Site-specific biology and pathology of gastroenteropancreatic neuroendocrine tumors

Klöppel, Günter; Rindi, Guido; Anlauf, Martin; Perren, Aurel; Komminoth, Paul

doi:10.1007/s00428-007-0461-0

Cited by 166 publications

(178 citation statements)

References 146 publications

(174 reference statements)

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“…The present study reveals the stomach as the preferential location (22.8% of all GEP-NETs) as suspected by Kloppel & Clemens (1996) and Kloppel et al (2007). This is in contrast to other studies (Modlin et al 2003, Maggard et al 2004, Helland et al 2006, LombardBohas et al 2009) describing NETs of the small intestine most frequently.…”

Section: Stomachcontrasting

confidence: 66%

Gastroenteropancreatic neuroendocrine tumours: the current incidence and staging based on the WHO and European Neuroendocrine Tumour Society classification: an analysis based on prospectively collected parameters

Niederle

Hackl²,

Kaserer³

et al. 2010

Endocrine-Related Cancer

412

303

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As incidence data on gastroenteropancreatic neuroendocrine tumours (GEP-NETs) have so far only been retrospectively obtained and based on inhomogeneous material, we conducted a prospective study in Austria collecting all newly diagnosed GEP-NETs during 1 year. Using the current WHO classification, the tumor, nodes, metastases (TNM) staging and Ki67 grading and the standard diagnostic procedure proposed by the European Neuroendocrine Tumor Society (ENETS), GEP-NETs from 285 patients (male: 148; female: 137) were recorded. The annual incidence rates were 2.51 per 100 000 inhabitants for men, 2.36 per 100 000 for women. The stomach (23%) was the main site, followed by appendix (21%), small intestine (15%) and rectum (14%). Patients with appendiceal tumours were significantly younger than patients with tumours in any other site. About 46.0% were classified as benign, 15.4% as uncertain, 31.9% as well differentiated malignant and 6.7% as poorly differentiated malignant. Patients with benign or uncertain tumours were significantly younger than patients with malignant tumours. Among the malignant tumours of the digestive tract, 1.49% arose from neuroendocrine cells. For malignant gastrointestinal NETs, the incidence was 0.80 per 100 000: 40.9% were ENETS stage I, 23.8% stage II, 11.6% stage III and 23.8% stage IV. The majority (59.7%) were grade 1, 31.2% grade 2 and 9.1% grade 3. NETs of the digestive tract are more common than previously reported; the majority show benign behaviour, are located in the stomach and are well differentiated. G3 tumours are very rare.

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Section: Stomachcontrasting

confidence: 66%

Gastroenteropancreatic neuroendocrine tumours: the current incidence and staging based on the WHO and European Neuroendocrine Tumour Society classification: an analysis based on prospectively collected parameters

Niederle

Hackl²,

Kaserer³

et al. 2010

Endocrine-Related Cancer

412

303

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“…[1][2][3][4] Affected patients seek medical assistance due to symptoms resulting from either hormonal hypersecretion or mass. Thus, pancreatic endocrine tumors are clinically defined as functioning or nonfunctioning depending on the presence of a syndrome related to inappropriate hormone secretion.…”

mentioning

confidence: 99%

Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients

et al. 2010

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Pancreatic endocrine tumors are rare diseases and devising a clinically effective prognostic stratification of patients is a major clinical challenge. This study aimed at assessing whether the tumor-node-metastasis (TNM)-based staging and proliferative activity-based grading recently proposed by the European NeuroEndocrine Tumors Society (ENETS) have clinical value. TNM was applied to 274 patients with histologically diagnosed pancreatic endocrine tumors operated from 1991 to 2005, with last follow-up at December 2007. According to World Health Organization (WHO) classification, 246 were well-differentiated neoplasms (51 benign, 56 uncertain behavior, 139 carcinomas) and 28 poorly differentiated carcinomas. Grading was based on Ki67 immunohistochemistry. Survival analysis not only ascertained the prognostic value of the TNM system but also highlighted that in the absence of nodal and distant metastasis, infiltration and tumor dimensions over 4 cm had prognostic significance. T parameters were then appropriately modified to reflect this weakness. The 5-year survival for modified TNM stages I, II, III and IV were 100, 93, 65 and 35%, respectively. Multivariate analysis identified TNM stages as independent predictors of death, in which stages II, III and IV showed a risk of death of 7, 29 and 58 times higher than stage I tumors (Po0.0001). Ki67-based grading resulted an independent predictor of survival with cut-offs at 5 and 20%. In conclusion, WHO classification assigns clinically significant diagnostic categories to pancreatic endocrine tumors that need prognostic stratification by applying a staging system. The ENETS-TNM provides the best option, but it requires some modifications to be fully functional. The modified TNM described in this study ameliorates the clinical applicability and prediction of outcome of the ENETS-TNM; it (i) assigns a risk of death proportional to the stage at the time of diagnosis, and (ii) allows a clinically based staging of patients, as the T parameters as modified permit their clinical-radiological recognition. Ki67-based grading discerns prognosis of patients with same stage diseases. Modern Pathology (2010) 23, 824-833; doi:10.1038/modpathol.2010 published online 19 March 2010 Keywords: pancreas; tumors; endocrine; staging; TNM; grading; prognosis Pancreatic endocrine tumors are rare and clinically taxing diseases, as their natural history is largely unknown. 1-4 Affected patients seek medical assistance due to symptoms resulting from either hormonal hypersecretion or mass. Thus, pancreatic endocrine tumors are clinically defined as functioning or nonfunctioning depending on the presence of a syndrome related to inappropriate hormone secretion. Such distinction, however, does not provide prognostic information. Pancreatic endocrine tumors are histologically divided into well-

