Carcinoid syndrome caused by a pulmonary carcinoid mimics intestinal manifestations of ulcerative colitis: A case report.

BACKGROUND: Pulmonary carcinoids are rare, low-grade malignant tumors characterized by neuroendocrine differentiation and relatively indolent clinical behavior. Most cases present as a slow-growing polypoidal mass in the major bronchi leading to hemoptysis and pulmonary infection due to blockage of the distal bronchi. Carcinoid syndrome is a paraneoplastic syndrome caused by the systemic release of vasoactive substances that presents in 5% of patients with neuroendocrine tumors. Due to such nonspecific presentation, most patients are misdiagnosed or diagnosed late and may receive several courses of antibiotics to treat recurrent pneumonia before the tumor is diagnosed. CASE SUMMARY: We report the case of a 48-year-old male who presented with cough, dyspnea, a history of recurrent pneumonitis, and therapy-refractory ulcerative colitis that completely subsided after the resection of a pulmonary carcinoid. CONCLUSION: We report and emphasize pulmonary carcinoid as a differential diagnosis in patients with nonresponding inflammatory bowel diseases and recurrent pneumonia.

Shifting Paradigms in the Pathophysiology and Treatment of Carcinoid Crisis.

Carcinoid crisis is a potentially fatal condition characterized by various symptoms, including hemodynamic instability, flushing, and diarrhea. The incidence of carcinoid crisis is unknown, in part due to inconsistency in definitions across studies. Triggers of carcinoid crisis include general anesthesia and surgical procedures, but drug-induced and spontaneous cases have also been reported. Patients with neuroendocrine tumors (NETs) and carcinoid syndrome are at risk for carcinoid crisis. The pathophysiology of carcinoid crisis has been attributed to secretion of bioactive substances, such as serotonin, histamine, bradykinin, and kallikrein by NETs. The somatostatin analog octreotide has been considered the standard of care for carcinoid crisis due to its inhibitory effect on hormone release and relatively fast resolution of carcinoid crisis symptoms in several case studies. However, octreotide's efficacy in the treatment of carcinoid crisis has been questioned. This is due to a lack of a common definition for carcinoid crisis, the heterogeneity in clinical presentation, the paucity of prospective studies assessing octreotide efficacy in carcinoid crisis, and the lack of understanding of the pathophysiology of carcinoid crisis. These issues challenge the classical physiologic model of carcinoid crisis and its common etiology with carcinoid syndrome and raise questions regarding the utility of somatostatin analogs in its treatment. As surgical procedures and invasive liver-directed therapies remain important treatment modalities in patients with NETs, the pathophysiology of carcinoid crisis, potential benefits of octreotide, and efficacy of alternative treatment modalities must be studied prospectively to develop an effective evidence-based treatment strategy for carcinoid crisis.

Carcinoid Syndrome: Updates and Review of Current Therapy.

OPINION STATEMENT: Carcinoid syndrome (CS) is a complex disorder caused by functional neuroendocrine tumors (NETs). This debilitating disease is characterized by hyper-secretion of biologically active substances eliciting major hormonal symptoms burden and fibrotic changes that are often challenging for management. There have been a number of insights that have substantially advanced treatments since the introduction of somatostatin analogs (SSAs). Second-line treatments are needed in a substantial proportion of patients with advanced disease that have uncontrolled hormone secretion on the highest labeled doses of SSAs. International guidelines suggest several available options including dose escalation of SSAs, interferon alpha, everolimus, radionuclide therapy, liver-directed therapies, and the novel tryptophan hydroxylase 1 inhibitor, telotristat ethyl. The clear preference of one second-line therapy over the other is not stated since their relative and long-term efficacy are largely unknown, and standardized approach of hormonal response assessment is lacking in the literature. In the clinical setting, the treatment of CS is guided in conjunction with patients' performance status, tumor origin, grade, stage, and growth rate, with regard to both anti-hormonal, as well as anti-proliferative effect. There is an unmet need for further well-designed randomized placebo-controlled and head-to-head studies that systematically assess CS symptom control and biochemical response following a specific intervention.

Influence of carcinoid syndrome on the clinical characteristics and outcomes of patients with gastroenteropancreatic neuroendocrine tumors undergoing operative resection.

