Elevated sortilin expression discriminates functional from non-functional neuroendocrine tumors and enables therapeutic targeting.

A subset of neuroendocrine tumors (NETs) can cause an excessive secretion of hormones, neuropeptides, and biogenic amines into the bloodstream. These so-called functional NETs evoke a hormone-related disease and lead to several different syndromes, depending on the factors released. One of the most common functional syndromes, carcinoid syndrome, is characterized mainly by over-secretion of serotonin. However, what distinguishes functional from non-functional tumors on a molecular level remains unknown. Here, we demonstrate that the expression of sortilin, a widely expressed transmembrane receptor involved in intracellular protein sorting, is significantly increased in functional compared to non-functional NETs and thus can be used as a biomarker for functional NETs. Furthermore, using a cell line model of functional NETs, as well as organoids, we demonstrate that inhibition of sortilin reduces cellular serotonin concentrations and may therefore serve as a novel therapeutic target to treat patients with carcinoid syndrome.

Serotonin pathway in carcinoid syndrome: Clinical, diagnostic, prognostic and therapeutic implications.

Carcinoid syndrome represents the most common functional syndrome that affects patients with neuroendocrine neoplasms. Its clinical presentation is really heterogeneous, ranging from mild and often misdiagnosed symptoms to severe manifestations, that significantly worsen the patient's quality of life, such as difficult-to-control diarrhoea and fibrotic complications. Serotonin pathway alteration plays a central role in the pathophysiology of carcinoid syndrome, accounting for most clinical manifestations and providing diagnostic tools. Serotonin pathway is complex, resulting in production of biologically active molecules such as serotonin and melatonin, as well as of different intermediate molecules and final metabolites. These activities require site- and tissue-specific catalytic enzymes. Variable expression and activities of these enzymes result in different clinical pictures, according to primary site of origin of the tumour. At the same time, the biochemical diagnosis of carcinoid syndrome could be difficult even in case of typical symptoms. Therefore, the accuracy of the diagnostic methods of assessment should be improved, also attenuating the impact of confounding factors and maybe considering new serotonin precursors or metabolites as diagnostic markers. Finally, the prognostic role of serotonin markers has been only evaluated for its metabolite 5-hydroxyindole acetic acid but, due to heterogeneous and biased study designs, no definitive conclusions have been achieved. The most recent progress is represented by the new therapeutic agent telotristat, an inhibitor of the enzyme tryptophan hydroxylase, which blocks the conversion of tryptophan in 5-hydroxy-tryptophan. The present review investigates the clinical significance of serotonin pathway in carcinoid syndrome, considering its role in the pathogenesis, diagnosis, prognosis and therapy.

Retrospective review of serotonergic medication tolerability in patients with neuroendocrine tumors with biochemically proven carcinoid syndrome.

BACKGROUND: Patients with carcinoid tumors frequently could benefit from the pharmacologic treatment of depression and anxiety. However, many prescribers avoid serotonergic medications due to the theoretical risk of exacerbating carcinoid syndrome. METHODS: The authors conducted a retrospective chart review of patients with carcinoid tumors and elevated serotonin levels (as measured by 24-hour urine 5-hydroxyindoleacetic acid [5-HIAA]) at Dana-Farber/Brigham and Women's Cancer Center who initiated treatment with serotonergic antidepressants after a carcinoid diagnosis from 2003 to 2016. Each medication regimen was categorized based on the presence of adverse interactions as defined by clinical worsening of symptoms of carcinoid syndrome in the absence of progressive disease that temporally correlated with a serotonergic medication trial. RESULTS: A total of 73 serotonergic regimens received by 52 patients were included in the primary analysis. Among these medication trials, 8.2% of the regimens (6 regimens) were categorized as being associated with a likely adverse interaction, 61.6% of the regimens (45 regimens) were categorized as having no adverse reaction, 9.6% of the regimens (7 regimens) were categorized as an unlikely adverse reaction, and 20.6% of the regimens (15 regimens) were categorized as unknown. It is interesting to note that none of the 73 trials resulted in a carcinoid crisis requiring emergency care or hospitalization. Only 3 patients discontinued serotonergic medications due to worsening carcinoid syndrome. CONCLUSIONS: Serotonergic medications appear to be a safe option for the treatment of depressive and anxiety symptoms in the majority of patients with neuroendocrine tumors and carcinoid syndrome. In the current study, <10% of patients developed a combination of flushing, diarrhea, and bloating after the initiation of serotonergic medications. Clinicians can begin with low doses, monitor these symptoms, and reduce the dose or discontinue the medication if necessary. Cancer 2017;123:2735-42. © 2017 American Cancer Society.

