Neuroendocrine tumours (NETs) are rare malignancies that can develop from a diffuse network of neuroendocrine cells throughout the body. Their incidence is increasing, with Surveillance, Epidemiology, and End Results (SEER) data showing a five-times increase from 1973 to 2004 and an annual incidence of 5·25 per 100 000 people in the USA in 2004.1 This increase is probably multifactorial and related to improvements in detection and diagnosis, as well as a true rise in incidence. Given the indolent nature of well differentiated NETs, many patients live for more than 5 years with metastatic disease and have symptoms for substantial periods of time.
Extrapancreatic NETs are historically known as carcinoids because of their carcinoma-like histology. These NETs can secrete bioactive amines causing carcinoid syndrome.2 These symptoms consist of wheezing, skin flushing, diarrhoea, and fibrotic valvular heart disease.3 Consistent with observations that serotonin is a product of the enterochromaffin cells4 considered the non-malignant counterparts of gastrointestinal NETs, serotonin secretion is associated with carcinoid syndrome in patients with NETs.5 Similarly, urinary excretion of the downstream serotonin metabolite 5-hydroxyindoleacetic acid is elevated in patients with carcinoid syndrome, more so than that of serum serotonin, which fluctuates substantially.6 Hormone secretion and associated symptoms can be reduced but not eliminated in most patients using somatostatin analogues, such as octreotide.7, 8, 9
Research in context
Evidence before this study
A search of PubMed between Jan 1, 2000, and Oct 15, 2016, with the Medical Education Subject Headings “malignant carcinoid syndrome/epidemiology” and “carcinoid tumor”, with no language restrictions, revealed 44 publications. Two studies included more than 150 patients. One study included 2001 patients and the other included 3379 patients with pancreatic neuroendocrine tumours (NETs) and 8088 patients with gastrointestinal NETs. Carcinoid syndrome was estimated to occur in 3·2% of patients in the larger study using retrospective questionnaires and 21·4% of patients in the other study.
Added value of this study
This study used prospective databases to identify 9512 patients with extrapancreatic NETs and used claims data to identify those with carcinoid syndrome. To our knowledge, it is the largest, most rigorous analysis of the epidemiology of carcinoid syndrome and associated clinicopathological factors. Nearly 20% of patients with NETs had carcinoid syndrome in our study, which was associated with tumour grade, stage, and primary tumour site. Carcinoid syndrome was also associated with survival.
Implications of all the available evidence
This work highlights the prognostic importance of prioritisation of the diagnosis of carcinoid syndrome in patients with NETs and raises potential future research questions regarding the survival benefit of carcinoid syndrome control. Patients with carcinoid syndrome might need more aggressive tumour monitoring and management than might patients without, and a deeper understanding of tumour serotonin synthesis than at present might provide additional actionable insights into tumour biology.
However, the frequency of carcinoid syndrome among patients with NETs has not been systematically assessed. Although previous studies10, 11, 12, 13 have attempted to estimate this frequency, the wide range identified (3–74%) suggests methodological limitations and the need to establish a more accurate incidence than at present in the broad NET patient population. Indeed, previous analyses were small retrospective studies from single centres or relied on surveys, with potential ascertainment bias.
Although the reported frequency of carcinoid syndrome among patients with NETs has been inconsistent, the effect of carcinoid syndrome on patient quality of life is clear.2, 14, 15, 16 Patients with NETs and carcinoid syndrome show marked impairments in multiple areas, namely fatigue, general health, and physical function, compared with both the general population15, 16 and with patients with NETs without overt carcinoid syndrome,2 using metrics such as the Patient-Reported Outcomes Measurement Information System (PROMIS) 29 and 36-Item Short Form Health Survey (SF-36). Additionally, findings from small studies6, 17, 18 have suggested that potentially because of subclinical niacin deficiency from tumour consumption of tryptophan to produce serotonin, even patients with NETs on therapeutic somatostatin analogues have modest subjective and objective cognitive impairments.19, 20 Given the importance of understanding the symptom burden of this growing patient population, this study used SEER-Medicare, a large, population-based database, to examine trends in the incidence of carcinoid syndrome and associated symptoms. We compared demographic and clinical characteristics between patients with and without carcinoid syndrome to establish factors associated with NETs and carcinoid syndrome. We also assessed treatment selection and patient outcomes.