Natural history of intestinal carcinoids

Historically, carcinoids are a morphologically distinct class of rare intestinal tumours that behave less aggressively than the more common intestinal adenocarcinomas. Some authors restrict the term carcinoid to intestinal endocrine tumours, and others include a large variety of neuroendocrine tumours. Within the gastrointestinal tract, carcinoids are most commonly found in the appendix, followed by the distal small bowel, rectum and stomach. In the vast majority of cases, the carcinoid syndrome is associated with carcinoid tumours of the small intestine that have metastasised to the liver. Episodic flushing and diarrhoea are the most common initial symptoms. Metastatic disease may require no treatment for months or even years in the patient whose symptoms are not seriously interfering with quality of life and if the tumour is not exhibiting a biologically aggressive growth pattern.     

Expression of connective tissue growth factor and IGF1 in normal and neoplastic gastrointestinal neuroendocrine cells and their clinico-pathological significance

Connective tissue growth factor (CTGF) and IGF1 are both expressed in a variety of tumours and are involved in tumourigenesis. However, information about their expression in the gastrointestinal (GI) neuroendocrine (NE) cells and tumours is mainly limited, with the exception of midgut carcinoids where abundant CTGF expression has been demonstrated. Normal mucosa specimens from stomach and ileum, as well as tumour tissue specimens from gastric NE tumours (GNETs; n=58) and midgut NETs (n=38) were included. Immunohistochemical techniques were used to investigate the possible expression of CTGF and IGF1 in GI NE cells and tumours. The latter results were correlated with various clinico-biochemical and histopathological variables. CTGF was expressed in a proportion of NE cells of the normal GI mucosa but not in enterochromaffin-like (ECL) cells, whereas IGF1 was undetectable. CTGF was absent in the foci of ECL cell hyperplasia, and in most of the poorly differentiated carcinomas, but present in some GNETs (mainly in type III ECL cell carcinoids (ECL-CCs)) and in all but one midgut NETs. CTGF correlated with tumour stage in well-differentiated GNETs and with size larger than 1 cm but only in the subgroup of type I ECL-CCs. IGF1 was detected in the foci of ECL cell hyperplasia and in all GI NETs. These findings suggest that both CTGF and IGF1 may be involved in the neoplastic transformation of GI NE cells, whereas IGF1 may play an important role even at early stage.     

Glucocorticoid responsive ACTH secreting bronchial carcinoid tumours contain high concentrations of glucocorticoid receptors

Cushing's syndrome due to a bronchial ACTH secreting carcinoid tumour may be difficult to distinguish from a pituitary microadenoma (corticotrophinoma) causing Cushing's disease, since in both disorders ACTH secretion may be responsive to glucocorticoids. Why some bronchial carcinoid tumours are responsive is unknown but it could be because of co-secretion of corticotrophin releasing factor (CRF) and/or expression of glucocorticoid receptors. We report two patients with glucocorticoid responsive ACTH secreting bronchial carcinoid tumours, neither of whom produced or responded to CRF. Significant glucocorticoid receptor binding capacity (92 and 102 pmol/g protein), compared with control lung tissue, was found in extracts from both tumours. These findings suggest that corticotrophinoma-like responses to glucocorticoids observed in some ACTH secreting bronchial carcinoids result from expression of glucocorticoid receptors and are not necessarily related to the production of CRF.     

Interventional treatment of gastrointestinal neuroendocrine tumours

Neuroendocrine (NE) tumours of the gastrointestinal tract (carcinoids and endocrine pancreatic tumours) are rare diseases. In the presence of liver metastases these patients may suffer from disabling symptoms due to hormone overproduction. Patients with localized disease can be resected for cure and also patients with liver metastases can undergo potentially curative tumour resection. However, long-term follow-up of the latter cases indicates frequent recurrence of tumour. Using close biochemical monitoring of tumour markers combined with newer techniques for tumour visualization, these recurrences can often be diagnosed at an early stage so that repeat surgical procedures can be performed. During the last years very active surgery has been recommended for NE tumours, many of which have a relatively slow growth. Even in patients not amenable to curative liver surgery, debulking can be considered if the main tumour burden can be safely excised. The primary aim of this type of treatment is palliation of hormonal symptoms. An important question is whether the aggressive treatment actually prolongs survival. No prospective studies have been performed. Such studies are hampered by the lack of strict surgical programs running over long periods and the relative rarity of NE tumours. Liver transplantation may be another treatment modality in selected cases.     

