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ARTICLE TYPE:Original articleTITLE:Impact of neuroendocrine morphology on cancer outcomes and stage at diagnosis: a UK nationwide cohort study 2013–2015 RUNNING HEAD:NEUROENDOCRINE NEOPLASMS: A UK COHORT STUDYAUTHORS:Tracey Genus1,2, Catherine Bouvier1, Kwok F. Wong2, Rajaventhan Srirajaskanthan3,4, Brian A. Rous5, Denis C. Talbot6, Juan W Valle7, Mohid Khan8, Neil Pearce9, Mona Elshafie10, Nicholas S. Reed11, Eileen Morgan12, Andrew Deas13, Ceri White14, Dyfed Huws14, John Ramage3,4.AFFILIATIONS:1Neuroendocrine Tumour Patients Foundation, Leamington Spa, UK.2National Cancer Registration and Analysis Service, Public Health England, Birmingham, UK.3Department of Gastroenterology, Kings College Hospital, London, UK.4ENETS Centre of Excellence, Neuroendocrine Tumour Unit, King's College Hospital, London, UK.5National Cancer Registration and Analysis Service, Public Health England, Cambridge, UK.6ENETS Centre of Excellence, Oxford University Hospitals Trust, Oxford, UK.7Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.8Department of Gastroenterology, University Hospital of Wales, Cardiff & ValeUniversity Hospital Board, Cardiff, UK.9Department of Hepatobiliary and Pancreatic Surgery, University Hospital Southampton NHS Foundation Trust, Southampton, UK.10Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.11Beatson Oncology Centre, Gartnavel General Hospital, Glasgow, UK.12Northern Ireland Cancer Registry, Centre for Public Health, Queen's University Belfast, Belfast, UK.13Information Services Division, NHS National Services Scotland, Edinburgh, UK.14Welsh Cancer Intelligence & Surveillance Unit, Public Health Wales, Cardiff, UK.CORRESPONDENCE ADDRESS:Miss Tracey Genus, National Cancer Registration and Analysis Service,Public Health England,5 St Philips Place,Birmingham. B3 2PWTel: 0121 232 9425Email:tracey.genus@.uk FIGURE LEGENDFigure 1: Annual incidence (line graph) and count (bar chart) of NENs diagnosed in England 2001–2015, and UK 2015 (cross markers)ABSTRACT:BackgroundThe diagnosis of neuroendocrine neoplasms (NENs) is often delayed. This first UK population-based epidemiological study of NENs compares outcomes with non-NENs to identify any inequalities.MethodsAge-standardised incidence rate (ASR), 1-year overall survival, hazard ratios, and standardised mortality rates (SMRs) were calculated for all malignant NENs diagnosed 2013–2015 from UK national Public Health records. Comparison with non-NENs assessed 1-year overall survival (1YS) and association between diagnosis at stage IV and morphology.ResultsA total of 15 222 NENs were identified, with an ASR (2013–2015 combined) of 8·6 per 100 000 (95% CI 8·5–8·7); 4·6 per 100 000 (95% CI, 4·5–4·7) for gastro-entero-pancreatic (GEP) NENs. The 1YS was 75% (95% CI, 73·9–75.4) varying significantly by sex. Site and morphology were prognostic.NENs (predominantly small cell carcinomas) in the oesophagus, bladder, prostate, and female reproductive organs had a poorer outcome and were three times more likely to be diagnosed at stage IV than non-NENs. ConclusionAdvanced stage at diagnosis with significantly poorer outcomes of some NENs compared with non-NENs at the same anatomical site, highlight the need for improved access to specialist services and targeted service improvement. SUBJECT ONTOLOGY:Neuroendocrine cancer; epidemiology; incidence; survival; mortality BACKGROUNDNeuroendocrine neoplasms (NENs) occur throughout the body, the most common sites including pulmonary, digestive and skin. NENs range from well differentiated neuroendocrine tumours (NETs) to poorly differentiated carcinomas (NECs, small- and large-cell type) (World Health Organisation [WHO] Classification 2017) having varying potential, low grade and indolent to high grade and aggressive. The heterogeneous clinical presentation and biology of NENs cause significant challenges in diagnosis and management,1 with NENs often misdiagnosed, or diagnosis frequently delayed.2The UK cancer registries in England, Scotland, Wales and Northern Ireland systematically collect high quality histologically-confirmed and validated data on all malignant cancers diagnosed. However, previous coding systems have made comprehensive isolation of NEN data for epidemiological studies impossible. Registration in the ICD-O-3 (combined topology and morphology) coding system for cases diagnosed from 2013 onward,3 and TNM staging of GEP-NENs from 20104 have now allowed the first descriptive epidemiological study of NENs diagnosed in the UK, and the first analysis by TNM stage. The aim of this study was to determine the epidemiology of NENs diagnosed in the UK, and to ascertain whether there are any disparities in outcomes between NENs and non-NENs at the same anatomical site.?METHODSStudy PopulationA comprehensive population-based cohort study was undertaken for all persons diagnosed with NENs in the UK between 1st January 2013 and 31st December 2015 with follow-up to the week commencing 12th January 2017, using patient-level data collected by Public Health England National Cancer Registration and Analysis Service (PHE NCRAS), and pseudo-anonymised data from NHS National Services Scotland, Public Health Wales Welsh Cancer Intelligence & Surveillance Unit and Public Health Agency Queen's University Belfast. These registries had coverage of a 2015 mid-year total population of 65 110 000. Socioeconomic status (not available for Scotland) was measured by deprivation quintiles based on: area deprivation for England and N. Ireland, produced by the Ministry of Housing, Communities and Local Government (formerly the Department for Communities and Local Government); and aspects of deprivation experienced in income for Wales, produced by the Welsh Government using the Welsh Index of Multiple Deprivation. English data for non-NENs was also available for comparison. Tumour classificationNENs were defined by the WHO 2015 classification excluding diffuse pulmonary neuroendocrine hyperplasia. Tumours occurring at all anatomical sites between C00 and C80 according to the 10th edition of the WHO International Classification of Disease (ICD-10) codes were included, and morphology codes included 8013 (excluding lung [C34 and C78]), 8041–8045 (excluding lung), 8150–8158, 8240–8247, 8249, and 9091 according to the WHO International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3). All were behaviour code 3 (malignant), 6 (metastatic) or 9 (malignant, uncertain whether primary or metastatic). Tumours were staged according to the American Joint Committee on Cancer (AJCC) TNM staging for NENs5 and the European Neuroendocrine Tumor Society (ENETS) recommendations for the staging of GEP-NENs6 and graded using the ENETS grading system (WHO 2010) for GEP-NENs,7–9 or according to pathological grading of differentiation for other sites. Ki-67 status was not uniformly captured and is not recognised yet in many organ systems. Due to this being a registry study, we were unable to revisit each tissue specimen to acquire it, most grades were therefore based on a morphology of “poorly-differentiated” or “well-differentiated” so grade 1 and grade 2 were combined to reduce inaccuracies. Tumour grades were classified: grade 1 and grade 2 combined — NET G1/G2 (functioning tumours including insulinomas, glucagonomas etc. with morphology codes 8150–8153, 8155–8158 and tumours with morphology codes 8240–8242, 8249, and 9091); grade 3 — NEC G3 (large cell carcinoma, small cell carcinoma, combined small cell