Carcinoid syndrome-Symptoms and therapeutic approaches.

The carcinoid syndrome (CS) is a constellation of symptoms attributed to hypersecretion of amines, prostaglandins and polypeptides. The cardinal symptoms of CS are flushing, diarrhea and bronchospasm; however, CS may present with various symptoms and signs, as: Skin: cutaneous flushes, cyanosis, pellagra, Gastrointestinal: diarrhea, nausea, abdominal cramps, vomiting, Heart: tricuspid and pulmonic valve thickening causing right heart failure, edema, Respiratory: wheezing, dyspnea.

Transarterial Chemoembolization for Metastatic Neuroendocrine Tumors With Massive Hepatic Tumor Burden: Is the Benefit Worth the Risk?

BACKGROUND: Neuroendocrine tumors (NETs) have a propensity to metastasize to the liver, often resulting in massive tumor burden and hepatic dysfunction. While transarterial chemoembolization (TACE) is effective in treating patients with NET metastatic to the liver, there are limited data on its utility and benefit in patients with large hepatic involvement. The aim of our study was to determine the clinical benefit and complication rate of TACE in patients with massive hepatic tumor burden. METHODS: Medical records were reviewed in patients with grade 1 or 2 NETs with hepatic metastasis at our institution from January 2000 to September 2014 who underwent TACE. Of 201 total patients, 68 had massive hepatic tumor burden involving >75 % of liver parenchyma. RESULTS: Carcinoid syndrome was present in 40 (59 %) patients, and 57 (84 %) of the 68 patients were symptomatic from their disease. Complications beyond post-TACE syndrome occurred in 21.7 % of patients, with the most common complication being cardiac arrhythmias. The 30-day mortality rate was 7 %. Biochemical response was observed in 78 % of patients, while symptomatic relief and radiographic response was achieved in 85 and 82 % of patients, respectively. Median overall survival following TACE was 28 months, with 1-, 2-, and 5-year overall survival of 76, 54, and 26 %, respectively. CONCLUSIONS: In spite of massive tumor burden, clinical and biochemical improvements were seen in the majority of patients. Morbidity was acceptable and reversible but with a fairly high mortality rate of 7 %. TACE should still be considered in selective patients with massive hepatic tumor burden from metastatic NET for symptom control and palliation.

Stenting of the superior mesenteric vein in midgut carcinoid disease with large mesenteric masses.

BACKGROUND: Midgut carcinoid (MGC) tumors generally develop in the small intestine and in >50% of cases also present with lymph node metastases in the mesentery. The majority of these tumors are surgically resectable, but a fraction are inoperable and may cause obstruction of the superior mesenteric vein (SMV), often associated with stasis of the intestinal wall and severe symptoms. These symptoms include severe abdominal pain, attacks of diarrhea, and malnutrition. METHODS: Seven patients with severe MGC including a large fibrotic inoperable mesenteric mass and severe symptoms were studied. After an obstructed SMV and signs of venous stasis in the small intestine were demonstrated, an expandable stent was inserted after puncturing an intrahepatic portal venous branch. The associated venography, patient symptoms, and radiological signs on computed tomography (CT) scans were evaluated. RESULTS: Four patients demonstrated resolution of their symptoms. In one patient who had intra-abdominal lymph leakage/chyloperitoneum, a complete normalization of the circulation followed and the intra-abdominal lymph leakage stalled. The venographies demonstrated normalization of the venous blood flow through the SMV, and CT scans demonstrated reduction in the thickness of the intestinal wall. In two cases there were no changes in the symptoms, and in one case a slight worsening of the symptoms ensued. In general, reductions of symptoms were associated with the degree of normalization of venous blood flow. CONCLUSIONS: We conclude that in selected patients with MGC stenting of the SMV may improve symptoms.

[Right ventricular failure as the presenting manifestation of a carcinoid syndrome]. / Atteinte cardiaque droite révélatrice d'un syndrome carcinoïde.