Telotristat ethyl: a new option for the management of carcinoid syndrome.

INTRODUCTION: Many patients with neuroendocrine tumour-related carcinoid syndrome treated with somatostatin analogues (SSA) won't achieve adequate symptom relief with the SSA alone; new treatment options are required. Telotristat ethyl is a tryptophan hydroxylase inhibitor, developed for the treatment of carcinoid syndrome. Areas covered: This review summarises the evidence supporting the role of telotristat ethyl in the management of carcinoid syndrome. Rationale, pharmacodynamics, pharmacokinetics, metabolism, clinical experience, efficacy and toxicity profiles are covered. Expert opinion: The efficacy of telotristat ethyl in producing a statistically-significant and clinically-meaningful reduction in daily bowel movements has been confirmed in phase III clinical trials. Two pivotal trials, TELESTAR and TELECAST, explored the role of telotristat ethyl in the management of patients with carcinoid syndrome refractory to SSAs focusing on patients with ≥4 and <4 daily bowel movements, respectively. In addition, benefit was confirmed in patient-reported outcomes. Based on activity and safe toxicity profile, telotristat ethyl is pending regulatory agencies evaluation and is likely to add to the armamentarium used to treat carcinoid syndrome. Long-term safety and efficacy data will be available from the ongoing TELEPATH study. The impact on carcinoid heart disease, mesenteric fibrosis and other long-term complications of carcinoid syndrome as well as its role earlier in patients' pathways remain investigational.

Clinical Syndromes Related to Gastrointestinal Neuroendocrine Neoplasms.

Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of tumors derived from multipotent neuroendocrine cells that have the inherent ability to synthesize and secrete a variety of substances (peptides and amines). When these substances are bioactive, NENs can present with a related clinical syndrome (functioning NENs) and/or symptoms of mass effects (functioning and nonfunctioning NENs). NENs differ in their pathogenesis, clinical syndromes produced, aspects of biological behavior and response to certain antitumor treatment. The carcinoid syndrome (CS) is the clinical constellation of secretory diarrhea, flushing, wheezing and dyspnea as a result of serotonin production mainly from small intestinal NENs. Complications of CS are frequent and include extensive mesenteric fibrosis, carcinoid heart disease and the life-threatening carcinoid crisis. A variety of substances (mainly hormones) are produced from NENs originating from the pancreas associated with specific symptoms that can lead to their precise diagnosis. NENs may also secrete substances characteristic of other sites of origin and produce a variety of paraneoplastic syndromes and/or change their secretory status with time. Surgery remains the best option for complete tumor resection and symptom relief. Surgery may also be used when medical treatment fails to obtain control of the symptoms along with cytoreductive techniques. Somatostatin analogs (octreotide and lanreotide) constitute the backbone of medical treatment for the majority of functioning NENs as they can alleviate symptoms, stabilize tumor growth and improve the quality of life. Telotristat etiprate is a novel oral agent that inhibits tryptophan hydroxylase, the key enzyme responsible for serotonin production, and can improve the symptoms of CS. Nonspecific and supportive therapies are also used for refractory cases. In this chapter the clinical features of functioning NENs will be analyzed as well as aspects of their diagnosis based on secretory substances and treatment of the hormonal excess.

Circulating serotonin and bone density, structure, and turnover in carcinoid syndrome.