carcinoma, neuroendocrine carcinoma NOS with morphology codes 8013, 8041-8045, and 8246); Mixed Adeno-Neuroendocrine Carcinoma (MANEC) (goblet cell carcinoid, mixed adenoneuroendocrine carcinoma, tubular adenocarcinoid tumour with morphology codes 8243-8245); and ‘other’ (pancreatic endocrine tumour malignant, mixed pancreatic endocrine and exocrine tumour malignant, and Merkel cell carcinoma morphology codes 8150, 8154, and 8247, respectively). Statistical AnalysisAll analyses were performed using STATA/MP 15.1 for Windows software program. ASRs for the UK 2013–2015 combined, UK 2013-2015 annual, and 2001–2015 time series (England only) were calculated using ICD-O-2 codes for diagnoses between 2001–2012 (morphology codes 8013 [large cell neuroendocrine carcinoma], and 8249 [atypical carcinoid tumour] were not available), 1971–2015 mid-year population estimates Office of National Statistics (ONS) data,10 and the 2013 European standard population. Of the cohort, 15 106 persons were included in survival and mortality analyses, excluding those with a death certificate only registration and including the first tumour in those with multiple tumours, or the tumour with known stage if multiple tumours had the same diagnosis date.1YS estimates (also for non-NENs) were made using the Kaplan-Meier method with log rank tests. Multivariable survival analysis using Cox (proportional hazards) regression and likelihood ratios were performed with the model adjusting for clinically relevant independent variables sex, age, stage, site, morphology, grade, deprivation and year of diagnosis (all assessed for significant association with overall survival at p<0·05). Standardised mortality rates, for those diagnosed between 1st January 2013 and 31st December 2015, for all-cause mortality over the disease duration, adjusting for explanatory variables age, sex and calendar period, were calculated by means of the life-table approach using ONS death registrations, including persons aged 0–100 years.11,12 Multiple logistic regression estimated the OR and 95% confidence intervals (CI) for association of diagnosis at stage IV with morphology (NEN or non-NEN), for all people diagnosed with cancer between 2013 and 2015 in England, adjusting for sex and age. Vital status on 1st January 2017 was acquired from ONS.RESULTSPatientsOverall, 15 145 persons were diagnosed with 15 222 NENs between 2013 and 2015, of which 7 640 (50·4%) were female. The average age at diagnosis was 65–69 years old with variation between sites (Table 1). The median follow-up time was 19.6 months (range 0–49.2 months) and 24.8% (3 766) died within one year of diagnosis. TumoursThe most common primary tumour sites were pulmonary 20%, small intestine (13%, appendix 12%, pancreas 9%, skin 7%, colon and caecum 5%, stomach 5%, rectum 4%, bladder 3%, and oesophagus 3%. Stage distribution was 37% localised (18% stage I, 9% stage II, and 11% stage III), 23% metastasized (stage IV) and 39% unknown. Around 42% of the neoplasms were NETs, 28% neuroendocrine carcinomas, and 9% small cell carcinomas (8041). Nearly half of the tumours (48%) were low grade (grade 1 or 2) and over a third (35%) high grade (grade 3), the remaining tumours were MANEC (3·5%) and other (13%). Tumour breakdown by proportion of stage IV, grade 3 and by morphology for the most common sites is shown in Table 1. IncidenceThe UK ASR was 8·6 per 100 000 (2013–2015 combined), 8·1 in females and 9·1 in males; 4·6 for GEP-NENs overall, the second most common gastrointestinal tumour.13 Incidence by other sites are listed in Table 2. The 2015 UK annual incidence was 8·7 per 100 000 (8·2 [95% CI, 7.8–8.5] in females and 9.2 in males [95% CI, 8.8–9.6]). It increased steadily, from 3·9 cases per 100 000 in 2001 to 7·9 per 100 000 in 2012 in England, at around 0·4 cases per 100 000 per year (Figure 1 and Table 2), although it must be noted that these figures are from ICD-O-2 coded data so do not include morphology codes 8013, and 8249. Survival The overall 1YS probability for persons diagnosed with NENs was 74% (Table 2), significantly higher in females 78% than in males 71% (p<0·001 for comparison between sexes). There was a small but significant difference between the least deprived 77% and most deprived 73%. As expected, small cell neuroendocrine carcinoma had the poorest survival probability of all morphologies, 41·4%, whilst NETs had the highest at >90% (inclusive of all sites). The median survival for oesophageal, prostate, and bladder NENs were 5.7 (4.5–7.5), 7.8 (5.8–9.1), and 11.3 (9.9–12.8) months, respectively. Survival for the other sites exceeded 50% at the longest time period so median survival could not be calculated for these. The 1YS probability for people diagnosed with pulmonary, pancreatic, stomach and small intestine NENs, were much higher than for non-NENs at these sites. Conversely, the 1YS probability for people diagnosed with oesophageal, prostate, bladder, and to a lesser extent female reproductive organ, colon, and breast NENs, predominantly well differentiated NETs, were much lower than for non-NENs at these sites (Table 3) and were at least three times more likely to be diagnosed at stage IV. Around 42% of oesophageal NENs were stage IV and grade 3 tumour pathology with a 1YS probability of 22% (95% CI 16·7–28·5); the predominant morphology at this site was small cell neuroendocrine carcinoma (Table 1). Likewise, 75% of bladder and 74% of prostate NENs were small cell or combined small cell carcinomas. Survival decreased more with increasing stage (p<0·001 for comparison between all stages) and grade (p<0·001, for comparison between all grades) combined, identifying the combination as potentially a better prognostic indicator than each variable independently (S2). This was particularly noticeable for grade 1 and 2 combined vs grade 3 survival probabilities in those with stage IV: lung NENs, 65·1% (56·2–72·6) vs 26·2% (22·5–30), colon NENs, 81·7% (73·1–87·8) vs 21·6% (14·7–29·5); and pancreatic NENs 86·8% (81·4–90·8) vs 41·1% (34·6–47·4). Univariable Cox regression analysis determined that the hazard of death increased by 4% (HR 1·04 95% CI [1·03–1·06]) for each increase in deprivation of 1 quintile; 21% (HR 1·21 95% CI [1·19–1·22]) for every 5 year increase in age; and 35% (HR 1·35 95% CI [1·32–1·38]) with each one increment increase in stage at diagnosis. Risk decreased by 5% (HR 0·95 95% CI [0·92–0·98]) for each year of diagnosis between 2013 and 2015. Multivariable Cox analysis adjusting for predictor variables sex, age, stage, site, morphology, grade, deprivation, and year of diagnosis on mortality (Table 2) determined the hazard of death was up to 18% lower for women than men; those aged over 75 years three times that of those aged under 54 years; and those with stage IV NENs more than twice that of those with stage III NENs. Some sites were associated with increased hazard, the hazard in those with gallbladder, anal, and oesophageal NENs was similar to that of those with secondary tumours (HR 3.2 95% CI [2·5–4.1]) (S1). Those who lived in the most deprived areas had up to a 41% increase in hazard of death when compared with the least deprived. MortalitySMRs were used to measure survival relative to the general population (Table 2). Deaths occurred nearly 4 times more frequently in those diagnosed with NENs; varying from nearly 3 times more in those aged over 75 years to 10 times more in those aged 55-64 years at diagnosis, and with the same frequency as those in the general public for those with stage I to 10 times