Percutaneous Image-Guided Core Needle Biopsy of Neuroendocrine Tumors: How Common Is Intraprocedural Carcinoid Crisis?

PURPOSE: To retrospectively evaluate the incidence of carcinoid crisis, other complications, and physiologic disturbances during percutaneous image-guided core needle biopsy of neuroendocrine tumors (NETs) in the lung and the liver. MATERIALS AND METHODS: Between January 2010 and January 2020, 106 computed tomography (CT) or ultrasound (US)-guided core needle biopsies of lung and liver NETs were performed in 95 consecutive adult patients. The mean age was 64 ± 13 years, and 48% were female. The small bowel was the most common primary site (33%, 31/95), and 32 (34%) patients had pre-existing symptoms of carcinoid syndrome. The mean tumor size was 3.2 ± 2.6 cm, and mean number of passes was 3.4 ± 1.6. A 17/18-gauge needle was used in 91% (96/106) of the biopsies. Thirteen (12%) patients received either outpatient or prophylactic octreotide. RESULTS: No patients experienced carcinoid crisis or needed octreotide, inotropes, vasopressors, or resuscitation. A single biopsy procedure (0.9%, 1/106) was complicated by bleeding that required angiographic hepatic artery embolization. Changes in pre-biopsy- versus post-biopsy systolic blood pressure and heart rate were -1.6 mm Hg (P = .390) and 0.6 beat/min (P = .431), respectively. Tumor functional status, overall tumor burden, and the elevation of neuroendocrine markers were not associated with intraprocedural physiologic disturbances. There were 4 minor complications (0.4%, 4/106) associated with the biopsy procedure that were not attributed to hormone excretion from tumor manipulation. CONCLUSIONS: Percutaneous image-guided core biopsy of NETs is safe, with low complication rate and no definite carcinoid crisis in the current cohort.

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.

Cost-of-illness of metastatic gastroenteropancreatic neuroendocrine tumours in Sweden-A population-based register-linkage study.

The objective was to estimate the cost-of-illness of grades 1 and 2 metastatic gastroenteropancreatic neuroendocrine tumours (GEP-NETs) in Sweden in 2013 in a population-based study including all patients diagnosed between 2005 and 2013. Data were obtained from national registers, and patients who utilised healthcare resources due to metastatic GEP-NETs in 2013 were included. The study included 478 patients (mean age 64 [SD=11] years, 51% men). The majority (80%) had small intestinal NET, 10% had pancreatic NET, and 41% had carcinoid syndrome. The total cost-of-illness was €12,189,000 in 2013, of which direct costs constituted 77% and costs from production loss constituted 22%. The largest contributor to the direct medical costs was prescription drugs (54%; primarily somatostatin analogues [91% of the total drug cost]). Production loss due to sickness absence constituted 52% of the total costs of production loss. The total annual cost per patient was €25,500. By patient group, the cost was €24,800 (95% CI €21,600-€28,100) for patients with small intestinal NET, €37,300 (95% CI €23,300-€51,300) for those with pancreatic NET and €18,600 (95% CI €12,600-€24,500) for patients with other GEP-NETs. To conclude, the total annual cost of grades 1 and 2 metastatic GEP-NETs in Sweden was €25,500 per patient and year.

Economic analysis of inadequate symptom control in carcinoid syndrome in the United States.

AIM: We investigated the healthcare resource utilization and costs of patients with dose escalations beyond recommended levels of long-acting octreotide for persistent carcinoid syndrome (CS) symptoms. MATERIALS & METHODS: A retrospective study of US health insurance claims included 358 adults with ≥1 medical claim for CS and ≥6 claims for long-acting octreotide (10-30 mg) between 1 July 2006 and 31 December 2013. RESULTS: Pre-escalation per-patient per-month outcomes and costs were lower versus post-escalation, including vascular conditions (0.11 vs 0.21), metastasis/secondary neoplasms (0.45 vs 0.74), total all-cause costs (US$4116 vs US$8305; p < 0.001) and CS-related costs (US$3156 vs US$7101; p < 0.001). CONCLUSION: Higher mean pre-escalation per-patient per-month resource use and costs post-escalation primarily attributable to CS-related ambulatory care suggests continuing challenges in managing CS despite octreotide dose escalation.