CONTEXT: Gut-derived serotonin has been proposed as a regulator of bone formation, and inhibition of gut serotonin synthesis increases bone formation in rodents. Carcinoid neuroendocrine tumors can produce very high levels of circulating serotonin and so offer a model of serotonin excess in humans. OBJECTIVES: The objective of the study was to determine whether patients with carcinoid syndrome have lower bone formation markers, lower bone density, or poor bone structure compared with healthy controls. DESIGN: We conducted a cross-sectional study of 25 patients with carcinoid syndrome and 25 healthy controls, individually matched to carcinoid patients by gender, age, height, and body mass index. OUTCOME MEASURES: We measured circulating serotonin in blood and plasma and 5-hydroxyindoleacetic acid (5HIAA) in plasma and urine. We measured lumbar spine and hip bone mineral density by dual-energy x-ray absorptiometry, the distal radius and tibia with high-resolution peripheral quantitative computed tomography, and bone turnover with serum osteocalcin, amino-terminal propeptide of type I procollagen (PINP) and C-terminal telopeptide of type I collagen (CTX). RESULTS: All measures of serotonin and 5HIAA were higher in carcinoid patients than in controls. No measures of bone density or bone structure differed significantly between cases and controls. Osteocalcin was higher in the cases than controls (26.0 vs 21.1 ng/mL, P = .02). PINP and CTX did not differ between cases and controls. In patients with carcinoid syndrome, plasma 5HIAA was positively correlated with osteocalcin. In controls, whole-blood serotonin was positively correlated with osteocalcin, PINP, and CTX (R values = 0.40-0.47, all P < .05.). CONCLUSIONS: High circulating serotonin in carcinoid syndrome is not associated with clinically significant lower bone density, poorer bone structure, or lower bone formation markers.

5-HIAA excretion is not associated with bone metabolism in carcinoid syndrome patients.

In patients with a carcinoid syndrome and neuroendocrine tumors of the digestive tract (carcinoids), elevated circulating serotonin (5-hydroxytryptamine, 5-HT) levels can be demonstrated. It can be hypothesized that bone metabolism will be affected in these patients, since serotonin receptors are expressed on bone cells and serotonin effects on bone have been demonstrated. However, to date, no data are available on bone metabolism parameters in patients with neuroendocrine tumors of the digestive tract (carcinoids). In the current retrospective study we have measured serum bone formation markers P1CP (pro-collagen type I C-terminal), and osteocalcin, and the bone resorption marker NTx (collagen breakdown product N-terminal), in a group of 61 carcinoid patients with increased circulating serotonin levels as demonstrated by increased excretion of the serotonin breakdown product, 5-hydroxy indole acetic acid (5-HIAA), in the urine (>50 µmol/24 h, so-called "hyper-secretors") and a control group of 23 carcinoid patients, without increased 5-HIAA excretion (so-called non-secretors). The 24-h urinary excretion of 5-HIAA reflects the 24-h production of serotonin. Measurements of markers of bone metabolism were performed in serum samples obtained before the start of medical treatment. The hypersecretor group had on average a 10-fold higher urinary 5-HIAA excretion than the control (non-secretor) group. No significant differences in bone metabolism parameters could be demonstrated between hyper-secretors and controls (non-secretors). Correlation and regression analyses could not demonstrate significant age- and sex-adjusted correlations between urinary 5-HIAA excretion and any of the markers for bone turnover. A limitation is that the exposure time to elevated levels of serotonin is unknown, which might have been too short to induce effects on bone metabolism. Treatment of human pre-osteoblasts SV-HFO with serotonin didn't change alkaline phosphatase activity throughout differentiation as well as mineralization. In conclusion, the current study in a unique group of untreated carcinoid patients could not demonstrate a major role for circulating serotonin in the control of bone metabolism.

Serotonin-producing enterochromaffin cell tumors of the pancreas: clinicopathologic study of 15 cases and comparison with intestinal enterochromaffin cell tumors.