Appendiceal carcinoids in Crohn's disease.

Earlier investigations demonstrate an increased risk for colon cancer in Crohn's disease. For other intestinal neoplasms, such as carcinoids, studies are limited. In Crohn's disease, repeated endoscopic and imaging studies along with intestinal resections may facilitate clinical recognition of neoplastic diseases, including appendiceal neoplasms. To date, however, only sporadic cases of appendiceal carcinoids have been described in Crohn's disease. In the present study, in a single clinician database of 1000 Crohn's disease patients, three of the 441 patients who had undergone intestinal resection had appendiceal carcinoids, all of which were pathologically confirmed. All were observed in female patients and were not suspected before surgical treatment. In one case, even though management was not altered, the tumour had already invaded serosal fat indicating a potential for more advanced disease. In this series, a carcinoid tumour was found in a resection specimen during a later clinical case review and another was a microcarcinoid, implying that these tumours may be overlooked in Crohn's disease. The percentage detected in the entire database (0.3%) exceeds the reported rates of detection of appendiceal carcinoids after removal of the appendix for appendicitis, as well as the rate of detection of appendiceal carcinoids in autopsy studies. This percentage would be higher if only those having an intestinal resection were considered (0.68%). Additional studies are needed to further define this risk of appendiceal carcinoids in Crohn's disease.     

Clinical symptoms, hormone profiles, treatment, and prognosis in patients with gastric carcinoids

BACKGROUND: Type 1 gastric carcinoids are associated with hypergastrinaemia and chronic atrophic gastritis, type 2 occur in patients with multiple endocrine neoplasia type 1 combined with Zollinger-Ellison syndrome, and type 3 lack any relation to hypergastrinaemia. Type 1 tumours are usually benign whereas type 3 are highly malignant. AIMS: To identify possible tumour markers in patients with gastric carcinoids. PATIENTS/METHOD: Nine patients with type 1, one with type 2, and five with type 3 were evaluated with regard to symptoms, hormone profile, and prognosis. RESULTS: Plasma chromogranin A was increased in all patients but was higher (p < 0.01) in those with type 3 than those with type 1 carcinoids. All patients with type 3 carcinoids died from metastatic disease, but none of the type 1 patients died as a result of their tumours. One type 1 patient with a solitary liver metastasis received interferon alpha and octreotide treatment. Nine months later, the metastasis was no longer detectable. She is still alive eight years after diagnosis, without recurrent disease. This represents the only reported case of foregut carcinoid with an unresectable liver metastasis that seems to be have been cured by biotherapy. CONCLUSIONS: Plasma chromogranin A appears to be a valuable tumour marker for all types of gastric carcinoid. Combination therapy with interferon alpha and octreotide may be beneficial in patients with metastasising type 1 gastric carcinoids.     

Proliferative activity of neuroendocrine tumours of the gastroenteropancreatic endocrine system: DNA flow cytometric and immunohistological investigations.

The proliferative activity of 16 tumour specimens from 13 patients with neuroendocrine tumours of the gastroenteropancreatic endocrine system was studied by DNA flow cytometry and immunohistology for the nuclear Ki67 proliferation antigen. Equivalent results were obtained with both methods, which showed the proliferative activity of gastroenteropancreatic neuroendocrine tumours to be heterogeneous. In four malignant small intestinal carcinoids and one extravisceral carcinoid localised in the retroperitoneum the percentage (index) of proliferating tumour cells as measured by DNA flow cytometry ranged from 2.9 to 36.2% corresponding to low, moderate, or high proliferative activity. In four malignant pancreatic endocrine tumours and their metastases indices ranged from 8.7 to 18.3%, corresponding to low, moderate, or high proliferative activity. In four benign pancreatic endocrine tumours indices ranged from 4.3 to 7.7%, all corresponding to low proliferative activity. This heterogeneity of proliferative activity may in part explain the heterogeneous results reported of chemotherapy treatment. As chemotherapy of tumours is largely affected by favourable cell cycling kinetics, individual diagnostic investigations of the proliferative activity of these neuroendocrine tumours may be of value for identifying patients suitable for this treatment.     

