今日の臨床サポート

ガストリノーマ

著者: 土井隆一郎 大津赤十字病院

監修: 下瀬川徹 みやぎ県南中核病院企業団

著者校正済:2021/12/22
現在監修レビュー中
参考ガイドライン:
  1. 日本神経内分泌腫瘍研究会(JNETS)膵・消化管神経内分泌腫瘍診療ガイドライン第2版作成委員会:膵・消化管神経内分泌腫瘍(NEN)診療ガイドライン 2019年第2版
患者向け説明資料

概要・推奨   

  1. ガストリノーマ患者の鑑別診断のために、空腹時血清ガストリン濃度と、胃酸分泌測定検査あるいは24時間pHモニター検査が必須であり、カルシウム静注試験*が有用である。局在診断のため、US、CT、MRI、EUS検査、SASIテストが推奨される。MEN1の合併の有無の診断のために、血清Ca濃度測定とインタクトPTH測定が推奨される(推奨度1)。
  1. ガストリノーマと診断された場合、ガストリノーマ切除術が推奨される。十二指腸ガストリノーマに対してはリンパ節郭清を伴う十二指腸切除術が推奨される。膵ガストリノーマに対しては、リンパ節郭清を伴う膵切除術が推奨される(推奨度1)。
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
土井隆一郎 : 特に申告事項無し[2021年]
監修:下瀬川徹 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 膵・消化管神経内分泌腫瘍診療ガイドラインが2015年第1版から2019年第2版に更新されたことに伴って変更された内容を改訂に反映した。ガストリノーマについては大きな変更はなく、細部についてのレビューにとどまった。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. ガストリノーマは消化性潰瘍患者の1%程度を占め、膵神経内分泌腫瘍のなかで、非機能性腫瘍、インスリノーマについで多く、男女比は1.5~2である。
  1. ガストリノーマの20~25%は家族性であり、多発性内分泌腫瘍症1型(MEN1)の部分症である。
  1. ガストリノーマは多くの場合、膵臓または十二指腸に生じ、リンパ節転移や肝転移を来す悪性疾患である。
  1. ガストリノーマはガストリンの過剰産生によって胃酸分泌亢進が起こり、90%以上の患者に消化性潰瘍が認められる。1㎝未満の単発性潰瘍が多く、75%は一般的な十二指腸第1部に1cm以下の単発性潰瘍を生じる(ゾリンジャー・エリソン症候群)[1][2]
  1. ガストリノーマの14%は十二指腸第2部や第3部に、11%は空腸などの異常な部位に潰瘍を生じ、難治性かつ再発性である。
  1. ヘリコバクター・ピロリ菌感染やNSAIDs使用に起因する消化性潰瘍との鑑別が困難な症例がある。
 
ガストリノーマの好発部位

約90%のガストリノーマは点線内の膵頭三角内に発生することが知られている。

出典

img1:  The gastrinoma triangle: operative implications.
 
 Am J Surg. 1984 Jan;147(1):25-31.
問診・診察のポイント  
  1. ガストリノーマの症状はガストリノーマ以外の潰瘍とほぼ同じである。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

