Epidemiology, Incidence, and Prevalence of Neuroendocrine Neoplasms: Are There Global Differences?

Abstract

Purpose of Review

The purpose of our review is to explore global epidemiologic trends of gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). Specifically, we sought to examine whether there are differences in incidence, prevalence, distribution (by primary tumor site, tumor grade, tumor stage at presentation), and overall survival of GEP NETs between different regions of the world.

Recent Findings

GEP NET incidence rates are rising steadily in North America, Asia, and Europe, though this rise appears to be most pro found in North America. The distribution of GEP NETs differs regionally as in North America small intestinal and rectal NETs are most prevalent, in Asia rectal and pancreatic NETs are most prevalent, and in Europe small intestinal and pancreatic NETs are most prevalent. Overall survival for patients with GEP NETs appears to be improving with time.

Summary

Some of the global increase in GEP NET incidence can be explained by increased health care utilization. This factor alone, however, does not explain the rise completely. Population-based studies utilizing uniform data collection instruments and a standard pathologic grading system are needed to identify other factors which may be contributing to this phenomenon.

Introduction

Neuroendocrine neoplasms (NENs) represent a diverse group of tumors which most commonly arise from gastroenteropancreatic (GEP) structures [1]. Though most NENs are neuroendocrine tumors (NETs) and possess an indolent disease biology, 10–20% of NENs are neuroendocrine carcinomas (NECs) which are highly proliferative tumors characterized by rapid disease progression [2]. NET epidemiologic studies have been more commonly reported whereas NEC epidemiologic studies, largely due to issues pertaining to appropriate classification and disease rarity, have been reported much more infrequently. The incidence and prevalence of NETs continues to rise globally, with the greatest rates of increase in nations such as the USA, Canada, and Norway [3]. In the USA alone, the incidence of NETs has increased more than 6-fold over the last 4 decades, with a predominant rise in localized tumors rather than metastatic tumors; current disease prevalence of NETs in the USA approximates 170,000 patients [4••, 5]. GEP NETs represent the most common NET subtype, comprising 55–70% of all NETs [6••]. Herein, we discuss the incidence and prevalence of GEP NETs as reported in national registries and survey studies from countries around the world, to assess whether global differences in epidemiology may exist. We also highlight the many pitfalls present when comparing epidemiologic data for GEP NET patients across eras and regions. Finally, we explore some of the possible hypotheses behind the rising incidence of GEP NETs globally.

Epidemiology of GEP NECs

Few dedicated studies have solely explored the epidemiology of GEP NECs. One such study was an exploration of the Surveillance, Epidemiology and End Results (SEER) database from the National Cancer Institute where investigators assessed incidence rates of these tumors [7••]. Between 1973 and 2012, 6291 GEP NEC cases were identified. Of these cases, 38% of NECs originated in the colon, rectum, or anus while 23% originated in the pancreas. The incidence rates of GEP NECs increased consistently from 1.5 cases per 1,000,000 in 1973 to 4.6 cases per 1,000,000 in 2012. By histology, 34% of cases were small cell carcinomas. Certain primary tumor sites such as the anus and esophagus were more predominantly small cell histology. The presence of metastatic disease at diagnosis ranged from 40 to 76%, with pancreatic NECs most likely to present with metastatic disease.

Epidemiology of GEP NETs in North America

USA

In a recent exploration of the Surveillance, Epidemiology and End Results (SEER) database, 22,744 GEP NET cases were identified between 1975 and 2012 [8]. In this analysis, investigators evaluated annual incidence, age-adjusted incidence, annual percent change, and annual percent change by 5-year age intervals, of GEP NETs. Irrespective of age group, the incidence of GEP NETs rose from 1975 to 2012. Some variance however was demonstrated in the incidence rate patterns between age groups. In the 25–39 age group, a non-linear rise in GEP NET incidence was demonstrated, whereas in all other age groups, GEP NET incidence rose linearly. The > 50 age group demonstrated a higher absolute incidence rate compared to incidence rate in patients < 50. The maximum incidence rate was observed in patients > 70, where incidence rates reached 16–17 cases per 100,000. Focusing on change over time, patients aged 40–74 demonstrated the greatest increase (4–5%) in GEP NET annual incidence rates. When examining incidence rate by primary site of disease, patients with small intestinal, colon, rectal appendiceal, and pancreatic NETs all experienced increasing incidence rates across age groups. The highest absolute rise in incidence rates occurred in small intestinal (.8 cases per 100,000), rectal (.65 cases per 100,000), and pancreatic (.33 cases per 100,000) NETs.