BACKGROUND: The incidence, clinical characteristics, and long-term outcomes of patients with gastroenteropancreatic neuroendrocrine tumors and carcinoid syndrome undergoing operative resection have not been well characterized. METHODS: Patients undergoing resection of primary or metastatic gastroenteropancreatic neuroendrocrine tumors between 2000 and 2016 were identified from an 8-institution collaborative database. Clinicopathologic and postoperative characteristics as well as overall survival and disease-free survival were compared among patients with and without carcinoid syndrome. RESULTS: Among 2,182 patients who underwent resection, 139 (6.4%) had preoperative carcinoid syndrome. Patients with carcinoid syndrome were more likely to have midgut primary tumors (44.6% vs 21.4%, P < .001), lymph node metastasis (63.4% vs 44.3%, P < .001), and metastatic disease (62.8% vs 26.7%, P < .001). There was no difference in tumor differentiation, grade, or Ki67 status. Perioperative carcinoid crisis was rare (1.6% vs 0%, P < .01), and the presence of preoperative carcinoid syndrome was not associated with postoperative morbidity (38.8% vs 45.5%, P = .129). Substantial symptom improvement was reported in 59.5% of patients who underwent curative-intent resection, but occurred in only 22.7% who underwent debulking. Despite an association on univariate analysis (P = .04), carcinoid syndrome was not independently associated with disease-free survival after controlling for confounding factors (hazard ratio 0.97, 95% confidence interval 0.64-1.45). Preoperative carcinoid syndrome was not associated with overall survival on univariate or multivariate analysis. CONCLUSION: Among patients undergoing operative resection of gastroenteropancreatic neuroendrocrine tumors, the prevalence of preoperative carcinoid syndrome was low. Although operative intervention with resection or especially debulking in patients with carcinoid syndrome was disappointing and often failed to improve symptoms, after controlling for markers of tumor burden, carcinoid syndrome was not independently associated with worse disease-free survival or overall survival.

Grade 3 Neuroendocrine Tumor (G3 NET) in a Background of Multiple Serotonin Cell Neoplasms of the Ileum Associated with Carcinoid Syndrome and Aggressive Behavior.

Grade 3 well-differentiated neuroendocrine tumors (G3 NETs) have been characterized in the pancreas and stomach and distinguished from low-to-intermediate grade (G1-G2) NETs, as well as from highly malignant, poorly differentiated neuroendocrine carcinomas (NECs). Up to now, no G3 NET has been thoroughly described in the distal small intestine. We herein report a case of a 61-year-old man presenting with carcinoid syndrome. The surgical specimen showed, in a background of small G1 ileal NETs, a larger, grade 3 NET, which retained the nesting pattern and the expression of serotonin, chromogranin-A, and type 2A somatostatin receptors, typical of well-differentiated jejuno-ileal NETs. The patient had G3 NET metastasis to the liver and he died 14 months after surgery, due to deterioration in his clinical conditions.

Frequency of carcinoid syndrome at neuroendocrine tumour diagnosis: a population-based study.

BACKGROUND: Neuroendocrine tumours (NETs) can secrete bioactive amines into the bloodstream, causing carcinoid syndrome, with symptoms including flushing and diarrhoea. However, carcinoid syndrome frequency in the NET population has never been rigorously assessed, nor has its relationship to presenting clinicopathological characteristics. This analysis assessed the proportion of patients with NETs and carcinoid syndrome in the USA and associated clinical factors. METHODS: We identified patients (≥65 years of age) from the Surveillance, Epidemiology, and End Results-Medicare database, excluding those with pancreatic tumours or small-cell or large-cell lung cancer, as well as those without complete data. We assessed the incidence of patients with at least two insurance claims of flushing, diarrhoea, or carcinoid syndrome during the 3 months before and after NET diagnosis. We compared demographic and clinical characteristics between patients with and without carcinoid syndrome using χ2 tests. We used the Cochran-Armitage trend test to identify trends in carcinoid syndrome incidence and Cox regression to assess the relationship between carcinoid syndrome and survival. FINDINGS: Between April 1, 2000, and Dec 31, 2011, 9512 eligible patients were diagnosed with NETs, of whom 1786 (19%) had carcinoid syndrome. The number of patients with NETs and carcinoid syndrome increased from 50 (11%) of 465 patients in 2000 to 160 (19%) of 854 in 2011 (p<0·0001). The proportion of patients with carcinoid syndrome compared with those without did not differ significantly with respect to age at diagnosis (p=0·65), geographical region (p=0·054), or urban versus rural status (p=0·53). Patients with carcinoid syndrome were more frequently female than male (p=0·0003). Race was associated with a significant difference in the reported incidence of carcinoid syndrome (p<0·0001), as was tumour grade, stage, and primary tumour site (all p<0·0001). Patients with carcinoid syndrome had a shorter overall survival (median 5 years [95% CI 4·5-5·4]) than did those without carcinoid syndrome (5·6 years [5·4-5·9]; hazard ratio 1·102 [1·016-1·194]; p=0·019). Use of octreotide (p<0·0001) and chemotherapy (p=0·003) were more common in patients with carcinoid syndrome than in those without it, whereas surgery was used more frequently in patients without carcinoid syndrome (p=0·009); use of radiotherapy was not significantly associated with the presence of carcinoid syndrome at diagnosis (p=0·07). INTERPRETATION: This population-based analysis reveals that carcinoid syndrome is significantly associated with tumour grade, stage, and primary tumour site, and leads to shorter survival compared with those patients without carcinoid syndrome. An improved understanding of the heterogeneity of presenting symptoms among patients with NETs might permit more tailored assessment and management than at present and enable future research into the effect of carcinoid syndrome control on patient survival. FUNDING: Ipsen.

