European Neuroendocrine Tumor Society (ENETS) 2022 Guidance Paper for Carcinoid Syndrome and Carcinoid Heart Disease

• DOI: 10.1111/jne.13146
• Publication Date: 2022-04-25T16:10:03Z
• Authors: Simona Grozinsky‐...; Joseph Davar; Johannes Hofland; Rebecca Dobson; Vikas Prasad; Andreas Pascher; Timm Denecke; Margot E. T. Tess...; Francesco Panzuto; Anders Albåge; Heidi M. Connolly; Jean‐Francois Obadia; Rachel Riechelmann; Christos Toumpanakis
• Keywords: Carcinoid Heart Disease; Chromogranin A

Data regarding the diagnosis, management, and follow-up of carcinoid syndrome (CS) heart disease (CHD) were identified by searches MEDLINE database using specific terms in human studies: CS; CHD; screening; epidemiology; diagnosis; treatment; prognosis. The search results supplemented manual searching relevant journals, reference lists key articles other appropriate documents, expert opinion. All recommendations are offered on basis best available evidence, authors' experiences managing CS CHD. Each recommendation for treatment will have a level evidence grade as per GRADE system (adapted Infectious Disease society US Public Health Service grading system)1 (Tables 1 2). A list abbreviations is provided at end manuscript. Carcinoid most frequent hormonal complication accompanying neuroendocrine neoplasms (NENs) defined chronic diarrhoea and/or flushing presence systemic elevated levels serotonin or its metabolite 5-hydroxyindolacetic acid (5-HIAA). Importantly, causes these symptoms should be considered investigated depending clinical presentation. predominantly encountered patients with well-differentiated NENs (neuroendocrine tumours, NETs) intestinal origin, followed lung NETs, only minority pancreatic, ovarian, thymic, unknown origin (UKO) NETs. main defining skin flushing, secretory diarrhoea, bronchospasm, abdominal pain (in some cases advanced systemically biologically active amins peptides. Patients suffer from an impaired quality life (QoL), which lower when compared to without types cancer.2 rare complex cardiac occurring NETs CS, usually manifesting mainly right-sided valves regurgitation/stenosis (see Section A. d.) eventually leading right failure (RHF). caused tumoural secretion multiple amines Serotonin (5-hydroxytryptamine, 5-HT) major secretagogue proposed pathophysiological role fibrotic complications; hormones involved include histamine, tachykinins, kallikrein prostaglandins.2 Because tumour-released inactivated liver, indicates (metastatic) tumour sites outside portal venous drainage.3 Liver metastases present 87%–100% CS. However, 5%–13% cases, may develop absence liver metastases, particularly if primary arises ovary, testis very rarely lung, large burden retroperitoneal present.4, 5 CHD characterised plaque-like fibrous deposits endocardial surfaces, inducing tricuspid valve pulmonary regurgitation/stenosis, ultimately ventricular volume overload failure. Elevated hormones, serotonin, deemed causative CHD-associated plaque formation. Left-sided involvement occur either patent foramen ovale (PFO), functioning NET, high circulating vasoactive substances, overwhelming hepatic degradative capacity.6 prevalence among has varied widely, ranging 3% 74% past, 19% 35% date, world region management.7 Median overall survival significantly reduced 4.7 years 7.1 NET Tumour contributor CS-associated mortality.4 approximately 20%–50% prognostic indicator, 3 31% CHD, 69% CHD.8 crisis potentially life-threatening uncontrolled sudden release substances especially refractory (RCS; see C. b.). It can spontaneously, but more frequently result biopsy, surgical manipulation, use sympathomimetic drugs, anaesthesia different cytolytic therapies (hepatic embolisation) sometimes because peptide receptor radionuclide therapy (PRRT). abrupt severe shifts blood pressure haemodynamic instability, profuse distressing bronchospasm wheezing2 (Table 3). Other complications summarised Table 3.9 actively scrutinised history taking, physical examination, laboratory analysis. Flushing, hallmark reported over 90% (either patient his/her family members); it intermittent persistent sensation warmth together erythema, involving head, neck, upper part torso, telangiectasia longstanding disease. In not associated sweating (‘dry flushing’). cardiovascular abnormalities (hypo-/hypertension, brady-/tachycardia). Specific features depend four been described CS12: 5-HIAA measured presentation all lung/ovary any stage, every suspected 4A metabolised 5-HIAA. Plasma N-terminal pro-brain natriuretic (NT-proBNP) evaluated screening biomarker increased u5-HIAA suspicious symptoms, baseline (Figure 1). NT-pro-BNP belongs neurohormone released atria ventricles response increase wall stress overload.20, 21 For detection, NT-proBNP cut-off 235–260 pg mL–1 (31 pmoL L–1) had shown sensitivity specificity 87–92% 80–91%, respectively (NT-proBNP normal range: men under 70 years: < 100 mL–1, women 150 over: 300 mL–1). Quantitative assessment growth rate sequential cross sectional imaging studies provide useful information activity prognosis.25 3B Q2: What differential diagnosis CS? Diarrhoea always secretory, persists fasting, during night discomfort faecal urgency. treated somatostatin analogues (SSA) experience deterioration previously controlled ongoing never responded SSA. NET-related (steatorrhoea secondary SSA, small bacterial overgrowth, mesenteric ischaemia, bile salt malabsorption short-bowel syndrome), NEN-unrelated (colitis, gastroenteritis), need excluded. 