In another SEER database analysis, investigators identified 29,664 GEP NETs [9]. The most common primary sites of disease, in diminishing order, were the rectum (17.7%), small intestine (17.3%), pancreas (7%), stomach (6%), and appendix (3.1%). The largest change in age-adjusted incidence rates occurred in rectal NETs and small intestinal NETs, where incidence rates rose by .95 cases per 100,000 and .7 cases per 100,000, respectively, from 1973–2007. The incidence rate of GEP NETs rose from 1.0 case per 100,000 to 3.65 cases per 100,000 over this period. The median age of diagnosis for patients included in the analysis was 63 and peak incidence rate occurred at age 80. This largely held true for patients with all primary sites of disease except for rectal NETs where the peak incidence rate occurred at age 50. The observed 5-year overall survival (OS) rates for rectal, appendiceal, small intestinal, gastric, colon, and pancreatic NETs were 88.5%, 81.3%, 68.1%, 64.1%, 54.6%, and 37.6%, respectively.

The largest retrospective population-based study querying the SEER database identified 64,971 NET patients between 1973 and 2012 [6••]. Among primary tumor sites, GEP NETs demonstrated the highest incidence rate, with 3.56 cases per 100,000. Incidence rates of small intestinal, rectal, and pancreatic NETs were 1.05 cases per 100,000, 1.04 cases per 100,000, and .48 cases per 100,000, respectively. With regards to OS, patients with appendiceal and rectal NETs demonstrated the longest OS times of 30 and 24.6 years, respectively. Advancing disease stage was uniformly associated with worsening OS, irrespective of primary site. In patients with small intestinal, pancreatic, gastric, colon and rectal NETs, 5-year OS rates were 69%, 50%, 32%, 29%, and 28%, respectively. The investigators also reported on changes in GEP NET survival from 2000 to 2012, with the reference period being 2000–2004. OS of patients with distant pancreatic NETs improved by 24% and 44% from 2000 to 2004 to 2005 to 2008, and 2009 to 2012, respectively. OS of patients with distant gastrointestinal NETs improved by 24% and 29% from 2000 to 2004 to 2005 to 2008 and 2009 to 2012, respectively.

Another analysis, which compiled SEER patient data and SEER-Medicare data between 2000 and 2015, explored GEP NET epidemiology by race [10•]. In Caucasian patients, the incidence rates for distant, regional, and local GEP NETs was .76 cases per 100,000, .77 cases per 100,000, and 1.5 cases per 100,000, respectively. In Black patients, the incidence rates for distant, regional, and local GEP NETs was .9 cases per 100,000, .88 cases per 100,000, and 3.4 cases per 100,000, respectively. In Hispanic patients, the incidence rates for distant, regional, and local GEP NETs was .51 cases per 100,000, .42 cases per 100,000, and 1.54 cases per 100,000, respectively.

Canada

A retrospective population-based study was carried out via the Ontario Cancer Registry and included NET patients diagnosed between 1994 and 2009 [11]. Of the 5619 patients diagnosed, 3245 (57.7%) possessed GEP NETs. The median age at diagnosis for patients was 60.5. The most prevalent sites of disease by primary site were small intestine (18.2%), colon (12.9%), rectum (12.3%), and pancreas (9.3%). Irrespective of primary tumor site, incidence rates increased between 1994 and 2009. Between this time period, incidence rates increased by .74 cases per 100,000, .59 cases per 100,000, .5 cases per 100,000, .32 cases per 100,000, and .22 cases per 100,000 in patients with rectal, small intestinal, pancreatic, colon, and gastric NETs, respectively. Five-year OS rates for patients with rectal, small intestinal, pancreatic, colon, and gastric NETs were 73.4%, 64.3%, 87.2%, 48.8%, and 67.4%, respectively.