Coexisting carcinoid tumors in familial adenomatous polyposis-associated upper intestinal adenomas

Upper gastrointestinal polyps and extraintestinal tumors are well recognized in association with familial adenomatous polyposis (FAP). Although carcinoid tumors have been reported in association with sporadic colonic neoplasms and ulcerative colitis, to date, carcinoids have not been reported in association with FAP. We report a patient with FAP who has recurrent carcinoid tumors located at the bases of duodenal adenomas. The genetic basis of carcinoid neoplasms is still uncertain. This report may represent the clinical effect of the APC gene mutation on the enterochromaffin cell line manifesting as recurrent carcinoid tumors in physical association with intestinal adenomas. Future genetic analysis and epidemiological studies may be of value in determining whether a true association exists.     

Carcinoid tumours

Carcinoid tumours offer a diagnostic and therapeutic challenge. Although new biochemical markers and improved methods for tumour detection, including PET and somatostatin receptor scintigraphy, have been developed during the last two decades many patients are still diagnosed at late stages of the disease. This is supported by the fact that the age of diagnosis is about the same today as it was 10 years ago. It is our opinion that plasma chromogranin A levels should be be determined in all patients which are investigated because of symptoms that might be connected to a neuroendocrine tumour. In cases with flushing or diarrhoea, U-5-HIAA should also be determined and these two tumour markers are enough to diagnose most patients with midgut carcinoid tumours. In patients with foregut or hindgut tumours other specific hormones should be included. For the localization procedure conventional radiological techniques including CT, MRI and ultrasound investigations should be supplemented with somatostatin receptor scintigraphy. Endoscopic ultrasound investigations might in the future be relevant for diagnosis of duodenal carcinoids, whereas gastric and rectal carcinoids are diagnosed by endoscopy. A combination of more aggressive surgery combined with medical treatment such as somatostatin analogues and α-interferon has significantly increased the survival rates in patients with classical midgut carcinoid tumours. Metastatic foregut and hindgut tumours are still a therapeutic challenge and it is important in the future to classify all carcinoid tumours based on specific tumour biology patterns. Such a tumour biology based treatment is a prerequisite for a more individually based therapy in the future.     

Clinical presentation and prognosis of gastrointestinal carcinoid tumours

Clinical data about 104 patients with gastrointestinal carcinoids emphasized the heterogeneous nature of these tumours in different organs. The sites of the primary tumours were the stomach in 12 (11%), the duodenum in 3 (3%), the small bowel in 48 (45%), the appendix in 28 (26%), the colon in 6 (6%), and the rectum in 6 cases (6%). Gastric carcinoids were multiple in 4 (33%) and small-bowel carcinoids in 11 cases (23%). None of the gastric, duodenal, or rectal carcinoids had generated metastases, as contrasted to 34 (72%) small-bowel carcinoids. Twelve patients had symptoms of the carcinoid syndrome caused by hepatic metastases from ileal (11) or appendiceal (1) primary tumours. At least two patients with duodenal carcinoids had Zollinger-Ellison syndrome produced by the tumours. The cumulative 5-year survival rate was 91-100% for gastric, appendiceal, and rectal carcinoids, 77% for small-bowel carcinoids, and 33% for colonic carcinoids. Resectable mesenteric lymph node metastases did not affect the 5-year survival of patients with small-bowel carcinoids as compared with the tumours confined to the bowel wall. Poor prognosis was associated with hepatic metastases at the time of diagnosis. Small-bowel carcinoids remain a challenge in clinical work because of their distinct metastatic propensity and problematic diagnosis.     

