Duodenal carcinoid syndrome (DCS) refers to a complex of cardiovascular, respiratory, and gastrointestinal symptoms triggered by a functional neuroendocrine tumor developing in the proximal part of the small intestine. These symptoms may be associated with gastrointestinal complaints suggestive of local mass effects. The complete resection of the duodenal carcinoid and existing metastases is the preferred approach to therapy, but it may not be feasible in advanced stages of the disease. Here, palliative treatment and alleviation of DCS-related symptoms may be achieved with somatostatin analogs.
DCS refers to the sum of systemic symptoms provoked by the mediators released by tumor cells in the duodenum. These symptoms may include gastrointestinal complaints, but they don't allow for the localization of the pathological process to the duodenum. Indeed, DCS patients frequently report diarrhea. Numerous episodes of watery stools are not uncommon and may cause dehydration and weight loss . Additionally, patients may describe episodic hot flushes. These may or may not involve the whole body, but frequently affect the face, neck, and thorax . Mediators released by tumor cells may induce cardiac damage, namely tricuspid and pulmonary insufficiency, as well as endomyocardial fibrosis. Patients may thus present with heart murmurs and signs of right-sided heart failure . Respiratory symptoms may also be observed. Bronchoconstriction is often induced and may lead to a dry cough .
Besides DCS, affected individuals may describe upper abdominal pain, presumably attributable to the primary tumor in the duodenum or any of its metastases . Duodenal carcinoids may also lead to gastrointestinal hemorrhages, melena, and anemia . Non-specific gastrointestinal symptoms related to duodenal carcinoids comprise nausea, vomiting, gastroesophageal reflux, bloating, and dyspepsia  . If the bile duct is obstructed, patients may develop jaundice.
In the absence of upper gastrointestinal symptoms, laboratory analyses of blood and urine samples may yield first hints at the primary disorder. If mediators are released by tumor cells, these mediators (or their metabolites) can be detected in body fluids. Their concentrations are likely to exceed the respective reference ranges. 5-hydroxyindoleacetic acid, for instance, is the end product of serotonin metabolism and is excreted by DCS patients if the primary tumor produces serotonin. Increased levels of urinary 5-hydroxyindoleacetic acid have a 100% specificity for carcinoid tumors . Of note, alterations of hepatic parameters may be due to metastases in the liver or may be caused by obstructive cholestasis.
Diagnostic imaging is the most important tool to confirm the tentative diagnosis of a gastrointestinal carcinoid, to assess whether there is a single or multiple tumors, whether there metastases in the liver or other organs. Computed tomography is most commonly used to this end, but sonography may yield conclusive findings, too. Scintigraphy using isotopes that bind to the receptor of neuroendocrine cells is another technique with high sensitivity for the detection of duodenal carcinoids, regardless of their functionality . In symptomatic patients, multiple tumors are a rather common finding . They are typically spread through the duodenum and more distal parts of the intestine. In one of eight patients, distant metastases are present at the time of diagnosis, and the share of patients with advanced-stage disease may be even higher among those presenting with DCS: Metastases most commonly form in the liver and bones, so biologically active substances that had previously been inactivated in the liver are now released into the systemic circulation without prior metabolization .
After the tumor has been localized to the duodenum, it may be visualized and accessed endoscopically. Surgeons may opt for a standard biopsy or choose to perform an excisional biopsy to obtain tissue samples . These specimens are subjected to a histopathological examination. Tumor cells are monomorphic, have rounded nuclei and abundant cytoplasm. They are arranged in a trabecular or cribriform pattern. Necrotic foci are not usually seen, and the mitotic rate is low . Carcinoids test positive for chromogranin A, the most valuable marker of neuroendocrine tumors . Staining for neuron-specific enolase and synaptophysin .
Patients diagnosed with duodenal carcinoids should undergo a thorough cardiological examination to evaluate the degree of DCS-related heart disease .
In case of a single, resectable duodenal carcinoid, the complete removal of the tumor is sought. In general, endoscopic mucosal resection is performed if the tumor measures <1 cm in diameter and hasn't invaded the muscular layer . Transduodenal resection, possibly combined with regional lymphadenectomy, is recommended in case of solitary tumors measuring >1 cm in diameter   . Depending on their localization and size, multiple tumors may be removed in a similar manner, or Whipple's pancreaticoduodenectomy and regional lymphadenectomy may be performed . Hepatic metastases may be treated by partial liver resection, radiofrequency ablation, cryoablation, and/or embolization.
If the patient isn't eligible for surgery or the resection of the primary tumor and its metastases isn't feasible, cytoreductive surgery plus pharmacological treatment should be considered. Long-term symptom control is feasible with somatostatin analogs, although these drugs don't affect tumor growth  . Octreotide and lanreotide are most widely used to alleviate DCS-related symptoms, with immediate-release formulations being used thrice daily at the beginning of therapy. Once tolerability and efficacy are established, the patients are switched to long-acting formulations, which are injected intramuscularly once a month . Other agents, such as interferon alfa and antihistaminics, should be applied as needed. The efficacy of systemic chemotherapy and radiotherapy has not been proven in DCS patients, so these treatments should be reserved for those with progressive disease and multiple metastases  . In any case, medical therapy should be supported by maximal, possibly repeated debulking .