OBJECTIVES: Serotonin-producing tumors of the pancreas are rare endocrine neoplasms composed of enterochromaffin (EC) cells that have been mainly described in the literature as case reports. This study analyzes the clinicopathologic features of a series of pancreatic EC cell neoplasms and their similarities to and differences from intestinal EC cell tumors. METHODS: The morphological, immunohistochemical, ultrastructural, and fluorescent in situ hybridization features of 15 pancreatic and 20 intestinal serotonin-producing neoplasms were compared. In addition, we reviewed the literature on pancreatic serotonin-producing tumors to better understand the clinicopathologic features of this rare tumor type. RESULTS: The lack of substance P and acidic fibroblast growth factor immunoreactivity; the low immunohistochemical expression of CDX2, vesicular monoamine transporter 1, connective tissue growth factor, and prostatic acid phosphatase; the lack of S100-positive sustentacular cells; the strong expression of vesicular monoamine transporter 2; and peculiar ultrastructural features characterize pancreatic EC cell tumors and differentiate them from intestinal ones, although both categories show similar chromosome 18 cytogenetic alterations. The review of the literature indicates that pancreatic functioning tumors associated with the carcinoid syndrome arise in younger patients and are larger, more frequently malignant, and more aggressive neoplasms than pancreatic nonfunctioning ones. CONCLUSIONS: Pancreatic EC cell tumors show several different morphological features compared with related intestinal tumors despite similar cytogenetic alterations on chromosome 18.

The endocrine tumor summit 2008: appraising therapeutic approaches for acromegaly and carcinoid syndrome.

The Endocrine Tumor Summit convened in December 2008 to address 6 statements prepared by panel members that reflect important questions in the treatment of acromegaly and carcinoid syndrome. Data pertinent to each of the statements were identified through review of pertinent literature by one of the 9-member panel, enabling a critical evaluation of the statements and the evidence supporting or refuting them. Three statements addressed the validity of serum growth hormone (GH) and insulin-like growth factor-I (IGF-I) concentrations as indicators or predictors of disease in acromegaly. Statements regarding the effects of preoperative somatostatin analog use on pituitary surgical outcomes, their effects on hormone and symptom control in carcinoid syndrome, and the efficacy of extended dosing intervals were reviewed. Panel opinions, based on the level of available scientific evidence, were polled. Finally, their views were compared with those of surveyed community-based endocrinologists and neurosurgeons.

Development and characterization of a novel in vivo model of carcinoid syndrome.

PURPOSE: Carcinoid syndrome, characterized by flushing, diarrhea, and valvular heart disease, can occur following carcinoid tumor metastasis to the liver and systemic release of bioactive hormones into the systemic circulation. Treatment of this devastating disease is hampered by the lack of an in vivo model that recapitulates the clinical syndrome. EXPERIMENTAL DESIGN: Here, we have injected BON cells, a novel human carcinoid cell line established in our laboratory, into the spleens of athymic nude mice to establish liver metastases. RESULTS: The majority of mice injected intrasplenically with BON cells developed significant increases in plasma serotonin and urine 5-hydroxyindoleacetic acid, and several mice exhibited mesenteric fibrosis, diarrhea, and fibrotic cardiac valvular disease reminiscent of carcinoid syndrome by both echocardiographic and histopathologic evaluation. Mice pretreated with octreotide, a long-acting somatostatin analogue, or bevacizumab, a vascular endothelial growth factor inhibitor, developed fewer liver metastases and manifestations of carcinoid syndrome, including valvular heart disease. CONCLUSION: We have provided an important in vivo model to further delineate novel treatment modalities for carcinoid syndrome that will also be useful to elucidate the factors contributing to the sequelae of carcinoid disease (e.g., mesenteric fibrosis and valvular heart disease).

Long-term survival in a patient with carcinoid syndrome receiving treatment for Zollinger-Ellison syndrome.

A case of carcinoid syndrome in a patient receiving treatment for a malignant non-B-cell tumor of the pancreas is presented, and a survival of >14 years is noted. The probable cause is discussed. The literature is reviewed. It was found that such a presentation is rare, and long-term survival in these cases exceedingly rare.