Epidemiology of GEP NETs in Asia

India

Findings from a multicenter longitudinal NET registry from India were reported in 2017 [12•]. Data was collected between 2001 and 2016 from 6 tertiary care centers and 407 GEP NET cases were identified; patients were categorized into 3 cohorts based upon time of diagnosis (cohort 1: 2001–2005; cohort 2:2006–2010; cohort 3: 2011–2016). Among the cohorts, localized disease at diagnosis was present in 51.4%, 46.3%, and 35% of cases in cohort 1, cohort 2, and cohort 3, respectively. Among the cohorts, metastatic disease at diagnosis was present in 45.9%, 46.3%, and 58.5% of cases in cohort 1, cohort 2, and cohort 3, respectively. The most common primary sites of disease, in diminishing order, were the pancreas (42.9%), small intestine (22.1%), colorectum (9%), and appendix (2.7%). By grade, 36 (8.8%) were classified as grade 3 or poorly differentiated NEC; however, it is not clear whether these were grade 3 well-differentiated NETs or true NECs. Incidence rates were not reported by cohort; however, increasing numbers of GEP NETs were registered with each enrolling cohort.

Japan

Investigators conducted a national survey in Japan in 2005 to examine the epidemiology of GEP NETs [13]. In this analysis, pancreatic NETs and gastrointestinal NETs were analyzed separately. The mean age of diagnosis for patients with pancreatic NETs was 57.6 while the mean age of diagnosis for patients with gastrointestinal NETs was 59.8. The overall prevalence of pancreatic NETs was 2.2 cases per 100,000; the prevalence of functional tumors was 1.3 cases per 100,000 and the prevalence of non-functional tumors was .95 cases per 100,000. At presentation, distant metastatic disease was observed in 21% of pancreatic NETs. The overall prevalence of gastrointestinal NETs was 3.5 cases per 100,000 with hindgut tumors being the most common. Hindgut, foregut and midgut NETs represented 60%, 30.4%, and 9.6% of cases, respectively. At presentation, distant metastatic disease was observed in 6% of gastrointestinal NETs. The rectum, small intestine, and stomach were the most common sites of primary disease.

China

In a retrospective analysis from China, 168 GEP NENs were diagnosed between 2003 and 2009 at two academic centers [14]. The predominant sites of disease were pancreatic, gastric, small intestinal, colonic, and appendiceal in 13.7%, 9.5%, 8.3%, 4.8%, and 4.7% of cases, respectively. NENs were classified according to 2000 WHO NET grading criteria with grade 1, grade 2, and grade 3 tumors being noted in 20.2%, 4.2%, and 7.7% of cases, respectively; most tumors were not assigned a tumor grade. Median OS was 9.4, 7.6, and 4.1 years in rectal, other, and pancreatic NENs, respectively. Median overall survival in NETs was 7.4 years while it was 2.8 years in NECs.

A subsequent analysis included 2010 GEP NEN cases collected from a nationwide retrospective multicenter study from 2001 to 2010 [15]. In this study, grade 1, grade 2, and grade 3 NENs were included; however, the distribution of NEC versus well-differentiated NETs in the grade 3 tumor category was not specified. The predominant primary tumor types represented in the analysis were pancreatic (35.1%), rectal (29.6%), and gastric (15.4%); small intestinal NENs represented only 5.6% of all cases. From 2001 to 2010, the incidence of NENs at each primary site increased (cases per 100,000 not reported). Tumor grade was associated with stage with grade 1, grade 2, and grade 3 tumors presenting with metastatic involvement in 8.7%, 16.9%, and 17.7% of cases, respectively.

Korea

In a national registry analysis from Korea, 4951 GEP NETs were identified between 2000 and 2009 [16]. By primary site of disease, GEP NETs were located in the rectum, stomach, pancreas, colon, small intestine, and appendix in 48%, 14.6%, 8.7%, 7.7%, 7.7%, and 2.5% of cases, respectively. By tumor grade, according to WHO 2010 grading criteria, 92.3%, 4.9%, and 2.8% of tumors were grade 1, grade 2, and NEC, respectively. GEP NET tumors increased in annual incidence from 2000 to 2009 and this was largely driven by the rise in rectal NETs. The 5-year OS rates were 93.5%, 66%, and 43% for grade 1, grade 2, and NEC patients, respectively. The 5-year OS rates by primary site were not reported.

In a smaller single-center retrospective analysis, 125 GEP NET cases were identified between 2009 and 2011 [17]. GEP NETs were primarily located in the rectum, duodenum, pancreas, stomach, and colon in 79.8%, 5.6%, 4.8%, 3.2%, and 2.4% of cases, respectively. According to 2010 WHO NET grading criteria, grade 1, grade 2, and grade 3 tumors were encountered in 74.5%, 13.7%, and 11.8% of cases, respectively. By disease stage, GEP NETs presented predominantly with stage I and stage IV disease in 84.7% and 8.9% of cases, respectively.