著者: Robert T Jensen, Guillaume Cadiot, Maria L Brandi, Wouter W de Herder, Gregory Kaltsas, Paul Komminoth, Jean-Yves Scoazec, Ramon Salazar, Alain Sauvanet, Reza Kianmanesh, Barcelona Consensus Conference participants
雑誌名: Neuroendocrinology. 2012;95(2):98-119. doi: 10.1159/000335591. Epub 2012 Feb 15.
Abstract/Text
PMID 22261919  Neuroendocrinology. 2012;95(2):98-119. doi: 10.1159/000・・・
著者: P K Roy, D J Venzon, H Shojamanesh, A Abou-Saif, P Peghini, J L Doppman, F Gibril, R T Jensen
雑誌名: Medicine (Baltimore). 2000 Nov;79(6):379-411.
Abstract/Text We prospectively evaluated the initial presenting symptoms in 261 patients with Zollinger-Ellison syndrome (ZES) over a 25-year period. Twenty-two percent of the patients had multiple endocrine neoplasia-type 1 (MEN-1) with ZES. Mean age at onset was 41.1 +/- 0.7 years, with MEN-1 patients presenting at a younger age than those with sporadic ZES (p < 0.0001). Three percent of the patients had onset of the disease < age 20 years, and 7% > 60 years. A mean delay to diagnosis of 5.2 +/- 0.4 years occurred in all patients. A shorter duration of symptoms was noted in female patients and in patients with liver metastases. Abdominal pain and diarrhea were the most common symptoms, present in 75% and 73% of patients, respectively. Heartburn and weight loss, which were uncommonly reported in early series, were present in 44% and 17% of patients, respectively. Gastrointestinal bleeding was the initial presentation in a quarter of the patients. Patients rarely presented with only 1 symptom (11%); pain and diarrhea was the most frequent combination, occurring in 55% of patients. An important presenting sign that should suggest ZES is prominent gastric body folds, which were noted on endoscopy in 94% of patients; however, esophageal stricture and duodenal or pyloric scarring, reported in numerous case reports, were noted in only 4%-10%. Patients with MEN-1 presented less frequently with pain and bleeding and more frequently with nephrolithiasis. Comparing the clinical presentation before the introduction of histamine H2-receptor antagonists (pre-1980, n = 36), after the introduction of histamine H2-receptor antagonists (1981-1989, n = 118), and after the introduction of proton pump inhibitors (PPIs) (> 1990, n = 106) demonstrates no change in age of onset; delay in diagnosis; frequency of pain, diarrhea, weight loss; or frequency of complications of severe peptic disease (bleeding, perforations, esophageal strictures, pyloric scarring). Since the introduction of histamine H2-receptor antagonists, fewer patients had a previous history of gastric acid-reducing surgery or total gastrectomy. Only 1 patient evaluated after 1980 had a total gastrectomy, and this was done in 1977. The location of the primary tumor in general had a minimal effect on the clinical presentation, causing no effect on the age at presentation, delay in diagnosis, frequency of nephrolithiasis, or severity of disease (strictures, perforations, peptic ulcers, pyloric scarring). Disease extent had a minimal effect on symptoms, with only bleeding being more frequent in patients with localized disease. Patients with advanced disease presented at a later age and with a shorter disease history (p = 0.001), were less likely to have MEN-1 (p = 0.0087), and tended to have diarrhea more frequently (p = 0.079). A correct diagnosis of ZES was made by the referring physician initially in only 3% of the patients. The most common misdiagnosis made were idiopathic peptic ulcer disease (71%), idiopathic gastroesophageal reflux disease (GERD) (7%), and chronic idiopathic diarrhea (7%). Other less common misdiagnosis were Crohn disease (2%) and various diarrhea diseases (celiac sprue [3%], irritable bowel syndrome [3%], infectious diarrhea [2%], and lactose intolerance [1%]). Other medical disorders were present in 55% of all patients; patients with sporadic disease had fewer other medical disorders than patients with MEN-1 (45% versus 90%, p < 0.00001). Hyperparathyroidism and a previous history of kidney stones were significantly more frequent in patients with MEN-1 than in those with sporadic ZES. Pulmonary disorders and other malignancies were also more common in patients with MEN-1. These results demonstrate that abdominal pain, diarrhea, and heartburn are the most common presenting symptoms in ZES and that heartburn and diarrhea are more common than previously reported. The presence of weight loss especially with abdominal pain, diarrhea, or heartburn is an important clue suggesting the presence of gastrinoma. The presence of prominent gastric body folds, a clinical sign that has not been appreciated, is another important clue to the diagnosis of ZES. Patients with MEN-1 presented at an earlier age; however, in general, the initial symptoms were similar to patients without MEN-1. Gastrinoma extent and location have minimal effects on the clinical presentation. Overall, neither the introduction of successful antisecretory therapy nor widespread publication about ZES, attempting to increase awareness, has shortened the delay in diagnosis or reduced the incidence of patients presenting with peptic complications. The introduction of successful antisecretory therapy, however, has dramatically decreased the rate of surgery in controlling the acid secretion and likely led to patients presenting with less severe symptoms and fewer complications. (ABSTRACT TRUNCATED)