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“…Duodenal tumors are not only smaller, but also are less likely to metastasize to the liver and have a better prognosis than pancreatic gastrinomas (Donow et al 1991, Imamura et al 1992, Yu et al 1999, Klöppel et al 2007. Furthermore, patients with a ZES-related death were more likely to have a gastrinoma in the pancreas and less likely to have a duodenal gastrinoma (Yu et al 1999).…”

mentioning

confidence: 99%

Sonic hedgehog and pancreatic-duodenal homeobox 1 expression distinguish between duodenal and pancreatic gastrinomas

Fendrich¹,

Ramerth²,

Waldmann³

et al. 2009

Endocrine-Related Cancer

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Some 80-90% of gastrinomas are located in the gastrinoma triangle, which includes the duodenum, the pancreatic head, and the hepatoduodenal ligament. The natural history of the tumors depends on their origin. Duodenal gastrinomas are much less aggressive than pancreatic primaries and infrequently develop liver metastases. The reason therefore is unclear. The transcription factor pancreatic-duodenal homeobox 1 (Pdx1) is important in differentiation and development of the pancreas and duodenum. In embryonic development, Sonic hedgehog (Shh) expression establishes a sharp molecular boundary, which allows for the proper patterning of the duodenal and pancreatic epithelium. Pancreatic polypeptide (PP) is expressed in pancreatic islets and is known to be expressed in pancreatic endocrine tumors. This study aims to clarify the expression pattern of Pdx1, Shh, and PP in duodenal and pancreatic gastrinomas. Tissue from 15 patients with duodenal and from 11 patients with pancreatic gastrinomas that underwent surgery between 1987 and 2007 at our institution because of a gastrinoma were evaluated by immunohistochemistry (IHC). Furthermore, tissue from lymph node metastases from two patients with a so far undetected primary gastrinoma was analyzed. IHC revealed strong Pdx1 expression in pancreatic gastrinomas, but not in duodenal gastrinomas. By contrast, there was no Shh expression detectable in pancreatic gastrinomas, but found in all duodenal gastrinomas. This pattern was also true for associated metastases. Shh expression combined with absence of Pdx1 expression in lymph node metastases from patients with an unknown location of the primary suggests a so far undetected duodenal gastrinoma. We show for the first time that only pancreatic, but not duodenal gastrinomas express Pdx1. Moreover, only duodenal gastrinomas express Shh, suggesting a different genetic background of these two tumors. Whereas the expression of Pdx1 in pancreatic gastrinomas might suggest their endocrine origin from islets, duodenal gastrinomas develop from a Pdx1 negative cell cluster. The expression pattern of Pdx1, Shh, and PP in resected metastases can help to locate an otherwise undetected primary gastrinoma.

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Site-specific biology and pathology of gastroenteropancreatic neuroendocrine tumors

Cited by 166 publications

References 146 publications

Gastroenteropancreatic neuroendocrine tumours: the current incidence and staging based on the WHO and European Neuroendocrine Tumour Society classification: an analysis based on prospectively collected parameters

Gastroenteropancreatic neuroendocrine tumours: the current incidence and staging based on the WHO and European Neuroendocrine Tumour Society classification: an analysis based on prospectively collected parameters

Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients

Sonic hedgehog and pancreatic-duodenal homeobox 1 expression distinguish between duodenal and pancreatic gastrinomas

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