Continuous infusion of octreotide combined with perioperative octreotide bolus does not prevent intraoperative carcinoid crisis.

BACKGROUND: Operations and anesthesia in carcinoid patients can provoke carcinoid crises, which can have serious sequelae, including death. Prophylactic octreotide is recommended to prevent crises. Recommended prophylaxis regimens vary from octreotide long-acting repeatable to preoperative bolus to continuous octreotide infusion; however, efficacy data are lacking. We have shown previously that crises correlated with major complications and that octreotide long-acting repeatable and preoperative bolus failed to prevent crises. This study examines the impact of continuous octreotide infusion. METHODS: A total of 127 patients (71% with liver metastases, 74% with carcinoid syndrome) who underwent 150 operations with continuous octreotide infusions were enrolled in this prospective case series. Our main outcome measures were the occurrence of intraoperative carcinoid crises and post-operative complications. RESULTS: Crises occurred at a rate of 30% as compared with 24% in our previous series, which examined the impact of preoperative octreotide bolus. Crises were significantly associated with the presence of hepatic metastases (P = .02) or history of carcinoid syndrome (P = .006), although neither was required for crises. Prompt vasopressor treatment shortened the mean duration of hypotension to 8.7 minutes, compared with 19 minutes in our prior series. Crises no longer correlated with major complications (P = .481) unless instability persisted for greater than 10 minutes (P = .011). CONCLUSION: Octreotide infusions do not prevent intraoperative crises. Patients without liver metastases or carcinoid syndrome can have intraoperative crises. Postoperative complications can be decreased by reducing the duration of crises. Further study is needed to determine how best to shorten hemodynamic instability during crises.

Paraneoplastic syndromes in patients with laryngeal neuroendocrine carcinomas: clinical manifestations and prognostic significance.

Paraneoplastic syndromes are associated with a variety of malignant neoplasms and are systemic and non-metastatic manifestations that develop in a minority of cancer patients. This review examines all published cases of paraneoplastic syndromes associated with neuroendocrine carcinomas of the larynx. There are a total of ten patients reported with paraneoplastic syndromes associated with laryngeal neuroendocrine carcinomas in the literature. Of these, nine died and the tenth is alive with liver metastases. There were five cases of small-cell neuroendocrine carcinoma, four cases of moderately differentiated neuroendocrine carcinoma, and one case of well-differentiated neuroendocrine carcinoma associated with paraneoplastic syndromes. As these syndromes have significant clinical relevance, physicians should be aware of the possible presence of paraneoplastic syndromes in the diagnostic process of patients with neuroendocrine carcinoma of the larynx.

Octreotide long-acting repeatable among elderly patients with neuroendocrine tumors: a survival analysis of SEER-Medicare data.

BACKGROUND: Octreotide long-acting repeatable (LAR) is approved in the United States for the management of carcinoid syndromes among patients with neuroendocrine tumors (NET). The objective of our study is to evaluate the impact of octreotide LAR on overall survival (OS), as it has not been established. METHODS: NET patients of 65 years and older diagnosed between January 1999 and December 2009 were identified from the SEER-Medicare database. We compared the OS of NET patients who started octreotide LAR within 12 months of diagnosis with those who did not receive it during the same period. We conducted Kaplan-Meier estimations and Cox proportional hazard models to examine the association between octreotide LAR and OS. RESULTS: Among 1,176 distant stage patients, 233 (20%) received octreotide LAR within 12 months of diagnosis, compared with 2% (96 in 5,764) of local/regional stage patients. Median OS for patients who started octreotide LAR within 12 months was 35.22 months [95% confidence interval (CI), 27.96-47.77], longer than those who did not receive it (19.15 months; 95% CI, 16.36-22.80; P < 0.0001). Multivariate analysis showed that octreotide LAR was associated with significant survival improvement for distant stage patients (HR, 0.68; P < 0.001) and in the subgroups with (HR, 0.65; P, 0.003) and without (HR, 0.55; P, 0.002) carcinoid syndrome. No survival benefit was found among local/regional stage patients. CONCLUSION: This population-based study suggests potential survival benefits of octreotide LAR among elderly distant stage NET patients, both with or without carcinoid syndrome. IMPACT: The study provides population-based evidence of a positive association between octreotide LAR and overall survival among elderly distant stage NET patients.