PMID 11144036  Medicine (Baltimore). 2000 Nov;79(6):379-411.
著者: Michihiko Wada, Izumi Komoto, Ryuichiro Doi, Masayuki Imamura
雑誌名: World J Surg. 2002 Oct;26(10):1291-6. doi: 10.1007/s00268-002-6528-9. Epub 2002 Sep 4.
Abstract/Text The current study evaluated efficacy of the intravenous calcium injection test as a new diagnostic approach to clarify the existence of gastrinoma, which often goes undetected with routine testing. Twenty-six patients with hypergastrinemia were studied. For the calcium injection test, blood samples were taken from 12 patients with hypergastrinemia (HG), and three healthy volunteers, and one patient with nonfunctioning endocrine tumor in the pancreas (control). We compared results of the calcium injection test with those of the secretin test and the selective arterial secretagogue injection (SASI) test. The SASI test with secretin was performed in 24 of 26 patients with hypergastrinemia, including 22 of 24 patients with Zollinger-Ellison syndrome (ZES). Accuracy in the diagnosis of tumor localization by the SASI test was 95% (21 of 22) in ZES patients. The secretin test was negative in 3 of 21 patients with ZES (14%). Either the secretin test or the SASI test was positive in 22 of 23 patients (96%). The calcium injection test was administered to 12 patients in the HG group and 4 controls. The HG group showed significantly higher serum gastrin levels than those of the control group in the calcium injection test. Eight of 10 ZES patients (80%) had a positive calcium injection test. We could diagnose gastrinomas in 100% of ZES patients by either the calcium injection test or the secretin test. We have thus confirmed the efficacy of the intravenous calcium injection test in the diagnosis of gastrinoma. The calcium injection test could become an adjunct in the diagnosis of gastrinoma, which often goes undetected with routine testing.

PMID 12205549  World J Surg. 2002 Oct;26(10):1291-6. doi: 10.1007/s002・・・
著者: M Imamura, K Takahashi, H Adachi, S Minematsu, Y Shimada, M Naito, T Suzuki, T Tobe, T Azuma
雑誌名: Ann Surg. 1987 Mar;205(3):230-9.
Abstract/Text Secretin was injected into a feeding or nonfeeding artery of a gastrinoma and blood samples were taken from the hepatic vein (HV) or a peripheral artery (PA) to measure the changes of serum immunoreactive gastrin concentration (IRG). The IRG in the HV rose within 40 seconds and in the PA rose within 60 seconds after the injection of secretin into a feeding artery, but not after secretin was injected into a nonfeeder. These results indicated that secretin directly stimulates a gastrinoma to release gastrin in vivo. The selective arterial secretin injection test (SASI test) was applied in three patients in whom gastrinomas could not be located by computed tomography, ultrasonography, or arteriography, and functioning gastrinomas were located in all three patients. In one patient, malignant gastrinomas in the head of the pancreas and in the duodenum could be resected radically with the help of this test.

PMID 3548610  Ann Surg. 1987 Mar;205(3):230-9.
著者: Masayuki Imamura
雑誌名: World J Gastroenterol. 2010 Sep 28;16(36):4519-25.
Abstract/Text Recent advances in localization techniques, such as the selective arterial secretagogue injection test (SASI test) and somatostatin receptor scintigraphy have promoted curative resection surgery for patients with pancreatic neuroendocrine tumors (PNET). For patients with sporadic functioning PNET, curative resection surgery has been established by localization with the SASI test using secretin or calcium. For curative resection of functioning PNET associated with multiple endocrine neoplasia type 1 (MEN 1) which are usually multiple and sometimes numerous, resection surgery of the pancreas and/or the duodenum has to be performed based on localization by the SASI test. As resection surgery of PNET has increased, several important pathological features of PNET have been revealed. For example, in patients with Zollinger-Ellison syndrome (ZES), duodenal gastrinoma has been detected more frequently than pancreatic gastrinoma, and in patients with MEN 1 and ZES, gastrinomas have been located mostly in the duodenum, and pancreatic gastrinoma has been found to co-exist in 13% of patients. Nonfunctioning PNET in patients with MEN 1 becomes metastatic to the liver when it is more than 1 cm in diameter and should be resected after careful observation. The most important prognostic factor in patients with PNET is the development of hepatic metastases. The treatment strategy for hepatic metastases of PNET has not been established and aggressive resection with chemotherapy and trans-arterial chemoembolization have been performed with significant benefit. The usefulness of octreotide treatment and other molecular targeting agents are currently being assessed.

