Special Issue "Neuroendocrine Tumors"

Quicklinks

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 November 2011)

Special Issue Editor

Guest Editor
Dr. med. Volker Fendrich

Department of Surgery, Philipps University Marburg, Baldingerstrasse, 35043 Marburg, Germany
Website | E-Mail
Fax: +49 06421 - 5862105
Interests: pancreatic cancer; neuroendocrine tumors; mouse models of cancer; chemoprevention

Special Issue Information

Dear Colleagues,

Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) are uncommon but clinically challenging and fascinating tumors. GEP-NETs present as either functional or as non-functional tumors. Functional tumors are commonly associated with a specific hormonal syndrome directly related to a hormone secreted by the tumor, like gastrinomas with a Zollinger-Ellison-Syndrome or carcinoid syndrome in patients with neuroendocrine tumors (NET) of the ileum. Non-functional tumors do not secrete a hormone resulting in a clinical syndrome. The natural course of GEP-NETs is highly variable. Small, benign neoplasms such as 90% of all insulinomas or gastric endocrine tumors type 1 are readily curable by surgical resection; however, most other GEP-NETs 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. This special issue focuses on the current standards of management of gastric endocrine tumors, NETs of the pancreas (PNET) and NETs of the ileum. Although the evidence level is low in many instances due to the lack of randomized controlled trials, important treatment recommendations can be given.

Dr. Volker Fendrich
Guest Editor

Keywords

  • neuroendocrine gastrointestinal tumor
  • neuroendocrine tumors of the ileum
  • neuroendocrine tumors of the pancreas
  • surgical therapy

Published Papers (10 papers)

View options order results:
result details:
Displaying articles 1-10
Export citation of selected articles as:

