Foregut Tumours Research Articles

Expression of cadherin 17 in well-differentiated neuroendocrine tumours.

Cadherin 17 (CDH17) is expressed primarily in normal intestinal epithelium and digestive tract tumours, and has limited expression in other neoplasms. The aims of this study were to examine CDH17 expression in well-differentiated neuroendocrine tumours (WDNETs) from various primary sites, representing the foregut, midgut, and hindgut, and tumours metastasizing to the liver, and to correlate the differences between the expression of CDH17, CDX2, and thyroid transcription factor 1 (TTF1). We investigated CDH17 immunohistochemical expression in 150 primary WDNETs from eight anatomical sites, including 68 from the foregut, 70 from the midgut, and 12 from the hindgut, and 15 metastases. CDH17 immunoreactivity increased significantly from foregut to hindgut WDNETs (P < 0.0001). Pancreatic WDNETs expressed CDH17 at a significantly higher frequency than other foregut tumours. Within the midgut, appendiceal and small-intestinal WDNETs were more frequently positive for CDH17 than for CDX2. All hindgut WDNETs expressed CDH17, in contrast to CDX2 (positive in one rectal case). CDH17 expression in liver metastases was similar to that of the primary tumours. This study is the first to comprehensively examine CDH17 expression in WDNETs from different sites. CDH17 is a sensitive marker for midgut WDNETs, and the CDH17+/CDX2-/TTF1- phenotype was found to be sensitive (92%) and specific (91%) for hindgut WDNETs.

MTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumours

Clinical trials indicate efficacy of drugs inhibiting the mammalian target of rapamycin (mTOR) in the treatment of gastroenteropancreatic neuroendocrine tumours (GEP-NET); however, information on detailed expression and activity patterns of mTOR in these tumours is sparse. We investigated the expression of mTOR and expression as well as phosphorylation of its downstream targets 4EBP1, S6K and eIF4E in a cohort of 99 human GEP-NET by immunohistochemistry. We correlated our findings with clinicopathological variables and patient prognosis. We found that 61, 93, 80, 69, 57 and 79% of GEP-NET were positive for mTOR, 4EBP1, cytoplasmic phospho-4EBP1 (p-4EBP1), nuclear p-4EBP1, phospho-S6K (p-S6K) and phospho-eIF4E (p-eIF4E) respectively. mTOR expression and activity were higher in foregut than in midgut tumours. In foregut tumours, expression of mTOR was higher when distant metastases were present (P=0.035). Strong mTOR activity was associated with higher proliferative capacity. In patients with stage IV midgut tumours, strong p-S6K expression was associated with poor disease-specific survival (P=0.048). In conclusion, mTOR shows considerable variations in expression and activity patterns in GEP-NET in dependence of tumour location and metastatic status. We hypothesise that these differences in mTOR expression and activity might possibly influence response to mTOR inhibitors.

Gastrin-releasing-peptide in neuroendorine tumours

In a substantial proportion of cases with endocrine malignant disease the primary lesion cannot be localised and the pathologist hesitates upon the origin of the tumour. Well differentiated neuroendocrine carcinomas of the small bowel can usually be identified by the strong serotonin immunoreactivity, but foregut carcinoids may also stain positive for serotonin and the differential diagnosis between the various foregut tumours may be difficult. We examined if immunostaining for gastrin-releasing-peptide (GRP) may aid in establishing the origin of an unknown neuroendocrine tumour. Tumour tissue from 79 patients (27 lung carcinoids, 4 thymic carcinoids, 4 gastric neuroendocrine tumours, 17 pancreatic well differentiated neuroendocrine carcinomas, 1 duodenal well differentiated neuroendocrine tumour and 26 well differentiated neuroendocrine carcinomas of the small bowel) were immunostained with antibodies against GRP and serotonin. Positive staining for GRP was found in 12/27 lung carcinoids. All other tumour types were consistently GRP-negative (p < 0.0001). We conclude that immunostaining for GRP may aid in defining the origin of the tumour, and that GRP-immunoreactivity increases the suspicion of a lung carcinoid.

RASSF1A promoter methylation and 3p21.3 loss of heterozygosity are features of foregut, but not midgut and hindgut, malignant endocrine tumours

The Ras-association domain family 1A (RASSF1A) tumour suppressor gene is inactivated in a variety of solid tumours, usually by epigenetic silencing of the promoter and/or allelic loss of its locus at 3p21.3. RASSF1A induces cell cycle arrest through inhibition of cyclin D1 accumulation. In this work, 62 endocrine tumours from different sites in the gut were investigated for methylation of the RASSF1A promoter using the polymerase chain reaction, the presence of 3p21.3 deletions by loss of heterozygosity analysis, and cyclin D1 expression by immunohistochemistry. Methylation was found in 20/62 (32%) cases and was restricted to foregut tumours; deletion at 3p21.3 was found in 15/58 (26%) informative cases and restricted to malignant foregut tumours; cyclin D1 hyper-expression was found in 31/58 (53%) cases and correlated with RASSF1A methylation. Our data suggest that RASSF1A is involved in the development of endocrine tumours derived from the foregut only, and that the presence of both RASSF1A methylation and 3p21.3 deletion is associated with malignancy. These results may provide a rationale for foregut-targeted therapy for aggressive endocrine carcinomas entailing the use of demethylating agents.