PMID 20857521  World J Gastroenterol. 2010 Sep 28;16(36):4519-25.
著者: Marc J Berna, K Martin Hoffmann, Jose Serrano, Fathia Gibril, Robert T Jensen
雑誌名: Medicine (Baltimore). 2006 Nov;85(6):295-330. doi: 10.1097/01.md.0000236956.74128.76.
Abstract/Text The assessment of fasting serum gastrin (FSG) is essential for the diagnosis and management of patients with the Zollinger-Ellison syndrome (ZES). Although many studies have analyzed FSG levels in patients with gastrinoma, limited information has resulted from these studies because of their small size, different methodologies, and lack of correlations of FSG levels with clinical, laboratory, or tumor features in ZES patients. To address this issue, we report the results of a prospective National Institutes of Health (NIH) study of 309 patients with ZES and compare our results with those of 2229 ZES patients in 513 small series and case reports in the literature. In the NIH and literature ZES patients, normal FSG values were uncommon (0.3%-3%), as were very high FSG levels >100-fold normal (4.9%-9%). Two-thirds of gastrinoma patients had FSG values <10-fold normal that overlap with gastrin levels seen in more common conditions, like Helicobacter pylori infection or antral G-cell hyperplasia/hyperfunction. In these patients, FSG levels are not diagnostic of ZES, and gastrin provocative tests are needed to establish the diagnosis. Most clinical variables (multiple endocrine neoplasia type 1 status, presence or absence of the most common symptoms, prior medical treatment) are not correlated with FSG levels, while a good correlation of FSG values was found with other clinical features (prior gastric surgery, diarrhea, duration from onset to diagnosis). Increasing basal acid output, but not maximal acid output correlated closely with increasing FSG. Numerous tumoral features correlated with the magnitude of FSG in our study, including tumor location (pancreatic > duodenal), primary size (larger > smaller) and extent (liver metastases > local disease). In conclusion, this detailed analysis of FSG in a large number of patients with ZES allowed us to identify important clinical guidelines that should contribute to improved diagnosis and management of patients with ZES.

PMID 17108778  Medicine (Baltimore). 2006 Nov;85(6):295-330. doi: 10.1・・・
著者: Marc J Berna, K Martin Hoffmann, Scott H Long, Jose Serrano, Fathia Gibril, Robert T Jensen
雑誌名: Medicine (Baltimore). 2006 Nov;85(6):331-64. doi: 10.1097/MD.0b013e31802b518c.
Abstract/Text In two-thirds of patients with Zollinger-Ellison syndrome (ZES), fasting serum gastrin (FSG) levels overlap with values seen in other conditions. In these patients, gastrin provocative tests are needed to establish the diagnosis of ZES. Whereas numerous gastrin provocative tests have been proposed, only the secretin, calcium, and meal tests are widely used today. Many studies have analyzed gastrin provocative test results in ZES, but they are limited by small patient numbers and methodologic differences. To address this issue, we report the results of a prospective National Institutes of Health (NIH) study of gastrin provocative tests in 293 patients with ZES and compare these data with those from 537 ZES and 462 non-ZES patients from the literature. In 97%-99% of gastrinoma patients, an increase in serum gastrin post secretin (Delta secretin) or post calcium (Delta calcium) occurred. In NIH ZES patients with <10-fold increase in FSG, the sensitivity/specificity of the widely used criteria were as follows: Delta secretin > or =200 pg/mL (83%/100%), Delta secretin >50% (86%/93%), Delta calcium > or =395 pg/mL (54%/100%), and Delta calcium >50% (78%/83%). A systematic analysis of the sensitivity and specificity of other possible criteria for a positive secretin or calcium test allowed us to identify a new criterion for secretin testing (Delta > or =120 pg/mL) with the highest sensitivity/specificity (94%/100%) and to confirm the commonly used criterion for calcium tests (Delta > or =395 pg/mL) (62%/100%). This analysis further showed that the secretin test was more sensitive than the calcium test (94% vs. 62%). Our results suggest that secretin stimulation should be used as the first-line provocative test because of its greater sensitivity and simplicity and lack of side effects. In ZES patients with a negative secretin test, 38%-50% have a positive calcium test. Therefore the calcium test should be considered in patients with a strong clinical suspicion of ZES but a negative secretin test. Furthermore, we found that some clinical (diarrhea, duration of medical treatment), laboratory (basal acid output), and tumoral (size, extent) characteristics correlate with the serum gastrin increase post secretin and post calcium. However, using the proposed criteria, the result of these provocative tests (that is, positive or negative) is minimally influenced by these factors, so secretin and calcium provocative tests are reliable in patients with different clinical, laboratory, and tumor characteristics. A systematic analysis of meal testing showed that 54%-77% of ZES patients have a <50% postprandial serum gastrin increase. However, 9%-20% of ZES patients had a >100% increase post meal, causing significant overlap with antral syndromes. Furthermore, we could not confirm the usefulness of meal tests for localization of duodenal gastrinomas. We conclude that the secretin test is a crucial element in the diagnosis of most ZES patients, the calcium test may be useful in selected patients, but the meal test is not helpful in the management of ZES. For secretin testing, the criterion with the highest sensitivity and specificity is an increase of > or =120 pg/mL, which should replace other criteria commonly used today.