5A Flushing context B. Q3: Which tools needed characterise severity CHD? monitoring quantification challenging focusses functional left chambers heart. Q4: principles/aims CS?34, 35 Long-term adverse events nodules injection sites, cholelithiasis exocrine pancreatic insufficiency, 5%–15% cases; diabetic close follow-up, anti-glycaemic intensification needed. RCS recurring persisting increasing persistently despite maximum label doses divided into non-aggressive aggressive, based (< ≥ 4 BM/day, episodes/day, respectively) stability (stable progressive), 50% involvement), Differential 2) includes problems SSA administration, tachyphylaxis, SSA-induced infectious/inflammatory fibrosis, worsening whose bowel was surgically removed. Worsening 2–3 weeks after imply tachyphylaxis; (octreotide LAR 30 mg/2–3 lanreotide Autogel® 120 mg/2 weeks), [2bA] octreotide dosage 60 mg switching alternative considered. 3bA Overall, dose-escalation offers symptom improvement nearly 80% whereas 29% show further reduction levels.42 Treatment radiologically stable indolent progression low symptom/tumour TACE/SIRT reserved G2 non-intestinal NET. 3bB conclusive data trans-arterial efficient, selection made individual factors such load, topography arterial anatomy. progressive and/ We recommend prophylactic short-acting prior invasive procedures—to tapered down afterwards, continuous infusions surgical/loco-regional interventions there concurrent 3b Ultimately, symptomatic Therefore, once initiated, physicians monitor patient's status clinical, biochemical, radiological response. Symptom relief monitored monthly first months and, achieved, intervals 4–6 months. Biochemical tests 4B. Q6: general initial management CHD?56 two goals aggressive RHF, present. holistic approach must taken, consideration status, severity/symptoms, nutritional performance patient.58, 59 Q7: Do's don'ts CS/severe RV dilatation represent, se, indication surgery asymptomatic patients. Cardiac surgery, primarily consists replacement, effective option recent metanalysis74 consisting 416 pre-operative patients, 97% moderate TR, 72% PR, 33% PS regurgitation. Left characteristics included mitral regurgitation (MR) 24% aortic (AR) 18% Additional procedures PFO closure removal intramyocardial metastasis. mechanical discouraged having several disadvantages: Bioprosthetic recommended option73 inherent risk bleeding high-volume dysfunction likelihood requiring temporary discontinuation anticoagulant agents, lesser extent, thrombosis. Post-operatively, following bioprosthetic VKA novel oral anticoagulants 3–6 months, preference albeit supported randomised trials (Consensus opinion). 5B minimally options (percutaneous catheter-based interventions, valve-in-valve replacements) limited; however, this play growing future, as: Valve-in-valve replacement feasible degenerated bioprosthesis, choice patients.79 Q10: advantages MDT improving patients? Decisions optimal NEN require “holistic” well collaboration between Physicians Specialists. dedicated facilitate medical define type, timing intervention (surgical/catheter based). MDT, run separately discuss significant (moderate/severe progressing) who assessed cardiology/CHD clinic fulfil echocardiogram criteria intervention. If runs separately, referred discussed meeting, where decisions about control made. mandatory members physician(s), cardiologist(s) expertise (preferable), cardio-thoracic surgeon(s), anesthetist, cardiology specialist nurses, nutritionist. Several heart, patient’ preferences Cardiovascular (NYHA class), function, left-sided (through echocardiography) TTE/TOE, CCT/CMRI) thoroughly reviewed alongside (stable/progressing) burden, patient-related including comorbidities, organ status. related unmet needs: This ENETS guidance paper, developed multidisciplinary consensus task force, provides up-to-date practical advice developments Echo synoptic report patients.31 Hopefully, pave road standardised care our resulting improved outcomes. Upcoming aimed fulfill gap allow us focus many needs field. Simona Grozinsky-Glasberg: Conceptualization; curation; formal analysis; methodology; project administration; supervision; validation; writing – original draft; review editing. Joseph Davar: resources; Johannes Hofland: investigation; Rebecca Dobson: Vikas Prasad: Andreas Pascher: Timm Denecke: Investigation; Margot E.T. Tesselaar: Francesco Panzuto: Anders Albage: Heidi Connolly: Jean-Francois Obadia: Rachel Riechelmann: Toumpanakis: visualization; authors paper grateful Advisory Board their suggestions comments common effort improve manuscript (the participants appears Appendix S1). peer article https://publons.com/publon/10.1111/jne.13146. sharing applicable no new created analyzed study. S1. Supporting information. Please note: publisher responsible content functionality supporting supplied authors. Any queries (other than missing content) directed corresponding author article.