We report a 75-year-old woman with a severe and symptomatic valvular tricuspid dysfunction, revealing a carcinoid syndrome, confirmed by an octreotid scan and liver biopsy. Carcinoid heart disease is a common complication of carcinoid syndrome associated with poor prognosis. Despite new pharmacological treatment, valve replacement surgery is the only curative treatment. Early diagnosis and multidisciplinary management could improve prognosis and quality of life of these patients.

Carcinoid syndrome: update on the pathophysiology and treatment.

Approximately 30-40% of patients with well-differentiated neuroendocrine tumors present with carcinoid syndrome, which is a paraneoplastic syndrome associated with the secretion of several humoral factors. Carcinoid syndrome significantly and negatively affects patients' quality of life; increases costs compared with the costs of nonfunctioning neuroendocrine tumors; and results in changes in patients' lifestyle, such as diet, work, physical activity and social life. For several decades, patients with neuroendocrine tumors and carcinoid syndrome have been treated with somatostatin analogues as the first-line treatment. While these agents provide significant relief from carcinoid syndrome symptoms, there is inevitable clinical progression, and new therapeutic interventions are needed. More than 40 substances have been identified as being potentially related to carcinoid syndrome; however, their individual contributions in triggering different carcinoid symptoms or complications, such as carcinoid heart disease, remain unclear. These substances include serotonin (5-HT), which appears to be the primary marker associated with the syndrome, as well as histamine, kallikrein, prostaglandins, and tachykinins. Given the complexity involving the origin, diagnosis and management of patients with carcinoid syndrome, we have undertaken a comprehensive review to update information about the pathophysiology, diagnostic tools and treatment sequence of this syndrome, which currently comprises a multidisciplinary approach.

Cases in a series of carcinoid syndrome and carcinoid heart disease.

Although carcinoid syndrome is regarded as a rare entity, carcinoid patients with evidence of cardiac involvement show a markedly reduced survival time. Patients with advanced signs of right-sided heart failure represent a subgroup at particularly high risk. Echocardiography remains the gold standard to diagnose or confirm structural cardiac involvement in patients with underlying carcinoid disease. This is the notion that propelled us to report on cases of carcinoid syndrome with cardiac involvement. We also review carcinoid syndrome and carcinoid heart disease, and challenges regarding the diagnosis and management of carcinoid heart disease.

Factors associated with progression of carcinoid heart disease.

BACKGROUND: By releasing vasoactive substances into the circulation, carcinoid tumors can cause right-sided valvular heart disease. Factors associated with the progression of carcinoid heart disease are poorly understood. We conducted a retrospective study to identify such factors. METHODS: Our sample included 71 patients with the carcinoid syndrome who underwent serial echocardiographic studies performed more than one year apart and 32 patients referred directly for surgical intervention after an initial echocardiographic evaluation. A score for carcinoid heart disease was determined on the basis of an assessment of valvular anatomy and function and the function of the right ventricle. An increase of more than 25 percent in the score between studies was considered suggestive of disease progression. Tumor progression was assessed on the basis of abdominal computed tomographic scans and changes in the level of urinary 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of serotonin. RESULTS: Of the patients with serial echocardiographic studies, 25 (35 percent) had an increase of more than 25 percent in the cardiac score. As compared with patients whose score changed by 25 percent or less, these patients had higher urinary peak 5-HIAA levels (median, 265 mg per 24 hours [interquartile range, 209 to 593] vs. 189 mg per 24 hours [interquartile range, 75 to 286]; P=0.004) and were more likely to have biochemical progression (10 of 25 patients vs. 9 of 46, P=0.05) and to have received chemotherapy (13 of 25 vs. 10 of 46, P=0.009). Logistic-regression analysis showed that a higher peak urinary 5-HIAA level and previous chemotherapy were predictors of an increase in the cardiac score that exceeded 25 percent (odds ratio for each increase in 5-HIAA of 25 mg per 24 hours, 1.08 [95 percent confidence interval, 1.03 to 1.13]; P=0.009); odds ratio associated with chemotherapy, 3.65 [95 percent confidence interval, 1.74 to 7.48]; P=0.001). CONCLUSIONS: Serotonin is related to the progression of carcinoid heart disease, and the risk of progressive heart disease is higher in patients who receive chemotherapy than in those who do not.

