal tumors and other primary gastrointestinal neoplasms

AIM： To review clinical and pathologic features of Gastrointestinal strornal tumors （GISTs） occurring synchronously with other primary gastrointestinal neoplasms. METHODS： 28 patients with primary GIST were treated at our institution between 1989 and 2005. Clinical and pathologic records were reviewed. RESULTS： The gastrointestinal stromal tumor occurred simultaneously with other primary GI malignancies in 14% of all patients with GIST. The synchronous stromal tumors were located in the stomach and were incidentally found during the operation. The coexistent neoplasms were colon adenocarcinoma, gastric cancer （2 cases） and gastric lymphoma. CONCLUSION： The synchronous occurrence of GISTs and other gastrointestinal malignancies is more common than it has been considered. The development of gastrointestinal stromal tumors and other neoplasms may involve the same carcinogenic agents.

Treatment of patients with advanced gastrointestinal stromal tumor of small bowel: Implications of imatinib mesylate

AIM： To examine the impact of imatinib mesylate （Glivec） on patient survival and response and its safety, and the correlation of the response rate with the kit gene mutation status. METHODS： Thirty-three of 74 （44.6%） small bowel gastrointestinal stromal tumor （GIST） patients who developed recurrence after curative resection and not treated with Glivec were classified as group A patients. Twenty-two advanced small bowel GIST patients treated with Glivec were classified as group B patients. Clinicopathological features, post-recurrence and overall survival rates were compared. Each tumor in group B patients was investigated for mutations of kit or plateletderived growth factor alpha （PDGFRA）. The mutation type was correlated with clinical outcomes. The antitumor effect and safety of Glivec in group B patients were also assessed. RESULTS： Advanced small bowel GIST patients treated with Glivec had substatntially longer post-recurrence survival and higher overall survival rates than those not treated with Glivec. A total of 15 patients had a partial response （PR） （67.8%）. Activated mutations of c-kit were found in 16 of 19 tested patients and no PDGFRA mutant was identified. In 13 patients with GISTs harboring exon 11 kit mutations, the partial response rate （PR） was 69.3%, whereas two of three patients with tumors containing an exon 9 kit mutation had an overall response rate （ORR） of 66.7% （not significant）. CONCLUSION： Glivec significantly prolongs the postrecurrence and overall survival of Asian patients with advanced GISTs. Glivec induces a sustained objective response in more than half of Asian patients withadvanced small bowel GISTs. Activated mutations of kit exon 11 are detectable in the vast majority of GISTs. There is no difference in the PR rate for patients whose GISTs have kit exon 9 and exon 11 mutations.

Perforation of the colon by invading recurrent gastrointestinal stromal tumors during sunitinib treatment

The molecular targets of sunitinib are receptor tyrosine kinases (RTKs),and this drug has also been known to exert blocking effects on the activation of KIT,which is similar to the mechanism of action of imatinib. Moreover,sunitinib has an additional anti-angiogenic effect through its inhibition of the vascular endothelial growth factor receptor activation. We report here a 70-year-old patient diagnosed with a recurrent gastrointestinal stromal tumor (GIST),which invaded the transverse colon and led to a perforation during sunitinib treatment. A computed tomography scan and 3-dimensional reconstruction showed necrosis of the recurrent hepatic mass and perforation of the invaded transverse colon. After percutaneous drainage of the intraperitoneal abscess,antibiotic treatment and restricted diet,the condition of the patient improved. The present case is the first to report that sunitinib,which is administered to treat GIST resistant to imatinib,can cause unexpected colon perforation and subsequent peritonitis.

Giant malignant gastrointestinal stromal tumors: Recurrence and effects of treatment with STI-571

AIM: Malignant gastrointestinal stromal tumors (GISTs)are rare. Tumors larger than 10 cm tend to recur earlier:the larger the volume of the tumor, the worse the prognosis.We hypothesized that treatment with imatinib mesylate (Gleevec; STI-571), a c-kittyrosine kinase inhibitor, as palliative therapy would prolong the survival of patients with recurrent giant malignant GISTs after resection.METHODS: We performed a retrospective analysis of the effects of resection on patients with giant GISTs (＞10 cm in diameter) to determine the overall survival and recurrence rates. Twenty-three patients diagnosed with giant GISTs were included from June 1996 to December 2003. STI571 was not available until January 2000. After that time,9 patients received this drug. The factors of age, sex, tumor location, histological surgical margin, and STI-571, tumor size changes and drug side effects were reviewed. We compared the survival rate to determine the prognostic factors and the effects of STI-571 on patients with recurrent malignant gastrointestinal stromal tumor.RESULTS: The positive surgical margin group had a significantly higher recurrence rate than the negative margin group (P = 0.012). A negative surgical margin and palliative treatment with STI-571 were significant prognostic variables (Log-rank test,P＜0.05). Age, sex and tumor location were not significant prognostic variables. The 5-year survival rate of the surgical margin free patients was 80%and the 2-year survival rate of the surgical margin positive patients was 28%. The 5-year survival rate was 80% for the patients given STI-571 and 30% for the patients not given STI-571. The use of STI-571 gave a significant tumor shrinkage (6/9) rate in patients with giant GIST recurrence after resection.CONCLUSION: A negative surgical margin and the use of STI-571 after surgical resection were good prognostic indicators. Achieving a tumor-free surgical margin is still the best primary treatment for patients with such tumors.If STI-571 is used immediately when the surgical margin is positive and the tumor recurs after resection, then the prognosis of patients with giant GISTs can be improved.