PMID 17108779  Medicine (Baltimore). 2006 Nov;85(6):331-64. doi: 10.10・・・
著者: P K Roy, D J Venzon, K M Feigenbaum, P D Koviack, S Bashir, J V Ojeaburu, F Gibril, R T Jensen
雑誌名: Medicine (Baltimore). 2001 May;80(3):189-222.
Abstract/Text We prospectively studied 235 patients with Zollinger-Ellison syndrome (ZES) (205 without and 30 with prior acid-reducing surgery) and compared the results with 984 patients from 182 reports in the literature. The aims of the study were to evaluate the sensitivity of proposed acid secretory criteria for the diagnosis of ZES, propose new criteria, evaluate the variability and methodology of gastric secretory testing, and correlate the symptoms and signs of ZES, tumor extent, and primary tumor size and location with the degree of gastric acid hypersecretion. Multiple endocrine neoplasia-type 1 (MEN1) occurred in 22% of patients. The mean basal acid output (BAO) in patients without and with prior acid-reducing surgery was 41.2 +/- 1.7 mEq/hr (range, 1.6-118.3 mEq/hr) and 27.6 +/- 3.5 mEq/hr (range 5.9-102.9 mEq/hr), respectively. In patients with MEN1, those with female gender, Hispanic, or Asian race had lower BAOs. Diarrhea, esophageal stricture, and pyloric scarring were associated with a higher BAO. Neither other symptoms nor the tumor extent, primary tumor location, or size correlated with the magnitude of acid hypersecretion. ZES diagnosis was delayed a mean of 5.5 +/- 0.4 yr. Patients who were misdiagnosed as having either Crohn or celiac disease had higher BAOs. The sensitivities from our study and the literature review of the proposed BAO criteria for the diagnosis of ZES in patients without previous gastric acid-reducing surgery were 91% and 90% for BAO > or = 15 mEq/hr, 86% and 82% for BAO > or = 18 mEq/hr, 69% and 67% for BAO > 25 mEq/hr, and < 60% for BAO > 31 mEq/hr, respectively. The specificities of all the proposed BAO criteria were high. Both the criterion of BAO > or = 15 mEq/hr and BAO > or = 18 mEq/hr had good specificities and equal sensitivity. With prior acid-reducing surgery, the sensitivities in our study and from the literature review were 100% and 81% for BAO > or = 5 mEq/hr, 73% and 45% for BAO > 14.4 mEq/hr, and 37% and 31% for BAO > 19.2 mEq/hr, respectively. The reported mean specificity for the criterion of BAO > or = 5 mEq/hr was 85%, while it was 100% for the other 2 criteria. The maximal acid output (MAO) criterion of > 70 mEq/hr had sensitivities in the present National Institutes of Health (NIH) study and the literature review of 39% and 31%, respectively, and the criterion of MAO > 100 mEq/hr had a sensitivity of < 15% in patients with no prior acid-reducing surgery. The proposed criterion of BAO/MAO ratio > 0.6 had a low sensitivity. The proposed criterion of the ratio of basal and maximal acid H+ concentration (BAC/MAC ratio) > or = 0.6 had an excellent sensitivity-- > or = 89% in patients with or without previous acid-reducing surgery. The reported specificity for both the BAO/MAO criterion and the BAC/MAC criterion were similar, but BAC/MAC had a better sensitivity. Combination criteria of BAO generally did not improve sensitivity. The criterion of pH < or = 1 was met by only 27% of patients, and pH < or = 0.96 by 21% of patients with previous acid-reducing surgery. For patients with MEN1 with no prior acid-reducing surgery, the sensitivities were lower compared with patients with the sporadic form of ZES. The mean gastric volume in patients without prior acid-reducing surgery was 314 +/- 10 mL/hr and 247 +/- 25 mL/hr in patients with prior acid-reducing surgery. A basal volume criteria of > 160 mL/hr in patients without prior acid-reducing surgery occurred in > 86% of patients, and > 140 mL/hr in 87% of patients with prior acid-reducing surgery; these, thus, are neglected findings that have good sensitivities. Our analysis shows criteria based on MAO, pH, and BAO/MAO ratio do not have high sensitivities and thus are not useful. In patients without prior acid-reducing surgery, the criteria of BAO > or = 15 mEq/hr, BAC/MAC ratio > or = 0.6, and basal gastric volume > 160 mL/hr are useful for the diagnosis of ZES and have good specificities. In patients with prior acid-reducing surgery, the criteria of BAO > or = 5 mEq/hr, BAC/MAC ratio > or = 0.6, and basal gastric volume > 140 mL/hr have high sensitivities. In patients with sporadic ZES without acid-reducing surgery, the criterion of BAO > or = 18 mEq/hr is recommended as it has a similar sensitivity but higher specificity than the criterion of BAO > or = 15 mEq/hr. Only 1 patient in either data set (NIH or the literature) with or without previous acid-reducing surgery had a basal gastric pH > 2, therefore this finding essentially excludes the diagnosis of ZES. Gastric secretory measurements for 30 minutes, but not 15 minutes, give results comparable to those for a full hour. On the basis of these results, a number of gastric secretory criteria are proposed, including some for the first time, and alterations in methodology are proposed that should prove useful in the diagnosis of ZES.