Research

Jump to: Review, Other

Open AccessArticle Succinate Dehydrogenase B Subunit Immunohistochemical Expression Predicts Aggressiveness in Well Differentiated Neuroendocrine Tumors of the Ileum
Cancers 2012, 4(3), 808-820; doi:10.3390/cancers4030808
Received: 18 July 2012 / Revised: 6 August 2012 / Accepted: 9 August 2012 / Published: 16 August 2012
Cited by 1 | PDF Full-text (365 KB) | HTML Full-text | XML Full-text
Abstract
Immunohistochemical loss of the succinate dehydrogenase subunit B (SDHB) has recently been reported as a surrogate biomarker of malignancy in sporadic and familial pheocromocytomas and paragangliomas through the activation of hypoxia pathways. However, data on the prevalence and the clinical implications of SDHB
[...] Read more.
Immunohistochemical loss of the succinate dehydrogenase subunit B (SDHB) has recently been reported as a surrogate biomarker of malignancy in sporadic and familial pheocromocytomas and paragangliomas through the activation of hypoxia pathways. However, data on the prevalence and the clinical implications of SDHB immunoreactivity in ileal neuroendocrine tumors are still lacking. Thirty-one consecutive, advanced primary midgut neuroendocrine tumors and related lymph node or liver metastases from 24 males and seven females were immunohistochemically assessed for SDHB. All patients were G1 tumors (Ki-67 labeling index ≤2%). SDHB immunohistochemistry results were expressed as immunostaining intensity and scored as low or strong according to the internal control represented by normal intestinal cells. Strong positivity for SDHB, with granular cytoplasmatic reactivity, was found in 77% of primary tumors (T), whilst low SDHB expression was detected in 90% of metastases (M). The combined analysis (T+M) confirmed the loss of SDHB expression in 82% of metastases compared to 18% of primary tumors. SDHB expression was inversely correlated with Ki-67 labeling index, which accounted for 1.54% in metastastic sites and 0.7% in primary tumors. A correlation between SDHB expression loss, increased Ki-67 labeling index and biological aggressiveness was shown in advanced midgut neuroendocrine tumors, suggesting a role of tumor suppressor gene. Full article
(This article belongs to the Special Issue Neuroendocrine Tumors)
Open AccessArticle Epithelial-Mesenchymal Transition Is a Critical Step in Tumorgenesis of Pancreatic Neuroendocrine Tumors
Cancers 2012, 4(1), 281-294; doi:10.3390/cancers4010281
Received: 21 February 2012 / Revised: 27 February 2012 / Accepted: 1 March 2012 / Published: 8 March 2012
Cited by 6 | PDF Full-text (3700 KB) | HTML Full-text | XML Full-text
Abstract
The transcription factors Snail, Slug and Twist repress E-cadherin and induce epithelial-mesenchymal transition (EMT), a process exploited by invasive cancer cells. In this study, we evaluated the role of EMT in the tumorgenesis of neuroendocrine tumors of the pancreas (PNETs) in vitro,
[...] Read more.
The transcription factors Snail, Slug and Twist repress E-cadherin and induce epithelial-mesenchymal transition (EMT), a process exploited by invasive cancer cells. In this study, we evaluated the role of EMT in the tumorgenesis of neuroendocrine tumors of the pancreas (PNETs) in vitro, in vivo and human tumor specimen. Expression of EMT markers was analyzed using immunohistochemistry and real-time PCR. For in vitro studies, BON-1 cells were analyzed regarding expression of EMT markers before and after transfection with siRNA against Slug or Snail, and cell aggregation assays were performed. To asses in vivo effects, Rip1Tag2 mice were treated with vehicle or the snail-inhibitor polythlylenglykol from week 5-10 of age. The resected pancreata were evaluated by weight, tumor cell proliferation and apoptosis. Snail and Twist was expressed in 61 % and 64% of PNETs. This was associated with loss of E-cadherin. RT-PCR revealed conservation of the EMT markers Slug and Snail in BON-1 cells. Transfection with siRNA against Slug was associated with upregulation of E-cadherin, enhanced cell-cell adhesion and inhibition of cell proliferation. Snail-inhibition in vivo by PEG was associated with increased apoptosis, decreased tumor cell proliferation and dramatic reduced tumor volume in Rip1Tag2 mice. The presented data show that EMT plays a key role in tumorgenesis of PNETs. The activation of Snail in a considerable subset of human PNETs and the successful effect of Snail inhibition by PEG in islet cell tumors of transgenic mice provides first evidence of Snail as a drug target in PNETs. Full article