Taiwan

Investigators queried the Taiwan Cancer Registry to identify NET cases between 1996 and 2008 [18]. A total of 2187 cases were identified of which 1230 (56.2%) were GEP NETs. Among the represented GEP NETs, primary sites of disease were the rectum, stomach, colon, small intestine, appendix, liver, esophagus, and biliary tree in 45.1%, 13.2%, 10.6%, 9.5%, 9.3%, 6.3%, 3%, 1.7%, and .9% of cases, respectively. The age-adjusted incidence rate of all GEP NET tumors increased from 1996 to 2008, though not in a uniform fashion. The absolute increase in incidence rates per 100,000 of rectal, stomach, pancreatic, colon, and small intestinal NETs over this period were .31, .11, .11, .07, and .03, respectively. The 5-year OS for patients with rectal, appendiceal, small intestinal, pancreatic, hepatic, biliary, and esophageal NETs was 80.9%, 75.7%, 47.9%, 46.4%, 30.4%, 23.5%, 15%, and 14.3%, respectively.

Epidemiology of GEP NETs in Europe

Norway

A population-based analysis was conducted on GEP NEN cases diagnosed between 2003 and 2013 at a large regional hospital in south-western Norway [19]. GEP NENs were classified by 2010 WHO NET grading criteria. The crude annual incidence of all GEP NENs was 5.83 cases per 100,000. The crude annual incidence of GEP NENs rose from 2.37 cases per 100,000 in 2003 to 8.35 cases per 100,000 in 2009; there was an increasing linear trend in crude incidence rates during the study period. The incidence of GEP NENs by tumor site per 100,000 was 1.7, 1.4, .94, .51, .46, and .31 in small intestinal, appendiceal, pancreatic, rectal, colon, and gastric NETs, respectively. Median age at diagnosis of all patients was 61 years. By tumor grade, 53.4% of cases were grade 1, 24% were grade 2, and 19.6% were categorized as G3 NEC; incidence rates decreased with increasing grade.

Norwegian Registry of Cancer data between 1994 and 2003 was analyzed and compared against US-based SEER data from that identical period to assess whether epidemiologic patterns of NETs varied between the two countries [20]. In the Norwegian patients, 59.3% had GEP NETs with the predominant primary tumor sites being small intestinal, rectal, pancreatic, colonic, and gastric. The incidence rates per 100,000 of small intestinal, rectal, colonic, gastric, pancreatic, appendiceal, and esophageal NETs were .81, .24, .25, .18, .23, .16, and .01, respectively. The incidence rate of GEP NETs rose from 1.4 to 2.4 cases per 100,000 from 1993 to 1997 and 2000 to 2004. The greatest increase in incidence rate among GEP NET tumors was in small intestinal NETs which rose from .6 cases per 100,000 in 1993 to 1997 to 1.1 cases per 100,000 in 2000 to 2004. The proportion of patients with localized, regional, or metastatic disease was not specified for GEP NET patients. Five-year OS rates among patients with GEP NET tumors were 74%, 74%, 59%, 45%, 43%, and 41% for tumors arising in the rectum, appendix, small intestine, stomach, pancreas, and colon, respectively.

Iceland

A population-based national registry analysis was carried out by Icelandic investigators to investigate GEP NET epidemiology [21•]. A total of 364 GEP NET cases identified between 1985 and 2014 were included and the study period was divided into two periods 1985–1999 and 2000–2014 to facilitate epidemiologic comparisons. The unadjusted incidence rate was 3.4 cases per 100,000 from 1985 to 1999 and was 3.9 cases per 100,000 from 2000 to 2014; no statistically significant difference was observed between the two periods. By age-adjusted incidence rate, appendiceal, small intestinal, gastric, pancreatic, rectal, and colon NET cases were noted in 1.4, .95, .59, .33, .28, and .16 cases per 100,000. No statistically significant differences in 5 and 10-year OS rates were observed between tumors, when compared by primary tumor site, between 1985 and 1999 and 2000 and 2014.

