Abstract

Background: Neuroendocrine tumors (NETs) are an unusual family of neoplasms with a wide and complex spectrum of clinical behavior. Here, we present the first report of a National Cancer Registry of gastroenteropancreatic neuroendocrine tumors from a Southern European country.

Patients and methods: Data was provided online at www.retegep.net by participating centers and assessed for internal consistency by external independent reviewers.

Results: The study cohort comprised 907 tumors. The most common tumor types were carcinoids (55%), pancreatic nonfunctional tumors (20%), metastatic NETs of unknown primary (9%), insulinomas (8%) and gastrinomas (4%). Forty-four percent presented with distant disease at diagnosis, most often those from small intestine (65%), colon (48%), rectum (40%) and pancreas (38%), being most unusual in appendix primaries (1.3%). Stage at diagnosis varied significantly according to sex, localization of primary tumor, tumor type and grade. Overall 5-year survival was 75.4% (95% confidence interval 71.3% to 79.5%) and was significantly greater in women, younger patients and patients with hormonal syndrome and early stage or lower grade tumors. Prognosis also differed according to tumor type and primary tumor site. However, stage and Ki-67 index were the only independent predictors for survival.

Conclusion: This national database reveals relevant information regarding epidemiology, current clinical practices and prognosis of NETs in Spain, providing valuable insights that may contribute to understand regional disparities in the incidence, patterns of care and survival of this heterogeneous disease across different continents and countries.

introduction

Neuroendocrine tumors (NETs) comprise a heterogeneous family of neoplasms with a wide and complex spectrum of clinical behavior [1, 2]. They originate in a great diversity of tissues and are characterized by their ability to produce different peptides that cause distinct hormonal syndromes. However, many are clinically silent until late advanced disease. Although they are generally more indolent than carcinomas, they often have unpredictable biological behavior and are on occasions associated with a very aggressive clinical course. Recent international efforts are helping to improve the prognostic classifications of this type of tumors and to better tailor therapeutic strategies in these patients [3–6].

The incidence of NETs ranges from 2.5 to 5 cases per 100 000 in Caucasian population [7–10]. The reported incidence has substantially increased over the last decades, partially due to improved diagnostic techniques and clinical awareness. However, incidence rates overall and per individual anatomic site are widely variable in the literature. Many issues may account for these discrepancies, including differences in patient selection, specific institutional or registration biases, racial disparities and other as yet unknown genetic and environmental factors. These issues along with patterns of care may greatly differ across countries and may ultimately influence outcome in a significant way.

To provide information regarding demographic characteristics, diagnostic procedures, tumor features, therapeutic interventions and survival of patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a national tumor registry was launched in 2001 by GETNE, the Spanish Scientific Society of Neuroendocrine Tumors. We present here the results of this broad-based multi-institutional registry that comprises 46 academic and community sites representing all regions of Spain. To date, published data mostly refer to United States, UK and Northern European populations [7–15]. This is to our knowledge the first study providing information on this type of tumors from a Southern European country.

patients and methods

The study population was obtained from the National Cancer Registry for Gastroenteropancreatic Neuroendocrine Tumors (RGETNE). RGETNE was launched by the scientific society GETNE, which is composed by specialists from multiple disciplines (oncologists, 77%; endocrinologists, 18%; surgeons, 4%; pathologists; biologists; …) and leads at the national level multiple educational and research projects on NETs. This broad-based multi-institutional registry comprises 46 academic and community sites representing all regions of Spain (Appendix 1). Data collection was provided online at www.retegep.net by investigators or study nurses from participating institutions and assessed for internal consistency by external independent reviewers. The registry database and standard operating procedures were approved by a National Scientific and Ethics Committee.

From June 2001 through December 2008, 907 tumors from 887 patients were prospectively registered. Only patients with survival data have been included in this report (855 tumors and 837 patients). The medical records were systematically reviewed to collect the following data: age, gender, functional syndrome, familial hereditary syndrome, diagnostic procedures, localization of the primary tumor, histopathological features (World Health Organization classification [16], immunohistochemical staining, grade and vascular invasion), tumor stage at diagnosis, therapeutic interventions and outcomes (surgery, local–regional therapies, hormone therapy, chemotherapy, radiotherapy and radionuclide therapy), date of diagnosis, date of relapse or disease progression, date of last visit or death and cause of death. Tumor stage was classified as localized (confined to the organ of origin), regional (invasion of surrounding organs or tissues or regional lymph nodes) or distant (spread to distant organs). Number (i.e. single or multiple) and size of primary tumors and specific sites of distant metastasis were also recorded.

