[page 11↓]

3.  Introduction

Neuroendocrine gastrointestinal tumors are rare and usually slowly-growing neoplasms originating from the neuroendocrine cell system. These neoplasms may occur either sporadically or in association with familial syndromes, i.e. multiple endocrine neoplasia type 1 (MEN-1). The neuroendocrine cells can be subdivided into cells from the neuroectodermal cells or endodermal origin. Neuroectodermal cells are located in the suprarenal medulla from where pheo-chromocytomas and neuroblastomas arise and in the paraganglia where paragangliomas develop. Endodermal tumors originate from the pituitary and the parathyroid glands, the C-cells of the thyroid gland, the pancreatic islets or from the diffuse endocrine cell system of luminal organs (Wilander and Grimelius 1993). These tumors have been called APUDomas; the idea of the APUD (Amine Precursor Uptake and Decarboxylation) system was first brought up in 1974 by Pearse who detected that cells of neural crest origin move to other tissues such as the intestine, pan-creas and a number of endocrine glands (Pearse 1974). These cells are specialized to accumulate amine precursors (e.g. DOPA or 5-hydroxytryptophan) and to then decarboxylate them to biogenic amines (catecholamines or serotonin), they also produce peptides. Even though this concept was later abandoned by most researchers it still helps to understand the capacity of these cells to produce various hormones and amines. The assessment has been made that de-fective DNA-mismatch repair plays a role in the tumorigenesis of gastrointestinal cancers. For carcinoids, however, this could not be proved (Ghimenti, Lonobile et al. 1999). The prognosis of non-metastatic, resectable neoplasms is excellent (79% 5-year survival rate), whereas metastatic resectable tumors that have metastasized to the liver have a worse diagnosis (30% 5-year survival rate) (Tiensuu Janson and Oberg 1996). However, the patients have a realistic chance to survive for a longer period if treated by a combination of surgery and medication. Histopathological diagnosis is achieved by conventional HE-staining and immunohistochemistry of chromogranin A and synaptophysin. Silver staining (Grimelius and Wilander 1980) as well as the use of neuron-specific-enolase (NSE) as a histopathological marker has been abandoned. Chromogranin A is also analyzed in the patients´ plasma, 80-100 % of patients with diagnosed neuroendocrine tumors present with elevated levels of chromogranin A. Complementary to this and depending on the clinical manifestation of the tumor, other peptide hormones may be analyzed, as well as urine 5-HIAA in cases with midgut carcinoids. In recent years, somatostatin receptor scintigraphy and endoscopic ultrasonography have improved diagnostic results as adjuncts investigations to CT and MRI techniques. In almost 80% of the tumors, somatostatin receptor subtype 2 binding 111Indium-labelled octreotide is found which can be used for both tumor staging and to give an indication of effect of treatment with somatostatin analogues. Rather aggressive surgery has emerged in the past years in order to improve the clinical conditions even if the patients are beyond cure. As for medical treatment, chemotherapy as well as somatostatin analogues and alpha-interferon (in particular for midgut carcinoids) are used. For the present, malignant tumors can be controlled but not cured by this treatment. More information about tumor proliferation, expression of adhesion molecules, growth factors and their receptors will help to focus on individual treatment in the future (Oberg 1996).

3.1. Carcinoid tumors

Cells of the neuroendocrine cell system are dispersed along the gastrointestinal tract mucosa as well as in many other organs. In 1907 Oberndorfer described small, slowly growing ileal tumors that showed a more benign course than more commonly recognized carcinomas in the same region introducing the term carcinoid. In 1949 their true malignant potential was emphasized by Pearson and Fitzgerald when they reported on several patients with metastasising carcinoid tumors (Pearson and Fitzgerald 1949). Carcinoid tumors contain well differentiated neuro-endocrine tumor cells, secreting various bioactive and hormonal products. The term carcinoid has been used for an enlarged spectrum of tumors. In 1963, Williams and Sandler classified carcinoid tumors, according to their embryological origin, into foregut carcinoids (occurring in the lungs, thymus, stomach, proximal duodenum and pancreas), midgut carcinoids (originating from the distal duodenum to the mid-transverse colon) and hindgut carcinoids (with origin in the distal colon and the rectum) (Williams and Sandler 1963). Carcinoids supposedly originate from heterogenous neuroendocrine cells and show common features such as specific staining reactions, e.g. argyrophilia(Grimelius and Wilander 1980) the presence of secretory granules and characteristic clinical features.

Midgut carcinoid tumors are usually argentaffin, the other two subgroups are not. They derive from enterochromaffin cells (Kulschinsky cells) in the small intestinal crypts of Lieberkuehn, and are usually depicted as the classical carcinoids. Histologically, midgut carcinoids tend to grow in nests disconnected from the normal tissue. Other carcinoid subtypes (foregut carcinoids) show a more trabecular pattern (Tiensuu Janson and Oberg 1996). Midgut carcinoids and occasionally foregut carcinoids characteristically produce high levels of serotonin (Lembeck 1953). The latter lesions may [page 12↓]also exhibit in rare cases the synthesis of adrenocorticotrophic hormone (ACTH), gastrin, calcitonin and histamine. Regarding hindgut carcinoids, no serotonin is produced but other hormones such as somatostatin and peptide YY (PYY) may occur within the tumor. In all carcinoids high levels of chromogranin A, pancreatic polypeptide (PP) and human chorionic gonadotropin (HCG)-alpha and-beta are often found (Wilander, Lundqvist et al. 1989).