Carcinoid crisis after injection of 6-18F-fluorodihydroxyphenylalanine in a patient with metastatic carcinoid.

A carcinoid crisis is a severe complication of the carcinoid syndrome that can arise in patients with advanced metastatic neuroendocrine tumors. It can be initiated by stress, catecholamines, and tumor manipulation. In this article, we report a case in which an injection with the catecholamine tracer 6-18F-fluorodihydroxyphenylalanine, used for PET, induced a carcinoid crisis. Octreotide can be used for treatment and should be available. Tracer injection should be slow.

Combined diagnostic imaging with 131I-metaiodobenzylguanidine and 111In-pentetreotide in carcinoid tumours.

Carcinoid tumours derived from the neural crest are usually associated with the symptoms of flushing and diarrhoea in the presence of liver metastases. Scintigraphs with 131I-metaiodobenzylguanidine (131I-MIBG) which is accumulated in the argentaffin granules of the cell, as well as with 111In-pentetreotide for the imaging of somatostatin receptors on the cell surface, are positive in a large proportion of carcinoid patients. To evaluate the complementary role of both radionuclide tests, we studied 20 consecutive carcinoid patients: 14 with the characteristic carcinoid syndrome and 6 with tumour symptoms, such as pain or obstruction. A positive test was found in 84% with either 131I-MIBG or 111In-pentetreotide; the combination yielded a sensitivity of 95%. A positive correlation was found with the presence of the carcinoid syndrome, but not with 5-HIAA excretion. A positive test may help in adjusting treatment: either to predict the response to octreotide or to select patients for 131I-labelled MIBG treatment. Application of a therapeutic dose of 111In-pentetreotide may be limited by the high normal uptake in the kidneys.

Systemic radionuclide therapy using indium-111-DTPA-D-Phe1-octreotide in midgut carcinoid syndrome.

A 55-yr-old woman with a midgut carcinoid syndrome due to metastatic spread of an ileal tumor to the liver, paraortic and mediastinal lymph nodes and to the skeleton was given systemic radionuclide therapy with 111In-DTPA-D-Phe1-octreotide. Before therapy, dosimetric calculations were performed on whole-body scintigraphs and 111In retention was shown to be long-lasting. Excretion was mainly seen during the first 24 hr after injection; thereafter whole-body retention remained stationary at 30%. Indium-111 activity in tumor biopsies and blood was measured using a gamma counter. Very high tumor-to-blood ratios were obtained: 150 for the primary tumor and 400-650 for liver metastases, which further justified radiation therapy. Indium-111-DTPA-D-Phe1-octreotide treatment was given on three separate occasions (3.0, 3.5 and 3.1 GBq) 8 and 4 wk apart. After each therapy, the patient experienced facial flush and pain over the skeletal lesions followed by symptomatic relief, even though no objective tumor regression was found radiologically after 5 mo. After initiation of octreotide treatment, there was a 14% reduction of the main tumor marker, urinary 5-HIAA. After three subsequent radionuclide therapies, there was a further 31% reduction of 5-HIAA levels. No adverse reactions, other than a slight decrease in leukocyte counts, were seen. The mean absorbed radiation dose after the three treatments was estimated to be about 10-12 Gy in liver metastases and 3-6 Gy in other tumors, depending on the size and location of the metastases. Assuming internalization of 111In into tumor cells and a radiobiological effect from short range Auger and conversion electrons, there might be a therapeutic effect on the tumor.

Sequential hypoglycemia, hyperglycemia, and the carcinoid syndrome arising from a plurihormonal neuroendocrine neoplasm.