more in those with stage IV cancer. DISCUSSIONIncidenceThe incidence of NENs appears to be rising in this and other international studies.14,15 This rise may be real, or may be an artefact of the use of diagnostic imaging15 with improved sensitivity, and increased clinical vigilance resulting in incidental detection of asymptomatic lesions.14 Also, in this study the upward trend in incidence between 2013, the beginning of ICD-O-3 coding in the UK, and 2015 is less pronounced than that seen previously. We need future studies using a wider timeframe to determine whether the incidence of NENs is still rising or beginning to plateau. In the UK, the incidence of NENs in the rectum ranked after lung, small intestine, appendix, pancreas, stomach, and colon and caecum combined, in comparison with the most recent international study, in the USA,15 where rectum was the 3rd most common after lung and small intestine, with appendix last. In the USA, colorectal screening starts at 50 years old16 compared with 55 years in the UK and could be improving detection; appendiceal NETs only became reportable in the USA from January 2015 (SEER personal communication), explaining the comparatively lower incidence.Survival and MortalityMultivariable analysis identified sex, age, site, stage, cell morphology and deprivation to be independently associated with mortality. Survival probabilities for NENs in the UK had similar trends to previous international studies with male sex, increasing age, stage, and grade and decreasing socioeconomic status associated with a poorer outcome.13,15 The much reduced 1YS and mortality in metastatic tumours (stage IV) when compared with localised tumours (stage I–III) was particularly notable and in-line with a study of “all cancers“ diagnosed in the UK,17 warranting further measures to ensure that the early diagnosis of NENs is a priority. People diagnosed with oesophageal, bladder, prostate, and female reproductive NENs had predominantly small cell carcinoma morphology, significantly poorer outcomes consistent with the results of previous smaller studies and case series,18–21 and were more likely to be diagnosed at stage IV. Some morphologies exhibited poorer survival probabilities than expected. This was the first large series study of MANEC reported and demonstrated a survival probability of 84% in comparison with the 95% previously reported.22 These findings highlight the need for the development of sub-specialist services to match the clinical need in the groups which have poorer outcomes. LimitationsTumours with uncertain behaviour (behaviour code 1) are not consistently captured by UK cancer registries because they have historically been deemed ‘benign’ and were not included. This means that many small and indolent NETs of the stomach, rectum, appendix and pancreas may not have been included in historical data. There is an under representation of type 1 gastric NETs and stage I and II rectal NETs - that all have excellent 5- and 10-year survivals. This under representation may be significantly skewing the survival statistics presented in this study. Also the high incidence of G3 NECs in this study, particularly those in the lung, are not representative of previous findings. In the lung, G3 NEC is used when there has been insufficient information to classify the tumour as either small cell carcinoma or large cell neuroendocrine carcinoma. Thus the high incidence of G3 NEC in the lung is likely to represent small cell carcinoma, large cell neuroendocrine carcinomas and mixed tumours. This misclassification of G3 NECs could also be skewing the survival analysis. This is a caveat for ongoing classification recommendations for the purposes of analysis and audit. In the future, many of these tumours will be more consistently captured with improvements in WHO terminology.The completeness of stage was only 61% for this cohort but is improving year on year. ICD-O-3 coding was implemented in 95% of the UK in 2013 (the exception Wales in 2016), prior to this morphology codes 8013, and 8249 were not available, many of these tumours coded carcinoma or adenocarcinoma NOS (not otherwise specified). Therefore, our incidence counts are underestimates, and survival analysis limited to only 1-year. We calculated that the missing tumours from the Welsh cohort would equate to approximately 62 from common sites. Also, an audit of the English data using data collected by the NET Centre of Excellence at King’s College Hospital found 14·6% of the tumours captured were not captured by NCRAS, many behaviour 1. This would suggest the true incidence of NENs could be as high as 10 per 100 000 per year. The capture of NENs irrespective of behaviour code, ICD-O-3 coding in Wales from 2016, and improvements in data completeness will resolve the afore mentioned issues in the future. We were unable to calculate disease-specific survival and mortality due to death registrations by ICD-10 coding. However, recently it has become possible to link morphology to death registrations which will allow this in future studies.ConclusionThis is the first population-based epidemiological study of NENs diagnosed in the UK, the results of which will be of value in future service planning. We determined that outcomes varied greatly between sites and morphologies. Comparison of NENs with non-NENs at the same site also found disparities. These differing outcomes between patient groups have a direct relationship with the healthcare resource required to manage them; and highlight the need for NENs to be seen at Centres of Excellence. Earlier diagnosis is necessary, and the identification of more diagnostic markers for NENs, particularly for extrapulmonary small cell carcinomas, required. Future studies will allow 3- and 5-year survival estimates and the availability of treatment data will allow more in-depth studies, and we are developing ways of collecting more detailed imaging, biochemistry, screening and symptom data which ultimately will be linked to the current cancer registry data. Pathologists have been instructed to include small benign pancreatic NETs as malignant as per WHO terminology and detail Ki67 on all specimen. Ki67 has not been routinely captured by the UK cancer registries to date, however this will change in mid 2020 with the implementation of version 9 of the Cancer Outcome and Services Data set (COSD), the national standard for reporting cancer in the NHS in England, in which Ki67 will be a required field and so captured by the English registry. Although the UK cancer registries do not currently hold complete data on MEN-1 diagnosis, the recent addition of genetic data means that this may also be available for future studies. ADDITIONAL INFORMATION:ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Data is collected by the UK cancer registries (PHE NCRAS, NHS National Services Scotland, Public Health Wales Welsh Cancer Intelligence & Surveillance Unit and Public Health Agency Queen's University Belfast) under Regulations 2 and 5 of Section 251 of the NHS Act 2006. The Regulation provides the legal context to set aside the common-law duty of confidence to allow data to be collected without direct consent to support core public health functions. It is this permission that enables the UK cancer registries to collect detailed information from all people resident in the UK who have cancer or a reasonable suspicion of cancer. CONSENT FOR PUBLICATION: No individual’s personal data was included, only aggregated data is presented.AVAILABILITY