In 1999, the World Health Organization (WHO) revised the clinicopathological classification of neuroendocrine tumors of the gastroenteropancreatic (GEP) tract (Rindi, Capella et al. 2000). Criteria for classification of these tumors are both tumor cell type and the clinical status of the patient, whether associated or not to a tumor-related hyperfunctional syndrome. As for the latter approach, tumors may be divided into functioning or non-functioning tumors. Carcinoids pre-senting with unique features corresponding to the secretion of biologically active substances are called functional tumors. Those tumors refraining from synthesis of biologically active peptide hormones are depicted as non-functioning tumors. The first approach refers to immuno-histochemical cell typing of GEP neuroendocrine tumors providing morphofunctional infor-mation. Correlation between these data and the level of circulating hormones as well as the patient´s clinical symptoms is required. Most tumors are composed of different cell types of which one may be related to a hyperfunctional syndrome. As for the tumor´s natural history and tumor behaviour the hyperfunctional syndrome is per se more predictive than identification of a specific hormone cell content in a tumor. Non-functioning tumors present either with a tumor mass or are an unexpected finding at operation. It is recommended to call such growths non-functional neuroendocrine tumors mainly composed of a specific cell type (e.g. „ non-functional tumors of the pancreas mainly composed of glucagon-producing A-cells“) while reserving the term glucagonoma of the pancreas for tumors causing a hyperfunctional syndrome.

Current clinicopathological classification of neuroendocrine tumors of the GEP tract is, according to anatomy, as follows: Neuroendocrine tumors of the pancreas: Well-differentiated functioning (insulinoma) or non-functioning endocrine tumors with benign behaviour (1a), functioning (gastrinoma, insulinoma, vipoma, glucagonoma, somatostatinoma) or inappropriate syndrome tumor (inappropriate hormone syndromes: Cushing (ACTH), acromegaly or gigantism (GHRH), hypercalcemia, etc.) or non-functioning well-differentiated endocrine tumors with uncertain behaviour (1b), well-differentiated low grade malignant endocrine carcinoma, functioning (gastrinoma, glucagonoma, insulinoma, vipoma, somatostatinoma or inappropriate syndrome tumor) or non-functioning (2) and poorly differentiated, highly malignant endocrine carcinoma (3). Neuroendocrine tumors of the stomach: Well-differentiated tumors with benign behaviour (ECL cell tumor associated with chronic atrophic gastritis or MEN-1 syndrome or sporadic, serotonin-producing tumor, gastrin-producing tumor) (1a), well-differentiated tumors with uncertain behaviour (ECL cell tumor, gastrin-, serotonin- or somatostatin-producing tumors or sporadic) (1b), well-differentiated, low grade malignant functioning (gastrinoma, serotonin-producing tumor with carcinoid syndrome, ECL cell tumor with atypical carcinoid syndrome or ACTH-producing tumor with Cushing syndrome) or non-functioning endocrine carcinoma (ECL cell tumor, gastrin-, somatostatin- or serotonin-producing tumors) (2) and poorly differentiated, highly malignant endocrine carcinoma (3). Endocrine tumors of the duodenum and uppermost jejunum: Well-differentiated endocrine tumors with benign behaviour (gastrin- or serotonin-producing tumor, gangliocytic paraganglioma (1a), well-differentiated tumors with uncertain behaviour (somatostatin-producing tumors with or without Recklinghausen´s disease, gastrin- or serotonin-producing tumors) (1b), well-differentiated, low grade malignant endocrine carcinoma (gastrin-or serotonin-producing tumor, somatostatin-producing tumor with or without Recklinghausen´s disease) (2) and poorly differentiated, highly malignant endocrine carcinoma.

Midgut carcinoid tumors (Jejunum, ileum, right colon and appendix) or remaining colon and rectum (hindgut) tumors are classified, as shown above, into well-differentiated endocrine tumors with benign behaviour (serotonin- or enteroglucagon-producing tumors) (1a) and with un-certain behaviour (1b), well-differentiated low grade malignant endocrine carcinomas (sero-tonin-producing carcinoma with or without carcinoid syndrome) (2) and poorly differentiated highly malignant endocrine carcinoma.

The subdivision of carcinoids referring to the anatomical origin of the tumors is rather con-fusing. It has been suggested that the term midgut carcinoid or classical midgut carcinoid should be kept for traditional neuroendocrine midgut carcinoid neoplasms1. Other tumors should be referred to as neuroendocrine tumors followed by their primary site and, in addition the predominantly secreted hormone may be added, e.g. gastrin-producing neuroendocrine duo-denal tumor (Kloppel, Solcia et al. 1999).


[page 13↓]

3.1.1. Features regarding the different carcinoid subgroups

3.1.1.1. • Foregut carcinoids

In 1960, bronchial carcinoid tumors were declared to be related to carcinoid tumors arising in the gut (Williams and Azzopardi 1960).Bronchial carcinoids tend to become clinically manifest at earlier age than other carcinoids. Bronchial carcinoids can produce serotonin (these patients may develop the carcinoid syndrome) and other hormones such as ACTH, growth hormone releasing hormone (GHRH) and histamine. ACTH and GHRH production will lead to specific syndromes comprising Cushing´s syndrome and acromegaly, respectively. Histamin secretion may give rise to the histamine-flush, a bright red flush combined with face-swelling and lacrimation. Bronchial carcinoids can be classified according to their histological appearance: Typical carcinoids, atypical carcinoids and small cell lung carcinomas. Typical carcinoids are generally of a more benign nature than atypical carcinoids. However, both types are able to present with a high mitotic count and a high amount of cells staining positive for Ki-67, both prognostically unfavorable factors (Granberg, Wilander et al. 2000). Malignant bronchial carcinoids may metastasize to regional lymphnodes, liver, skin, central nervous system and bones. The 5-year survival rate for patients with typical carcinoids is 87-94% and 56% for atypical carcinoids (Granberg, Wilander et al. 2000).

