Carcinoids are neuroendocrine tumors most commonly originating from the midgut. Primary tumors and possibly existing metastases produce a variety of hormones and hormone-like mediators that provoke systemic symptoms like flushing, diarrhea and cardiac insufficiency - the entirety of these symptoms is referred to as malignant carcinoid syndrome.
Only minor shares of gastrointestinal NET ever become symptomatic and if patients experience complaints, they have usually been living with carcinoid tumors for years. NET may cause local and systemic symptoms, whereby the former are generally not considered part of the MCS. Either type of symptom may dominate the clinical picture and thus, MCS-associated complaints may be the cause of initial presentation. In these cases, a diagnosis of gastrointestinal NET has not been established previously.
The most characteristic symptoms of MCS are flushing, diarrhea, cardiac insufficiency, and bronchoconstriction.
With regards to local symptoms induced by the respective primary tumor, appendiceal carcinoids may mimic acute appendicitis, i.e., they may cause an acute onset of abdominal pain in the lower right quadrant, nausea, vomiting and/or acute abdomen.
If a patient's medical history comprises a previous diagnosis of gastrointestinal NET, diagnosis of MCS is largely facilitated. In most cases, though, the treating physician has to make both the diagnosis of malignant NET and MCS.
With regards to the former, magnetic resonance imaging and computed tomography scans are first-line diagnostic tools to detect gastrointestinal tumors, hepatic and extra-hepatic metastases. It is not uncommon to see multiple carcinoid tumors in the digestive tract and multiple metastases. Findings obtained by diagnostic imaging are very helpful when establishing a therapeutic plan.
Diagnosis of MCS is based on the presence of characteristic symptoms in a patient who has been shown to suffer from metastatic NET. In order to assess which mediators account for the observed symptoms, laboratory analyses of blood samples should be conducted.
MCS treatment consists in a cure of the underlying disease and symptomatic therapy of MCS-associated disturbances as long as they persist.
With respect to the primary NET and its metastases, only surgical resection has been proven effective. Neither radiation therapy nor chemotherapy is indicated in case of carcinoids; symptoms relieve may be achieved by applying these techniques, but recurrence has to be expected. Resection of regional lymph nodes and hepatic metastases is usually a greater challenge than complete removal of the primary tumor. Nevertheless, surgery is recommended and patients may even benefit from incomplete resection: Symptoms subside and life quality improves. Because NET are very slow growing tumors, survival times can be significantly prolonged by such measures. Complete resection often leads to a permanent cure.
Distinct drugs are available to counteract peripheral effects of hormones and hormone-like substances produced by the tumor. Octreotide is a somatostatin analogue that binds to surface receptors expressed by NET cells and thereby inhibits release of the aforementioned substances, mainly of serotonin . It is currently the mainstay of drug therapy of MCS. Serotonin synthesis inhibitors like telotristat etiprate may be used in patients who don't respond satisfactorily to octreotide . Conventional antihistamines may be applied to further reduce flushing and bronchoconstriction. MCS-related diarrhea may be treated with antidiarrheals like loperamide, diphenoxylate, and opiates.
According to the pathophysiological mechanisms that lead to MCS, the vast majority of patients presenting with this syndrome suffers from a malignant neoplasm that already spread to the liver and/or regional lymph nodes. However, these tumors are generally very slow growing and thus, the overall prognosis is relatively good when compared with individuals affected by other types of cancer.
The individual prognosis of a patient may depend on whether the primary tumor and all metastases can be removed surgically. If the entire tumor tissue can be resected, complete cure is possible. Life quality and life expectancy can also be improved or prolonged by debulking, i.e., by removal of as much cancerous tissue as possible. A 5-year survival rate of 76% has been reported for those patients whose primary tumor has been resected . This value decreases drastically if untreated patients are considered. Urinary excretion of serotonin metabolites has been proposed as a prognostic factor whereby excretion of high quantities of 5-hydroxyindoleacetic acid relates to a worse outcome.
Precise triggers of carcinoid development or malignant degeneration of NET are not known. In some cases, they may be presented by patients who suffer from multiple endocrine neoplasia, a genetic disorder characterized by multiple tumors of endocrine glands.
MCS, in turn, does directly result from metastasizing NET. The primary tumor is most often located in ileum or cecum, but may also be encountered in the colon. Rectal carcinoids are rarely associated with MCS. Of note, malignant NET may also originate from other tissues, namely from the lungs, ovaries, and testes. Malignant carcinoids in other organs have only been described in isolated cases.
Epidemiological data regarding NET and MCS are scarce and their reliability is doubtful. With respect to gastrointestinal NET, annual incidence rates of 1-2 per 100,000 inhabitants have been reported . These values are most likely underestimates since the majority of NET patients never manifests any symptoms. Thus, retrospective studies can only be based on symptomatic NET.
Soga and colleagues conducted such a study and reported the following :
Neither racial nor gender predilections have been reported.