(This article belongs to the Special Issue Neuroendocrine Tumors)
Open AccessArticle Chromogranin A as Serum Marker for Gastroenteropancreatic Neuroendocrine Tumors: A Single Center Experience and Literature Review
Cancers 2012, 4(1), 141-155; doi:10.3390/cancers4010141
Received: 30 December 2011 / Revised: 30 January 2012 / Accepted: 10 February 2012 / Published: 15 February 2012
Cited by 10 | PDF Full-text (160 KB) | HTML Full-text | XML Full-text
Abstract
The aim of this study was to assess the clinical sensitivities of the tumor markers chromogranin A (CgA), urinary 5-hydroxyindoleacetic acid (5-HIAA) and alkaline phosphatase (AP) in neuroendocrine tumors (NETs) of the GastroEnteroPancreatic-(GEP-) system depending on tumor primary location and metastatic spread. In
[...] Read more.
The aim of this study was to assess the clinical sensitivities of the tumor markers chromogranin A (CgA), urinary 5-hydroxyindoleacetic acid (5-HIAA) and alkaline phosphatase (AP) in neuroendocrine tumors (NETs) of the GastroEnteroPancreatic-(GEP-) system depending on tumor primary location and metastatic spread. In a retrospective single-center series, sensitivities were evaluated in serum samples from 110 patients with midgut (n = 62) and pancreatic (n = 48) NETs. CgA levels were analyzed by a commercially-available immunoradiometric assay (CIS-bio) during routine follow-up in the years 2000–2009. CgA showed a higher sensitivity for midgut (68%) than pancreatic (54%) NETs. A higher CgA sensitivity and significantly higher median CgA values were found in patients with liver metastases than in those without, and in patients with hepatic and additionally extra-hepatic metastases than in those with hepatic and nodal metastases alone, respectively. We found an overall sensitivity for elevated 5HIAA excretion of 69% for midgut NETs and a significant correlation between median CgA and 5-HIAA values. The sensitivity of AP and the correlations of AP/CgA-data-pairs were low in both midgut and pancreatic NETs, although highest for metastatic pancreatic NETs. The sensitivity of CgA measurement depends on the NET primary location and spread of disease. 5-HIAA and CgA showed comparable sensitivity in midgut NETs, while AP does not seem to be useful as a tumor marker in GEP-NETs. Full article
(This article belongs to the Special Issue Neuroendocrine Tumors)
Open AccessArticle PET-Guided Surgery — High Correlation between Positron Emission Tomography with 11C-5-Hydroxytryptophane (5-HTP) and Surgical Findings in Abdominal Neuroendocrine Tumours
Cancers 2012, 4(1), 100-112; doi:10.3390/cancers4010100
Received: 29 November 2011 / Revised: 29 January 2012 / Accepted: 30 January 2012 / Published: 8 February 2012
Cited by 1 | PDF Full-text (211 KB) | HTML Full-text | XML Full-text
Abstract
Positron emission tomography (PET) with 11C-labeled 5-hydroxytryptophane (5-HTP) is a sensitive technique to visualize neuroendocrine tumours (NETs), due to high intracellular uptake of amine-precursors like L-dihydroxyphenylalanine (L-DOPA) and 5-HTP. NETs are often small and difficult to localize in spite of overt clinical
[...] Read more.
Positron emission tomography (PET) with 11C-labeled 5-hydroxytryptophane (5-HTP) is a sensitive technique to visualize neuroendocrine tumours (NETs), due to high intracellular uptake of amine-precursors like L-dihydroxyphenylalanine (L-DOPA) and 5-HTP. NETs are often small and difficult to localize in spite of overt clinical symptoms due to hormonal excess. In our study, 38 consecutive NET patients underwent 11C-5-HTP-PET and morphological imaging by CT within 12 weeks prior to surgery. Surgical, histopathological and 5-HTP PET findings were correlated. 11C-5-HTP-PET corresponded to the surgical findings in 31 cases, was false negative in six, and true negative in one case resulting in 83.8% sensitivity and 100% specificity. Positive predicted value was 100%. In 11 patients 11C-5-HTP-PET was the only imaging method applied to localize the tumour. Thus, we could demonstrate that functional imaging by 11C-5-HTP-PET in many cases adds vital preoperative diagnostic information and in more than every fourth patient was the only imaging method that will guide the surgeon in finding the NET-lesion. Although the present results demonstrates that 11C-5-HTP may be used as an universal NET tracer, the sensitivity to visualize benign insulinomas and non functioning pancreatic NETs was lower. Full article
(This article belongs to the Special Issue Neuroendocrine Tumors)