Carcinoids with origin in the thymus occur more rarely. They show serotonin-, ACTH- and calcitonin- production and characteristically a tendency for local recurrences after surgery. Thymic carcinoid tumors may compress large vessels and the trachea and thus be symptomatic. Spreading of the disease goes hand-in-hand with bad prognosis and short survival.

Gastric carcinoids can be subdivised into well-differentiated tumors (1) (Argyrophil cell tumors, mainly composed by ECL cells or gastrin-producing cells (G cells)) or poorly differentiated tumors (2) (Rindi, Bordi et al. 1996). ECL-omas may be subgrouped into tumors with chronic atrophic gastritis (CAG), achlorhydria and pernicious anemia (type 1), tumors associated with hypertrophic gastropathy and hypergastrinaemia due to Zollinger-Ellison syndrome with MEN1 (type 2) and sporadic gastric carcinoids with sporadic Zollinger-Ellison syndrome and hypergas-trinaemia (type 3). ECL-omas originate from the histamine-producing and -storing entero-chromaffine-like cells. Type 1 ECL-omas are mostly multiple and occur in the gastric fundus and corpus. Gastrin-producing tumors (type 2) may present with G-cell hyperplasia in the gastric antrum. Gastric carcinoids are rarely malignant. ECL-omas may develop histopatho-logically from small ECL-cell nests via linear hyperplasia to solid polyps. Hypergastrinaemia and its trophic effect on ECL-cell seems to play the striking role pathogenetically. Also Zollinger-Ellison syndrome, sporadic or in association with MEN1, may be the cause of hyper-gastrinaemia and gastrin-dependent carcinoids (type 2). As for diagnosis, gastroscopy and histo-pathology are most efficient.

3.1.1.2. • Hindgut carcinoids

Hindgut carcinoids can be subgrouped into tumors of the transverse and descending colon or the rectum. Rectal carcinoids represent the majority and are malignant in 5-40% of the cases (Mani, Modlin et al. 1994).Colonic neoplasms are rare and diagnosed at later stages than rectal lesions. Hindgut carcinoids are generally non-functional but the tumor cells may contain hormones such as PP, PYY and somatostatin (Wilander, Lundqvist et al. 1989). At time of first diagnosis, patients more often suffer from intestinal obstruction, bleeding or having a large palpable abdominal mass abdomen rather than from symptoms due to excessive hormone production.

3.1.2. Midgut carcinoids

3.1.2.1. Incidence

Midgut carcinoid tumors represent a small percentage (0.5-1.5%) of clinically diagnosed intestinal neoplasms compared to e.g. colorectal adenocarcinomas which occur at least 60 times more frequently (Moertel, Sauer et al. 1961; Godwin 1975). Classical midgut carcinoids2 occur with a clinical incidence of approximately 0.3/100000-0.7/100000 (Skogseid 2001). They are most often diagnosed [page 14↓]in patients of 50-60 years of age but do occur even in children patients. 40-70% of patients with midgut carcinoid syndrome have multicentric disease at time of first diagnosis (Skogseid 2001). However, carcinoid tumors may be detected in about 1% of routine autopsies, thus showing that those tumors often remain silent throughout lifetime (Moertel, Sauer et al. 1961; Godwin 1975). Still, small bowel carcinoids are the most common neuroendocrine tumors of the gastrointestinal tract. As midgut carcinoids are the most common cause of the carcinoid syndrome, they tend to prevail in clinical series with about the same frequency as adenocarcinomas of the small bowel (Thompson, van Heerden et al. 1985).

Midgut carcinoid tumors can be subdivided into two separate entities. Appendiceal carcinoids have by far the highest incidence and are mainly detected at appendectomy. They rarely become clinically manifest by the typical hypersecretive syndrome except for those large metastatic tumors associated with the carcinoid syndrome. Appendiceal carcinoids seem to arise from sub-epithelial cells in contrast to carcinoids with origin outside the appendix arising from the aforementioned enterochromaffine cells in the crypts of the bowel wall.

Those latter carcinoids with origin outside the appendix are strikingly more prevalent at autopsy and most tumors may not reach clinical significance during the patient`s lifetime.

3.1.2.2. Clinical presentation

Midgut carcinoid tumors are characteristically slowly-growing neoplasms and therefore most patients will experience prodromal symptoms for quite some time before the disease itself be-comes clinically manifest. Midgut carcinoids are typically located in the terminal ileum. The primary tumor characteristically is inconspicuous in size. It is located deep in the mucosal tissue and of fibrotic nature. Occasionally, intestinal bleeding might occur with large and ulcerating tumors or as a consequence of venous stasis in an intestinal segment. When the tumor is growing larger it may extend directly into mesenteric lymphatic glands. This almost invariably is the case with patients undergoing surgery for abdominal complaints (Davis, Moertel et al. 1973; Strodel, Talpos et al. 1983; Moertel 1987). The patients may initially exhibit the carcinoid syndrome or mainly show abdominal complaints and have to undergo surgery for intestinal obstruction, often without the actual diagnosis being overt (Moertel 1987; Feldman 1989). Most carcinoids with appendiceal origin are found at the tip of the appendix and thus seldom cause intestinal obstruction. Neoplasms evolving at the appendix base, however, might indicate surgery due to obstruction. Tumors of the appendix larger than 2 cm in diameter tend to metastasize. Also goblet cell carcinoids (those producing mucus) have malignant potential (Tiensuu Janson and Oberg 1996). These latter tumors are of endocrine origin apparently from specialized subepithelial neuroendocrine cells (Wilander, Lundqvist et al. 1989) and are thus mixed tumors of neuroendocrine- and adenocarcinoma-population. Prognosis for patients with these neoplasms is similar if not worse than for colorectal cancers.