Gastrointestinal hemorrhage needing blood transfusion as the first manifestation of small bowel carcinoid tumor

Carcinoid tumors arise from enterochromaffin or enterochromaffin-like cells that are present in the gastrointestinal tract, ovaries, and lungs. Over 90% of carcinoids originate in the gastrointestinal tract with the most common sites in order of frequency being the appendix, terminal ileum, rectum, and the remainder of the colon. Gastroduodenal and pancreatic carcinoids are infrequent. Carcinoid syndrome is associated with small intestine carcinoids in about 40%. Common symptoms include intermittent intestinal obstruction with crampy abdominal pain and vomiting, and weight loss. Upper gastrointestinal bleeding with melaena or hematochezia is a relatively rare early symptom of patients with small intestine carcinoid tumors. We report on a 69-year-old man, treated with acenocoumarol for previous thromboembolic complications of hereditary protein S deficiency. He was admitted to hospital because of an acute episode of hematochezia followed by melaena. Endoscopic evaluation of esophagus, stomach, duodenum and colonoscopy revealed no apparent source of bleeding. Selective angiographic evaluation of mesenterial arteries showed pathologic vasculature approximately in mid jejunum. Laparotomy revealed bleeding from a small submucosal malignant carcinoid tumor in small intestine and multiple large metastases within mesenteric tissue. Segmental resection of small intestine and exstirpation of the metastatic masses was performed. Postoperative period was uneventful. Cytotoxic chemotherapy in this adjuvant setting has not been recommended. Small intestinal carcinoid tumor has to be considered as a rare cause of gastrointestinal bleeding with melaena or hematochezia. Nevertheless, bleeding is a relatively rare early symptom of patients with small intestine carcinoid tumor.     

消化道类癌的内镜特征和治疗

背景：近年来消化道类癌的检出呈上升趋势,正确认识其内镜特征并选择合理的治疗措施具有重要意义。目的：探讨内镜在消化道类癌诊治中的应用价值。方法：2005年1月～2011年8月于淮北市人民医院行局部内镜切除术的21例消化道类癌患者纳入研究,回顾性分析其内镜特征、治疗和预后情况。结果：本组患者以直肠类癌最为多见（14例）,多位于低位直肠;胃类癌多位于胃体大弯,1例十二指肠类癌位于球部前壁。多数消化道类癌呈半球形隆起,表面光滑,分布网状毛细血管,球部类癌中央稍凹陷。12例患者行内镜黏膜切除术（EMR）,8例行内镜黏膜下剥离术（ESD）,1例行高频电切术。20例患者病变完整切除,随访期内未见复发。结论：内镜检查是诊断消化道类癌的重要手段。对于未超过黏膜下层的小的消化道类癌,EMR和ESD是可靠的治疗选择。     

Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid beta protein precursor.

We have isolated a cDNA from a mouse brain library that encodes a protein whose predicted amino acid sequence is 42% identical and 64% similar to that of the amyloid beta protein precursor (APP). This 653-amino acid protein, which we have termed the amyloid precursor-like protein (APLP), appears to be similar to APP in overall structure as well as amino acid sequence. The amino acid homologies are concentrated within three distinct regions of the two proteins where the identities are 47%, 54%, and 56%. The APLP cDNA hybridizes to two messages of approximately 2.4 and 1.6 kilobases that are present in mouse brain and neuroblastoma cells. Polyclonal antibodies raised against a peptide derived from the C terminus of APLP stain the cytoplasm in a pattern reminiscent of Golgi staining. In addition to APP, APLP also displays significant homology to the Drosophila APP-like protein APPL and a rat testes APP-like protein. These data indicate that the APP gene is a member of a strongly conserved gene family. Studies aimed at determining the functions of the proteins encoded by this gene family should provide valuable clues to their potential role in Alzheimer disease neuropathology.     

Malignant thymic carcinoid is not prevented by transcervical thymectomy in multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant tumour syndrome. It is characterized by primary hyperparathyroidism, pituitary neoplasia and foregut lineage neuroendocrine neoplasia. Malignant thymic carcinoid tumours are an uncommon but important manifestation of MEN 1. Transcervical thymectomy is often advocated as prophylaxis against thymic carcinoids, although there is a paucity of evidence to support the efficacy of this procedure. This is the first report of a malignant thymic carcinoid occurring in an MEN 1 patient following prior parathyroidectomy and transcervical thymectomy. It is concluded that transcervical thymectomy does not reliably provide prophylaxis against thymic carcinoid.     