Telotristat ethyl: a novel agent for the therapy of carcinoid syndrome diarrhea.

Carcinoid syndrome (CS), characterized by diarrhea and flushing, is present in 20% of patients with neuroendocrine tumors at diagnosis and becomes more frequent with progression. The diarrhea of CS is caused mainly by tumoral secretion of serotonin. It may not be fully controlled by somatostatin analogs, the currently indicated drugs for symptomatic relief. Telotristat ethyl is a novel inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in serotonin biosynthesis. Administration of the drug decreases diarrhea in patients with CS. Telotristat ethyl was approved in February 2017 (USA) and September 2017 (European Commission) for the treatment of CS diarrhea in adults inadequately controlled by somatostatin analog alone. This drug is expected to greatly improve the health and quality of life of patients with CS diarrhea.

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.

Carcinoid Syndrome and Costs of Care During the First Year After Diagnosis of Neuroendocrine Tumors Among Elderly Patients.

BACKGROUND: Neuroendocrine tumors (NETs) can secrete hormonal peptides that lead to additional symptom burdens. However, it is largely unknown whether and to what extent the additional symptom burdens translate into higher costs of care. This study aimed to examine the cost pattern of elderly NET patients during the first year of diagnosis, taking into account of the carcinoid syndrome status. METHODS: We used Surveillance, Epidemiology, and End Results Medicare data to identify elderly NET patients diagnosed between January 2003 and December 2011. Patients who had at least two claims indicative of carcinoid syndrome during the 3 months before and after the NET diagnosis were considered to have carcinoid syndrome. We adopted a payer's perspective and quantified economic outcomes using the following three measures: (a) total Medicare reimbursement amount, (b) inpatient amount, and (c) outpatient amount. We used a generalized linear model (GLM) to examine the association between syndrome and costs. RESULTS: Our study cohort included 6,749 elderly NET well-differentiated and moderately differentiated patients. Of these patients, 5,633 (83%) were alive 1 year after diagnosis with continuous enrollment, and 1,116 (17%) died within 1 year. The multivariable GLM showed significant association between the syndrome and higher total, inpatient, and outpatient costs among the group who survived the whole year; the association was insignificant among the group who died within the first year of diagnosis. CONCLUSION: This population-based study showed that NET patients with carcinoid syndrome incurred higher costs of care especially among those who survived the first year of diagnosis. IMPLICATIONS FOR PRACTICE: This is the first population-based study that examines the health care costs associated with carcinoid syndrome among neuroendocrine tumor patients. Among patients alive throughout the first year, the unadjusted analyses showed that total median monthly costs were above $1,000 higher ($3,801 vs. $2,481) for patients with carcinoid syndrome compared with patients without. A significant association was found between carcinoid syndrome and higher total inpatient and outpatient costs among the group that survived the whole year even after controlling for clinical factors, treatment received, and demographics and neighborhood socioeconomic status; the association was insignificant among the group that died within the first year of diagnosis.

Arterial function, biomarkers, carcinoid syndrome and carcinoid heart disease in patients with small intestinal neuroendocrine tumours.

PURPOSE: Carcinoid heart disease (CHD) is a life-threatening complication of carcinoid syndrome (CS) characterised by tricuspid regurgitation (TR). However, there is an unmet need for earlier diagnosis of CHD. We cross-sectionally assessed the prevalence and potential predictive or diagnostic markers for CS and CHD in a contemporary cohort of patients with small intestinal neuroendocrine tumours (SI-NETs). METHODS: Biochemical characteristics, hepatic tumour load, measures of arterial and endothelial function, atherosclerosis, and transthoracic echocardiography were analysed in a prospective cross-sectional setting. RESULTS: Among the 65 patients studied, 29 (45%) had CS (CS+ ), and 3 (5%) CHD. CS+ was characterised by significantly higher hepatic tumour load, S-5-HIAA and fP-CgA, higher frequency of diarrhoea and flushing, and more frequent PRRT compared to CS- (for all, P < 0.05). Central systolic, central mean, and central end-systolic blood pressures were significantly higher in CS+ than in CS- (for all, P < 0.05). Subjects with grades 2-4 TR had higher hepatic tumour burden, fP-CgA, and S-5-HIAA compared to those with grades 0-1 TR, but measures of vascular function did not differ. fP-CgA (P = 0.017) and S-5-HIAA (P = 0.019) but not proBNP increased significantly according to the severity of TR. CONCLUSION: Although CS is common, the prevalence of CHD was found to be lower in a contemporary cohort of SI-NET patients than previously anticipated. Measures of arterial or endothelial function or carotid atherosclerosis do not identify subjects with mild TR. Echocardiography remains the most sensitive means to diagnose CHD in CS patients with high tumour burden and elevated CgA and 5-HIAA.