Carcinoid metastases often are considerably larger than the primary tumor and characteristically can provoke pronounced desmosomic reactions. The mesenteric neoplasms and its fibrotic growth, rather than the primary lesion per se commonly tend to cause partial or complete small bowel obstruction by entrapping and kinking the small intestine.The tumor also tends to occlude or compress the neighbouring mesenteric vessels resulting in venous and, less commonly arterial ischemia. The intestinal vascular deterioration in advanced midgut carcinoid tumors may be intensified by a specific angiopathy exhibiting elastic tissue proliferation (elastic vascular scle-rosis) within the adventitia of the intestinal vessels (Anthony and Drury 1970; Eckhauser, Argenta et al. 1981). The mesenteric desmoplasia and the vascular elastosis have been suggested to result from local effects of growth factors and other substances released from carcinoid metastases (Funa, Papanicolaou et al. 1990). Carcinoid tumors commonly spread to the liver and might then become hormonally symptomatic with features of the carcinoid syndrome. Hormones released by gastroenteropancreatic primary tumors are generally metabolized by the hepatic drainage system, whereas those released from metastases of the liver or extraperitoneal sites might by-pass the liver. However, only at advanced disease stages do carcinoid tumors spread to extraabdominal sites such as peripheral lymph nodes, lungs, central nervous system, ovary, skin and skeleton, even though a neck lymph node may be a first clinical sign of the tumor (Sanders and Axtel 1964; Moesta and Schlag 1990; Makridis, Rastad et al. 1996).


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3.2.  The carcinoid syndrome

Diarrhea and cutaneous flushing are the prominent and often debilitating symptoms of the carcinoid syndrome. Further possible symptoms are bronchoconstriction, elevated urinary 5-hydroxy-indole aceticacid (5-HIAA) levels and a fibrotic carcinoid heart disease with pulmonary stenosis and tricuspid regurgitation (Janson, Holmberg et al. 1997).

Classical midgut carcinoids are the most common cause of the carcinoid syndrome and may generate a complex of symptoms comprising the carcinoid syndrome long before local growth or metastatic spread is otherwise apparent. Presence of the syndrome is synonymous with extensive disease and incurability in the majority of the cases. Presence of the carcinoid syndrome has been attributed to secretion of a number of bioactive agents by carcinoid hepatic metastases, e.g. serotonin,prostaglandin, kallikrein/bradykinin, dopamine, tachykinines etc. (Lucas and Feldman 1986)). About 5% of all patients with carcinoid tumors present with one ore more symptoms of the carcinoid syndrome, 30-60% of small intestinal carcinoids but only 3.5 % of bronchial, 1% of appendiceal and no rectal carcinoids are associated with the syndrome. Individual patients may present with symptoms to a different extent. For the development of the syndrome in patients with intestinal carcinoids the patient must have liver metastases (the secretion products by-pass hepatic metabolization). Bronchial and extraintestinal carcinoids whose hormones are not immediately detoxified by the liver may present with the syndrome without metastatic disease to the liver. Occasionally, manifestations of the syndrome may be expressed in patients with mere ovarian or large retroperitoneal metastases as a consequence of venous effluents directly draining into the systemic circulation (Makridis, Rastad et al. 1996).

Flush is the most striking feature of the syndrome, sometimes evoked by physical and psychic stress, meals and alcohol. Release of endothelium-derived vascular-relaxing factor upon stimu-lation with serotonin, substance P and VIP seems to contribute to an important paracrine mecha-nism (Regoli and Nantel 1991). Tachikinin secretion by carcinoids also contributes to the flush symptom, however, preventing the flush symptom pharmacologically has not always been asso-ciated with tachykinin level normalization (Makridis, Rastad et al. 1996).

Carcinoid heart disease includes morphological and functional changes of the tricuspid and pul-monary valves, enlargement of the right heart cavities and paradoxical septal contraction patterns. Cardiac sequelae may be diagnosed by echocardiography, especially by the trans-eosophageal route. Microscopically, the pathognomonic carcinoid cardiac lesions consist of fibrous tissue on mural and valvular endocardium, predominantly if not exclusively on the right side of the heart. The lesions may infiltrate into underlying endo- and myocardium. Knowledge about the etiology of carcinoid heart disease is scarce. However, there seems to be a relation bet-ween the extent of the disease and the amount of circulating substances secreted by the tumors, i.e. serotonin and tachykinins. Severe carcinoid heart disease resulting in right ventricular failure is an indication to reconstructive valvular surgery when the malignant disease is under control and when there are no possibilities to cure clinical signs of right heart failure medically (Lundin 1991).