Regular assessments of the urinary excretion of 5-hydroxyindoleacetic acid and plasma levels of chromogranin A may help to evaluate the patient's response to therapy and to predict an imminent relapse  .
DCS may be fatal due to severe cardiac damage and right-sided heart failure, or due to a carcinoid crisis. Such a crisis may be triggered by drugs, especially by anesthetics, or by manipulation of the tumor during surgery. As a result, large quantities of biologically active substances are released from the tumor, and life-threatening drops in blood pressure may occur .
Duodenal carcinoids may be benign or malignant tumors. The latter tend to grow invasively, to spread to the regional lymph nodes and to form hematogenic metastases in distant organs. The distinction of benign and malignant carcinoids may pose a major challenge but is essential to the prognosis. Additionally, high plasma concentrations of chromogranin A have been related to a worse outcome and may indicate a relapse . In sum, even malignant variants of duodenal carcinoids tend to grow slowly, so the prognosis remains favorable if DCS-related symptoms can be controlled. Due to the rarity of duodenal carcinoids, reliable data regarding the outcome are scarce, but for patients diagnosed with any carcinoid, the five-year survival rate is 67% . About 40% of individuals diagnosed with metastatic small intestine carcinoids remain alive after five years . If the neoplasm can be removed in its entirety, the patient has an excellent prognosis .
DCS comprises the systemic effects of mediators released by neuroendocrine tumor cells, but little is known about the genesis of carcinoid tumors. Multiple endocrine neoplasia type 1 is a hereditary disorder known to predispose to neuroendocrine tumors and a variety of other neoplasms, but it accounts for a small percentage of DCS cases only. On the other hand, duodenal carcinoids are rare manifestations of multiple endocrine neoplasia type 1  .
Duodenal carcinoids are rare and account for <2% of gastrointestinal carcinoid tumors. Considering an overall incidence of carcinoid tumors of approximately 2 per 100,000 inhabitants and year, duodenal carcinoids probably affect about 2-3 per 10,000,000 people a year . DCS is even rarer because the majority of duodenal carcinoids remains non-functional for prolonged periods of time. There are no larger studies, but available case reports describe both male and female patients, most of them in middle and advanced adulthood   .
Carcinoids are slow-growing tumors, and those that develop in the duodenum are rarely functional. On rare occasions though, duodenal carcinoid tumors produce and release biologically active substances, such as serotonin, histamine, prostaglandins, kallikrein, adrenocorticotropic hormone, gastrin, calcitonin, and growth hormone, among others .
Interestingly, the synchronous or metachronous development of an adenocarcinoma of the colon is observed in up to 25% of patients presenting with functional carcinoids. Presumably, this is due to the effects of carcinoid-derived growth factors on susceptible cells .
The causes of duodenal carcinoids remain elusive, so no recommendations can be given to prevent the development of this type of tumor. Factors contributing to the neuroendocrine activity of tumor cells are neither known. In a patient diagnosed with duodenal carcinoids, however, treatment with somatostatin analogs may alleviate systemic symptoms and prevent the manifestation of DCS. Similarly, the pre-surgical administration of somatostatin analogs like octreotide reduces the risk of a carcinoid crisis during tumor manipulation .
Carcinoids are uncommon, well-differentiated neuroendocrine tumors. About two-thirds of carcinoids develop in the gastrointestinal tract, although the duodenum is rarely affected . Regardless of their location, these tumors may produce hormones and hormone-like mediators that exert systemic effects. The entirety of these effects is referred to as carcinoid syndrome. If it is caused by a duodenal neoplasm, the patient may be diagnosed with DCS. When DCS manifests, the patient has probably been living with the primary tumor for more than five years . It should be noted that functionality does not allow for a reliable conclusion regarding the grade of the tumor, so DSC may be associated with benign or malignant processes . Both the diagnosis of a duodenal carcinoid and an assessment of its malignancy require the histopathological examination of tissue samples.
Carcinoids are tumors deriving from cells that are able to produce and release hormones and hormone-like mediators; they are so-called neuroendocrine tumors. They may develop in distinct organ systems but are most frequently found in the gastrointestinal tract. Accordingly, they may also develop in the duodenum, the most proximal part of the small intestine. Carcinoids are slow-growing neoplasms and although they rarely interfere with the intestinal transit, they may induce epigastric pain. Most patients remain asymptomatic, though, and their tumors are detected incidentally during endoscopic examinations realized for other reasons.
Few patients with duodenal carcinoids develop what is referred to as duodenal carcinoid syndrome (DCS). This term describes a complex of systemic complaints, namely hot flushes, cardiac disease, respiratory difficulties, and diarrhea, which are triggered by the biologically active substances released by the tumor. If these substances reach the circulation, they can affect the function of distant organs and tissues. This can be a greater burden for the patients than the underlying disease, and DCS may significantly reduce their quality of life. Indeed, DCS-associated cardiac disease may have fatal consequences.
In an ideal scenario, where the whole tumor can be removed in a surgical intervention, cure of DCS and duodenal carcinoids is feasible. The surgical removal of the tumor poses a major challenge, though, if metastases have formed in the liver, bones, or other organs. DCS patients with metastatic disease are usually offered pharmacological treatment. They are administered so-called somatostatin analogs, which impair the production of hormones by the tumors. Because duodenal carcinoids and metastatic tumors follow a slowly progressive course, their prognosis is favorable.