Endocrine tumors of the gastrointestinal and pancreatic systems. Multiple endocrine adenoma from another viewpoint

The 24 endocrine pancreatic tumors and 14 carcinoids were examined immunohistochemically for cholecystokinin, insulin, gastrin, GIP, glucagon, sercretin, VIP, motilin, neurotensin, pancreatic polypeptide (PP), somatostatin, and ACTH. In 12 tumors of the pancreas more than one peptide-containing cell type was observed. The clinical symptoms showed hypersecretion of only one of the hormones, however. The midgut carcinoids (jejunum, appendix) represented the classical view of the carcinoid as an argentaffin cell tumor secreting 5-hydroxytryptamine. Tumors originating in the foregut (bronchus, stomach, duodenum) and hindgut carcinoids (rectum) were nonargentaffine, containing and secreting various polypeptide hormones. We conclude that light microscopic immunohistochemical methods are useful in distinguishing endocrine from nonendocrine tumors and multihormonal syndromes (MEA) in the classification of predominant hormone-secreting tumors.     

Two von Recklinghausen''s disease cases with pheochromocytomas and gastrointestinal stromal tumors (GIST) in combination

We here document two cases of von Recklinghausen's disease with both pheochromocytomas and gastrointestinal stromal tumors (GIST). It is very rare that these three disorders are found to occur simultaneously, although the fact that preoperative detection of GIST is difficult except with large tumors may be important in this respect. In the present cases, GIST were not evident on preoperative computed tomography and magnetic resonance imaging, and were identified unexpectedly during surgery. Our findings indicate that investigation of the intraperitoneal space should be performed during adrenalectomy for pheochromocytomas with von Recklinghausen's disease.     

Anomalous overexpression of p27(Kip1) in sporadic pancreatic endocrine tumors

BACKGROUND: Little is known about the cellular defects and molecular mechanisms leading to pancreatic endocrine tumors (PETs). p27(Kip1) is a universal cyclin-dependent kinase inhibitor (CDKI), which acts as a tumor suppressor and a negative regulator of cell cycle. From previous reports, quiescent cells show high levels of p27(Kip1) expression while neoplastic and proliferating cells show no detectable p27(Kip1) expression. We hypothesize that in malignant sporadic PETs, p27(Kip1) expression would be decreased compared with benign PETs and normal pancreatic tissue. METHODS: Western analysis was performed on 28 PETs (7 malignant, 21 benign), 2 nonendocrine cell lines, and 5 endocrine cell lines. Signal intensities were quantitated using densitometry and standardized to normal pancreas. RESULTS: Unexpectedly, increased p27(Kip1) expression as compared with control was seen in both benign and malignant tumors, as well as in all four pancreatic islet tumor cell lines, but not fibroblast or pituitary cell lines, evaluated. There was no difference in p27(Kip1) level between benign and malignant tumors. CONCLUSION: This represents the first report of anomalous p27(Kip1) overexpression in sporadic PETs, and is part of a growing literature describing the paradoxical overexpression of p27(Kip1) in human tumors that includes other endocrine tumors. These studies suggest a unique molecular pathway leading to endocrine tumorigenesis.     

Loss of membrane localization and aberrant nuclear E-cadherin expression correlates with invasion in pancreatic endocrine tumors