Diarrhea is nearly as common as flush but both symptoms are not necessarily present simul-taneously (Davis, Moertel et al. 1973). Diarrhea in carcinoid patients can be caused by ileal resection resulting in reduction of bile salt absorption and dysfunction of motility and secretion in the distal ileum. A short bowel syndrome or intestinal bypass after surgery, partial intestinal obstruction, ischemia and venous stasis may also lead to severe watery diarrhea and malnutrition in some patients. Not only anatomical aberrations may induce diarrhea but also humoral factors produced by the carcinoid tumor, mainly excessive release of serotonin, motilin and substance P (Feldman and O'Dorisio 1986; Norheim, Theodorsson-Norheim et al. 1986). Serotonin, however, does not seem to mediate the diarrhea alone. Local intestinal paracrine mechanisms, such as increased intestinal secretion of prostaglandin (PG) E2 and tachykinins exerting substantial effects on intestinal motility and secretion may also be pathophysiologically involved in carcinoid diarrhea, especially substance P, neurokinin A, neuropeptide K and eledoisin (Brunsson, Fahrenkrug et al. 1990; Sjokvist, Brunsson et al. 1993). Bronchoconstriction and asthma occur in about 10-20% of patients suffering from the carcinoid syndrome.

3.3. Diagnosis

Characterization and diagnosis of a carcinoid tumor can be achieved by considering the following aspects: hormone production, histopathological features and certain aspects of tumor biology, radiological and radionuclear examinations.


[page 16↓]

3.3.1.  Hormones

Especially midgut carcinoid tumors and also foregut carcinoids but never hindgut carcinoids show characteristic serotonin- production (Lembeck 1953). The serotonin metabolite U-5-HIAA is the most commonly used biochemical marker to be measured in the urine as well as serotonin in plasma. Chromogranin A, chromogranin B/secretogranin I and chromogranin C/secretogranin II constitute a family of water-soluble acidic glycoproteins and are stored in large dense core vesicles in endocrine and neuroendocrine cells. Tumors originating from those cells are thus associated with elevated plasma levels of chromogranin A (99%), B (88%) and C (6%) which can serve as early markers for neuroendocrine tumors comprising foregut, midgut and hindgut carcinoid tumors. Although less reliable, urinary measurements usually also reveal elevated levels of chromogranins (Eriksson, Arnberg et al. 1990; Stridsberg, Oberg et al. 1995). Furthermore, elevated levels of substance P and neuropeptide K from the tachykinin family are found especially in patients with midgut carcinoids. Flush provocation with pentagastrin is followed by an increase in plasma levels of neuropeptide K so this test may indicate the carcinoid disease in patients with normal basal levels of the peptide at an early stage (Norheim, Theodorsson-Norheim et al. 1986). The serum concentration of the alpha-and beta-subunits of HCG may be raised in midgut carcinoids, the alpha-subunit may be raised in foregut and hindgut carcinoids. However, this increase usually is not impressive enough to serve as a means of monitoring.

3.3.2. Histopathology

Carcinoid tumors all react positively to the argyrophilic stain of Grimelius (Grimelius and Wilander 1980) and stain immunohistochemically with antibodies against chromogranin A (Stridsberg, Oberg et al. 1995). Additionally, midgut carcinoids show argentaffinity whereas foregut and hindgut carcinoids do not (Wilander, Lundqvist et al. 1989). Immunohistochemistry with antibodies against the proliferation marker Ki-67 antigen may serve as a method to observe the proliferation activity in carcinoid tumors. Findings of splice variants of CD44 in a primary tumor may indicate a more malignant nature of the tumor and a metastatic potential (La Rosa, Sessa et al. 1996).

3.3.3. Radiological and radionuclear examinations

Conventional radiology, computerized tomography (CT), magnetic resonance imaging (MRI) and ultrasonography are used to stage carcinoid tumors. Staging of the disease is important in order to aim at identification of those patients suitable for resection of the liver metastases, e. g. solitary or unilobular metastases and no further spread.

Often, the carcinoid causes only discrete stenosis which is difficult to detect by small bowel study. However, a plain abdominal film may reveal a distended small bowel loop or a thickened bowel wall if the patient is suffering from bowel ischemia or mechanical obstruction. Also, radiographic contrast examination by enteroclysm according to Sellink may detect a tumor in the small intestine in patients suffering from intestinal obstruction. CT scans, MRI and ultra-sonography are valuable tools in evaluating hepatic metastases whereas the sensitivity for de-tecting the primary tumor is low.

If the site of the primary tumor is unknown, further investigations will be necessary, e.g. selective arteriography or more frequently somatostatin receptor scintigraphy. Selective angio-graphy may show the affected branches in patients with abdominal angina. However, a normal angiogram does not exclude ischemia as it only shows larger vessels whereas ischemia expresses itself mostly in smaller vessels which are not visualized by angiography.

However, substances labelled with radioactive compounds have been more frequently serving as a base for tumor diagnosis and biological characterization of the tumors. Carcinoid tumors are well known for characteristic expression of somatostatin receptors, midgut carcinoids to a larger extent than other carcinoids and carcinoids with elevated urinary 5-HIAA to a larger extent than non-secreting carcinoids (Reubi, Kvols et al. 1990). So far, five subtypes of the somatostatin receptor have been cloned of which subtype 2 binds the somatostatin analogue used in the clinic with the highest affinity and subtypes 1 and 4 with the lowest affinity. A correlation is assumed between somatostatin receptor expression and the response to treatment with somatostatin analogues. Binding a somatostatin analogue to a radioisotope serves as a tool for visualizing the tumor. A technique in which indium-labelled (111IN-DTPA-D-Phe) octreotide (=Octreoscan) is intravenously injected provides knowledge about the somatostatin receptor status of the patient´s tumor(s) and tumoric lesions outside the abdomen (Bakker, Albert et al. 1991). This somatostatin receptor status will then predict the success [page 17↓]regarding the decrease in hormone levels after medical treatment with somatostatin analogues. Somatostatin scintigraphy is not necessarily superior to CT or ultrasound in detecting primary tumors larger than 2 cm or hepatic metastases whereas it is superior in detecting extra abdominal metastases. However, 20% of the patients with tracer uptake in the lesions might not respond to treatment with somatostatin analogues. The reason for this might be the tracer binding to different receptor subtypes but not all of which inhibit hormone secretion. In contrast to midgut carcinoids, colorectal carcinomas are negative on Octreoscan. In contrast to octreotide, which is attached to cell surface receptors, Iodine131-meta-iodobenzylguanidine (MIGB) is taken up in carcinoid cells or neuroendocrine cells in general and accumulates in the argentaffin granules. Combination of MIGB scintigraphy and octreotide scan may result in a rather high sensitivity.