Clinicopathological and immunohistochemical analysis of gastrointestinal stromal tumor

AIM： To investigate the clinicopathological features of gastrointestinal stromal tumor （GIST） and to study the reference indexes for malignancy. METHODS： Fifty-two cases of primary GIST were distinguished from a group of gastrointestinal mesenchymal tumors using a panel of antibodies such as CD117 and CD34 by immunohistochemical SP method. Their biological behaviors were analyzed using the expression of p21WAF1 and Bax in 52 cases of GIST. RESULTS： Grossly, the tumor size was between 1.5 cm and 13 cm （mean： 5.5 cm）. Focal areas of hemorrhage, necrosis, or small cyst formation could be seen. Microscopically, the tumor was composed of spindle cells （20 cases）, epithelioid cells （20 cases） and mixed cells （12 cases）. Immunohistochemically, CDl17 and CD34 showed diffuse strong positive expressions, the positive rates were 98.1% and 92.3%. SMA, S-100, NSE, NF and MBP showed focal positive expressions, the positive rates were 48.1%, 28.8%, 25%, 21.2% and 42.3% respectively. Vimentins were all positive desmin and CgA were all negative. In normal adult stomach and intestine, the immunoreactive staining for CD117 and CD34 showed immunoreactive interstitial cells of Cajal in myenteric neuroplexus. Among the 52 cases of GIST, 27 were positive for p21WAF1 （51.9%）, 29 for Bax （55.8%）. The expression of p21WAF1 and Bax had no significent difference with the localization, size, histological subtype of GIST, but had a significent difference with the histological grade （P = 0.000, respectively）, p21WAF1 expression had a positive correlation to Bax expression （r = 0.461, P = 0.001, k = 0.459）. CONCLUSION： GIST has complicated arrangements and various cell types. Positivity of CD117 and CD34 is the most valuable factor in diagnosing GIST. Expression of p21WAF1 and Bax plays an important role in potential malignancy and malignancy rather than in benign GIST. p21WAF1 and Bax may be used as the markers in the assessment of GIST malignant potential.

Advanced gastrointestinal stromal tumor patients with complete response after treatment with imatinib mesylate

AIM： Most gastrointestinal stromal tumors （GISTs） express constitutively activated mutant isoforms of kit kinase or platelet-derived growth factor receptor alpha （PDGFRA）, which are potential therapeutic targets for imatinib mesylate （Glivec）. Partial response occurred in almost two thirds of GIST patients treated with Glivec. However, complete response （CR） after Glivec therapy was sporadically reported. Here we illustrated advanced GIST patients with CR after Glivec treatment. METHODS： Between January 2001 and June 2005, 42 advanced GIST patients were treated with Glivec. Patients were administered 400 mg of Glivec in 100-mg capsules, taken orally daily with food. The response of the tumor to Glivec was evaluated after one month, three months, and every three months thereafter or whenever medical need was indicated. Each tumor of patients was investigated for mutations of kit or PDGFRA. RESULTS： The median follow-up time of the 42 ad-vanced GIST patients treated with Glivec was 16.9 months （range, 1.0- 47.0 months）. Overall, 3 patients had complete response CR （7.1%）, 26 partial response （67.8%）, 5 stationary disease （11.9%）, and 3 progressive disease （11.9%）. The median duration of Glivec administration for the three patients was 36 months （range, 23-36 months）. The median time to CR after Glivec treatment was 20 months （range, 9-26 months）. Deletion and insertion mutations of c-kit exon 11 and insertion mutation of c-kit exon 9 were found in two cases and one case, respectively. CONCLUSION： Complete response （CR） can be achieved in selected advanced GIST patients treated with Glivec. The median time to CR after Glivec treatment was 20 months. Deletion and insertion mutations of kit exon 11 and insertion mutation of kit exon 9 contribute to the genetic features in these selected cases.