Decrease in E-cadherin is considered a molecular event in dysfunction of the cell-cell adhesion system, triggering invasion and metastasis in many malignancies, including those of endocrine origin. In addition, alterations in the cadherin-catenin system may also be involved in tumorigenesis. E-cadherin and beta-catenin, components of the Wnt signal transduction pathway, may serve as a common switch in central processes that regulate cellular differentiation and growth. The purpose of this study was to examine if abnormalities of the Wnt signaling pathway, specifically, E-cadherin and beta-catenin, occur in pancreatic endocrine tumors (PETs) and correlate these with clinicopathologic parameters. Tissue microarrays were constructed from 57 cases with 4 to 14 cores measuring 1.0 mm from each case. Size of tumor, presence or absences of necrosis, gross invasiveness/demarcation, lymphovascular invasion, and lymph node involvement and liver metastasis were recorded. The mitotic count, expressed per 50 high power fields (HPF) and MIB-1 index of the entire tumor were assessed. All the tissue microarray blocks were stained with commercially available antibodies to E-cadherin (cytoplasmic and extracellular domains), beta-catenin, APC, and GSK-3beta. Twenty-seven were male patients and 30 female, ranging in age from 23 to 80 years (mean, 51.7 y). Six patients had MEN1 syndrome and 1 von Hippel Lindau disease. The tumors ranged in size from 0.8 to 9.8 cm with a mean of 3.4 cm. Sixteen patients had lymph node spread and 7 had liver metastasis. The Ki-67 labeling index ranged from 1% to 30% and the mitotic counts from 0 to 27 per 50 HPF. Thirty of 57 cases (52.6%) cases showed abnormal beta-catenin expression. Thirteen of the 16 cases with lymph node metastasis and all 7 cases with liver spread showed abnormalities of beta-catenin immunostaining. Only 2 cases showed nuclear beta-catenin. The average size of tumors with beta-catenin abnormalities was 4.8 cm. Thirty-four of the 57 (59.6%) cases showed loss of normal membranous immunoreactivity for both antibodies E-cadherin, including nuclear localization in 18 cases with the antibody that recognizes the cytoplasmic domain. E-cadherin decrease and/or loss was identical to beta-catenin with the same 13 cases showing nodal involvement and all 7 cases with liver metastasis displaying aberrant E-cadherin staining. Seven of the 18 cases with nuclear E-cadherin had lymph node spread and 3 liver metastases. The mean size of the 34 cases with abnormal E-cadherin expression was 4.4 cm, compared to the series mean of 3.4 cm. Interestingly, cases with nuclear E-cadherin had a mean size of 5.2 cm. beta-catenin and E-cadherin abnormalities did not correlate with other clinicopathological parameters. All 57 cases showed cytoplasmic immunoreactivity for APC, and cytoplasmic and nuclear positivity for GSK-3beta. APC and GSK-3beta did not show any correlation with beta-catenin or E-cadherin staining.Abnormalities of beta-catenin and E-cadherin immunoexpression are seen in the majority of PETs. Nuclear beta-catenin is rare in PET but nuclear E-cadherin, a previously unrecognized staining pattern in PETs was seen 18 of 57 cases with the antibody detecting the cytoplasmic fragment of E-cadherin. Aberrant expression of both beta-catenin and E-cadherin correlated strongly with lymph node spread and liver metastases.     

Cox-2和VEGF在胃肠道间质瘤中的表达及其相关性研究

目的：探讨环氧合酶-2（Cox-2）和血管内皮生长因子（VEGF）在胃肠道间质瘤（GIST）中的表达及其与临床病理特征的关系,分析两者在GIST中的作用及相关性。方法：用免疫组织化学染色检测104例GIST中Cox-2和VEGF的表达．分析Cox-2和VEGF的表达与GIST临床病理特征的关系及其相关性。结果：①104例GIST中Cox-2和VEGF的阳性表达率分别为76．0％、68.3％。②Cox-2和VEGF的表达与病人的性别、年龄、肿瘤部位、大小等临床病理特征无关．而与组织学分级有关。③Cox-2和VEGF的表达呈正相关。结论：Cox-2和VEGF的表达与组织学分级相关,提示Cox-2和VEGF在GIST的发生、发展中发挥重要作用,可作为GIST组织学良恶性评价的潜在指标.     

Gut-endocrinomas (carcinoids and related endocrine variants) of the breast: an analysis of 310 reported cases

The purpose of this study was to analyze the present status of gut-endocrinomas (carcinoids and related endocrine variants) of the breast, an extremely rare site for primary growth of such neoplasms, and to provide precise and reliable information concerning these neoplasms on varying clinicopathological aspects for investigators engaged in relevant research fields. A total of 310 cases presented in this analysis consisted of 196 carcinoids, 102 typical and 94 atypical, and 114 related endocrine variants; in the last group, the expression of "breast carcinoma with (neuro-) endocrine differentiation" was often used without referring to the term "carcinoid." A statistical evaluation was performed on most occasions based on a comparison among three groups of typical carcinoids, atypical carcinoids and related endocrine variants, or between the former two series of carcinoids and the third series of endocrine carcinomas. Statistically significant differences between the groups of carcinoids and endocrine carcinomas were recognized in terms of average age, tumor size categories of < or = 20 mm and 21-50 mm, rates of metastases, and positive neuron-specific enolase (NSE) immunohistochemistry. Contrary to our expectations no statistically significant difference between these two groups was evident in terms of overall average tumor size, Grimelius argyrophilia for endocrine nature, or postoperative 5-year survival rates in curative resection cases. It seems important to establish more precise diagnostic criteria for "endocrine carcinomas" from the viewpoint of a certain possibility that some of these neoplasms may belong to the atypical carcinoid group.     