PMID 11388095  Medicine (Baltimore). 2001 May;80(3):189-222.
著者: David C Metz, Robert T Jensen
雑誌名: Gastroenterology. 2008 Nov;135(5):1469-92. doi: 10.1053/j.gastro.2008.05.047. Epub 2008 Aug 12.
Abstract/Text Pancreatic endocrine tumors (PETs) have long fascinated clinicians and investigators despite their relative rarity. Their clinical presentation varies depending on whether the tumor is functional or not, and also according to the specific hormonal syndrome produced. Tumors may be sporadic or inherited, but little is known about their molecular pathology, especially the sporadic forms. Chromogranin A appears to be the most useful serum marker for diagnosis, staging, and monitoring. Initially, therapy should be directed at the hormonal syndrome because this has the major initial impact on the patient's health. Most PETs are relatively indolent but ultimately malignant, except for insulinomas, which predominantly are benign. Surgery is the only modality that offers the possibility of cure, although it generally is noncurative in patients with Zollinger-Ellison syndrome or nonfunctional PETs with multiple endocrine neoplasia-type 1. Preoperative staging of disease extent is necessary to determine the likelihood of complete resection although debulking surgery often is believed to be useful in patients with unresectable tumors. Once metastatic, biotherapy is usually the first modality used because it generally is well tolerated. Systemic or regional therapies generally are reserved until symptoms occur or tumor growth is rapid. Recently, a number of newer agents, as well as receptor-directed radiotherapy, are being evaluated for patients with advanced disease. This review addresses a number of recent advances regarding the molecular pathology, diagnosis, localization, and management of PETs including discussion of peptide-receptor radionuclide therapy and other novel antitumor approaches. We conclude with a discussion of future directions and unsettled problems in the field.

PMID 18703061  Gastroenterology. 2008 Nov;135(5):1469-92. doi: 10.1053・・・
著者: Robert T Jensen, Bruno Niederle, Emmanuel Mitry, John K Ramage, Thomas Steinmuller, V Lewington, Aldo Scarpa, Anders Sundin, Aurel Perren, David Gross, Juan M O'Connor, Stanislas Pauwels, Gunter Kloppel, Frascati Consensus Conference, European Neuroendocrine Tumor Society
雑誌名: Neuroendocrinology. 2006;84(3):173-82. doi: 10.1159/000098009. Epub 2007 Feb 20.
Abstract/Text
PMID 17312377  Neuroendocrinology. 2006;84(3):173-82. doi: 10.1159/000・・・
著者: Jeffrey A Norton, Robert T Jensen
雑誌名: Ann Surg. 2004 Nov;240(5):757-73.
Abstract/Text OBJECTIVE: Highlight unresolved controversies in the management of Zollinger-Ellison syndrome (ZES).
SUMMARY BACKGROUND DATA: Recent studies have resolved some of the previous controversies including the surgical cure rate in patients with and without Multiple Endocrine Neoplasia-type1 (MEN1), the biological behavior of duodenal and pancreatic gastrinomas, role of imaging studies to localize tumor, and gastrectomy to manage acid output.
METHODS: Review of the literature based on computer searches in Index Medicus, Pubmed and Ovid.
RESULTS: Current controversies as identified in the literature include the role of endoscopic ultrasound (EUS), surgery in ZES patients with MEN1, pancreaticoduodenectomy (Whipple procedure), lymph node primary gastrinoma, parietal cell vagotomy, reoperation and surgery for metastatic tumor, and the use of minimally invasive surgical techniques to localize and remove gastrinoma.
CONCLUSIONS: It is hoped that future studies will focus on these issues to improve the surgical management of ZES patients.