OBJECTIVE: To describe the first patient with a neuroendocrine tumor secreting serotonin, insulin, and glucagon and having the corresponding clinical syndromes. METHODS: We present a detailed case report, including serial laboratory and clinical findings, in a man with type 2 diabetes, symptomatic hypoglycemia, and the carcinoid syndrome and in whom a plurihormonal metastatic neuroendocrine neoplasm was ultimately diagnosed. RESULTS: In a 58-year-old man with type 2 diabetes, which was treated effectively with a sulfonylurea for 7 years, episodes of hypoglycemia developed. After discontinuation of the orally administered agent, the hypoglycemic episodes initially resolved but then recurred and were associated with inappropriately increased plasma insulin concentrations. In addition, the patient had symptoms and biochemical evidence of the carcinoid syndrome. Computed tomography of the abdomen showed multiple hypodense lesions in the liver, and ultrasound-guided fine-needle aspiration of a liver mass was performed. Undifferentiated neuroendocrine tumor with hepatic metastatic involvement was diagnosed. After a hepatic artery embolization procedure, the hypoglycemia was alleviated, but hyperglycemia soon recurred, associated with inappropriately increased serum glucagon concentrations. The patient's course strongly suggested the presence of a plurihormonal tumor secreting serotonin, insulin, and glucagon. CONCLUSION: To our knowledge, this is the first reported case of a patient with a neuroendocrine neoplasm secreting serotonin, glucagon, and insulin, manifested by the carcinoid syndrome, hyperglycemia, and hypoglycemia.

Thymic carcinoid.

Carcinoid of the thymus is a rare neoplasm. Differentiation from thymoma is important because they have entirely different prognosis. A patient in whom a 19 x 18 x 12 cm carcinoid tumor of the thymus was surgically removed is presented. The tumor metastasized to peritracheal and internal mammary nodes, and invaded the SVC, pleura, lung, and pericardium. This is apparently the largest reported tumor of its kind. Prior to induction of anesthesia cardiopulmonary bypass and rigid bronchoscopy were readily available. Awake intubation was utilized. Even though long-term prognosis is poor, an aggressive surgical approach and adjuvant radiotherapy may achieve extended survival with excellent quality of life. Central aspects of the disease as well as pivotal therapeutic points are discussed.

Bone lesion in a patient with transplanted liver for a metastatic carcinoid. The role of somatostatin receptor scintigraphy.

A patient who had previously undergone ileal resection and liver transplantation for a gastroenteropancreatic (GEP) tumor was evaluated with somatostatin receptor scintigraphy (SRS) using 111In-DTPA-D-Phe1-pentetreotide. Eighteen months after surgery, during follow-up procedures, conventional imaging techniques (ultrasound, computed tomography, magnetic resonance imaging) only showed a relapse in the gastropancreatic lymph nodes, while SRS demonstrated skeletal spread. This case report emphasizes the clinical impact of SRS on the management of patients affected by neuroendocrine gastroenteropancreatic tumors.

[Bronchopulmonary carcinoid tumours]. / I tumori carcinoidi broncopolmonari.

Carcinoids are neuroendocrine neoplasms. Bronchial carcinoids are unusual, malignant primary neoplasms that characteristically involve the central airways and typically exhibit well-defined margins and bronchial-related growth. Bronchial carcinoids include low-grade typical carcinoids and the more aggressive atypical ones. They usually affect patients in the 3rd through the 7th decade of life who are often symptomatic with cough, hemoptysis or obstructive pneumonia. Rarely, the initial symptoms are related to the secretion of hormones causing carcinoid or other endocrine syndromes. Bronchial carcinoids radiologically manifest as hilar or perihilar masses, with or without associated atelectasis, pneumonia or bronchiectasis. At CT-scan the relationship of these tumors with the bronchial tree is usually seen, and they show contrast enhancement or calcification. Even if the radiological signs may be suggestive for bronchial carcinoid, the definitive diagnosis is reached only by the tissue sampling. Bronchoscopic biopsy is the more effective way to identify the nature of carcinoid tumors because of their frequent central location. The treatment of choice is the surgical resection which should be carried out with maximum respect for the residual lung and bronchial tissues. Endoscopic ablations in well defined cases, bronchotomy and lung resections with or without bronchoplastic procedures have been described. Hilar and mediastinal lymph node sampling and examination should be ever performed during open procedures. Positivity of the nodal tissues could influence the resection procedure and is related with the prognosis, specially for the atypical carcinoids. Chemo- and radiation therapy are not effective in improving the long-term outcome in those patients with advanced disease. The long-term outcome is strictly related with the histological subtype and the lymph node status. Local recurrences and distant metastases are more frequent in the atypical carcinoids which manifest a more aggressive behavior. During the last decade, the importance of the use of somatostatine analogues (octreotide) in the staging, early detection of the recurrent disease and its management such as that of the associated carcinoid syndrome became clear.