胃肠道间质瘤的诊断及外科治疗体会

目的分析胃肠道间质瘤（GIST）的临床特征及手术方式。方法回顾性分析2001年1月至2005年12月经手术病理证实的GIST47例资料。结果肿瘤发生于胃部18例，十二指肠8例，小肠19例，直肠2例。4例因肿瘤广泛转移行姑息性切除，1例直肠GIST经肛门切除，其余42例均达到外科根治性切除，其中行受累脏器局部切除4例，大部切除26例，多脏器切除12例。术后平均随访20个月，术后复发和转移9例，复发问期平均为13个月。其中8例行再次手术治疗，1例再复发后行3次手术治疗。本组无手术死亡病例，术后并发细菌性腹膜炎1例，切口裂开1例，均治愈。结论外科手术是GIST治疗的首选，对复发病例仍应争取再手术治疗。     

"Seedling" mesenchymal tumors (gastrointestinal stromal tumors and leiomyomas) are common incidental tumors of the esophagogastric junction

Gastrointestinal stromal tumors (GISTs) are the most common nonepithelial neoplasm of the gastrointestinal tract and show a predilection for the stomach. Most are detected because of symptoms, but some are incidental findings at autopsy or surgery for other reasons. Incidental GISTs tend to be smaller at diagnosis, but even small (<1 cm) GISTs have been shown to harbor activating KIT mutations at rates similar to advanced GISTs. However, the prevalence and characteristics of small GISTs in surgical resections of the esophagogastric junction (EGJ) remains unclear. We studied 150 esophagogastric resections for esophageal or EGJ carcinomas (100 with preoperative chemoradiation and 50 untreated cases) that had been extensively embedded for histologic examination (mean 30 sections/case). Number, size, morphology, and location of all GISTs and leiomyomas were recorded. All potential GISTs were evaluated with CD117 and CD34 immunohistochemistry, and a subset (35) leiomyomas with smooth muscle actin, desmin, and CD117. We found 18 incidental GISTs in 15 of 150 (10%) patients; 3 patients harbored 2 separate lesions. Prevalence of GIST was identical in treated (10 of 100) and untreated (5 of 50) cases. All (100%) showed positivity for both CD117 and CD34 and all were of spindle cell morphology. Lesions ranged from 0.2 to 3.0 mm in size (mean 1.3 mm). Eight (44%) were based in the outer muscularis propria, 7 (39%) in inner muscularis, and 3 (17%) between the muscle layers. The lesions tended to cluster near the EGJ, with 8 (44%) on the gastric side, 9 (50%) on the esophageal side, and 1 (6%) undetermined owing to overlying ulceration. Leiomyomas were even more common than GIST, occurring in 47% of patients (44% of treated and 52% of untreated, P=0.39), with a mean of 3 leiomyomas per patient (range 1 to 13) and mean size of 1.7 mm (range 0.2 to 12 mm). Unlike colorectal leiomyomas, most (91%) EGJ leiomyomas were located in the inner muscularis propria and only rarely (1%) in muscularis mucosa. These results suggest that GIST and leiomyoma are common incidental "seedling" lesions of the EGJ, found in 10% and 47% of patients undergoing surgery for esophageal carcinoma. The common occurrence of microscopic GISTs compared with the rarity of clinically manifest and malignant esophagogastric GISTs suggests that additional genetic or epigenetic alterations must happen for neoplastic progression.     

46例胃肠道间质瘤的临床诊治分析

目的探讨胃肠道间质细胞瘤的诊断和治疗。方法回顾性分析1997年1月至2005年1月收治的46例胃肠道间质细胞瘤的临床资料。结果本组46例均行手术治疗。无手术中死亡病例。术后在切口感染及其它严重并发症。术后获得随访42例。其中良性及交界性GIST获得随访26例（26／28）,平均随访30个月,为无瘤生存。恶性GIST获得随访15例,平均随访21个月。其中7例为无瘤生存,2例分别于术后第10及21个月发生肝多发性转移。1例术后20个月发生全身骨转移,3例分别于术后第6、9及11个月死于多发性远处转移。结论GIST由于缺乏特异的临床表现,影像学及内镜检查往往在术前亦难以作出定性诊断,但B超内镜引导下细针穿刺活检及免疫组化检查对诊断比较可靠。手术治疗效果良好。手术治疗的原则是：良性及交界性GIST以局部切除为主,恶生GIST宜行较大范围的手术,必要时须行联合脏器切除术。     