PMID 15492556  Ann Surg. 2004 Nov;240(5):757-73.
著者: Volker Fendrich, Jens Waldmann, Detlef K Bartsch, Peter Langer
雑誌名: Nat Rev Clin Oncol. 2009 Jul;6(7):419-28. doi: 10.1038/nrclinonc.2009.82. Epub 2009 Jun 9.
Abstract/Text Pancreatic endocrine tumors (PETs) are uncommon but clinically challenging and fascinating tumors with an annual incidence of 1 per 100,000 people. PETs present as either functional pancreatic tumors or as nonfunctional pancreatic tumors. Functional tumors are commonly associated with a specific hormonal syndrome directly related to a hormone secreted by the tumor, such as Zollinger-Ellison syndrome or organic hyperinsulinism. Nonfunctional tumors do not secrete a hormone resulting in a pathologic syndrome of clinical symptoms. The natural history of PETs is highly variable. Small, benign neoplasms, such as 90% of all insulinomas, are readily curable by surgical resection; however, most other functional and all nonfunctional pancreatic tumors have a much less favorable prognosis. Patients with completely resected tumors generally have a good prognosis, and an aggressive surgical approach in patients with advanced disease may also prolong survival. Many features of the management of pancreatic endocrine tumors, such as timing and extent of resection, and the use of laparoscopic procedures, are currently under debate. This Review describes the current status of surgical treatment for pancreatic endocrine tumors, and discusses the new developments in this field.

PMID 19506584  Nat Rev Clin Oncol. 2009 Jul;6(7):419-28. doi: 10.1038/・・・
著者: J A Norton, D L Fraker, H R Alexander, D J Venzon, J L Doppman, J Serrano, S U Goebel, P L Peghini, P K Roy, F Gibril, R T Jensen
雑誌名: N Engl J Med. 1999 Aug 26;341(9):635-44. doi: 10.1056/NEJM199908263410902.
Abstract/Text BACKGROUND AND METHODS: The role of surgery in patients with the Zollinger-Ellison syndrome is controversial. To determine the efficacy of surgery in patients with this syndrome, we followed 151 consecutive patients who underwent laparotomy between 1981 and 1998. Of these patients, 123 had sporadic gastrinomas and 28 had multiple endocrine neoplasia type 1 with an imaged tumor of at least 3 cm in diameter. Tumor-localization studies and functional localization studies were performed routinely. All patients underwent surgery according to a similar operative protocol, and all patients who had surgery after 1986 underwent duodenotomy.
RESULTS: The 151 patients underwent 180 exploratory operations. The mean (+/-SD) follow-up after the first operation was 8+/-4 years. Gastrinomas were found in 141 of the patients (93 percent), including all of the last 81 patients to undergo surgery. The tumors were located in the duodenum in 74 patients (49 percent) and in the pancreas in 36 patients (24 percent); however, primary tumors were found in lymph nodes in 17 patients (11 percent) and in another location in 13 patients (9 percent). The primary location was unknown in 24 patients (16 percent). Among the patients with sporadic gastrinomas, 34 percent were free of disease at 10 years, as compared with none of the patients with multiple endocrine neoplasia type 1. The overall 10-year survival rate was 94 percent.
CONCLUSIONS: All patients with the Zollinger-Ellison syndrome who do not have multiple endocrine neoplasia type 1 or metastatic disease should be offered surgical exploration for possible cure.

PMID 10460814  N Engl J Med. 1999 Aug 26;341(9):635-44. doi: 10.1056/N・・・
著者: Martin Anlauf, Nele Garbrecht, Tobias Henopp, Anja Schmitt, Regina Schlenger, Andreas Raffel, Markus Krausch, Oliver Gimm, Claus F Eisenberger, Wolfram T Knoefel, Henning Dralle, Paul Komminoth, Philipp U Heitz, Aurel Perren, Gunter Klöppel
雑誌名: World J Gastroenterol. 2006 Sep 14;12(34):5440-6.
Abstract/Text Gastrinomas are defined as gastrin secreting tumors that are associated with Zollinger-Ellison syndrome (ZES). ZES is characterized by elevated fasting gastrin serum levels, positive secretin stimulation test and clinical symptoms such as recurrent peptic ulcer disease, gastroesophageal reflux disease and occasional diarrhea. Genetically, nonhereditary (sporadic) gastrinomas are distinguished from hereditary gastrinomas, which are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome. In general, duodenal gastrinomas are small and solitary if they are sporadic and multiple as well as hereditary. The sporadic gastrinomas occur in the duodenum or in the pancreas while the hereditary gastrinomas almost all occur in the duodenum. Our series of 77 sporadic duodenal neuroendocrine tumors (NETs) includes 18 patients (23.4%) with gastrinomas and ZES. Of 535 sporadic NETs in the pancreas collected from the NET archives of the departments of pathology in Zurich, Switzerland, and Kiel, Germany, 24 patients (4.5%) suffered from sporadic pancreatic gastrinomas and ZES. These NETs have to be distinguished from tumors with immunohistochemical positivity for gastrin but without evidence of ZES. An additional 19 patients suffered from MEN1 and ZES. These patients showed exclusively duodenal gastrinomas, but not pancreatic gastrinomas. The prognosis of sporadic and MEN1-associated duodenal gastrinomas is better than that of pancreatic gastrinomas, since they progress slowly to liver metastasis. In summary, sporadic and MEN1-associated gastrinomas in the duodenum and pancreas show different clinico-pathological and genetic features. The incidence of sporadic duodenal gastrin-producing tumors is increasing, possibly due to optimized diagnostic procedures. In contrast, pancreatic MEN1-associated gastrinomas seem to be extremely rare. A considerable subset of tumors with immunohistochemical expression of gastrin but without evidence of ZES should be designated as functionally inactive NETs expressing gastrin, but not as gastrinomas.