VIP receptor scintigraphy as another imaging procedure resulted in positive scans in patients with carcinoids but even colorectal adenocarcinomas present with VIP receptors .

C-labelled 5-hydroxytryptophan (HTP), a precursor in the biosynthesis pathway of serotonin, is taken up by the carcinoid tumor in positron emission tomography (PET), the actual tumor detection limit is 5mm. PET gives information about tumor metabolism as well as effects of treatment. It is as sensitive as somatostatin receptor scintigraphy but less reliable than CT-scanning. Labelling of various tracer molecules helps to observe tumor biology in vivo (Tiensuu Janson and Oberg 1996).

3.4. Treatment

3.4.1. Medical treatment of metastatic carcinoid tumors

3.4.1.1. Somatostatin analogues

Treatment of somatostatin receptor positive tumors with somatostatin analogues labelled with radioactive substances, e.g. octreotide in patients with midgut carcinoid patients can improve or sometimes prevent flushing and diarrhea (Tiensuu Janson, Westlin et al. 1994). Long acting analogues require less frequent injections. Interference of somatostatin analogues with exo- and endocrine pancreas function may cause side effects such as diarrhea, steatorrhea, flatulence, nausea, vomiting and mild hyperglycaemia.

Also, Iodine131-metaiodobenzylguanidine (I131-MIBG) has treatment potential, both „cold“ and radiolabelled MIBG may alleviate symptoms of the carcinoid syndrome. Functioning tumors are resistant to radiotherapy.

3.4.1.2. Interferon-alpha

Interferon-alpha may be administered alone or in combination with somatostatin analogues (octreotide) depending on the individual tolerance of the medication. Symptomatic improvement of flush, diarrhea and bronchoconstriction after treatment with interferon-alpha is achieved in 60% of patients with metastasizing carcinoids. The anti-tumor effect in neuroendocrine tumors is due to biochemical and tumor response and includes induction of apoptosis and reduction of tumor size (Oberg, Eriksson et al. 1994; Imam, Eriksson et al. 1997). Stabilisation of the carcinoid disease is possible.

The patients may develop neutralizing antibodies against recombinant interferon-alpha resulting in abolishment of the anti-tumor effect and thus, a lower regress rate. Interferon-alpha-related adverse reactions include flu-like symptoms, fatigue and weight loss and are dose-dependent.

3.4.2. Chemotherapy

Interferone-alpha may also be combined with systemic chemotherapy with single-therapy or combinations of streptozotocin, 5-fluoruracil, cyclophosphamide, and/or doxorubicin (Plöckinger and Wiedenmann 2000) or a combination of dactinomycin (actinomycin D), dacarbazine (Van Hazel, Rubin et al. 1983).

Lower biochemical response rates (urinary 5-HIAA levels) and poor subjective improvement among [page 18↓]patients with carcinoid tumors originating in the small bowel was noted after chemo-therapy when compared to interferone-alpha treatment. This is suggestive of the fact that today, as for quality of life, interferone-alpha treatment is superior to chemotherapy (Oberg, Norheim et al. 1989). Side effects of chemotherapy are, nausea, vomiting, leukopenia, thrombocytopenia and nephrotoxity.

To conclude, patients with the carcinoid syndrome generally die from carcinomatosis rather than from the pharmacological effects of the tumor.

3.4.3. Surgery

Radical surgery, i.e. curative resection of the primary tumor, is indicated when the tumor is re-sectable. In most cases, patients present with multiple primary tumors. The metastatic mass in the mesentery and liver are usually larger than the primary tumor. A potentially curative, radical re-section of liver metastases is recommended if the metastases constitute a substantial part of the tumor burden. In most cases, resection of liver metastases can only lead to palliation. However, liver metastases are often irresectable due to multiplicity. In that case, palliative resection of the primary tumor may help to prevent from obstruction and ischemia and thus, maintain bowel function. Intestinal resection of mesenteric lymphnode metastases must be performed. Tumor re-moval may result in clinical and biochemical complete remission and the patient may live symptom-free for a long time after tumor removal. Life expectancy and quality of life may im-prove after curative and even palliative resection. The perioperative treatment with octreotide gives surgery a chance even in advanced stages of the carcinoid disease and helps to avoid a car-cinoid crisis with circulatory chock, excessive flush and bronchoconstriction.

3.4.4. Hepatic embolization

For patients with liver metastases not exceeding 50% of the liver volume, embolization of the hypervascularized liver is a possibility to achieve a biochemical and tumor response. The blood supply of the liver is mainly arterial. The hepatic tissue is supplied by both hepatic artery (20-25%) and portal vein (75-80%). Hepatic embolization (dearterialisation of the liver metastases) will result in ischaemia and necrosis of the metastases but will affect normal tissue to a lesser degree and be followed by regeneration of the parenchyma. However, this procedure might pro-voke severe complications such as liver abscesses and intestinal ischemia. Hepatic embolisation may require laparotomy but may also be performed by radiological intervention. In case of laparotomy, cholecystectomy is advocated prior to embolisation in order to prevent gall-bladder necrosis. Prophylactic octreotide should be given when patients undergo hepatic emboli-zation and surgery in order to prevent a carcinoid crisis with the aforenamed complex of symptoms (Makridis, Rastad et al. 1996; Eriksson, Larsson et al. 1998).