Germany

German investigators assessed GEP NET epidemiologic changes between 1976 and 1988 and 1998 and 2006 through data mining of the former East German National Cancer Registry and the subsequent Joint Cancer Registry [22]. A total of 2821 GEP NET cases were identified. The crude incidence rate of GEP NETs rose from .45 cases per 100,000 in 1976 to 2.5 cases per 100,000 in 2006. Across all tumor sites, crude incidence rate and age-adjusted incidence rate rose between 1976 and 2006. This pattern held true even when cases were categorized by gender. By age-adjusted incidence rates, the largest and smallest increases in absolute incidence rate occurred in small intestinal NETs and appendiceal NETs, respectively. OS rates increased between 1976 and 1988 and 1998 and 2006 for all GEP NET patients with 1-, 5-, and 10-year OS rates of 59%, 50%, and 47% and 79%, 63%, and 50%, respectively.

England/United Kingdom (UK)

An early population-based cancer registry study in England reported on 10,324 GEP NET cases diagnosed between 1971 and 2006, with results reported in the context of gender [23]. Appendiceal, small intestinal, colon, and rectal NETs occurred in 38%, 29%, 13%, and 8% of cases, respectively. While incidence rates for rectal, gastric, and colon NETs were similar between men and women, small intestinal NETs occurred more frequently in men while appendiceal NETs occurred more frequently in women. Appendiceal NETs demonstrated the largest absolute increase in incidence rates in both men (.38 cases per 100,000) and women (.54 cases per 100,000).

A recent 2019 UK NET registry analysis included NET patients diagnosed between 2013 and 2015 [24]. Among the 15,222 cases, 7724 (50.7%) were diagnosed with GEP NENs; this patient cohort included both NETs and NECs, with the latter comprising 37% of all patients. The age-adjusted incidence rate of all GEP NENs was 4.8 cases per 100,000; however, this also included NEC patients (unspecified percentage); thus, the true incidence rate of GEP NETs was not specified. Small intestinal, appendiceal, pancreatic, colonic, gastric, and rectal NENs were encountered in 25.6%, 23.6%, 17.7%, 9.8%, 9.8%, and 7.8% of all cases, respectively. The observed 1-year OS rate, by primary tumor site, was 91.2%, 77.6%, 76.4%, 67.4%, 63.4%, and 35.3%, for small intestinal, pancreatic, rectal, colonic, gastric, and esophageal NENs, respectively.

Spain

A Spanish national registry study analyzed 837 GEP NET cases diagnosed between 2001 and 2008 [25]. Of the included cases, 1.7% of were categorized as poorly differentiated tumors. Small intestinal, pancreatic, and unknown primary of suspected gastrointestinal origin NETs represented 55%, 36.3%, and 9.1% of cases, respectively. By stage, 44% of tumors were metastatic at diagnosis while 36% of patients presented with localized disease. Stage at diagnosis differed by primary tumor type with small intestinal, colon, rectal, and pancreatic NETs demonstrating metastatic involvement in 65%, 48%, 40%, and 38% of cases, respectively. Appendiceal NETs, in contrast, were metastatic in only 1.8% of cases.

Greece

NET patient data was collected in a prospective multicenter tumor registry in Greece between October 2010 and November 2012 [26]. Data on 246 cases were collected with 156 (63.4%) representing GEP NETs. Among GEP NET patients, the predominant tumor sites were gastric (35%), pancreatic (23%), small intestinal (14%), rectal (12%), appendiceal (11%), and colon (5%). With regard to tumor grade, 54% had grade 1 tumors, 26.9% had grade 2 tumors, and 10.8% had grade 3 tumors. The unaccounted patients presumably possessed NEC; however, this was not specified. During the follow-up period, only 8 deaths among GEP NET patients were recorded.

Portugal

In a cross-sectional multicenter study in Portugal, 293 GEP NENs were identified [27]. Of these cases, 88.7% were categorized as grade 1 and grade 2 NETs while 11.3% were categorized as NECs. As all tumors were classified by 2010 WHO NET grading criteria, it is not clear whether these latter cases represented well-differentiated grade 3 NETs or true NECs. The primary tumor types represented in this cohort were pancreatic (31.1%), small intestinal (24.7%), gastric (13.7%), rectal (8.5%), duodenal (6.8%), appendiceal (6.8%), colon (5.5%), unspecified (2.4%), and esophageal (1%). By stage, 44.4%, 20.1%, and 35.5% of patients presented with distant, regional, and local disease, respectively.