PMID 17006979  World J Gastroenterol. 2006 Sep 14;12(34):5440-6.
著者: Ellen H Morrow, Jeffrey A Norton
雑誌名: Surg Clin North Am. 2009 Oct;89(5):1091-103. doi: 10.1016/j.suc.2009.06.018.
Abstract/Text Much has been learned about the diagnosis and treatment of Zollinger-Ellison Syndrome (ZES), and certain questions require further investigation. Delay in diagnosis of ZES is still a significant problem, and clinical suspicion should be elevated. The single best imaging modality for localization and staging of ZES is somatostatin receptor scintigraphy. Goals of surgical treatment for ZES differ between sporadic and MEN-1-related cases. All sporadic cases of ZES should be surgically explored (including duodenotomy) even with negative imaging results, because of the high likelihood of finding and removing a tumor for potential cure. Surgery for MEN-1-related cases should be focused on prevention of metastatic disease, with surgery being recommended when pancreatic tumors are greater than 2 cm. The role of Whipple procedure, especially for MEN-1 cases, should be explored further. Laparoscopic and endoscopic treatments are more experimental, but may have a role.

PMID 19836486  Surg Clin North Am. 2009 Oct;89(5):1091-103. doi: 10.10・・・
著者: S L Sugg, J A Norton, D L Fraker, D C Metz, J R Pisegna, V Fishbeyn, R V Benya, T H Shawker, J L Doppman, R T Jensen
雑誌名: Ann Surg. 1993 Aug;218(2):138-44.
Abstract/Text OBJECTIVE: This study determined, prospectively, whether duodenotomy (DX) should be routinely performed in explorations for patients with Zollinger-Ellison syndrome (ZES).
SUMMARY BACKGROUND DATA: Duodenal gastrinomas are now being found with increasing frequency in patients with Zollinger-Ellison syndrome. The surgical approach used to detect these tumors is controversial. Some recommend intraoperative endoscopy with transillumination (IOE) at surgery, while others recommend routine DX.
METHODS: Beginning in 1989, the authors prospectively compared the ability of palpation, intraoperative ultrasound (IOUS), IOE, and DX (in that sequence) to detect gastrinomas in 35 consecutive patients with ZES. Each patient also underwent preoperative localization studies.
RESULTS: Thirty-three of 35 patients (94%) had tumor detected and excised; duodenal gastrinomas were excised in 27 patients (77%). The average size of the duodenal tumors was 0.8 cm, significantly smaller (p < 0.005) than the pancreatic and lymph node tumors in this series. Standard palpation after a Kocher maneuver identified 19 of the 31 duodenal tumors (61%) in the 27 patients. IOUS revealed only eight duodenal tumors (26%) and no new lesions. IOE identified 20 duodenal gastrinomas (64%) and 6 new lesions. DX identified 31 duodenal tumors (100%) and 5 additional tumors. The morbidity rate was 17%. One patient had a duodenal fistula after operation (2.8%) and subsequently recovered. No patient died.
CONCLUSIONS: These results demonstrate that the duodenum is the most common location for gastrinoma in patients with ZES (77%) and that DX to detect and remove duodenal gastrinomas should be routinely performed in all explorations for patients with ZES.

PMID 8342993  Ann Surg. 1993 Aug;218(2):138-44.
著者: R C Franz, H O Penzhorn
雑誌名: S Afr J Surg. 2007 May;45(2):58-60.
Abstract/Text
PMID 17674564  S Afr J Surg. 2007 May;45(2):58-60.

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