Side effects of dearterialisation of liver metastases is the post embolization syndrome character-ized by pain in the liver region lasting for several days as well as febrile temperatures in the patient.

3.4.5. Radio frequency ablation (RFA)

More recently, liver metastases that are unresponsive to hepatic artery embolization have been treated with thermal ablation using radio frequency ablation as a salvage treatment. RFA therefore is a useful adjunct to decrease symptoms, to lower octreotide treatment and to slow the progression of the disease (Wessels and Schell 2001).

3.4.6. Cryosurgery

The role of cryosurgery in palliative care has yet to be assessed. To treat hepatic metastases by cryotherapy an ice ball is formed around the metastatic structure. However, this makes it difficult to reposition the metastasis later on for optimal targeting. Side effects of cryotherapy might be cracking of the liver and thus causing massive haemorrhage after thawing.

3.4.7. Heart valve surgery

Reconstructive tricuspidal valve replacement is indicated for patients with carcinoid heart disease and right heart failure.


[page 19↓]

3.5.  Survival and prognosis

Although carcinoid tumors were first believed to be of benign nature, it is nowadays known that for tumors in the midgut region this is only true for small neoplasms arising in the appendix. Other midgut carcinoids may very well be malignant. However, there is a realistic chance for the patient to be cured if the primary tumor and regional lymph nodes are surgically removed. Over-all median survival is 12 years from the onset of any features of the carcinoid syndrome.

Survival of 14 years is found in patients who have undergone radical removal of the primary tumor and mesenteric carcinoid metastases. Irresectable mesenteric lymph node dissemination, however, decreases survival to 11 years, presence of liver metastases to 5-7 years, depending on the degree of liver envolvement (Tiensuu Janson, Westlin et al. 1994). Expected survival for individuals with extended regional metastases or peritoneal carcinoidosis with massive weight loss (>9 kg) as well as for patients with diagnosed valvular heart disease or clinically manifest heart failure is 2.5-5 years. Even shorter survival is found in patients with extraabdominal metastases. Other unfavourable prognostic parameters are raised plasma chromogranin A and neuropeptide K levels as well as high urinary 5-HIAA levels (>500µmol/24h) (Tiensuu Janson and Oberg 1996; Makridis, Ekbom et al. 1997).

A 3-4-year period before recurrence of the tumor has been reported for carcinoid patients but might as well be as long as 16 years (Moertel 1987). Massive liver involvement thus requires more radical treatment but also patients with less metastases to the liver should be given the best medical treatment as they have a long life expectancy (Tiensuu Janson and Oberg 1996). Carcinoid-related heart disease and cachexia account for the principal cause of death in gastro-intestinal carcinoid patients. Increasing age, advanced disease stage, tumor location in the large bowel and presence of other malignancies are related to increased risk of death in these tumors (Greenberg, Baumgarten et al. 1987). Another investigation, however, did report that the male gender and the amount of metastases were predictive factors for the lethal outcome of the disease but that age was not. Also, the site of the primary tumor was of prognostic significance, with poor survival for carcinoids of the small intestine compared to appendiceal carcinoids, as well as the mode of discovery: Accidentally diagnosed carcinoids had a better prognosis (McDermott, Guduric et al. 1994). However, the patients may benefit markedly from a combination of surgical and medical treatment (Makridis, Ekbom et al. 1997).

3.6. Multiple Endocrine Neoplasia (MEN)

3.6.1. Clinical features

Multiple Endocrine Neoplasia belongs to the group of pluriglandular syndromes with endocrine tumors developing in more than one organ but also non-endocrine expressions of the disease. There are five major MEN syndromes: Multiple Endocrine Neoplasia type 1 (Wermer-Syndrome (Wermer 1963), which is characterized by a combined emergence of endocrine tumors in the anterior pituary and parathyroid gland (parathyroid adenoma), pancreas and duodenum (submucosal duodenal carcinoids) as well as less frequent tumors such as adenoma and carcinoma of the thyroid gland, adrenal cortical hyperplasia, hepatic focal nodular hyperplasia and renal angiomyolipoma, foregut carcinoid tumors (gastric enterochromaffin-like-cell carcinoids, thymus and bronchial carcinoids) (Lamberts and Gregor 1999) and non-endocrine tumors such as angiofibroma, lipoma, leiomyoma, as well as facial angiosarcomas and collagenomas, recently found but common skin manifestations (Marx, Agarwal et al. 1999). Multiple Endocrine Neoplasia type 2a (Sipple-Syndrome) (Wermer 1963) presents with c-cell carcinoma of the thyroid glands, hyperparathyroidism and pheochromocytoma. Type 2b includes mucosal neurinomas, intestinal ganglioneuromatosis and occasionally a marfanoid habitus. Von Hippel-Lindau Syndrome presents with pancreatic neuroendocrine tumors, pheochromocytoma and different neoplastic non-endocrine tumors in the CNS, retina, kidney, pancreas, endolymphe and epididymis. The Carney complex comprises endocrine neoplasms in Sertoli and Leydig cells, the pituitary, thyroid and adreno-cortical gland and non-endocrine neoplasms such as myxomas and lentigines. Mc Cune-Albright Syndrome presents with the symptoms of precocity, pituitary, thyroid and adrenocortical gland neoplasms as well as café-au-lait spots and non-neoplastic affection of heart and liver (Marx, Agarwal et al. 1999).