Descriptive statistics were used to characterize the most relevant clinical parameters. The association of categorical variables was assessed by the chi-square test or Fisher's exact test when appropriate. One-way analysis of variance was used for comparison of continuous variables between groups. Overall survival was defined as the time elapsed from the date of diagnosis to the date of death from any cause or last follow-up in alive patients. Survival was estimated according to the Kaplan–Meier product limit method, and differences observed among patient subgroups were assessed by the log-rank test. Multivariate analyses using the Cox proportional hazards model were carried out to identify factors independently associated with prognosis. Gender, age, hormonal syndrome, stage, Ki-67, tumor type and localization of primary tumor were included as covariates in the model. Two-sided P values were computed; P <0.05 was considered statistically significant. All analyses were carried out using the SPSS statistical package (SPSS version 16.0 for Windows; SPSS Inc., Chicago, IL).

results

patient population

Of 837 assessable patients with GEP-NETs, 458 (55%) were men and 379 (45%) were women. The median age at diagnosis was 59 years (range 10–99 years), and 25% presented with hormone hypersecretion symptoms, with no significant differences according to gender (Table 1). Appendix primaries and functional tumors were diagnosed at younger ages (median age at diagnosis: appendix primary, 42 years; insulinoma, 48 years and gastrinoma, 52 years). Multiple endocrine neoplasia was diagnosed in 43 patients (5%). Of them, 91% had hyperparathyroidism, 42% pituitary adenomas, 23% adrenal adenomas and 5% pheochromocytomas. Both adrenal adenomas (30% versus 17%) and pheochromocytomas (10% versus 0%) were more commonly observed in men as compared with women.

Table 1.

Characteristics of study population (N = 837 patients)