Duodenal carcinoid with carcinoid syndrome.

Carcinoid tumours are uncommon well-differentiated neuroendocrine tumours. Primary duodenal carcinoids account for less than 2% of all gastrointestinal carcinoids. Duodenal carcinoids are seldom associated with carcinoid syndrome. We report a rare case of duodenal carcinoid presenting as a carcinoid syndrome in a middle-aged man with upper abdominal pain, hot flushes, diarrhoea and dry cough. Endoscopy-guided biopsy and 24 h urine 5-hydroxyindoleacetic acid (5-HIAA) proved the diagnosis. He was further evaluated and managed with definitive surgical treatment.

[Bronchial carcinoid tumor: study of 60 patients]. / Tumor carcinoide bronquial: análisis de 60 pacientes.

BACKGROUND AND OBJECTIVE: To describe the casuistry of bronchial carcinoid tumor in the last 20 years in our hospital and determine survival after surgical treatment. PATIENTS AND METHOD: We retrospectively reviewed the medical records from January 1992 to June 2012 of patients diagnosed with carcinoid tumor by the pulmonary service. RESULTS: Fifty-two patients (87%) had typical carcinoid and 8 (13%) atypical carcinoid. The mean age at diagnosis was 60 years (SD: 14.4). There was no relationship between consumption of tobacco and carcinoid tumor. Twenty-two per cent were asymptomatic radiographic finding (incidental finding) Three patients showed carcinoid syndrome and one patient had Cushing syndrome. There was a right dominance and the mean lesion size was between 2.1 and 5 cm. Nine per cent had lymph node involvement, predominantly in atypical carcinoid. Overall survival at 3.5 and 10 years was 94%, 86% and 82%. Survival at 5 years was 90% for typical and 86% for atypical and survival at 10 years was 85% for typical and 57% for atypical carcinoids. CONCLUSION: Carcinoid tumors are malignant tumors by their ability to metastasize. In our study, both histological type and staging were predictors of survival.

Octreotide LAR and bolus octreotide are insufficient for preventing intraoperative complications in carcinoid patients.

BACKGROUND AND OBJECTIVES: Surgery in carcinoid patients can provoke a carcinoid crisis, which can have serious sequelae, including death. Octreotide prophylaxis is recommended to prevent carcinoid crisis, however there are few reports of outcomes and no large series examining its efficacy. We hypothesized that a 500 µg prophylactic octreotide dose is sufficient to prevent carcinoid crisis. METHODS: Records of carcinoid patients undergoing abdominal operations during years 2007-2011 were retrospectively reviewed. Octreotide use and intraoperative and postoperative outcomes were analyzed. RESULTS: Ninety-seven intraabdominal operations performed by a single surgeon were reviewed. Ninety percent of patients received preoperative prophylactic octreotide. Fifty-six percent received at least one additional intraoperative dose. Twenty-three patients (24%) experienced an intraoperative complication. Intraoperative complications correlated with presence of hepatic metastases but not presence of carcinoid syndrome. Postoperative complications occurred in 60% of patients with intraoperative complications versus 31% of those with none (P = 0.01). CONCLUSIONS: Significant intraoperative complications occur frequently in patients with hepatic metastases regardless of presence of carcinoid syndrome and despite octreotide LAR or single dose prophylactic octreotide. Occurrence of such events correlates strongly with postoperative complications. Randomized controlled trials are needed to determine whether the administration of prophylactic octreotide is beneficial.

[Carcinoid syndrome in neuroendocrine tumors--not easy to recognize].

Neuroendocrine tumors (NET) are solid potentially malignant tumors originated from the diffuse neuroendocrine system. They could origin in many organs, with highest prevalence in lungs, small intestine and rectum. Characteristics of NET are slow growth, non-specific clinical presentation causing diagnostic problems. Thus, in majority of patients diagnosis is established in the metastatic phase of the disease. Hopefully, there are new and very potent treatment options capable to successfully control the disease. Clinical presentation cause local tumor growth or para-neoplastic syndrome. Secretory active tumors produce peptides or hormones causing different clinical syndromes. In most cases NET cause carcinoid syndrome. It is often misinterpreted, because similar symptoms are present in more prevalent disorders. Symptoms are not specific and include flashing, diarrhea, abdominal pain, right heart disease, bronchoconstriction ... and to establish the right diagnosis medical doctor have to think about NET as a possibility. Thus, it is very important to recognize symptoms and signs of the carcinoid syndrome, and distinguish them from other gastrointestinal disorders. Early diagnosis and treatment have significant impact in control of the disease, and overall treatment results.