Review

Jump to: Research, Other

Open AccessReview Neuroendocrine Tumors of the Lung
Cancers 2012, 4(3), 777-798; doi:10.3390/cancers4030777
Received: 21 May 2012 / Revised: 4 July 2012 / Accepted: 13 July 2012 / Published: 31 July 2012
Cited by 11 | PDF Full-text (2275 KB) | HTML Full-text | XML Full-text
Abstract
Neuroendocrine tumors may develop throughout the human body with the majority being found in the gastrointestinal tract and bronchopulmonary system. Neuroendocrine tumors are classified according to the grade of biological aggressiveness (G1–G3) and the extent of differentiation (well-differentiated/poorly-differentiated). The well-differentiated neoplasms comprise typical
[...] Read more.
Neuroendocrine tumors may develop throughout the human body with the majority being found in the gastrointestinal tract and bronchopulmonary system. Neuroendocrine tumors are classified according to the grade of biological aggressiveness (G1–G3) and the extent of differentiation (well-differentiated/poorly-differentiated). The well-differentiated neoplasms comprise typical (G1) and atypical (G2) carcinoids. Large cell neuroendocrine carcinomas as well as small cell carcinomas (G3) are poorly-differentiated. The identification and differentiation of atypical from typical carcinoids or large cell neuroendocrine carcinomas and small cell carcinomas is essential for treatment options and prognosis. Pulmonary neuroendocrine tumors are characterized according to the proportion of necrosis, the mitotic activity, palisading, rosette-like structure, trabecular pattern and organoid nesting. The given information about the histopathological assessment, classification, prognosis, genetic aberration as well as treatment options of pulmonary neuroendocrine tumors are based on own experiences and reviewing the current literature available. Most disagreements among the classification of neuroendocrine tumor entities exist in the identification of typical versus atypical carcinoids, atypical versus large cell neuroendocrine carcinomas and large cell neuroendocrine carcinomas versus small cell carcinomas. Additionally, the classification is restricted in terms of limited specificity of immunohistochemical markers and possible artifacts in small biopsies which can be compressed in cytological specimens. Until now, pulmonary neuroendocrine tumors have been increasing in incidence. As compared to NSCLCs, only little research has been done with respect to new molecular targets as well as improving the classification and differential diagnosis of neuroendocrine tumors of the lung. Full article
(This article belongs to the Special Issue Neuroendocrine Tumors)
Open AccessReview Gastroenteropancreatic Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type 1
Cancers 2012, 4(2), 504-522; doi:10.3390/cancers4020504
Received: 17 February 2012 / Revised: 10 April 2012 / Accepted: 18 April 2012 / Published: 7 May 2012
Cited by 6 | PDF Full-text (153 KB) | HTML Full-text | XML Full-text
Abstract
We reviewed the literature about entero-pancreatic neuroendocrine tumors in Multiple Endocrine Neoplasia type 1 syndrome (MEN1) to clarify their demographic features, localization imaging, practice, and appropriate therapeutical strategies, analyzing the current approach to entero-pancreatic neuroendocrine tumors in MEN1. Despite the fact that hyperparathyroidism
[...] Read more.
We reviewed the literature about entero-pancreatic neuroendocrine tumors in Multiple Endocrine Neoplasia type 1 syndrome (MEN1) to clarify their demographic features, localization imaging, practice, and appropriate therapeutical strategies, analyzing the current approach to entero-pancreatic neuroendocrine tumors in MEN1. Despite the fact that hyperparathyroidism is usually the first manifestation of MEN1, the penetrance of these tumors is similar. They are characterized by multiplicity of lesions, variable expression of the tumors, and propensity for malignant degeneration. Both the histological type and the size of MEN1 neuroendocrine tumors correlate with malignancy. Monitoring of pancreatic peptides and use of imaging exams allow early diagnosis and prompt surgical treatment, resulting in prevention of metastatic disease and improvement of long-term survival. Surgery is often the treatment of choice for MEN1-neuroendocrine tumors. The rationale for surgical approach is to curtail malignant progression of the disease, and to cure the associated biochemical syndrome, should it be present. Full article
(This article belongs to the Special Issue Neuroendocrine Tumors)
Open AccessReview Medical Treatment of Gastroenteropancreatic Neuroendocrine Tumors
Cancers 2012, 4(1), 113-129; doi:10.3390/cancers4010113
Received: 1 December 2011 / Revised: 23 January 2012 / Accepted: 30 January 2012 / Published: 8 February 2012
Cited by 6 | PDF Full-text (155 KB) | HTML Full-text | XML Full-text
Abstract
Treatment of the clinically and prognostically heterogeneous neuroendocrine neoplasms (NEN) should be based on a multidisciplinary approach, including surgical, interventional, medical and nuclear medicine-based therapeutic options. Medical therapies include somatostatin analogues, interferon-a, mTOR inhibitors, multikinase inhibitors and systemic chemotherapy. For the selection of
[...] Read more.