Clinical and biochemical aspects of the carcinoid syndrome in neuroendocrine tumors of the abdominal and retroperitoneal organs and its impact for the disease prognosis.

Overall and relapse-free survival of 238 patients with neuroendocrine tumors of the abdominal and retroperitoneal organs was evaluated with consideration for the presence of the carcinoid syndrome. The incidence of the carcinoid syndrome was 15.6%. The presence of the carcinoid syndrome was inessential for survival and relapse prognosis in patients with neuroendocrine tumors of the abdominal and retroperitoneal organs. A trend to the development of earlier relapses was noted in patients with this syndrome. Diarrhea was found to be a prognostically unfavorable factor. The time of the carcinoid syndrome development was prognostically significant in patients with malignant neuroendocrine tumors. The mean secretion of epinephrine, norepinephrine, and dopamine with daily urine was significantly higher in patients with the carcinoid syndrome. A significant positive correlation between urinary excretion of catecholamines was detected (r=0.53; p<0.05).

Burden of Carcinoid Heart Disease in Patients With Carcinoid Syndrome Initiating Somatostatin Analogues.

PURPOSE: As a result of overproduction of serotonin, patients with uncontrolled carcinoid syndrome (CS) may develop carcinoid heart disease (CaHD). However, the prevalence and health care resources to manage CaHD are not well understood. This study investigated the prevalence and economic burden of CaHD among adults with CS in the United States. METHODS: This retrospective study analyzed insurance claims of patients with CS initiating somatostatin analogue (SSA) therapy. Eligible patients had ≥1 medical claim for CS with continuous insurance coverage for 1 year before and at least 30 days after initiating SSA therapy. Markers for CaHD were identified using a predetermined list of medical and/or procedural claims based on the clinical experience of a practicing cardiologist. Case subjects had a documented medical/procedural claim for a marker of CaHD during the study period; control subjects had no markers for CaHD. Baseline characteristics were assessed during the pre-SSA treatment initiation period. Economic outcomes (health care resources and expenditures) were assessed in the follow-up period after SSA treatment initiation and compared between incident case subjects and control subjects. Descriptive statistics were used to assess demographic and clinical characteristics. Univariate and multivariate models were used to assess differences in health care resource use and costs between case subjects and control subjects. FINDINGS: A total of 654 patients met the eligibility criteria; 248 (38%) had a prevalent marker of CaHD and were excluded from the economic analysis. The analytic sample included 406 patients with CS, 185 (46%) of whom had an incident CaHD marker (case subjects) and 221 were controls. Baseline characteristics between the case subjects and control subjects were similar with the exception that case subjects tended to be older. Average health care resource use and costs were higher among case subjects (total costs, $51,825 vs $29,068; P < 0.01), driven by average hospital admissions (1.4 vs 0.7) with increased length of stay (4.3 vs 2.0 days), office visits (22.8 vs 19.8), and outpatient services (22.3 vs 15.4; all, P < 0.05). IMPLICATIONS: CaHD may be common among patients with CS before initiating SSA therapy and within 2 years of starting SSA therapy, suggesting suboptimal control of serotonin production. Patients with CaHD incur substantial economic costs in addition to the clinical morbidity compared with patients with CS and no CaHD.

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.

Carcinoid-syndrome: recent advances, current status and controversies.