Tachykinins in endocrine tumors and the carcinoid syndrome.

OBJECTIVE: A new antibody, active against the common tachykinin (TK) C-terminal, was used to study TK expression in patients with endocrine tumors and a possible association between plasma-TK levels and symptoms of diarrhea and flush in patients with metastasizing ileocecal serotonin-producing carcinoid tumors (MSPCs). METHOD: TK, serotonin and chromogranin A (CgA) immunoreactivity (IR) was studied by immunohistochemistry in tissue samples from 33 midgut carcinoids and 72 other endocrine tumors. Circulating TK (P-TK) and urinary-5 hydroxyindoleacetic acid (U-5HIAA) concentrations were measured in 42 patients with MSPCs before treatment and related to symptoms in patients with the carcinoid syndrome. Circulating CgA concentrations were also measured in 39 out of the 42 patients. RESULTS: All MSPCs displayed serotonin and strong TK expression. TK-IR was also seen in all serotonin-producing lung and appendix carcinoids. None of the other tumors examined contained TK-IR cells. Concentrations of P-TK, P-CgA, and U-5HIAA were elevated in patients experiencing daily episodes of either flush or diarrhea, when compared with patients experiencing occasional or none of these symptoms. In a Spearman partial rank test, the correlation of P-TK with daily diarrhea was independent of both U-5HIAA and CgA levels. CONCLUSION: We found that TK synthesis occurs in serotonin-IR tumors and that P-TK levels are significantly correlated with symptoms of flush and diarrhea in patients with MSPCs. This is, to our knowledge, the first report demonstrating an independent correlation of P-TKs with carcinoid diarrhea, a symptom that is customarily regarded as serotonin mediated. Further investigations may present opportunities for new therapeutic possibilities.

Recent advances in understanding the role of serotonin in gastrointestinal motility in functional bowel disorders: alterations in 5-HT signalling and metabolism in human disease.

Serotonin (5-hydroxytryptamine, 5-HT) is present in abundance within the gut, most stored in enterochromaffin cell granules. It is released by a range of stimuli, most potently by mucosal stroking. Released 5-HT stimulates local enteric nervous reflexes to initiate secretion and propulsive motility. It also acts on vagal afferents altering motility and in large amounts induces nausea. Rapid reuptake by a specific transporter (serotonin transporter, SERT) limits its diffusion and actions. Abnormally increased 5-HT is found in a range of gastrointestinal disorders including chemotherapy-induced nausea and vomiting, carcinoid syndrome, coeliac disease, inflammatory bowel disease and irritable bowel syndrome (IBS) with diarrhoea (IBS-D), especially that developing following enteric infection. Impaired SERT has been described in IBS-D and might account for some of the increase in mucosal 5-HT availability. 5-HT(3) receptor antagonists inhibit chemotherapy-induced nausea and diarrhoea associated with both carcinoid syndrome and IBS. While IBS-D is associated with increased 5-HT postprandially, IBS with constipation (IBS-C) is associated with impaired 5-HT response and responds to 5-HT(4) agonists such as Prucalopride and 5-HT(4) partial agonists such as Tegaserod.

Rapid and sustained relief from the symptoms of carcinoid syndrome: results from an open 6-month study of the 28-day prolonged-release formulation of lanreotide.