Angiography in the diagnosis of carcinoid syndrome.

The diagnosis of carcinoid syndrome has been confirmed by selective abdominal angiography in a consecutive series of 18 patients. In eight patients the primary carcinoid tumour was removed before angiography. The primary lesion was demonstrated in eight of ten cases. Metastases from the carcinoid tumours was present in all 18 patients. All cases of mesenteric metastases and 12 of 14 cases with liver metastases were visualized by angiography. All but one of the liver metastases were highly vascularized and therefore easy to recognize, making angiography a good monitor in the control of medical therapy or in planning of surgical intervention.

CT scanning in patients with Zollinger-Ellison syndrome and carcinoid syndrome.

Computed tomography of the upper abdomen was performed in 11 patients with Z--E syndrome and 6 patients with carcinoid syndrome. The liver, pancreas, spleen and upper part of the retroperitoneal space were examined to localize a primary tumour and/or metastases. The CT findings were correlated to the final diagnoses obtained by operation or by other diagnostic procedures. The correlation between CT and the clinical findings was acceptable, and we are of the opinion that with further experience this new noninvasive radiological technique might be a helpful tool in the preoperative evaluation in these diseases. Furthermore, CT is an easy method in the control of a tumour or metastases during treatment.

Primary neuroendocrine mediastinal tumor presenting with carcinoid syndrome and left supraclavicular lymphadenopathy: clinico-radiological and pathological features.

Primary mediastinal neuro-endocrine tumor is very rare. The primary modality to evaluate the lesion is computed tomography, to know disease extent, involvement of various structures, vascular invasion and metastasis. Histo-pathological and immuno-histochemical confirmation is mandatory. We report a rare case of primary neuroendocrine mediastinal tumor/atypical carcinoid in a young male who presented with carcinoid syndrome and left supraclavicular lymphadenopathy. Complete diagnostic work up was done followed by histo-pathological and immuno-histochemical confirmation. Later on patient underwent radical surgery followed by chemotherapy. The patient is currently on follow up. Neuroendocrine carcinoma of the thymus generally follows an aggressive clinical course.The biologic behavior is directly related to grade and degree of differentiation. This case report of primary low grade neuroendocrine tumor/atypical carcinoid adds to the biological behavior of this tumor and sheds light on the radiological and pathological features of neuroendocrine carcinomas.

Carcinoid syndrome: update on the pathophysiology and treatment

Approximately 30-40% of patients with well-differentiated neuroendocrine tumors present with carcinoid syndrome, which is a paraneoplastic syndrome associated with the secretion of several humoral factors. Carcinoid syndrome significantly and negatively affects patients' quality of life; increases costs compared with the costs of nonfunctioning neuroendocrine tumors; and results in changes in patients' lifestyle, such as diet, work, physical activity and social life. For several decades, patients with neuroendocrine tumors and carcinoid syndrome have been treated with somatostatin analogues as the first-line treatment. While these agents provide significant relief from carcinoid syndrome symptoms, there is inevitable clinical progression, and new therapeutic interventions are needed. More than 40 substances have been identified as being potentially related to carcinoid syndrome; however, their individual contributions in triggering different carcinoid symptoms or complications, such as carcinoid heart disease, remain unclear. These substances include serotonin (5-HT), which appears to be the primary marker associated with the syndrome, as well as histamine, kallikrein, prostaglandins, and tachykinins. Given the complexity involving the origin, diagnosis and management of patients with carcinoid syndrome, we have undertaken a comprehensive review to update information about the pathophysiology, diagnostic tools and treatment sequence of this syndrome, which currently comprises a multidisciplinary approach.