Experimental study on carbohydrate metabolism and pancreatic endocrine function after pancreatectomy--influence of islet activating protein (IAP)

The influences of IAP on the residual pancreatic endocrine function and carbohydrate metabolism after extensive pancreatectomy in the rat were studied with oral glucose tolerance test (OGTT), arginine tolerance test (ATT), and measurement of hepatic glycogen, and hepatic glycolytic enzyme activity, and histological examination, etc. Wistar male rats weighing around 300 g were divided into the groups with IAP treatment and without it, and in the group with IAP treatment IAP 10 micrograms/kg was administered without anesthesia via the tail vein. In each group 60 and 90% pancreatectomies were performed in accordance with Scow's method, and the simple laparotomy group was used as control. Slight abnormality of glucose tolerance was shown in 60% pancreatectomy. The abnormality became worse with time in 90% pancreatectomy. Glucagon secretion was not damaged markedly even after extensive pancreatectomy. IAP stimulated IRI secretory response and improved glucose tolerance in 60% pancreatectomy group. IAP showed no effect in 90% pancreatectomy group. IAP did not stimulate IRG secretory response after pancreatectomy. Hepatic glycolytic enzyme activity was high in the group with IAP treatment. From the above observation, it has been suggested that IAP may be indicated for the abnormal carbohydrate metabolism after pancreatectomy, if pancreatectomy is not too extensive.     

中期因子在胰腺癌组织中的表达及其临床意义

目的探讨中期因子 (midkine,MK)的蛋白表达水平与胰腺癌血管生成、生物学特性和预后的关系。方法采用免疫组织化学方法检测 5 2例胰腺癌组织中MK的蛋白表达和微血管密度(MVD) ,并与临床病理及预后指标作对照分析。结果胰腺癌的MVD平均为 6 4± 18,MK表达阳性率为 73%。有淋巴结转移、Ⅲ～Ⅳ期和MVD高的患者 ,MK阳性表达率明显高于无淋巴结转移、Ⅰ～Ⅱ期和MVD低的患者 (P <0 0 1)。MK高表达患者术后生存时间比MK低表达患者明显缩短 (P <0 0 1)。结论MK的蛋白表达水平能反映胰腺癌细胞的恶性程度 ,可作为胰腺癌转移和预后分析的指标。     

Laparoscopic resection of gastric gastrointestinal stromal tumors (GIST) is safe and effective, irrespective of tumor size

Background

Feasibility and long-term safety of laparoscopic removal of gastric gastrointestinal stromal tumors (GISTs) of the stomach is well established for lesions smaller than 2 cm. Our specific aim was to explore whether laparoscopic treatment is equally applicable for gastric GISTs larger than 2 cm.

Methods

Between 1997 and 2010, 31 consecutive patients presenting with a primary gastric GIST were scheduled for laparoscopic resection, irrespective of tumor size. Prerequisites for laparoscopic approach were the absence of metastases and the presence of a well-defined tumor on CT scanning without involvement of adjacent organs, the esophagogastric junction, or the pylorus of the stomach. Data were retrieved retrospectively from a prospectively collected database, including information on patient demographics, surgical procedure, complications, hospital stay, and recurrence. Diagnosis of GIST was based on microscopic analysis, including immunohistochemistry with a panel of antibodies: CD117, CD34, DOG1, S100, desmin, and smooth muscle actin.

Results

All 31 laparoscopic resections were carried out successfully. The most common symptoms were melena, anemia, and abdominal pain. In one case we performed a laparoscopic approach for a GIST with acute bleeding. Tumor size was smaller than 2 cm in 5 patients and larger than 2 cm in 26 patients. The median tumor size was 4.4 cm (range = 0.4–11.0 cm). Median blood loss was identical in both groups (20 ml), but duration of operation (60 vs. 103 min) and duration of hospital stay (6 vs. 8 days) were lower when tumor size was less than 2 cm. Only one patient (with tumor size <2 cm) experienced a postoperative hemorrhage. After a median follow-up of 52 months, there were no recurrences or metastases.

Conclusion

The low morbidity rates and the long-term disease-free interval of 100% observed in our cohort indicate that laparoscopic resection is safe and effective in treating gastric GISTs, even for tumors larger than 2 cm.