OF DATA AND MATERIAL:Data for this study is available on request from PHE NCRAS, NHS National Services Scotland, Public Health Wales Welsh Cancer Intelligence & Surveillance Unit and Public Health Agency Queen's University Belfast.CONFLICT OF INTEREST:The authors declare no conflict of interest.FUNDING:This project was funded by the NET Patient Foundation. AUTHORS’ CONTRIBUTION:TG did the literature search; study design; English data extraction; data collection; data analysis; data interpretation; wrote manuscript; created figures; and created tables. KW did data analysis and data interpretation. EM extracted Northern Irish data. AD extracted Scottish data. CW extracted Welsh data and edited manuscript. DH edited manuscript. CB, RS, BR, DT, JV, MK, NP, ME, NR, and JR were the steering committee for the project; defined the cohort; did study design; data interpretation; and reviewed and edited the manuscript.ACKNOWLEDGMENTS:We would like to thank Sean McPhail, John Broggio, Jackie Charman, James Charnock, Sam Winters, Luke Hounsome and the PHE NCRAS team for all their help with data extraction and analysis.This work uses data provided by patients and collected by the NHS as part of their care and support. Supplementary information is available at the British Journal of Cancer’s website.REFERENCES1Kunz PL, Reidy-Lagunes D, Anthony LB, Bertino EM, Brendtro K, Chan JA et al. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas 2013; 42(4): 557–77.2Singh S, Granberg D, Wolin E, Warner R, Sissons M, Kolarova T et al. Patient-reported burden of a neuroendocrine tumor (NET) diagnosis: results from the first global survey of patients with NETs. J Glob Oncol 2016; 3(1): 43–53.3Fritz A, Percy C, Jack A, Shanmugaratnam K, Sobin L, Max Parkin D (eds). International Classification of Diseases for Oncology, 3rd edn., first revision. World Health Organization: Geneva, Switzerland, 2013. 4Sobin L H, Gospodarowicz M K, Wittekind C (eds). International Union Against Cancer TNM Classification of Malignant Tumors. 7th edn. John Wiley & Sons: Hoboken, NJ, USA, 2011. 5Edge SE, Byrd DR, Carducci MA, Compton CC, Fritz AG, Greene FL et al (eds). American Joint Committee on Cancer (AJCC) TNM staging for NETs. AJCC Cancer Staging Manual. 7th edn. Springer: New York, NY, USA, 2010.6Kloppel G, Couvelard A, Perren A, Komminoth P, McNicol AM, Nilsson O et al. ENETS consensus guidelines for the standards of care in neuroendocrine tumors: towards a standardized approach to the diagnosis of gastroenteropancreatic neuroendocrine tumors and their prognostic stratification. Neuroendocrinology 2009; 90(2): 162–66. 7Bosman FT, Carneiro F, Hruban RH, Theise, N.D (eds). World Health Organisation classification of tumours of the digestive system. 4th edn. IARC: Lyon, France, 2010. 8Rindi G, Kloppel G, Alhman H, Caplin M, Couvelard A, de Herder WW et al. TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2006; 449(4): 395–01. 9Rindi G, Kloppel G, Couvelard A, Komminoth P, K?rner M, Lopes JM et al. TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2007; 451(4): 757–62. 10Office for National Statistics, (2016). Mid-2015 Population estimates for lower layer super output areas in England and Wales by single year of age and sex —supporting information (SAPE18DT1) annual small area population estimates, Office for National Statistics. London: ONS, 2016. 11Cronin KA, Feuer EJ. Cumulative cause-specific mortality for cancer patients in the presence of other causes: a crude analogue of relative survival. Stat Med 2000; 19(13): 1729–40. 12Office for National Statistics, (2018). National Records of Scotland, Northern Ireland Statistics and Research Agency. Death registrations by single year of age, United Kingdom, 1974–2017. London: ONS, 2018. 13Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008; 26(18): 3063–72. 14Hallet J, Law CH, Cukier M, Saskin R, Liu N, Singh S. Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer 2015; 121(4): 589–97. 15Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y et al. Trends in the Incidence, Prevalence, and Survival Outcomes in Patients with Neuroendocrine Tumors in the United States. JAMA Oncol 2017; 3(10): 1335–42. 16Wolf AMD, Fontham ETH, Church TR, Flowers CR, Guerra CE, LaMonte SJ et al. Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin 2018; 68(4): 250–81. 17Bannister N, Broggio J (eds). Cancer survival by stage at diagnosis for England (experimental statistics): adults diagnosed 2012, 2013 and 2014 and followed up to 2015. London: Office for National Statistics, 2016. 18Hudson E, Powell J, Mukherjee S, Crosby TD, Brewster AE, Maughan TS et al. Small cell oesophageal carcinoma: an institutional experience and review of the literature. Br J Cancer 2007; 96(5): 708–11. 19Emmett M, Gildea C. Cervical cancer — does the morphological subtype affect survival rates? J Obstet Gynaecol 2018; 38(4): 548–55. 20Watson GA, Ahmed Y, Picardo S, Chew S, Cobbe S, Mahony C et al. Unusual sites of high-grade neuroendocrine carcinomas: a case series and review of the literature. Am J Case Rep 2018; 19: 710–23. 21Eltawil KM, Gustafsson BI, Kidd M, Modlin IM. Neuroendocrine tumors of the gallbladder: an evaluation and reassessment of management strategy. J Clin Gastroenterol 2010; 44(10): 687–95. 22Brathwaite S, Rock J, Yearsley MM, Bekaii-Saab T, Wei L, Frankel WL et al. Mixed adeno-neuroendocrine carcinoma: An aggressive clinical entity. Ann Surg Oncol 2016; 23(7): 2281–86Tracey GenusNational Cancer Registration and Analysis ServicePublic Health England5 St Philips PlaceBirmingham B3 2PW0121 232 9425tracey.genus@.ukProf. Adrian L HarrisUniversity of Oxford, UKEditor-in-ChiefEditorial officeBJC Main Editorial OfficeCancer Research UKAngel Building407 St John StreetLondon EC1V 4AD20th January 2019Dear Prof. Harris,I am pleased to submit an original research article entitled “Impact of neuroendocrine morphology on cancer outcomes and stage at diagnosis: a UK nationwide cohort study 2013–2015” for consideration for publication in the British Journal of Cancer. Neuroendocrine neoplasms (NENs) are a group of rare cancers that differ greatly symptomatically from other tumours at the same anatomical site because of the neuroendocrine syndromes that are often associated with them. We previously determined that the diagnosis of neuroendocrine neoplasms is often delayed in the UK ‘Basuroy R et al. Presenting Symptoms and Delay in Diagnosis of Gastrointestinal and Pancreatic Neuroendocrine Tumours. Neuroendocrinology 2018;107(1):42-49.’ In this manuscript, we undertake the first in-depth epidemiological characterization of these tumours in the UK, and comparison with non-NENs at the same anatomical site, to identify areas of unmet need with an aim to inform service improvement.We believe that this manuscript is appropriate for publication by the British Journal of Cancer because it is an up to date population-based statistical analysis of NENs, which will provide the most current standard indicators for incidence, survival, and mortality to inform cancer healthcare professionals and services worldwide. Our manuscript is one of the most comprehensive studies of NENs, characterizing all anatomical sites, and the first population-based study to separate tumours by TNM stage. It is the largest single country population study of NENs in Europe, limited to the smallest study window to date, 2013-2015, thus eliminating confounders such as changes in diagnosis and treatment methods.This manuscript has not been published and is not under consideration for publication elsewhere. We have no conflicts of interest to disclose. If this manuscript is appropriate for your journal, we would like to suggest the following reviewers:Prof. Dermot O’Toole, Professor of Gastroenterology and Clinical Medicine at Trinity College Dublin, Eire.