Introduction
Neuroendocrine tumors (NETs) are a group of highly heterogeneous neoplasms that arise from cells of the diffuse neuroendocrine system that extend throughout the body. Initially described over a century ago by Oberndorfer [
1], NETs are characterized by the secretion of biologically active peptides or neuropeptides that give rise to a variety of clinical syndromes, including the carcinoid syndrome. Despite this, in certain cases, NETs can remain clinically silent and undiagnosed until advanced stage disease. Anatomically, NETs are frequently located in the gastrointestinal tract; however, they can also originate in other organs such as the pancreas, lungs, adrenal glands, and the thyroid. Indeed, the vast majority of NET cases (75%) originate in the gastroenteropancreatic (GEP) system [
2] and these cases are collectively referred to as GEP-NETs.
Still regarded as relatively rare tumors, several studies have previously reported NET incidence rates across North American [
3,
4], Western European [
5‐
8], and Asian [
9,
10] countries. Interestingly, studies in North America and the United Kingdom (UK) indicate a significant increase in the incidence of NETs over the last decades. Data from the Surveillance, Epidemiology, and End Results (SEER) program registry in the USA involved > 35,000 patients and compared the NET age-adjusted incidence over the 1973–2004 period. This study found a significant increase in NET incidence from 1.9 to 5.25 per 100,000 per year during this period [
3]. Similarly, a study in Canada that involved > 5000 patients reported an increase in incidence from 2.48 to 5.86 per 100,000 per year over the period 1994–2009 [
4]. Furthermore, a study in the UK that identified > 10,000 cases of gastrointestinal NETs during the 1971–2007 period also found an increase from 0.27 to 1.32 per 100,000 in men and from 0.35 to 1.33 per 100,000 in women [
6]. Although this increase can be attributed to an improvement in diagnostic techniques and a rise in NET/cancer awareness, a definitive explanation for this phenomenon is still pending, as is the discrepancy in incidence between the UK and North America. These regional differences further highlight the need to establish and maintain regional and country-based tumor registries.
NET incidence and/or prevalence in Latin American countries remain largely unreported, and clinical literature is extremely scarce [
11,
12]. An observational study in Argentina documented a total of 532 NET cases that included 461 GEP-NETs and 71 bronchial NETs [
12]. This study demonstrated that 26.9% of GEP-NETs were located at the small bowel, followed by pancreas (25.2%), colon–rectum (12.4%), appendix (7.6%), gastric (6.9%), esophagus (2.8%), and duodenum (2.0%), with a further 16.3% reported as unknown origin. A NET registry from Brazil has documented baseline information on the first 1000 patients and classified the majority of tumors as thoracic (71.6%), followed by GEP-NETs (20.2%), head and neck (1.5%), skin (0.9%), genitourinary tract (0.6%), adrenal (0.4%), biliary (0.3%), prostate (0.3%), esophagus (0.1%), breast (0.2%), kidney (0.1%), ovary (0.2%), and 3.6% classified as unknown origin [
11].These results again demonstrate the population-specific incidence of the NET classified malignancies.
Herein, we deliver the first multicentric Chilean registry of NET patients. Of the 166 patients currently incorporated into this registry, we report that 115 are GEP-NETs and 51 classified as non-GEP-NETs. Interestingly, in contrast to previously reported finding from other NET registries, the Chilean registry data shows a high proportion of small-bowel tumors (46%) and stage IV metastatic disease at diagnosis (62%). Patient characteristics (age, sex, etc.) and survival rates were similar to those reported in other regions.
Materials and Methods
The First Chilean NET Patient Registry: Participating Institutions
A team of specialists that included medical oncologists, endocrinologists, gastroenterologists, nurses, and molecular biologists generated this registry. The registry was funded by Novartis, Chile. Novartis had no access to patient raw data or any participation in the establishment of the database, data acquisition, or analysis. This study was designed as an observational, multicenter, prospective, and retrospective registry, and approved by the institutional review board and ethics committee in all participating institutions, in accordance with the Declaration of Helsinki, Good Clinical Practices, and Chilean regulations. Participating institutions with ethics approval included the following: Hospital Base de Valdivia, Hospital de Punta Arenas, Hospital Dr. Sotero del Rio, Hospital Base de Osorno, Hospital Regional de Concepcion, and Hospital Clinico de la Universidad de Chile. Written informed consent was obtained from all participating patients.