Neuroendocrine tumours of the gastrointestinal tract

Gastrointestinal neuroendocrine tumours are classified as functioning or non-functioning according to the presence or absence of a clinically evident hypersecretion syndrome. In foregut tumours the presence of autonomous hormone secretion and the respective hypersecretion syndrome indicate functionality. Abdominal ultrasound (US), computed tomography (CT), magnetic resonance tomography (MRT) and somatostatin receptor scintigraphy (SRS) are used for localisation of the primary tumour and metastasis. Invasive procedures such as endoscopic US, intraoperative US or intraoperative duodenal transillumination are useful to localise small (< 1 cm) tumours. For localised tumours surgery is the first line treatment. In metastatic disease symptomatic therapy, biotherapy and chemotherapy are available. Cytoreductive therapy such as embolisation, chemoembolisation, thermo- or cryotherapy, or radio-receptor therapy are additional options. The first symptom of most neuroendocrine midgut tumours is abdominal pain. An increased chromogranin-A plasma concentration or 5-hydroxyindoleacetic acid 24-h urinary excretion indicates the neuroendocrine origin of the tumour or the possibility of a carcinoid syndrome, respectively. Surgical therapy prolongs survival but is rarely curative. Biotherapy is effective as symptomatic therapy. However, its cytoreductive potency is low. Chemotherapy is less effective in midgut tumours compared to foregut tumours. Cytoreductive strategies (chemoembolisation, thermo- or cryotherapy, cytoreductive surgery) and radio-receptor therapy may offer new therapeutic options. However, their definitive value has yet to be defined.

Analysis of sporadic neuroendocrine tumours of the enteropancreatic system by comparative genomic hybridisation

BACKGROUNDChromosomal instability is observed in a wide spectrum of human cancer syndromes. However, to date, little is known of the characteristic genetic changes in sporadic neuroendocrine tumours of the gastroenteropancreatic...

The management of carcinoid tumours.

The term ‘karzinoide’ was originally used by receptor subtypes, which are members of seven 5HT receptor groups distinguished according to their Obendorfer in 1907 to describe a carcinoma-like lesion without malignant qualities. These tumours coupling to particular signalling pathways and amino acid sequence identity.2 Apart from the 5HT3 recepare uncommon, and attract the interest of clinicians because of the spectacular symptoms that they cause. tor, which is a ligand-gated ion channel, they are all G-protein-coupled receptors. Stimulation of a These symptoms are so striking as to make clinical diagnosis obvious, but because of their range, unfornumber of the 5HT receptor subtypes has the potential to induce malignant transformation. Activation tunately result in patients being cared for by many different medical and surgical specialists. Carcinoid of rat 5-HT2c receptors induces malignant transformation of transfected N1H-323 cells.3 Activation tumours, even when there is metastatic spread, are generally thought to have a good prognosis and as of mouse 5HT2b receptors expressed in L+kD cells activates p21ras and p42mapk/p44mapk and leads to the a result, patients with this condition are managed symptomatically. development of 5HT2b-dependent 5HT-stimulated foci in confluent cells which are tumourigenic in However, Godwin et al. assessed survival in 2837 patients with carcinoids, and in patients with liver nude mice.4 metastases and raised urinary 5HIAA levels he reported a five-year survival of 18–38% and a median survival of 23 months.1 These figures suggest The treatment of metastatic carcinoid that carcinoid tumour is a rather more aggressive tumours disease than is generally appreciated. In this article we review recent clinical developments, make a The incidence of carcinoid tumours is 1.5, and the case for specialist care, and promote the view that prevalence of the carcinoid syndrome 0.5, per chemotherapy given with the aim of reducing tumour 100 000 population. Primary carcinoid tumours are bulk should have a more prominent position in the classified according to their embryonic site of origin therapeutic armamentarium. into foregut, midgut and hindgut tumours. The most common primary site is the appendix followed by the rectum. The carcinoid syndrome is most commonly due to metastatic midgut tumours, 50% of 5HT and its receptors which metastasize to the liver. Patients with carcinoid tumours may be treated The symptoms of carcinoid syndrome are caused by the tumours’ secretory products, and so palliative surgically, medically or radiologically. Where there is metastatic disease, surgery is generally limited to treatment has been designed to reduce circulating levels of these products, Serontonin, 5HT, is the those rare occasions where metastases are confined to one lobe of the liver. The majority of patients major secretory product of carcinoid tumours. Molecular cloning has identified 15 serotonin with metastatic midgut tumours have multiple meta-

Laparoscopic feeding jejunostomy tube in oncology patients

Laparoscopic-guided feeding jejunostomy tubes are being utilized in two specific groups of patients: (i) patients with resectable or locally advanced adenocarcinoma of the pancreas treated on a protocol of preoperative chemoradiation, who may require nutritional support, and (ii) patients with metastatic or obstructing foregut tumours who require a route for delivery of fluid and medication. The technique, rationale and results for our first 17 patients who underwent laparoscopic placement of a tube jejunostomy are described. Laparoscopic feeding tube placement is a safe and cost-effective method to gain enterai access and stage the oncology patient's disease. This procedure is less invasive than standard surgery for tumour staging and feeding tube placement, and facilitates formula advancement and the patient's early hospital release without morbidity or mortality.