Treatment of the clinically and prognostically heterogeneous neuroendocrine neoplasms (NEN) should be based on a multidisciplinary approach, including surgical, interventional, medical and nuclear medicine-based therapeutic options. Medical therapies include somatostatin analogues, interferon-a, mTOR inhibitors, multikinase inhibitors and systemic chemotherapy. For the selection of the appropriate medical treatment the hormonal activity, primary tumor localization, tumor grading and growth behaviour as well as the extent of the disease must be considered. Somatostatin analogues are mainly indicated in hormonally active tumors for symptomatic relief, but antiproliferative effects have also been demonstrated, especially in well-differentiated intestinal NET. The efficacy of everolimus and sunitinib in patients with pancreatic neuroendocrine tumors (pNET) has been demonstrated in large placebo-controlled clinical trials. pNETs are also chemosensitive. Streptozocin-based chemotherapeutic regimens are regarded as current standard of care. Temozolomide in combination with capecitabine is an alternative that has shown promising results that need to be confirmed in larger trials. Currently, no comparative studies and no molecular markers are established that predict the response to medical treatment. Therefore the choice of treatment for each pNET patient is based on individual parameters taking into account the patient’s preference, expected side effects and established response criteria such as proliferation rate and tumor load. Platin-based chemotherapy is still the standard treatment for poorly differentiated neuroendocrine carcinomas. Clearly, there is an unmet need for new systemic treatment options in patients with extrapancreatic neuroendocrine tumors. Full article
(This article belongs to the Special Issue Neuroendocrine Tumors)
Open AccessReview Diagnosis and Treatment of Gastrinomas in Multiple Endocrine Neoplasia Type 1 (MEN-1)
Cancers 2012, 4(1), 39-54; doi:10.3390/cancers4010039
Received: 1 December 2011 / Revised: 7 January 2012 / Accepted: 12 January 2012 / Published: 20 January 2012
PDF Full-text (124 KB) | HTML Full-text | XML Full-text
Abstract
Multiple endocrine neoplasia type 1 (MEN-1) is a rare autosomal-dominant disease. It is associated with a broad range of endocrine tumours, most frequently arising in the parathyroid glands, the pituitary and the pancreas. Most neuroendocrine tumours will be diagnosed in the pancreas as
[...] Read more.
Multiple endocrine neoplasia type 1 (MEN-1) is a rare autosomal-dominant disease. It is associated with a broad range of endocrine tumours, most frequently arising in the parathyroid glands, the pituitary and the pancreas. Most neuroendocrine tumours will be diagnosed in the pancreas as non-functioning neuroendocrine tumours or insulinomas. Forty-two percent of the patients will develop a gastrin-secreting neuroendocrine tumour, a gastrinoma. Gastrinomas in MEN-1 tend to be small, multiple and preferentially located in the duodenum. This paper will focus on the specific characteristics of gastrinomas in the setting of MEN-1 compared to sporadic gastrinomas. The developments in understanding the tumorigenesis of these tumours and the consequences for diagnosis and therapy will be discussed. Full article
(This article belongs to the Special Issue Neuroendocrine Tumors)
Open AccessReview Mixed Adenoneuroendocrine Carcinomas (MANECs) of the Gastrointestinal Tract: An Update
Cancers 2012, 4(1), 11-30; doi:10.3390/cancers4010011
Received: 2 December 2011 / Revised: 7 January 2012 / Accepted: 12 January 2012 / Published: 16 January 2012
Cited by 45 | PDF Full-text (1283 KB) | HTML Full-text | XML Full-text
Abstract
The systematic application of immunohistochemical techniques to the study of tumors has led to the recognition that neuroendocrine cells occur rather frequently in exocrine neoplasms of the gut. It is now well known that there is a wide spectrum of combinations of exocrine
[...] Read more.
The systematic application of immunohistochemical techniques to the study of tumors has led to the recognition that neuroendocrine cells occur rather frequently in exocrine neoplasms of the gut. It is now well known that there is a wide spectrum of combinations of exocrine and neuroendocrine components, ranging from adenomas or carcinomas with interspersed neuroendocrine cells at one extreme to classical neuroendocrine tumors with a focal exocrine component at the other. In addition, both exocrine and neuroendocrine components can have different morphological features ranging, for the former, from adenomas to adenocarcinomas with different degrees of differentiation and, for the latter, from well differentiated to poorly differentiated neuroendocrine tumors. However, although this range of combinations of neuroendocrine and exocrine components is frequently observed in routine practice, mixed exocrine-neuroendocrine carcinomas, now renamed as mixed adenoneuroendocrine carcinomas (MANECs), are rare; these are, by definition, neoplasms in which each component represents at least 30% of the lesion. Gastrointestinal MANECs can be stratified in different prognostic categories according to the grade of malignancy of each component. The present paper is an overview of the main clinicopathological, morphological, immunohistochemical and molecular features of this specific rare tumor type. Full article
(This article belongs to the Special Issue Neuroendocrine Tumors)