Chromogranin A, Intraplatelet Serotonin, and 5-Hydroxy-Indoleacetic Acid
Chromogranin A (CgA) levels were obtained from plasma samples using an ELISA kit from EURODIAGNOSTICA. Similarly, intraplatelet (I-P) serotonin levels were obtained from plasma by high-performance liquid chromatography (HPLC). 5-Hydroxy-indoleacetic acid (5-HIAA) was also obtained by HPLC but using 24-h collected urine samples.
Data Acquisition
The Chilean registry involved the development of an online database of NET patients. Collected patient data were entered into a virtual platform at
www.clinicaldata.cl. Patients were enrolled starting in July 2015 through July 2017. Data were also retrospectively collected from medical records at participating institutions. The database consisted of 86 validated entries that included basic information, demographics, onset symptoms, tumor characteristics, diagnostic procedures, treatment regime (if any), and clinical outcome. All physicians received prior training and were responsible for entering data into the registry. To assess the quality of the data entered in
www.clinicaldata.cl, a trained monitor for the study periodically visited each participating center to review the relevant patient medical records.
Inclusion and Exclusion Criteria
The registry included adult individuals (> 18 years old), diagnosed with histologically confirmed NETs and at least 3 months of follow-up with access to clinical information. Exclusion criteria consisted of patients with missing or incomplete information, absence of clinical follow-up data, or those unable or unwilling to sign written informed consent.
Statistical Analysis
Continuous variables entered in the registry were expressed as mean plus/minus standard deviation or by median values and range (minimum and maximum) values according to their distribution (normal vs. not normal). Categorical variables were expressed as percentages (%). Statistical comparisons among groups were performed by Student’s t test when data were normally distributed; otherwise, the Mann–Whitney U test was performed. The distribution of continuous variables for > 2 groups was analyzed by the ANOVA or Kruskal–Wallis test, depending on data normality. The differences in categorical variables were tested by Fisher’s exact test. Survival curves were calculated using the Kaplan–Meier estimate method and different variables were compared by the log-rank test. All statistical analyses were performed using GraphPad Prism 7 or R statistical software. All analyses were two-tailed and significance was set at p ≤ 0.05.
Discussion
To the best of our knowledge, this is the first NET registry in the Pacific South American region that describes epidemiologic and clinico-pathologic characteristics of patients. To date, the Chilean registry contains a relatively low number of recorded cases (
n = 166); however, it is important to note that Chile has a population of approximately 17.5 million which is notably lower than other countries with NET registries [
16]. While the largest NET database is currently maintained by the SEER program in the USA [
3], there exist only two reports of NET registries in Latin America [
11,
12], and from these, only an observational study from Argentina reports on 532 NET cases which include relevant clinical data.
Overall, the Chilean registry confirms that NETs are a highly heterogeneous group of neoplasms with a wide variety of clinical presentations and outcomes. NETs are commonly considered indolent tumors, especially when compared to carcinomas; however, the prognosis among Chilean patients was highly variable with median OS values that ranged from 168 months in small-bowel tumors, down to 31 months in gastric tumors. Despite this, the median OS for our study was 110 months, which is in line with Spanish and Argentinean NET registries that reported 144 and 121 months OS, respectively [
5,
12], and possibly reflecting the recent common heritage between these nations. Likewise, the median age at diagnosis in Chilean patients was 53 years, a value comparable to registries in China (53 years) [
13] and Argentina (53.2 years) [
12]. The Chilean registry also demonstrated a slight preponderance of males over females, a trend similar to that reported in a Spanish national NET registry [
5], yet differing from other reports that show a higher NET prevalence among the female population [
3,
17].
Chromogranin A (CgA) is widely used as a biomarker for NET diagnosis and monitoring [
18‐
20]. Although there are several methods to measure CgA levels, the only clinically validated method available in Chile is by ELISA; for consistency, all CgA measurements in our registry were performed at the same center using this method. Also, general consensus establishes ~ 100 ng/ml as a cutoff for normal CgA levels. However, as occurs with NET prevalence and incidence, the normal range of CgA levels in Latin American patients is somewhat uncertain. Currently, our research group is working on the assessment of CgA levels in Chilean healthy subjects and NET patients in order to obtain a more accurate CgA cutoff value.