Discussion

Several key insights become evident from the previously described global epidemiologic data. First, there is tremendous heterogeneity with regard to how the results from each of the studies were reported. Some studies reported age-adjusted incidence rates of GEP NETs; others reported unadjusted incidence rates of GEP NETs (Table 1) whereas others reported only disease prevalence due to their cross-sectional nature. Some studies reported GEP NET incidence rates by primary tumor site while others reported GEP NET incidence rates by disease stage or patient ethnic background. The heterogeneity of study reporting makes it a challenge to draw uniform conclusions about the epidemiology of GEP NETs on an intra- and inter-continental level. Second, pathologic classification of GEP NETs varied between studies. Many of the studies were conducted with data collected prior to 2017 and did not utilize the most recent WHO NET grading system to categorize GEP NETs. As such, the subgroup of tumors with the greatest likelihood of misclassification were NECs. It is highly possible that a swath of tumors characterized as NECs were in fact well-differentiated grade 3 NETs and that NECs were overrepresented in several analyses.

Table 1.

Unadjusted GEP NEN incidence rates by country

Country	GEP NEN incidence rate	Time period
USA [9]	3.65 cases per 100,000	2007
USA [6••]	3.56 cases per 100,000	2012
Norway [19]	8.35 cases per 100,000	2009
Iceland [21•]	3.9 cases per 100,000	2014
Germany [22]	2.5 cases per 100,000	2006
England [24]	4.8 cases per 100,000	2015

GEP NEN gastroenteropancreatic neuroendocrine neoplasm

Third, among the countries where studies were conducted, GEP NET incidence appears to be rising steadily; only Iceland appeared to be the exception to his trend. Though some of the reasons for this rise may be due to more frequent utilization of cross-sectional imaging and availability of more powerful functional imaging modalities (e.g., gallium-68 dotatate) able to capture occult disease, these factors do not completely explain the increase. Perhaps, as-of-yet undetermined environmental factors may also play a role in the global rise of GEP NET incidence. Fourth, the magnitude of rise in GEP NET incidence rates appears to be most profound in North America. The reason for this phenomenon is undefined though health care utilization and underlying patient biology are anticipated to be contributing factors.

Fifth, the most prevalent primary sites of GEP NETs appear to differ between North America, Asia, and Europe. In North America, small intestinal and colorectal NETs tend to be most common. In Asia, rectal, gastric, and pancreatic NETs tend to be predominant while in Europe, small intestinal and pancreatic NETs tend to be most prevalent. The reason for these differences is thought to be some combination of environmental factors and biological differences due to differing national demographics. Despite these general trends, certain countries appear to demonstrate differences in primary tumor prevalence patterns from others in the same region (e.g., India, Greece), suggesting the presence of regional heterogeneity (Table 2).

Table 2.

Leading primary sites of GEP NETs, by country

Country	First	Second	Third
USA [9]	Rectum	Small intestine	Pancreas
Canada [11]	Small intestine	Colon	Rectum
India [12•]	Pancreas	Small intestine	Colorectum
China [14]	Pancreas	Gastric	Small intestine
Korea [16]	Rectum	Gastric	Pancreas
Taiwan [18]	Rectum	Gastric	Colon
Norway [20]	Small intestine	Rectum	Pancreas
England [24]	Small intestine	Appendix	Pancreas
Greece [26]	Gastric	Pancreas	Small intestine
Portugal [27]	Pancreas	Small intestine	Gastric

GEP NETs gastroenteropancreatic neuroendocrine tumors

Two underlying themes are relevant to contextualizing the described GEP NET epidemiologic data. First, comparing epidemiologic data between populations from different eras is fraught with limitations. With the advent and widespread adoption of improved somatostatin receptor-based functional imaging, and more ready availability of cross-sectional imaging, detecting occult NETs has improved significantly. Health care utilization and access must be considered a significant influence when comparing GEP NET epidemiology between current and prior eras. Second, classifying GEP NET cases, even from shared databases, carries a degree of inherent subjectivity. Studies utilizing the same GEP NET national database (e.g., SEER) were not always consistent with one another, suggesting the difficulty and imprecise nature of using ICD codes or other deidentified means to identify true NET cases.

Conclusions

Uniformly conducted population-based epidemiologic studies are needed in each country to assess the true healthcare burden of GEP NETs. Standardized data collection methods utilizing an up-to-date pathologic grading system (e.g., 2019 WHO NET grading criteria) and common data collection tools and analysis metrics (e.g., crude incidence rate, age-adjusted incidence rate) are necessary to draw meaningful conclusions. Insights from these data may lead to the identification of the forces which contribute to the observed regional differences between GEP NETs globally.