(email: dermot.otoole@tcd.ie phone: +353 1896 4103452)Prof Martyn Caplin, Professor of Gastroenterology and Neuroendocrine Tumours at University College London and the Royal Free Hospital, London, UK. (email: admin@ phone: +44 020 7830 2867)Prof Anne Couvelard, Professor of Pathology at the University of Paris Diderot and Head of Pathology at Bichat Hospital AP-HP, Paris, France.(email: anne.couvelard@bch.aphp.fr phone: +33 01 40 25 80 12)Thank you for your consideration.Yours sincerely,Tracey GenusMiss Tracey GenusNational Cancer Registration and Analysis ServicePublic Health England5 St Philips PlaceBirmingham B3 2PW0121 232 9425tracey.genus@.ukProfessor Per Hall Epidemiology Subject Editor British Journal of Cancer BJC Editorial Office Dept of Medical Epidemiology & Biostatistics Karolinska Institutet P.O. Box 281 SE-171 77 Stockholm Sweden Phone: +46 8 524 85000/83962 Fax: +46 8 31 49 75 E-mail: bjc@.uk 5th September 2019Dear Prof. Hall,thank you for reviewing our manuscript. We are pleased to submit our revised version in accordance with the changes requested. Please find below our rebuttal to the reviewer’s comments.Referee #1 (Comments to the Author): 1. Please avoid using the term "carcinoid" (for example in the introduction). Lines 133, 136We have swapped the term ‘carcinoid’ for ‘NET’2. Please replace the term "goblet cell carcinoid" with "goblet cell appendiceal tumours" Lines 136We have put in a footnote to state change of nomenclature which is now ‘goblet cell adenocarcinomas’.3. Please make a comment why tumours of Grade 1 & Grade 2 were assessed together. 4. Please make a comment why Ki67 was not available to all cases.Lines 127-131Ki-67 status was not uniformly captured and is not recognised yet in many organ systems. Due to this being a registry study, we were unable to revisit each tissue specimen to acquire it, most grades were therefore based on a morphology of “poorly-differentiated” or “well-differentiated” so grade 1 and grade 2 were combined to reduce inaccuracies. 5. Please make a comment why duodenal NENs were not mentioned. Were there no data about those tumours? Table 2 and Supplementary table S1Added figures to tables for ‘NEN incidence, 1-year overall survival probability, multivariable analysis and mortality in UK (2013–2015 combined)’6. Were there any data about the precentage of tumour who were functioning or any MEN-1 data? The UK registries do not hold data on whether a tumour is functioning and very few patients have their carcinoid syndrome diagnosis captured in secondary care and therefore by the registry.Lines 331-333Although the UK cancer registries do not currently hold complete data on MEN-1 diagnosis, the recent addition of genetic data means that this may also be available for future studies.7. I would suggest that the Authors make some suggestions about the design of more detailed future epidemiological studies for NENs in UK. Lines 322-333Future studies will allow 3- and 5-year survival estimates and the availability of treatment data will allow more in-depth studies, and we are developing ways of collecting more detailed imaging, biochemistry, screening and symptom data which ultimately will be linked to the current cancer registry data. Pathologists have been instructed to include small benign pancreatic NETs as malignant as per WHO terminology and detail Ki67 on all specimen. Ki67 has not been routinely captured by the UK cancer registries to date, however this will change in mid 2020 with the implementation of version 9 of the Cancer Outcome and Services Data set (COSD), the national standard for reporting cancer in the NHS in England, in which Ki67 will be a required field and so captured by the English registry. Although the UK cancer registries do not currently hold complete data on MEN-1 diagnosis, the recent addition of genetic data means that this may also be available for future studies.Referee #2 (Comments to the Author): 1. The numbers - 35% of patients with NENS are reportedly G3NEC. This is much higher than previous published data and also much higher than the incidence in our own unit. Poorly diff (G3 NEC) remain the rarest type of NET, in almost all of the primaries. The fact that pulmonary NETs had 42% NEC G3 and that pulmonary NENs were now the most common primary leads me to question how many small cell lung cancers (which are not NEC) have been included. It also makes me question how many of the G3NEC are actually tumours with some NEC features rather than truly being NENS and have therefore been included in error. Lines 284-291Also the high incidence of G3 NECs in this study, particularly those in the lung, are not representative of previous findings. In the lung, G3 NEC is used when there has been insufficient information to classify the tumour as either small cell carcinoma or large cell neuroendocrine carcinoma. Thus the high incidence of G3 NEC in the lung is likely to represent small cell carcinoma, large cell neuroendocrine carcinomas and mixed tumours. This misclassification of G3 NECs could also be skewing the survival analysis.2. Grouping of patients based on morphology alone is not helpful and Grade with ki67 should haver been used to sub-group patients. With such variability in outcome based on Ki67 in terms of survival - this must be included where possible. Lines 127-131Ki-67 status was not uniformly captured and is not recognised yet in many organ systems. Due to this being a registry study, we were unable to revisit each tissue specimen to acquire it, most grades were therefore based on a morphology of “poorly-differentiated” or “well-differentiated” so grade 1 and grade 2 were combined to reduce inaccuracies. 3. classification has been demonstrated in table 1 it has been defined as carcinoid, small cell NEC, NEC, Merkel cell or Other. In the colon and caecum a large proportion of tumours are classified as other - does that mean they were actually adenocarcinoma's with NEC features and therefore should not be included. Carcinoid has been used to determine morphology and this is no longer an accurate use of the term. Morphology should be divided up into well differentiated, poorly differentiated which can then be divided into small or large. It is not useful to use Merkel cell as a one of the subgroups as this only applies to merkel cell(skin) and none of the other primaries. Lines 133, 136We have swapped the term ‘carcinoid’ for ‘NET’Line 130-140Tumour grades were classified: …. and ‘other’ (pancreatic endocrine tumour malignant, mixed pancreatic endocrine and exocrine tumour malignant, and Merkel cell carcinoma morphology codes 8150, 8154, and 8247, respectively).4. New Classification - there has been an update on classification in 2015 and this should have been applied. We have little or no long term data on the G3 well differentiated and this would have been a very good opportunity to obtain some. Not sure if this is referring to the 2018 update. We were unable to do this on this occasion but future studies will allow this.5. Omission of NETs with indolent behaviouir - how many tumours have not been included, there are very few rectal NETs and gastric NETs included and those that are have a high % of stage IV disease - 27% of rectal and 47% of gastric. This is not