PURPOSE OF REVIEW: To review recent advances and controversies in all aspects of carcinoid-syndrome. RECENT FINDINGS: Over the last few years there have been a number of advances in all aspects of carcinoid syndrome as well as new therapies. These include new studies on its epidemiology which demonstrate it is increasing in frequency; increasing insights into the pathogenesis of its various clinical manifestations and into its natural history: definition of prognostic factors; new methods to verify its presence; the development of new drugs to treat its various manifestations, both initially and in somatostatin-refractory cases; and an increased understanding of the pathogenesis, natural history and management of carcinoid heart disease. These advances have generated several controversies and these are also reviewed. SUMMARY: There have been numerous advances in all aspects of the carcinoid-syndrome, which is the most common functional syndrome neuroendocrine tumors produce. These advances are leading to new approaches to the management of these patients and in some cases to new controversies.

Partial hepatic resections for metastatic neuroendocrine tumors: perioperative outcomes.

STUDY OBJECTIVE: Partial hepatic resection reduces tumor burden in patients with metastatic neuroendocrine tumors, thereby improving quality and length of life. These procedures can be challenging as well as life-threatening. Our aim was to evaluate our patients' perioperative outcomes and propose a definition for an intraoperative carcinoid crisis relevant to this surgery, given its unique surgical considerations. DESIGN: Retrospective study. SETTING: Mayo Clinic, Rochester, Minnesota. PATIENTS: One hundred sixty-nine patients undergoing partial hepatic resection for metastatic neuroendocrine tumors between 1997 and 2015 were identified retrospectively from a surgical database at Mayo Clinic Rochester. INTERVENTIONS: None. MEASUREMENTS: Intraoperative carcinoid crisis for patients undergoing hepatic resection of neuroendocrine tumors was defined. Patients' medical records were reviewed and data were abstracted describing patient and procedural characteristics and perioperative outcomes. MAIN RESULTS: There were no documented cases of carcinoid crisis (0.0%, 95% C.I. 0.0% to 2.2%). One patient developed clinical findings of an emerging carcinoid crisis, but was successfully treated with doses of octreotide and findings resolved in <10 min. Prophylactically 500 µg octreotide was given subcutaneously in 77% (130/169) of patients preoperatively. CONCLUSIONS: There were no documented cases of carcinoid crisis (0.0%, 95% C.I. 0.0% to 2.2%). Adverse events were infrequent.

An update of lanreotide acetate for treatment of adults with carcinoid syndrome.

Carcinoid tumors are rare and usually slow-growing. Some patients with advanced metastatic disease however can develop symptoms of carcinoid syndrome, which results in debilitating diarrhea and flushing. Many treatments including chemotherapy were tried unsuccessfully in the past to treat this syndrome. The symptoms of carcinoid syndrome are thought to be related to the ability of the tumors to produce serotonin. The discovery that the production of this hormone can be inhibited by somatostatin led to the development of somatostatin analogues octreotide and lanreotide, which differ from native somatostatin in that they have a longer half-life. These compounds have shown dramatic responses in symptom control and reduction of serotonin metabolites including urinary 5-hydroxyindoleacetic acid (5-HIAA) levels. This review researches the origins of carcinoid tumors, the development of lanreotide as a treatment and future directions for the treatment of carcinoid syndrome.

Predictive factors associated with carcinoid syndrome in patients with gastrointestinal neuroendocrine tumors.

AIM: To discover unknown factors associated with carcinoid syndrome (CS) with the goal of earlier diagnosis of CS. METHODS: In this retrospective case-control study using United States administrative claims, patients (≥ 18 years) newly-diagnosed with gastrointestinal neuroendocrine tumors (GI NETs) without CS (controls) were exactly matched to patients with CS (cases) based on NET diagnosis date at a 3-to-1 ratio. Study index date was first CS diagnosis (controls: same distance from NET diagnosis as cases). The most observed conditions, excluding CS-associated symptoms/diagnoses, during the year before index date were assessed. Forward-stepwise logistic regression models were used to derive predictors, and were validation within another claims database. RESULTS: In the development database, 1004 patients with GI NETs were identified; 251 (25%) had CS and 753 (75%) were controls. In the validation database, 724 patients with GI NETs were identified; 181 (25%) had CS and 543 (75%) were controls. A total of 33 common diagnoses (excluding conditions already known to be associated with CS) in the development database were entered in forward step-wise logistic regression models. In the final, validated logistic regression model, three factors prior to CS diagnosis were found consistently associated with higher risks for CS, including liver disorder [odds ratio (95%CI): 3.38 (2.07-5.51)], enlargement of lymph nodes [2.13 (1.10-4.11)], and abdominal mass [3.79 (1.87-7.69)]. CONCLUSION: GI NET patients with CS were 2-4 times as likely to have preexisting diagnoses (i.e., liver disorder, enlarged lymph nodes, abdominal mass) than non-CS patients.