Assessment of gastrointestinal stromal tumors with computed tomography following treatment with imatinib mesylate

AIM: To evaluate and characterize the patterns of disease progression of metastatic or unresectable gastrointestinal stromal tumor (GIST) treated with imatinib mesylate, and to determine the prognostic significance associated with disease progression. METHODS: Clinical data and computed tomography (CT) images were retrospectively reviewed in 17 GIST patients who were treated with imatinib mesylate from October 2002 to October 2006. Apart from using size measurement for evaluation of tumor response [Response Evaluation Criteria in Solid Tumors (RECIST) criteria], patterns of CT changes during treatment were evaluated and correlated with clinical data. RESULTS: There were eight non-responders and nine responders. Five patterns of CT change during treatment were found: focal progression (FP), generalized progression (GP), generalized cystic change (GC), new cystic lesion (NC) and new solid lesion (NS). At the end of study, all non-responders showed GP, whereas responders showed cystic change (GC and NC) and response according to RECIST criteria. Overall survival was significantly better in patients with cystic change or response within the RECIST criteria compared with GP patients (P = 0.0271). CONCLUSION: Various patterns of CT change in patients with GIST who responded to imatinib mesylate were demonstrated, and might determine the prognosis of the disease. A combination of RECIST criteria and pattern of CT change are proposed for response evaluation in GIST.

KIT-negative gastrointestinal stromal tumors with a long term follow-up:A new subgroup does exist

AIM： To investigate the incidence of KIT immunohostochemical staining in （GI） stromal tumors （GISTs）, and to analyze the clinical manifestations of the tumors and prognostic indicators. METHODS： We retrospectively analyzed 50 cases of previously diagnosed GISTs. Tissue samples were assessed with KIT （CDl17 antigen）, CD34, SMA, desmin, S-100, NSE, PCNA, Ki-67, and BCL-2 for immunohistochemical study and pathological characteristics were analyzed for prognostic factors. RESULTS： Fifteen tumors （30%） were negative in KIT staining. A significant association was observed between gender （male patients： 14/15） and KIT-negative staining （P = 0.003）.The patients＇s mean age was 56.6 years. Tumors developed in stomach （n = 8）, small intestine （n = 5）, large intestine （n = 1） and oesophagus （n = 1）. The mean tumor size was 5.72 cm. The mitotic count ranged from 0-29/50 HPF （mean： 3.4） and 73% of tumors showed no necrosis. The majority of the tumors （67%） had dual or epithelioid differentiation. Tumors were classified as very low or low risk （n = 7）, intermediate risk （n = 5）, and high risk （n = 3） groups. Twelve （80%） patients were alive without evidence of residual tumor for an average period of 40.25 mo （12-82 too）; three patients developed metastatic disease to the liver and eventually died within 2-12 mo （median survival： 8.6 too）.CONCLUSION： A small subgroup of GISTs fulfils the clinical and morphological criteria of these tumors, and lacks KIT expression. These tumors predominantly developed in the stomach, being dual or epithelioid in morphology, which are classified as low risk tumors and presented a better survival status than KIT-positive tumors. The ability to diagnose GISTs still depends on immunohistochemical staining but the research should extend in gene mutations.

Expression of p16 gene and Rb protein in gastric carcinoma and their clinicopathological significance

AIM:To analyze the correlation between the protein expression of p16 and Rb genes in gastric carcinoma (GC), to investigate the role of p16 gene in invasion and lymph node metastasis of GC, and to examine the deletion and mutation in exon 2 of p16 gene in GC. METHODS: The protein expression of p16 and Rb genes was examined by streptavidin-peroxidase conjugated method (S-P) in normal gastric mucosa, dysplastic gastric mucosa and GC. The deletion and mutation of p16 gene were examined by polymerase chain reaction (PCR) and polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) respectively in normal gastric mucosa and GC. RESULTS: The positive rates of P16 and Rb protein expression respectively were 96% (77/80) and 99% (79/80) in normal gastric mucosa, 92% (45/50) and 80% (40/50) in dysplastic gastric mucosa, 48% (58/122) and 60% (73/122) in GC. The positive rates of P16 and Rb protein expression in GC were significantly lower than that in normal gastric mucosa and dysplastic gastric mucosa (P<0.05). The positive rate of P16 protein expression in mucoid carcinoma (10%, 1/10) was significantly lower than that in poorly differentiated carcinoma (51%, 21/41), undifferentiated carcinoma (58%, 15/26) and signet ring cell carcinoma (62%, 10/16) (P<0.05). The positive rates of P16 protein in 30 cases of paired primary and lymph node metastatic GC were 47% (14/30) and 17% (5/30) respectively, being significantly lower in the later than in the former (P<0.05). There was no mutation in exon 2 of p16 gene in the 25 freshly resected primary GCs. But five cases in the 25 freshly resected primary GCs displayed deletion in exon 2 of p16 gene. The positive rate of both P16 and Rb proteins was 16% (14/90), and the negative rate of both P16 and Rb proteins was 8% (7/90) in 90 GCs. The rate of positive P16 protein with negative Rb protein was 33% (30/90). The rate of negative P16 protein with positive Rb protein was 43% (39/90). There was reverse correlation between P16 and Rb expression in 90 GCs CONCLUSION: The loss protein expression of p16 and Rb genes is related to GC. The loss expression of P16 protein is related to the histopathologic subtypes and lymph node metastasis of GC. Expression of P16 and Rb proteins in GC is reversely correlated. The deletion but not mutation in exon 2 of p16 gene may be involved in GC.