This 6-month, open, non-controlled, multicenter, dose-titration study evaluated the efficacy and safety of 28-day prolonged-release (PR) lanreotide in the treatment of carcinoid syndrome. Eligible patients had a carcinoid tumor with > or =3 stools/day and/or > or =1 moderate/severe flushing episodes/day. Six treatments of 28-day PR lanreotide were administered by deep subcutaneous injection. The dose for the first two injections was 90 mg. Subsequent doses could be titrated (60, 90, 120 mg) according to symptom response. Seventy-one patients were treated. Flushing decreased from a mean of 3.0 at baseline to 2.3 on day 1, and 2.0 on day 2, with a daily mean of 2.1 for the first week post-treatment (p < 0.05). Diarrhea decreased from a mean of 5.0 at baseline to 4.3 on day 1 (p < 0.05), and 4.5 on day 2, with a daily mean of 4.4 for the first week post-treatment (p < 0.001). Symptom frequency decreased further after the second and third injections, and reached a plateau after the fourth injection. By month 6, flushing and diarrhea had significantly decreased from baseline by a mean of 1.3 and 1.1 episodes/day, respectively (both p < or = 0.001); 65% of patients with flushing as the target symptom and 18% of diarrhea-target patients achieved > or =50% reduction from baseline. Median urinary 5-hydroxyindoleacetic acid and chromogranin A levels decreased by 24 and 38%, respectively. Treatment was well tolerated. 28-day PR lanreotide was effective in reducing the symptoms and biochemical markers associated with carcinoid syndrome.

Increased intestinal non-substance P tachykinin concentrations in malignant midgut carcinoid disease.

BACKGROUND: Diarrhoea is an important feature of the carcinoid syndrome, and various agents which may be released from carcinoid tumours have been considered to contribute pathophysiologically. The aim of the present study was to determine luminal concentrations of possible chemical mediators in an uninvolved small intestinal segment using a two-balloon six-channel tube in nine patients with malignant midgut carcinoid disease. METHODS: All patients were treated with interferon and/or octreotide to alleviate the most severe flush. Ion transport was measured during luminal perfusion and luminal perfusate concentrations of calcitonin gene-related peptide, neurotensin, prostaglandin E (PGE)2, neuropeptide Y, somatostatin, vasoactive intestinal polypeptide, substance P and other tachykinins (neurokinin A, neurokinin B, neuropeptide K, eledoisin) were determined by separate assays. RESULTS: Carcinoid patients showed decreased absorption of Cl-, Na+, K+ and water and increased luminal content of non-substance P tachykinins to 424.5 fmol/cm per h, compared with 255.5 fmol/cm per h in control subjects. There were also increased luminal concentrations of PGE2, commonly claimed as a more general mediator of diarrhoea. CONCLUSIONS: The observed increase in intestinal tachykinins may involve extended activity from tachykinin-containing intrinsic neurones in the enteric nervous system, contributing to enhanced intestinal motility and secretory diarrhoea in patients with carcinoid syndrome.

Carcinoids of the colon and ileocecal region: a statistical evaluation of 363 cases collected from the literature.

The colon and ileocecal region are rare sites of origin for gastrointestinal carcinoids. This study evaluates the present status and characteristics of carcinoids of these particular sites in a statistically reliable number of cases and offers fundamental information for future analysis and treatment of these neoplasias. A total of 363 cases of colonic and ileocecal carcinoids were collected from international literature and evaluated in the computer analyzing system. For the final evaluation, 279 cases with sufficient information, consisting of 203 colonic and 76 ileocecal carcinoids, were selected for analysis. In addition, 69 cases of atypical varieties in identical sites were studied for a comparison of 5-year survival rates with the 279 ordinary colonic and ileocecal carcinoids. The characteristic features of colonic and ileocecal carcinoids included: 1) a female preponderance and older age group in the ileocecal carcinoids; 2) a higher incidence of carcinoids in the cecum as compared to those of the rest of the colon followed by the ileocecal region; 3) a high incidence of palpable abdominal tumors resulting from a tendency of the tumors to be large (89.7% were over 2 cm); 4) a high incidence of metastases (61.3%); 5) a high incidence of Grimelius argyrophilia (100.0%) and argentaffin cell type (85.7%) in ileocecal carcinoids; 6) a low detection rate of serotonin in immunohistochemical (66.7%) and laboratory (68.7%) evaluation; and 7) a low postoperative 5-year survival rate (40.5% by the crude calculation method and 65.3% by the Kaplan-Meier method). The present statistical evaluation disclosed a considerable delay in detecting colonic and ileocecal carcinoids resulting in extensive and aggressive surgical treatments and poor postoperative outcomes.