MANAGEMENT OF ENDOCRINE DISEASE: Flushing: current concepts.

OBJECTIVE: Flushing can be defined as a sensation of warmth accompanied by erythema that most commonly is seen on the face and which occurs in episodic attacks. Such a problem can be clinically problematic, since many conditions and drugs can be related to flushing, and while often there appears to be no underlying organic disease, it is important to exclude disorders since they may be life-threatening conditions. DESIGN AND METHODS: We performed a search in MEDLINE using the terms 'flushing' in combination with 'carcinoid syndrome', 'pheochromocytoma', 'mastocytosis', 'menopausal hot flush' and 'treatment'. European and American guidelines relating to neuroendocrine tumours, mastocytosis and menopause were reviewed. RESULTS: In this review, we discuss the main causes of flushing and propose an algorithm based on pathogenesis, which can be used to guide the clinical evaluation process. We also review recent significant developments in the assessment and treatment of the carcinoid syndrome and menopausal hot flushes, which should guide the clinical practice regarding this common but sometimes confusing condition. CONCLUSIONS: When evaluating flushing, a precise systematic approach is needed to exclude potentially serious underlying causes, although despite this, the cause of the disorder is not always found. If symptoms are not progressive, the patient should be advised about its apparently benign nature in order to avoid unnecessary studies or initiating treatments of minimal benefit.

Tumours of the midgut (jejunum, ileum and ascending colon, including carcinoid syndrome).

(Neuro-)endocrine tumours of the gastrointestinal tract are also called 'carcinoids'. (Neuro-)endocrine midgut tumours can be categorized according to their clinical behaviour. Most tumours are non-functioning. Functioning tumours are responsible for the carcinoid syndrome. The carcinoid syndrome is almost uniquely associated with midgut carcinoids. Symptoms of the carcinoid syndrome are caused by an excess of biogenic amines, peptides and other factors in the circulation. The typical symptoms of the carcinoid syndrome are diarrhoea, flushing, and carcinoid heart disease. Carcinoid heart disease involves the tricuspid and pulmonary valves and the endocardium. Serum chromogranin A and urinary excretion of 5-hydroxy-indoleacetic acid (5-HIAA) are biochemical markers. Carcinoid tumours express large numbers of high-affinity somatostatin receptors. These can bind the currently available octapeptide somatostatin analogues. In inoperable patients, biotherapy with somatostatin analogues and interferon-alpha is the treatment of choice. Somatostatin analogues and interferon-alpha significantly improve symptoms.

Epidemiological trends of pancreatic and gastrointestinal neuroendocrine tumors in Japan: a nationwide survey analysis.

BACKGROUND: Although neuroendocrine tumors (NETs) are rare, the number of patients with NET is increasing. However, in Japan, there have been no epidemiological studies on NET since 2005; thus, the prevalence of NET remains unknown. METHODS: We reported the epidemiology of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) [pancreatic neuroendocrine tumors (PNETs) and gastrointestinal neuroendocrine tumors (GI-NETs)] in Japan in 2005. Here, we conducted the second nationwide survey on patients with GEP-NETs who received treatment in 2010. RESULTS: A total of 3,379 patients received treatment for PNETs in 2010, representing a 1.2-fold increase in the number of patients from 2005 to 2010. The prevalence was estimated to be 2.69/100,000, with an annual onset incidence of 1.27/100,000 in 2010. Non-functioning tumor (NF)-PNETs comprised 65.5% of cases followed by insulinoma (20.9%) and gastrinoma (8.2%). Interestingly, the number of patients with NF-PNETs increased ~1.8 fold since 2005. A total of 19.9% of patients exhibited distant metastasis at initial diagnosis; 4.3% had complications with multiple endocrine neoplasia type 1 (MEN-1), and only 4.0% had NF-PNETs associated with MEN-1. Meanwhile, an estimated 8,088 patients received treatment for GI-NETs, representing a ~1.8-fold increase since 2005. The prevalence was estimated to be 6.42/100,000, with an annual onset incidence of 3.51/100,000. The locations of GI-NETs varied: foregut, 26.1%; midgut, 3.6%; and hindgut, 70.3%. Distant metastasis and complications with MEN-1 were observed in 6.0 and 0.42% at initial diagnosis, respectively. The frequency of carcinoid syndrome in patients with GI-NETs was 3.2%. CONCLUSION: We clarified the epidemiological changes in GEP-NETs from 2005 to 2010 in Japan.