Other

Jump to: Research, Review

Open AccessCase Report Primary Hepatic Gastrinoma Causing Zollinger-Ellison Syndrome: A Rare and Challenging Diagnosis
Cancers 2012, 4(1), 130-140; doi:10.3390/cancers4010130
Received: 6 December 2011 / Revised: 23 January 2012 / Accepted: 30 January 2012 / Published: 14 February 2012
Cited by 3 | PDF Full-text (1202 KB) | HTML Full-text | XML Full-text
Abstract
The majority of gastrinomas causing Zollinger-Ellison syndrome (ZES) are located in the duodenum or the pancreas. Primary hepatic gastrinomas (PHG) are extremely rare and difficult to diagnose because the liver is the commonest site of metastatic disease and gastrinomas can be very small.
[...] Read more.
The majority of gastrinomas causing Zollinger-Ellison syndrome (ZES) are located in the duodenum or the pancreas. Primary hepatic gastrinomas (PHG) are extremely rare and difficult to diagnose because the liver is the commonest site of metastatic disease and gastrinomas can be very small. Furthermore, gastrinomas are typically slow-growing thus a missed, occult primary tumour may not become evident for many years. The diagnosis of PHG is therefore dependent on a careful search for a primary and long-term biochemical follow-up following curative hepatic resection. We report a case of a 7 cm PHG in a 48 year old man with ZES. Preoperatively, both a basal and stimulated gastrin levels were elevated. Surgical exploration including intraoperative ultrasound and duodenotomy, failed to reveal a primary. Patient underwent a right hepatectomy. Yearly, gastrin and secretin stimulation tests remain normal 6 years following surgery. He remains symptom free off all medication. An additional 26 cases of PHG were found. Including this case, 21 had at least 1 year follow-up, however only eight had greater than 5 years (median 24 months). Post-op gastrin levels were reported in 25, however provocative testing was done in only 10. Persistence and recurrence occurred in one and four, respectively. PHG causing ZES is extremely rare. Although the current literature claims to include 26 additional cases of PHG, without a thorough search for the primary and long-term follow-up data including provocative testing, this diagnosis remains a challenge. Full article
(This article belongs to the Special Issue Neuroendocrine Tumors)

Journal Contact

MDPI AG
Cancers Editorial Office
St. Alban-Anlage 66, 4052 Basel, Switzerland
cancers@mdpi.com
Tel. +41 61 683 77 34
Fax: +41 61 302 89 18
Editorial Board
Contact Details Submit to Cancers
Back to Top