In relation to the primary tumor sites, we found that the majority of recorded tumors were reported as GEP-NETs, in accordance with previous registries [
5,
17]. However, when analyzed in further detail, the percentages of this classification of tumor displayed discrepancies across different geographic areas, for example, the percentage of small-bowel tumors in our cohort was 46%, a value higher than the 29% reported in Argentina [
12] and strikingly different from the 6% in a Chinese registry [
13]. Conversely, the proportion of stomach (27%) and rectum (30%) tumors in the Chinese registry was notoriously higher than that reported in the present study (8% and < 10% respectively, see comparative Table
2A). The high proportion of small-bowel NETs in our population study was even more evident when we compared other registries reporting only GI-NETs from England [
6] and Japan [
14] (see comparative Table
2B). Furthermore, comparative Table
2C shows that the proportion of small-bowel tumors in our cohort (32%) is twofold the reported value in the Spanish registry (16%) and higher than the SEER database (23%). Undoubtedly, a definitive explanation for this phenomenon remains pending; however, we speculate this is likely derived from a combination of ethnic and environmental influences, as genetically the Chilean population possess a high European ancestry component combined with Native American [
21] that might explain some similarities with the Spanish registry [
5] and the remarkable differences with Asian registries [
13,
14]. The comparative GEP-NET data alone (Table
2A) illustrates the need for national and regional databases. Regarding origin, Argentina and Chile in South America tend to have a lower percentage of stomach tumors and a higher proportion of small bowel; notably, an inverse distribution is observed in the available data from China. Furthermore, the combined proportion of GEP-NET/colon (this includes colon, appendix, and rectum) in Argentina (12%) and Chile (10%) are quite similar, in sharp contrast with the GEP-NET/colon percentage in China (30%). Apart from ethnic differences, an alternative explanation for these regional discrepancies is that several members of the medical team that elaborated this Chilean registry are gastroenterologist surgeons, and therefore, the high percentage of small-bowel tumors could be overestimated due to a registration bias. Similarly, we noticed a relatively small percentage of thoracic NETs in our registry (6.6%) that includes bronchial (
n = 8) and thymus (
n = 3) tumors. The SEER database indicates up to 23% of thoracic NETs among Caucasian males [
3]. Our cancer center is a national reference center for breast and gastric cancer patients, and therefore, the lack of thoracic NETs could also be attributed to a registration bias. Prospectively, our registry will seek to incorporate more centers in order to avoid this ascertainment bias.
Another interesting finding of our study is the significant proportion of stage IV metastatic patients (62%, Table
1); this is also notoriously different from other registries including the SEER database (21%) or the national registry from Spain (44%). Several factors could potentially explain these numbers: firstly, the Chilean registry is led by oncologists that frequently deal with more advanced disease patients compared to other medical professionals in the area such as endocrinologists or gastroenterologists, and as mentioned above, this could be another registration bias in our study. Second, this could be attributed to the late diagnosis of patients; in general, NETs are difficult to diagnose; as explained above, these tumors can sometimes remain asymptomatic for several years until the onset of metastatic disease. Finally, this could be attributed to a socioeconomic factor in Chile, the relatively high costs of treatment and diagnostic tests along with lack of medical insurance coverage may result in many patients receiving diagnosis and medical attention at a more advanced stage.
In summary, our study presents for the first time a Chilean NET registry including a wide range of primary sites, confirming the previously reported high heterogeneity of NETs. As discussed above, reported demographics and basic clinico-pathological characteristics of patients are in line with other NET registries. Remarkably, our study shows an unusual high proportion of small-bowel NETs and advanced stage IV tumors. The regional differences in NET primary site proportions and sub-types highlight the need for country-based NET databases in order to identify population-specific bias and may provide the basis for a better understanding of the regional discrepancies in incidence and distribution. A definitive explanation for these discrepancies remains pending and further registry-guided investigation will add to the knowledge on this seemingly rare and highly heterogeneous disease.