Solitary versus multiple carcinoid tumors of the ileum: a clinical and pathologic review of 68 cases.

It is well known that small intestinal carcinoid tumors may occur as solitary or multiple lesions. However, the biologic significance of multiple carcinoid tumors has not been clearly defined. The purpose of this study was to compare the clinical and pathologic features and prognosis of patients with solitary versus multiple carcinoid tumors of the ileum. Sixty-eight patients, including 50 with solitary and 18 with multiple carcinoid tumors, were included in the study. Hematoxylin and eosin-stained slides from routinely processed tumor resection specimens of the ileum were evaluated for a variety of histologic features such as tumor size, depth of invasion, tumor stage, and venous, perineural, and lymphovascular invasion. Follow-up and clinical data, such as patient age, gender, presenting complaints, presence of synchronous or metachronous malignancies, and presence of the carcinoid syndrome, were obtained and the results were compared between the two patient groups. Fifty patients with solitary carcinoid tumors (male/female ratio, 27:23) and 18 patients with multiple tumors (male/female ratio, 7:11) were identified. Patients with multiple carcinoid tumors were significantly younger than patients with solitary tumors at the time of diagnosis (55 years vs 63 years, p = 0.006). There was a high association between multiple carcinoid tumors and the carcinoid syndrome (4 of 18 vs 1 of 50, p = 0.004) as compared with patients with solitary carcinoid tumors. There was also an association between tumor multiplicity and venous invasion, but this relationship was not statistically significant (p = 0.07). The follow-up period was similar for both groups (mean 36 months, median 26 months, range 1-139 months). A significantly higher proportion of patients with multiple carcinoid tumors were either alive with disease or died of disease (56%) compared with those with solitary carcinoid tumors (18%, p = 0.002), and this relationship persisted in multivariate analysis (p = 0.02). Overall, no significant differences were observed between these two patient groups with respect to other clinicopathologic features such as tumor size, depth of invasion, presence of distant metastases, lymphatic or perineural invasion, or presence of an associated malignancy (p >0.05). In conclusion, we found that patients with multiple carcinoid tumors are younger, have a significantly greater risk of developing the carcinoid syndrome, and have a poorer prognosis than patients with solitary tumors.

Malignant carcinoids in the USA, SEER 1992-1999. An epidemiological study with 6830 cases.

Most of our knowledge on the epidemiology of carcinoid tumours in the USA relies on studies updated during the 1980s. The aim of this study was to describe USA population-based case-series incidence in the period 1992-1999. Data were retrieved from a Surveillance Epidemiology and End Results (SEER) Program public-use file. Incidence rates, male-to-female standardized ratios, estimated annual percentage changes and 5-year relative survival rates were computed, and 6830 malignant carcinoid incident during 1992-1999 were analysed. The overall age-adjusted incidence rates were 1.9 per 100 000 for men and women. There was an excess in women for lung and stomach carcinoids, while rates were higher among men for carcinoids of the small intestine and rectum. From 1992 to 1999, incidence rates showed a 3% estimated annual increase. Thirteen per cent of the cases had metastasis at diagnosis. In the present series, 24% of carcinoid patients had more than one tumour. The overall 5-year relative survival rate was 82%. In conclusion, improvements in diagnostic techniques seem to have influenced the epidemiology of carcinoid tumours, leading to a slightly different site distribution and a better stage distribution at diagnosis. Increasing incidence and improving survival rates were shown.