The likelihood of developing MCS in the case of NET correlates well with the presence of metastases. MCS is most commonly described in patients who present hepatic metastases of gastrointestinal NET; some MCS patients suffer from NET that spread to the regional lymph nodes, and in few cases, metastases cannot be encountered. The latter presumably results from the inability to detect small metastases with available imaging techniques. Induction of MCS by primary gastrointestinal tumors is unlikely since vasoactive substances secreted by these neoplasms are degraded upon the first pass through the liver and won't reach peripheral organs .
NET and their metastases may produce a plethora of biogenic amines, protein and peptide hormones, kinins, eicosanoids, growth factors and enzymes. The interested reader is referred to a recently published review regarding this broad topic .
Serotonin activity seems to play a major role in MCS pathophysiology and in general, serotonin activity is higher in NET patients with MCS than in those that do not present the syndrome . In fact, not too long ago a case report has been published about an older woman who manifested MCS because of a serotonin-secreting pituitary tumor . Serotonin has been shown to induce cardiac valve lesions and heart failure is the main cause of premature death in MCS patients. Although serotonin release has also been related to MCS-associated diarrhea, tachykinins may significantly contribute to it . Serotonin and tachykinins are also implied in bronchoconstriction . Flushing, in contrast, is primarily mediated by histamine. Therefore, histamine-producing stomach carcinoids may mimic an incomplete MCS.
Carcinoid, carcinoid tumor and neuroendocrine tumor (NET) are all medical termini referring to neoplasms originating from the neuroendocrine system. The vast majority of NET are located in the gastrointestinal tract, mainly in ileum and cecum, but such tumors may also be encountered in more proximal or distal parts of the digestive tract, in pancreas or lungs.
Most NET are functionally active, i.e., they produce hormones and hormone-like substances that may be released into circulation. Biogenic amines serotonin and histamine, as well as kinins, shall be mentioned as examples, but individual NET may differ largely regarding their secretory profiles. If the aforementioned mediators reach the bloodstream, they may exert distinct effects in peripheral organs, namely in the cardiovascular system, in the respiratory tract or in the gastrointestinal tract. This results in flushing, cardiac insufficiency, bronchoconstriction, and diarrhea, respectively. The entirety of these symptoms is known as carcinoid syndrome.
NET may be benign or malignant neoplasms. It has generally been assumed that NET who measure less than a centimeter in diameter are most likely benign; they have rarely been shown to grow invasively and spread lymphogenically or hematogenously. However, this hypothesis has recently been challenged . Retrospective studies have shown that 12% of small NET metastasize, mainly into local lymph nodes. The share of malignant tumors is even greater among NET measuring more than a centimeter in diameter.
According to current knowledge, carcinoid syndrome preferentially occurs in patients suffering from malignant NET, which is why this symptom complex is also designated as malignant carcinoid syndrome (MCS). Strictly speaking, MCS can only be diagnosed in patients who have previously been shown to suffer from malignant NET, which is most commonly achieved by demonstrating the existence of hepatic metastases  . Carcinoid syndrome in patients diagnosed with non-metastatic or benign NET is rare.
Ideally, gastrointestinal primary tumors and all metastases are surgically removed - if this can be achieved, complete cure of NET and MCS is possible. MCS itself is treated with medication that counteracts the effects of serotonin, histamine and possibly other mediators released by tumor metastases. Additionally, symptomatic treatment may be indicated to relieve cardiac disorders and diarrhea.
Carcinoid, carcinoid tumor and neuroendocrine tumor (NET) are all medical termini referring to neoplasms originating from hormone-producing cells located in distinct organs. Many NET develop in the gastrointestinal tract, and they may be either of benign nature or malignant.
NET often produce hormones and hormone-like substances themselves, in an uncontrolled manner. As long as the tumor does not spread from the intestines to other tissues, these substances are transported to the liver and degraded there before they can reach peripheral organs. However, malignant NET tend to spread to regional lymph nodes and the liver. Functionally active tumors may now release serotonin, histamine and a variety of other compounds that are directly secreted into the circulation. They easily reach the cardiovascular system, the bronchial tubes or different parts of the digestive tract. Here, they mediate flushing, cardiac insufficiency, bronchoconstriction, and diarrhea, respectively. The entirety of these symptoms is known as malignant carcinoid syndrome (MCS).
MCS may only be diagnosed in patients who have previously been found to suffer from NET. But because NET are generally very slow growing tumors, they may not cause symptoms for years, and MCS may be the first manifestation of this pathology. Thus, diagnostic imaging, localization of primary tumor and metastases, along with laboratory analyses of blood samples is applied to assess the dissemination of tumor cells and to identify those hormone-like substances that cause complaints.
Treatment consists in surgical resection of the primary tumor and all metastases as well as reduction of serotonin- and histamine-mediated effects. Life quality and life expectancy can be significantly improved by these measures; if all tumors can be resected, complete cure is possible.