in keeping with the true spectrum of NETs seen and therefore will have skewed the survival data significantly. Thee is an under representation of Type 1 Gastric NETs and Stage I and II rectal NETs - who all have excellent 5 and 10 year survivals. I appreciate that it has been difficult to collect this data but without this it gives misleading data on outcomes and if patients diagnosed with gastric or rectal WET were to read this they would get unnecessarily frightened. If the data is hard to come by - it be better to do this paper solely focusing on Stage IV NETS Lines 278-284Included the reviewers comments into ‘limitations’ section.Referee #3 (Comments to the Author): 1. Line 73/74: Specialist services are also indicated in NET patients despite the fact that their prognosis is often better than the respective adenocarcinoma at the same site. 2. I still do not clearly understand the criteria for patient selection. In line 120/121 it is stated that all have behaviour 3 malignant. Therefore, I supposed that small NETs of e.g. the stomach, duodenum, rectum, appendix were not included. This seems tob e supported by the data in table 1 with a relative high rate of stage IV in rectum and stomach NEN. On the other hand the rate of stage IV in appendix is low (6%) –what would be aspected by inclusion of appendecial NETs with low malignant potential. In the discussion lines 251-253 you mentioned that the incidence of Appendix NET in SEER could be lower as they were not included in earlier years so one might conclude that they are included here. So please clarify: Are NEN with low malignant potential like type I gastric NET, non functioning duodenal NET, small rectal NET G1/2 , small pancreatic NET G1/2 and appendecial NET included? Not included? Partially included? This of course influences outcome data. Lines 278-284Tumours with uncertain behaviour (behaviour code 1) are not consistently captured by UK cancer registries because they have historically been deemed ‘benign’ and were not included. This means that many small and indolent NETs of the stomach, rectum, appendix and pancreas may not have been included in historical data. There is an under representation of type 1 gastric NETs and stage I and II rectal NETs - that all have excellent 5 and 10 year survivals. This under representation may be significantly skewing the survival statistics presented in this study.3. Lines 134/135: Adenocarcinoma with neuroendocrine differentiation should not be included unless they clearly meet the definition of MANEC / MINEN. We have removed Adenocarcinoma with neuroendocrine differentiation from our cohort and redone the analysis4. Line 169: Unfortunately, the group of patients with unknown stage ist he largest group. This should be added to the limitations. Line 294Added to limitations5. Lines 200-207: You discuss the sites were NEN outcome (NEC predominantly) is poorer compared to non-NEN at the same site, but the opposite is true for sites where mainly well-differentiated NETs occur. This could be added (although the information is in table 3). Line 202-203The 1YS probability for people diagnosed with pulmonary, pancreatic, stomach and small intestine NENs, were much higher than for non-NENs at these sites.6. Do you have data for disease specific survival/mortality that could be added? We did not have cause-specific mortality for this group because they are defined by morphology. Cause specific data available to the UK registries is defined only by ICD-10 coding.6. There is no clear information on Ki67 data probably due to lacking information. If this information is available, please add. When I resd the title ?Impact of neuroendocrine morphology on cancer outcomes“ I expected some data on ?NET G3“ versus NEC G3 - although I understand that these data can?t be expected as this subclassification was definded in WHO 2017 (for pancreas) and not before. If you don?t have data on the proliferati rate this should also be added to limitations. Line 327-331Ki67 has not been routinely captured by the UK cancer registries to date, however this will change in mid 2020 with the implementation of version 9 of the Cancer Outcome and Services Data set (COSD), the national standard for reporting cancer in the NHS in England, in which Ki67 will be a required field and so captured by the English registry. 7. As already mentioned in ?limitations“ at the moment only 1 year survival data are available which hampers comparison with data from other registries. Still for the NEC group you could compare median OS with the outcome data of SEER (Dasari ref 15 and Dasari et al Cancer 2018 should be added) and other registries. We were unable to calculate median survival for the sites listed in Dasari et al , please see below:Line 198-201The median survival for oesophageal, prostate, and bladder NENs were 5.7 (4.5–7.5), 7.8 (5.8–9.1), and 11.3 (9.9–12.8) months, respectively. Survival for the other sites exceeded 50% at the longest time period so median survival could not be calculated for these.Kind regardsTracey GenusSiteMedian age at diagnosis (5-year age band)Males % (n)*Stage IV % (n)NEC G3 % (n)Morphology C S N M OAll65–6950 (7,656)38 (3,565)35 (5,404)?Appendix40–4441 (740)6 (1,124)5 (82)?Bladder70–7474 (372)37 (390)96 (484)?Breast65-69**99·9 (106)17 (92)52 (64)?Colon and caecum65–6953 (392)50 (569)26 (240)?Female reproductive organs (incl. C51-C57)60–64**100 (378)35 (249)70 (274)?Oesophagus70–7445 (211)63 (374)84 (426)?Pancreas65–6954 (765)52 (971)31 (432)?Prostate70–74137 (153)93 (101)82 (125)?Pulmonary65–6943 (1,274)34 (2,642)42 (1,256)?Rectum60–6454 (334)27 (379)26 (163)?Skin80–8452 (543)***N/A?Small intestine65–6957 (1,176)42 (1,310)10 (206)?Stomach65–6954 (402)47 (338)27 (209)?Table 1: Demographic and clinical characteristics table Morphology sparklines: represents the distribution of morphologies by site, the darkest column the most frequent morphology: C, Carcinoid tumour; S, Small cell neuroendocrine carcinoma; N, Neuroendocrine carcinoma; M, Merkel cell carcinoma; O, Other.NEC G3, neuroendocrine carcinoma grade 3; n, number of patients; N/A, not applicable.*Proportion of those with known stage.**Females.***Non-melanoma skin cancers are not currently staged. VariablesTumour CountIncidenceSurvival*Mortality*Age-standardised rate (ASR) (CI) (per 100,000 persons)1-year overall survival (Kaplan-Meier) (CI)Cox proportional hazards regression multi-variable (CI) Observed/ Expected deathsStandardised Mortality Ratio (SMR) (CI)All?15,2228.6 (8.46–8.74)74.7 (73.9–75.4)–5233/1442.63.6 (3.5–3.7)Sex17,5389.14 (8.93–9.35)71.3 (70.3–72.4)1 (reference)2884/821.53.5 (3.4–3.6)27,6848.06 (7.88–8.24)77.9 (76.9–78.8)0.9 (0.8–0.9)2349/621.13.8 (3.6–3.9)Age0–543,6681.88 (1.82–1.94)90.2 (89.2–91.2)0.5 (0.5–0.6)545/156.63.5 (3.2–3.8)55–642,8651.62 (1.56–1.68)78.7 (77.2–80.2)0.8 (0.7–0.8)553/56.69.8 (9–10.6)65–744,3022.47 (2.39–2.54)72.5 (71.1–73.9)1 (reference)1284/223.85.7 (5.4–6.1)75+4,3872.62 (2.54–2.7)60.5 (58.9–61.9)1.5 (1.4–1.6)2851/1005.72.8 (2.7–2.9)Deprivation1- least deprived2,8611.65 (1.59–1.71)77.3 (75.7–78.8)1 (reference)920/317.32.9 (2.7–3.1)22,9151.67 (1.61–1.73)75.3 (73.7–76.8)1.1 (1–1.2)990/303.63.3 (3.1–3.5)32,8351.62 (1.56–1.68)75.9 (74.3–77.5)1.1 (1–1.2)978/278.43.5 (3.3–3.7)426401.51 (1.45–1.57)73.1 (71.3–74.7)1.2 (1.1–1.3)946/240.13.9 (3.7–4.2)5- most deprived2,4651.39 (1.34–1.45)73.3 (71.5–75.1)1.3 (1.2–1.4)855/184.64.6 (4.3–5)Diagnosis Year 20134,8958·41 (8·18–8·66)74.1 (72.8–75.3)1 (reference)1997/622.73.2 (3.1–3.4)20145,1268·67 (8·43–8.92)74.4 (73.2–75.6)1 (0.9–1.1)1799/487.53.7 (3.5–3.9)20155,2018·68 (8·44–8.92)75.5 (74.3–76.7)1.1 (1–1.1)1437/332.54.3 (4.1–4.6)Site Appendix 1,8070.95 (0.9–0.99)96.4 (95.4–97.2)1 (reference)122/89.11.4 (1.1–1.6)Breast1070·06 (0·05–0·07)84.8 (76.3–90.4)1.5 (1–2.3)25/13.41.9 (1.3–2.8)Bladder5000.31 (0.28–0.34)51.2 (46.6–55.7)2.4 (1.9–3.1)323/59.95.4 (4.8–6)Colon and caecum7340.41 (0.38–0.44)72 (68.5–75.2)2.4 (1.9–3.1)249/62.94 (3.5–4.5)Female reproductive organs (incl.C51–C57)3780.2 (0.18–0.22)69.2 (64.1–73.7)2.8 (2.2–3.7)158/12.812.3 (10.6–14.4)Oesophagus4700.26 (0.24–0.29)35.5 (31–40.1)3.4 (2.7–4.4)366/26.114 (12.7–15.5)Pancreas1,4150.8 (0.76–0.84)80.6 (78.4–82.6)2 (1.6–2.5)421/112.93.7 (3.4–4.1)Prostate1370.08(0·07–0·10)31.5 (23.6–39.8)2.6 (1.9–3.5)114/8.613.2 (11–15.9)Pulmonary 2,9891.68 (1.62–1.74)73.7 (72–75.3)2.9 (2.3–3.6)1019/2324.4 (4.1–4.7)Rectum6220.32 (0.29–0.35)81 (77.6–83.9)2.7 (2–3.5)151/42.63.5 (3–4.2)Skin1,0440.62 (0.58–0.66)74.3 (71.5–76.9)2.1 (1.5–3)460/292.21.6 (1.4–1.7)**Small Intestine2,0541.17 (1.12–1.23)89.6 (88.1–90.8)1.3 (1–1.7)157/83.71.9 (1.6–2.2)Ileum1,0240.53 (0.5–0.57)92.8 (91–94.2)ND149/120.41.2 (1.0–1.4)Duodenum3160.18 (0.16–0.2)87.3 (83–90.6)ND54/34.81.5 (1.2–2.0)Jejunum400.02 (0.02–0.03)89.4 (74.1–95.9)ND8/5.71.4 (0.7–2.8)Stomach7490.43 (0.4–0.46)74.1 (70.8–77.2)2.4 (1.9–3.1)240/69.93.4 (3–3.9)StageI2,6911.48 (1.42–1.53)96.1 (95.3–96.8)1 (reference)208/234.40.9 (0.8–1)II1,4120.79 (0.75–0.84)87.6 (85.7–89.2)2.1 (1.8–2.6)283/150.51.9 (1.7–2.1)III1,6190.92 (0.87–0.97)81.7 (79.6–83.5)3.2 (2.7–3.8)477/161.13 (2.7–3.2)IV3,4932.01 (1.94–2.08)48.8 (47–50.5)8.2 (7.1–9.5)2141/217.19.9 (9.5–10.3)Unknown6,0073.39 (3.3–3.48)74.5 (73.3–75.6)3.6 (3.1–4.2)2124/679.63.1 (3–3.3)Grade***MANEC grade5370.3 (0.27–0.33)84.3 (80.8–87.2)0.5 (0.1–3.6)136/42.33.2 (2.7–3.8)NEC G35,4133.11 (3.03–3.2)51.2 (49.8–52.6)0.9 (0.8–1)3225/409.37.9 (7.6–8.2)NET G1/G27,3164.04 (3.95–4.14)92.7 (92.1–93.3)0.4 (0.2–1.1)940/648.11.5 (1.4–1.5)~Other grade1,9561.14 (1.08–1.19)65.8 (63.5–67.9)1 (reference)932/3432.7 (2.5–2.9)MorphologyAtypical carcinoid tumour8100.45 (0.42–0.48)89.8 (87.5–91.7)0.6 (0.2–1.6)162/75.12.2 (1.8–2.5)Carcinoid tumour6,4623.57 (3.48–3.66)93.1 (92.4–93.7)0.5 (0.2–1.2)771/570.71.4 (1.3–1.5)Combined small cell carcinoma2850.17 (0.15–0.19)54.8 (48.5–60.6)1 (reference)175/26.26.7 (5.8–7.7)Goblet cell carcinoid3350.18 (0.17–0.21)92.1 (88.6–94.5)1.1 (0.1–8.7)53/26.92 (1.5–2.6)Large cell neuroendocrine carcinoma2210.13 (0.11–0.14)43.1 (36.1–49.8)1.3 (1.1–1.7)151/14.310.6 (9–12.4)Merkel cell carcinoma1,0570.63 (0.59–0.67)73.4 (70.6–76)0.5 (0.4–0.7)469/288.21.6 (1.5–1.8)Mixed adeno-neuroendocrine carcinoma1880.11 (0.09–0.12)68.6 (61.2–74.9)1.6 (0.2–12.6)82/14.85.5 (4.4–6.9)Neuroendocrine carcinoma NOS4,3442.48 (2.41–2.56)55.1 (53.5–56.6)0.9 (0.7–1)2362/326.97.2 (6.9–7.5)^Other morphology1180.06 (0.05–0.08)89.4 (82.1–93.8)0.5 (0.3–0.8)26/7.43.5 (2.4–5.1)Small cell carcinoma1,4020.82 (0.77–0.86)41.4 (38.7–44.1)1.3 (1.1–1.5)982/9210.7 (10–11.4)Table 2: NEN incidence, 1-year overall survival probability, multivariable analysis and mortality in UK (2013–2015 combined) Socioeconomic status was not available for Scotland, so deprivation for Scotland was not included see Methods.Only the most common sites are listed, for additional sites see Supplementary Table 1*Excluding ‘death certificate only’ registration i.e. date of diagnosis = date of death.**Tumours of the small intestine included: C17.0 – duodenum; C17.1 – jejunum; C17.2 – ileum; C17.3 – Meckel's diverticulum; C17.8; overlapping lesion of small intestine; C17.9 small intestine, unspecified’.***Including goblet cell carcinoid, mixed adenoneuroendocrine carcinoma, tubular adenocarcinoid tumour.~Other grade includes: pathology-graded adenocarcinoma with neuroendocrine differentiation; pancreatic endocrine tumour malignant; mixed pancreatic endocrine and exocrine tumour malignant; neuroendocrine carcinoma NOS; small cell carcinoma NOS.^Other morphology includes: enterochromaffin carcinoid, gastrinoma malignant, glucagonoma malignant, insulinoma malignant, mixed pancreatic endocrine and exocrine tumour malignant, pancreatic endocrine tumour malignant, somatostatinoma malignant, tubular carcinoid, and vipoma malignant. ND Not determinedSiteTotal number of cases (stage I–IV) (n)1-year overall survival probability (%)Association between NEN morphology and a diagnosis at stage 4NENsNon-NENsNENs (95% CI)Non-NENs (95% CI)OR (95% CI)(unadjusted) p-valueOR (95% CI)(age-and sex-adjusted) p-valueBladdern=362n=19,85952.474.93·2<0·0003.2<0·000?? (47.4–57.1) (74.4–75.5) (2·6–4·0)? (2.6–4.1)?Breastn=51n=117,0528296.53.9<0·0003.7<0·000?? (68.3–90.2) (96.4–96.6) (1.9–8.2)? (1.8–7.7)?Colon and caecumn=458n=50,85067.482.64<0·0003.8<0·000?? (62.8–71.6) (82.3–82.9) (3.3–4.8)? (3.2–4.6)?Female reproductive organsn=202n=40,37664.789.54.2<0·0005.2<0·000?? (57.4–71.1) (89.2–89.8) (3.2–5.7)? (3.9–7)?Oesophagusn=296n=16,38335.3353.3<0·0003.6<0·000?? (29.6–41) (30·5–39·1) (2.6–4.2)? (2.8–4.5)?Pancreasn=838n=8,93677.6310·6<0·0000.5<0·000?? (74.5–80.3)(29·7–31·5) (0·5–0·7)? (0.5–0.7)?Prostaten=52n=98,96321.195·541·7<0·00045·1<0·000??(11.3–33.0) (95·4–95·6) (16.6–104.9)?(17.8–113·9)?Pulmonaryn=1,965n=72,67274.947.20·4<0·0000·4 <0·000?? (72.9–76.8) (46.8–47.6) (0·4–0·5)? (0·4–0·5)?Rectumn=333n=23,49876.486.81.6<0·0001·5 <0·000?? (71.4–80.7) (86.4–87.3) (1.3–2)? (1.2–2.0)?*Skin (non-melanoma)n=876n=81,67174·492NDNDNDND?? (71·6–77) (91·8–92·2)????Small Intestinen=1,164n=1,15791.2610·90·3140·90·326?? (89.4–92.7) (58·4–63·1) (0·8–1·1)? (0·8–1·1)?Stomachn=278n= 10,93863.4481·00·240.90·881?? (57.3–68.9) (47·4–49·1) (0·8–1·3)? (0.8–1.2)?Table 3: 1-year survival probability comparison between cancer morphology (NENs vs non-NENs), and association between stage at diagnosis (localised vs metastasized) and cancer morphology for people diagnosed in England 2013–2015ND, not determinedExcluding morphologies neoplasm NOS, carcinoma NOS, tumour cells NOS and basal cell carcinomas; *non-melanoma skin cancers not staged.VariablesTumour CountIncidenceSurvival*Mortality*Age-standardised rate (ASR) (CI) (per 100,000 persons)1-year overall survival (Kaplan-Meier) (CI)Cox proportional hazards regression univariable (CI)Cox proportional hazards regression multi-variable (CI) Observed/ Expected deathsStandardised Mortality Ratio (SMR) (CI)All?15,2228.6 (8.46–8.74)74.7 (73.9–75.4)––5233/1442.63.6 (3.5–3.7)Sex17,5389.14 (8.93–9.35)71.3 (70.3–72.4)1 (reference)1 (reference)2884/821.53.5 (3.4–3.6)27,6848.06 (7.88–8.24)77.9 (76.9–78.8)0.8 (0.7–0.8)0.9 (0.8–0.9)2349/621.13.8 (3.6–3.9)Age0–543,6681.88 (1.82–1.94)90.2 (89.2–91.2)0.3 (0.3–0.4)0.5 (0.5–0.6)545/156.63.5 (3.2–3.8)55–642,8651.62 (1.56–1.68)78.7 (77.2–80.2)0.7 (0.7–0.8)0.8 (0.7–0.8)553/56.69.8 (9–10.6)65–744,3022.47 (2.39–2.54)72.5 (71.1–73.9)1 (reference)1 (reference)1284/223.85.7 (5.4–6.1)75+4,3872.62 (2.54–2.7)60.5 (58.9–61.9)1.6 (1.5–1.7)1.5 (1.4–1.6)2851/1005.72.8 (2.7–2.9)Deprivation1- least deprived2,8611.65 (1.59–1.71)77.3 (75.7–78.8)1 (reference)1 (reference)920/317.32.9 (2.7–3.1)22,9151.67 (1.61–1.73)75.3 (73.7–76.8)1.1 (1–1.2)1.1 (1–1.2)990/303.63.3 (3.1–3.5)32,8351.62 (1.56–1.68)75.9 (74.3–77.5)1.1 (1–1.2)1.1 (1–1.2)978/278.43.5 (3.3–3.7)426401.51 (1.45–1.57)73.1 (71.3–74.7)1.2 (1.1–1.3)1.2 (1.1–1.3)946/240.13.9 (3.7–4.2)5- most deprived2,4651.39 (1.34–1.45)73.3 (71.5–75.1)1.1 (1–1.3)1.3 (1.2–1.4)855/184.64.6 (4.3–5)Diagnosis Year 20134,8958·41 (8·18–8·66)74.1 (72.8–75.3)1 (reference)1 (reference)1997/622.73.2 (3.1–3.4)20145,1268·67 (8·43–8.92)74.4 (73.2–75.6)1 (0.9–1)1 (0.9–1.1)1799/487.53.7 (3.5–3.9)20155,2018·68 (8·44–8.92)75.5 (74.3–76.7)0.9 (0.8–1)1.1 (1–1.1)1437/332.54.3 (4.1–4.6)Site Anus and anal canal 470.03 (0.02–0.04)39.1 (25.2–52.8)18.3 (12.5–26.9)4 (2.7–6)33/2.413.7 (9.7–19.3)Appendix 1,8070.95 (0.9–0.99)96.4 (95.4–97.2)1 (reference)1 (reference)122/89.11.4 (1.1–1.6)Breast1070·06 (0·05–0·07)84.8 (76.3–90.4)4 (2.6–6.1)1.5 (1–2.3)25/13.41.9 (1.3–2.8)Bladder5000.31 (0.28–0.34)51.2 (46.6–55.7)15.8 (12.8–19.5)2.4 (1.9–3.1)323/59.95.4 (4.8–6)Colon and caecum7340.41 (0.38–0.44)72 (68.5–75.2)6.7 (5.4–8.4)2.4 (1.9–3.1)249/62.94 (3.5–4.5)Digestive organs, other1520.09 (0.07–0.1)67.3 (58.8–74.4)9.6 (7.1–12.9)2.6 (1.9–3.6)70/15.74.5 (3.5–5.6)Female reproductive organs (incl.C51–C57)3780.2 (0.18–0.22)69.2 (64.1–73.7)8.6 (6.8–10.8)2.8 (2.2–3.7)158/12.812.3 (10.6–14.4)Gallbladder640.03 (0.03–0.04)57.9 (44.6–69)13.6 (9.3–19.8)3.6 (2.4–5.4)36/2.315.8 (11.4–21.9)Lip, oral cavity and pharynx610.03 (0.03–0.05)59.3 (45.6–70.6)13.7 (9.5–19.8)1.8 (1.2–2.7)37/5.56.8 (4.9–9.3)Liver and bile ducts1920.11 (0.09–0.13)65.1 (57.6–71.7)9.6 (7.3–12.7)3.4 (2.5–4.6)89/14.56.1 (5–7.6)Oesophagus4700.26 (0.24–0.29)35.5 (31–40.1)25.9 (21.1–31.9)3.4 (2.7–4.4)366/26.114 (12.7–15.5)Pancreas1,4150.8 (0.76–0.84)80.6 (78.4–82.6)5.2 (4.3–6.4)2 (1.6–2.5)421/112.93.7 (3.4–4.1)Prostate1370.08(0·07–0·10)31.5 (23.6–39.8)26.2 (20.3–33.9)2.6 (1.9–3.5)114/8.613.2 (11–15.9)Pulmonary2,9891.68 (1.62–1.74)73.7 (72–75.3)6.5 (5.4–7.9)2.9 (2.3–3.6)1019/2324.4 (4.1–4.7)Rectum6220.32 (0.29–0.35)81 (77.6–83.9)4.2 (3.3–5.4)2.7 (2–3.5)151/42.63.5 (3–4.2)Respiratory and intrathoracic organs excl. lung and bronchus1520.09 (0.07–0.1)66.6 (58.1–73.8)9.5 (7.1–12.8)1.8 (1.3–2.5)69/116.3 (5–7.9)Retroperitoneum and peritoneum810.05 (0.04–0.06)74.5 (63.3–82.7)6.5 (4.3–9.7)2 (1.3–3.1)30/13.42.2 (1.6–3.2)Secondary site11950.69 (0.65–0.73)50.1 (47.1–53)15.4 (12.7–18.7)3.8 (3–4.8)697/95.27.3 (6.8–7.9)Skin1,0440.62 (0.58–0.66)74.3 (71.5–76.9)8.1 (6.7–9.9)2.1 (1.5–3)460/292.21.6 (1.4–1.7)**Small Intestine2,0541.17 (1.12–1.23)89.6 (88.1–90.8)2.9 (2.4–3.6)1.3 (1–1.7)157/83.71.9 (1.6–2.2)Ileum1,0240.53 (0.5–0.57)92.8 (91–94.2)NDND149/120.41.2 (1.0–1.4)Duodenum3160.18 (0.16–0.2)87.3 (83–90.6)NDND54/34.81.5 (1.2–2.0)Jejunum400.02 (0.02–0.03)89.4 (74.1–95.9)NDND8/5.71.4 (0.7–2.8)Stomach7490.43 (0.4–0.46)74.1 (70.8–77.2)6.2 (5–7.7)2.4 (1.9–3.1)240/69.93.4 (3–3.9)Thyroid and other endocrine glands290.02 (0.01–0.02)65.6 (44.2–80.4)11.6 (6.7–20.1)3 (1.7–5.1)16/1.88.8 (5.4–14.3)Urinary tract, other660.04 (0.03–0.05)60.6 (47.4–71.4)10.8 (7.3–16)2 (1.3–3)32/4.47.3 (5.2–10.4)Ill–defined or unspecified site1650.09 (0.08–0.11)40.6 (32.5–48.6)20.7 (15.9–27)5 (3.7–6.7)104/911.6 (9.5–14)StageI2,6911.48 (1.42–1.53)96.1 (95.3–96.8)1 (reference)1 (reference)208/234.40.9 (0.8–1)II1,4120.79 (0.75–0.84)87.6 (85.7–89.2)2.8 (2.3–3.3)2.1 (1.8–2.6)283/150.51.9 (1.7–2.1)III1,6190.92 (0.87–0.97)81.7 (79.6–83.5)4.4 (3.7–5.1)3.2 (2.7–3.8)477/161.13 (2.7–3.2)IV3,4932.01 (1.94–2.08)48.8 (47–50.5)13.4 (11.6–15.4)8.2 (7.1–9.5)2141/217.19.9 (9.5–10.3)Unknown6,0073.39 (3.3–3.48)74.5 (73.3–75.6)5.5 (4.7–6.3)3.6 (3.1–4.2)2124/679.63.1 (3–3.3)Grade***MANEC grade5370.3 (0.27–0.33)84.3 (80.8–87.2)0.4 (0.4–0.5)0.5 (0.1–3.6)136/42.33.2 (2.7–3.8)NEC G35,4133.11 (3.03–3.2)51.2 (49.8–52.6)1.5 (1.4–1.6)0.9 (0.8–1)3225/409.37.9 (7.6–8.2)NET G1/G27,3164.04 (3.95–4.14)92.7 (92.1–93.3)0.2 (0.2–0.2)0.4 (0.2–1.1)940/648.11.5 (1.4–1.5)~Other grade1,9560.57 (0.54–0.59)65.8 (63.5–67.9)1 (reference)1 (reference)932/3432.7 (2.5–2.9)MorphologyAtypical carcinoid tumour8100.45 (0.42–0.48)89.8 (87.5–91.7)0.2 (0.2–0.3)0.6 (0.2–1.6)162/75.12.2 (1.8–2.5)Carcinoid tumour6,4623.57 (3.48–3.66)93.1 (92.4–93.7)0.1 (0.1–0.2)0.5 (0.2–1.2)771/570.71.4 (1.3–1.5)Combined small cell carcinoma2850.17 (0.15–0.19)54.8 (48.5–60.6)1 (reference)1 (reference)175/26.26.7 (5.8–7.7)Goblet cell carcinoid3350.18 (0.17–0.21)92.1 (88.6–94.5)0.2 (0.1–0.2)1.1 (0.1–8.7)53/26.92 (1.5–2.6)Large cell neuroendocrine carcinoma2210.13 (0.11–0.14)43.1 (36.1–49.8)1.4 (1.1–1.7)1.3 (1.1–1.7)151/14.310.6 (9–12.4)Merkel cell carcinoma1,0570.63 (0.59–0.67)73.4 (70.6–76)0.6 (0.5–0.7)0.5 (0.4–0.7)469/288.21.6 (1.5–1.8)Mixed adeno-neuroendocrine carcinoma1880.11 (0.09–0.12)68.6 (61.2–74.9)0.6 (0.5–0.8)1.6 (0.2–12.6)82/14.85.5 (4.4–6.9)Neuroendocrine carcinoma NOS4,3442.48 (2.41–2.56)55.1 (53.5–56.6)0.9 (0.8–1)0.9 (0.7–1)2362/326.97.2 (6.9–7.5)^Other morphology1180.06 (0.05–0.08)89.4 (82.1–93.8)0.2 (0.2–0.4)0.5 (0.3–0.8)26/7.43.5 (2.4–5.1)Small cell carcinoma1,4020.82 (0.77–0.86)41.4 (38.7–44.1)1.5 (1.2–1.7)1.3 (1.1–1.5)982/9210.7 (10–11.4)Table 2: NEN incidence, 1-year overall survival probability, multivariable analysis and mortality in UK (2013–2015 combined) Socioeconomic status was not available for Scotland, so deprivation for Scotland was not included see Methods.Only the most common sites are listed.*Excluding ‘death certificate only’ registration i.e. date of diagnosis = date of death.**Tumours of the small intestine included: C17.0 – duodenum; C17.1 – jejunum; C17.2 – ileum; C17.3 – Meckel's diverticulum; C17.8; overlapping lesion of small intestine; C17.9 small intestine, unspecified’.***Including goblet cell carcinoid, mixed adenoneuroendocrine carcinoma, tubular adenocarcinoid tumour.~Other grade includes: pathology-graded adenocarcinoma with neuroendocrine differentiation; pancreatic endocrine tumour malignant; mixed pancreatic endocrine and exocrine tumour malignant; neuroendocrine carcinoma NOS; small cell carcinoma NOS.^Other morphology includes: enterochromaffin carcinoid, gastrinoma malignant, glucagonoma malignant, insulinoma malignant, mixed pancreatic endocrine and exocrine tumour malignant, pancreatic endocrine tumour malignant, somatostatinoma malignant, tubular carcinoid, and vipoma malignant. ND Not determined?PulmonarySmall IntestineColonStomach?NET Grade 1/2NEC Grade 3MANECNET Grade 1/2NEC Grade 3MANECNET Grade 1/2NEC Grade 3MANECNET Grade 1/2NEC Grade 3MANECStage98·490·69096·981·9ND96·994·810098·259NDI or II(97·4–99)(87·1–93·2)(65·6–97·4)(93·1–98·6)(44·8–95·2)?(87·9–99·2)(68·2–99·3)?(93–99·6)(23·5–82·5)?Stage88·963·46095·787·566·798·973·172·51006366·7III(79·1–94·3)(55·2–70·6)(25·3–82·8)(93·5–97·2)(66·1–95·8)(5·5–94·6)(92·3–99·9)(58·1–83·4)(48·5–86·7)?(42·2–78·1)(5·5–94·6)Stage65·126·227·387·97433·481·721·641·774·420·285·8IV (56·2–72·6)(22·5–30)(6·6–53·9)(84·3–90·7)(63·2–82)(0·9–77·5)(73·1–87·8)(14·7–29·5)(15·3–66·6)(51·6–87·6)(12·9–28·7)(33·5–97·9)?AppendixPancreasRectumOesophagus?NET Grade 1/2NEC Grade 3MANECNET Grade 1/2NEC Grade 3MANECNET Grade 1/2NEC Grade 3MANECNET Grade 1/2NEC Grade 3MANECStage98·294·997·695·987·5ND98·591NDND56·666·7I or II(96·9–99)(81·1–98·7)(93·7–99·1)(92·9–97·7)(74·3–94·2)?(95·3–99·5)(68·3–97·7)??(38·6–71·2)(19·5–90·5)Stage10083·491·410055·6ND10061·675ND50·5NDIII?(27·4–97·5)(78·7–96·7)?(30·6–74·8)??(40·4–77·2)(12·8–96·1)?(38·6–61·2)?Stage77·3807386·841·15078·818·5ND5022·433·4IV(53·8–89·9)(20·4–97)(55·6–84·5)(81·4–90·8)(34·6–47·4)(0·6–91·1)(38·1–94·3)(10·3–28·6)?(0·6–91·1)(16·7–28·5)(0·9–77·5)SUPPLEMENTARY MATERIAL:S2: 1-year survival probability (%) for pulmonary, small intestinal, appendiceal, pancreatic, stomach, rectal, and oesophageal neuroendocrine tumours diagnosed in the UK between 2013 and 2015, by grade and stage (including adenocarcinoma with neuroendocrine differentiation, n=212) (ND = no data) (online only) Figure 1: Annual incidence (line graph) and count (bar chart) of NENs diagnosed in England 2001-2015, and UK 2015 (cross markers) ................
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