Intestinal infarction caused by carcinoid associated elastic vascular sclerosis: early presentation of a small ileal carcinoid tumour.

We describe a patient with extensive ischaemic necrosis of the ileum as a result of elastic vascular sclerosis (EVS). A 2 cm carcinoid tumour was located nearby with microscopic evidence of spread to regional lymph nodes. Severe intestinal ischaemia caused by carcinoid associated EVS may be the presenting feature of small carcinoid tumours resulting in their early diagnosis.     

Surgery for midgut carcinoid

Many clinicians prefer to avoid surgery in patients with carcinoid neoplasia, because of its slow growth and relatively favourable prognosis. Nevertheless, the commonest cause of death in patients with carcinoid is advanced metastatic disease, and both clinical and epidemiological data indicate that the more effectively the disease is ablated, the more long-lasting the benefit. Multidisciplinary management of patients with carcinoid must consider inherited risk, possible multiple carcinoids and/or synchronous non-carcinoid cancer, and the use of a range of investigations that also evaluate the 10% of patients with carcinoid syndrome with or without valvular heart disease. Although primary size is correlated with the presence of nodal with or without liver metastases, carcinoid tumours <1 cm in diameter may be metastatic at presentation, particularly those arising within the small intestine. In the jejunum and ileum, resection of all sizes of carcinoid with local and regional nodes is preferred, to prevent nodal dissemination causing mesenteric ischaemia with or without infarction. Resection of nodal metastases should be undertaken in those with persistent or recurrent nodal disease if possible. Appendiceal and right colonic carcinoids are most effectively treated by right hemicolectomy with local and regional nodal clearance, as for adenocarcinoma. However, for most appendiceal carcinoids which are <1 cm in diameter and non-invasive, appendicectomy alone is sufficient. For appendiceal carcinoids 1-2 cm in diameter, histopathological assessment helps to determine the need for hemicolectomy. Liver resection has been followed by prolonged 5 year survival in several series and is recommended in appropriate patients to attempt cure or to debulk metastatic disease. Liver transplantation has had only qualified success in highly selected patients without extra-hepatic disease in whom other therapies have failed.     

Midgut carcinoid tumours: surgical treatment and prognosis

Midgut carcinoids originating in the small intestine are the most common cause of the carcinoid syndrome. These tumours typically progress slowly and have an extended disease course, and although they often present with metastases at diagnosis, surgical treatment has become increasingly important for their management. Surgery should include efforts to remove mesenteric metastases, which may cause severe long-term abdominal complications with typical fibrotic intestinal entrapment and small-bowel ischaemia due to compression of mesenteric vessels. Attempts should also be made to surgically remove or ablate liver metastases, since this may provide considerable palliation of the carcinoid syndrome. For patients with the carcinoid syndrome surgery is combined with continuous biotherapy with long-acting somatostatin analogues, which may alleviate symptoms and stabilize disease or slow progression. Favourable survival and appreciable quality of life can be expected with this combined treatment, even in patients with advanced midgut carcinoids.     

Successful localization of an occult ACTH-secreting bronchial carcinoid tumour with 111indium-DTPA labelled octreotide

Ectopic ACTH secretion due to occult carcinoid tumours is an occasional cause of ACTH dependent Cushing's syndrome. In many cases the ectopic source may be obvious, but sometimes no obvious source is evident, the so-called occult ectopic syndrome. Due to their small size, localization of such occult tumours, particularly bronchial carcinoids, may be extremely difficult. Whole body CT and verious sampling studies have been used but are not always successful in determining the site of such lesions. We report a 40-year-old patient with the ectopic ACTH syndrome due to a 0.6-cm bronchial carcinoid tumour which was successfully localized by ¹¹¹indium-DTPA labelled octreotide scintigraphy.