MEN-1 is an autosomal-dominant hereditary disease and shows high penetration but irregular expressivity (Metz 1995). The population prevalence of the disease is advanced with 2-10 per 100000 (Marx, Agarwal et al. 1998). In MEN 1 tumor multiplicity is a characteristic feature referring both to tumors in multiple organs and to multicentric tumors in one organ, often bilateral neoplasms (Pipeleers-Marichal, Donow et al. 1993; Debas and Mulvihill 1994). 95% of the MEN-1 patients [page 20↓]present with hyperparathyroidism, often as the primary manifestation, 80% show pancreatic tumors, 50-65 % pituitary tumors are detected in autopsies. Diffuse hyperplasia or multiple adenomas and postoperative recurrence due to the multicentric origin of the disease, are characteristic for primary hyperparathyroidism. MEN-1 patients often show symptoms of sporadic hyperparathyroidism (hypercalcemia, nephrourolithiasis and ostitis fibrosis cystica). Important diagnostic features are raised parathyroid hormone (PTH), raised serum-calcium, lowered serum-phosphate, lowered urinary calcium and raised urinary phosphate levels. Surgery is considered as firstline therapy, either subtotal parathyroidectomy or total parathyroidectomy with simultaneous autogenous parathyroid transplantation e.g. to the forearm (Mallette 1994). Also the pancreatic lesions (nesidioblastosis, microadenoma or carcinoma) are multicentric and of endocrine differentiation, of which up to 40% are situated in the duodenal wall or the triangle between duodenal C, ventricle antrum and pancreatic head. The majority of MEN-1 patients with pancreatic tumors are asymptomatic (Skogseid, Eriksson et al. 1991). 50% of the cases present with clinical or pathological malignancy criteria (lymphnode or visceral metastases). The pancreatic lesion within MEN-1 is the most striking factor concerning the prognosis of the disease, that in up to 50% is malignant. The pituitary tumors are almost only benign, singular adenomas or multicentric tumors, of which about 15% are prolactinomas or growth hormone (GH)-producing tumors as well as raised ACTH (adenocorticotropic hormone) production (McCutcheon 1994), TSH-secreting and non-secreting tumors. Most common are chromophobe adenomas with the clinical manifestation of expanding growth or pituitary functional loss. Characteristic for prolactinomas are secondary amenorrhea, galactorrhea, loss of libido or infertility in females, impotence and loss of libido in males (Farid, Buehler et al. 1980) and, for GH-producing tumors, acromegalia. Stimulation tests with pituitary releasing and inhibiting factors as diagnostic means have proved to be more sensitive than basal hormone measurement. Ophtalmologic and perimetric examination of the patients is important. Therapy depends on the tumor entity: Prolactinomas and GH-producing tumors respond to medical treatment with dopamin analogues and/or transsphenoidal tumor resection as the surgical alternative, with or without radiotherapy. GH-producing tumors may also be treated with subcutaneous injections of somatostatin analogues (Lamberts and Gregor 1999).

3.7. Endocrine pancreas tumors (EPT)

3.7.1. Clinical features

Endocrine pancreas (EPT) tumors are a rare tumor type with an incidence of approximitely 4 per year and million population (Eriksson, Larsson et al. 1989). They behave more indolently than their highly malignant exocrine counterparts. They may arise within the tumor syndromes MEN 1 or von Hippel-Lindau (VHL) as well as sporadic neoplasms. When no metastases or local invasiveness are present, there are no indisputable clinical or histopathological methods to declare EPT as malignant. On the other hand, absence of cellular atypia, perineural infiltration, intracapsular growth and lymph or blood vessel invasion does not allow to exclude malignant nature (Pelosi, Bresaola et al. 1996). The majority of these tumors are clinically functioning tumors, i.e. they are associated to a syndrome related to hypersecretion of a specific hormone, 50% of them are gastrinomas, 25% insulinomas, 10% non-functioning tumors, including tumors secreting pan-creatic polypeptide (PP), chromogranin A, peptide YY (PYY) and neurotensin, and 2% glucagonomas, VIPomas (vasoactive intestinal peptide), and somatostatinomas (Lamberts and Gregor 1999). Gastrinoma or Zollinger-Ellisons syndrome can also be caused by duodenal carcinoids and more than 70% of these tumors have malignant potential (Zollinger, Ellison et al. 1980; Oberg 1996). Clinically they present gastric and duodenal ulcerations, diarrhea and malabsorption. Insulinomas are rarely malignant and small in size but nevertheless cause severe hypoglycemia syndrome. Signs of neuroglucopenia and increased catecholamine release are typical symptoms related to insulin/ proinsulin overproduction (Oberg 1996). Glucagonoma, somatostatinoma, Verner-Morrison or Watery Diarrhea Hypocalcemia Achlorhydria (WDHA) syndrome caused by VIP are more seldom syndromes but are more frequently of malignant potential. Glucagonomas are clinically characterized by a necrolytic migratory erythema, diabetic glucose tolerance, anaemia, weight loss and tromboembolism (Stacpoole 1981), while increased somatostatin production sometimes leads to gall bladder dysfunction, gall stones and diabetic glucose tolerance, malabsorption and diarrhea (Krejs, Orci et al. 1979).


Footnotes and Endnotes

1 In the present thesis I use the term carcinoid or carcinoid tumor for classical midgut carcinoid tumors.



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