 All patients, n (%) Men, n (%) Women, n (%) 
Age (years) 
    Median (range) 59 (10–99) 59 (16–86) 60 (10–99) 
Gender 
    Men 458 (54.7)   
    Women 379 (45.3)   
Hormonal Syndrome 210 (24.6) 113 (24.1) 97 (25.1) 
Incidental diagnosis 187 (21.9) 103 (22.0) 84 (21.7) 
Histological diagnosis 772 (92.2) 422 (91.1) 350 (92.3) 
MEN syndrome 43 (5.0) 20 (4.3) 23 (5.9) 
    Parathyroid hyperplasia 39 (90.7) 18 (90.0) 21 (91.3) 
    Pituitary adenoma 18 (41.9) 8 (40.0) 10 (43.5) 
    Adrenal adenoma 10 (23.3) 6 (30.0) 4 (17.4) 
    Lipoma 3 (7.0) 2 (10.0) 1 (4.3) 
    Pheochromocytoma 2 (4.7) 2 (10.0) 0 (0.0) 
Genetic test carried out 57 (6.7) 21 (4.5) 36 (9.3) 
Stage at diagnosis 
    Local 311 (36.4) 149 (31.8) 162 (41.9) 
    Regional 121 (14.2) 70 (15.0) 51 (13.2) 
    Distant 378 (44.2) 218 (46.6) 160 (41.3) 
    NR 45 (5.3) 31 (6.6) 14 (3.6) 
Primary tumor size (cm) 
    <1 87 (10.2) 41 (8.8) 46 (11.9) 
    1–2 154 (18.0) 82 (17.5) 72 (18.6) 
    2.1–4 149 (17.4) 83 (17.7) 66 (17.1) 
    >4 151 (17.7) 84 (17.9) 67 (17.3) 
    NR 314 (36.7) 178 (38.0) 136 (35.1) 
Multiple primary tumor 56 (6.7) 31 (6.8) 25 (6.6) 
Other NETs 17 (2.0%) 9 (2.0) 8 (2.1) 
Localization of metastases 
    Liver 360 (42.1) 202 (43.2) 158 (40.8) 
    Lymph nodes 87 (10.2) 51 (10.9) 36 (9.3) 
    Peritoneum 56 (6.5) 35 (7.5) 21 (5.4) 
    Bone 46 (5.4) 30 (6.4) 16 (4.1) 
    Lung 28 (3.3) 21 (4.5) 7 (1.8) 
    CNS 4 (0.5) 3 (0.6) 1 (0.3) 
    Adrenal 4 (0.5) 3 (0.6) 1 (0.3) 
 All patients, n (%) Men, n (%) Women, n (%) 
Age (years) 
    Median (range) 59 (10–99) 59 (16–86) 60 (10–99) 
Gender 
    Men 458 (54.7)   
    Women 379 (45.3)   
Hormonal Syndrome 210 (24.6) 113 (24.1) 97 (25.1) 
Incidental diagnosis 187 (21.9) 103 (22.0) 84 (21.7) 
Histological diagnosis 772 (92.2) 422 (91.1) 350 (92.3) 
MEN syndrome 43 (5.0) 20 (4.3) 23 (5.9) 
    Parathyroid hyperplasia 39 (90.7) 18 (90.0) 21 (91.3) 
    Pituitary adenoma 18 (41.9) 8 (40.0) 10 (43.5) 
    Adrenal adenoma 10 (23.3) 6 (30.0) 4 (17.4) 
    Lipoma 3 (7.0) 2 (10.0) 1 (4.3) 
    Pheochromocytoma 2 (4.7) 2 (10.0) 0 (0.0) 
Genetic test carried out 57 (6.7) 21 (4.5) 36 (9.3) 
Stage at diagnosis 
    Local 311 (36.4) 149 (31.8) 162 (41.9) 
    Regional 121 (14.2) 70 (15.0) 51 (13.2) 
    Distant 378 (44.2) 218 (46.6) 160 (41.3) 
    NR 45 (5.3) 31 (6.6) 14 (3.6) 
Primary tumor size (cm) 
    <1 87 (10.2) 41 (8.8) 46 (11.9) 
    1–2 154 (18.0) 82 (17.5) 72 (18.6) 
    2.1–4 149 (17.4) 83 (17.7) 66 (17.1) 
    >4 151 (17.7) 84 (17.9) 67 (17.3) 
    NR 314 (36.7) 178 (38.0) 136 (35.1) 
Multiple primary tumor 56 (6.7) 31 (6.8) 25 (6.6) 
Other NETs 17 (2.0%) 9 (2.0) 8 (2.1) 
Localization of metastases 
    Liver 360 (42.1) 202 (43.2) 158 (40.8) 
    Lymph nodes 87 (10.2) 51 (10.9) 36 (9.3) 
    Peritoneum 56 (6.5) 35 (7.5) 21 (5.4) 
    Bone 46 (5.4) 30 (6.4) 16 (4.1) 
    Lung 28 (3.3) 21 (4.5) 7 (1.8) 
    CNS 4 (0.5) 3 (0.6) 1 (0.3) 
    Adrenal 4 (0.5) 3 (0.6) 1 (0.3) 

MEN, multiple endocrine neoplasia; NR, not reported; NETs, neuroendocrine tumors; CNS, central nervous system.

diagnostic procedures

Incidental diagnosis occurred in 22% of cases. The most commonly carried out imaging studies included computed tomography (CT) scan, ultrasound and somatostatin receptor scintigraphy (octreotide scintigraphy). CT scan was the procedure with the highest yield of tumor detection (75%). Octreoscan® was done in 49% of patients and 81% of them were positive. Only about one-third of the registered patients underwent endoscopic procedures. Biochemical tests such as serum chromogranin A or urinary 5-hydroxyindole acetic acid (5-HIAA) levels were only done in 41% and 27% of the population and were increased in 67% and 45% of tested patients, respectively. Immunohistochemical staining for chromogranin and synaptophysin was done in 66% and 50% of tumors, being positive in 93% and 96% of reported cases, respectively. Ki-67 index was carried out in only 36% of tumors. Other diagnostic procedures are summarized in Table 2.

Table 2.

Diagnostic procedures

 Cases tested Elevated or positive tests
 
Biochemical tests 
n = 837 patients  n 
    5-hydroxyindole acetic acid 351 157 44.7 
    Chromogranin 234 156 66.7 
    Gastrin 183 73 39.9 
    Serotonin 112 67 59.8 
    Insulin 149 57 38.3 
    Glucagon 98 18 18.4 
    VIP 54 16 29.6 
    PP 52 11 21.2 
    ACTH 52 17.3 
    PTH-RP 24 29.2 
Immunohistochemistry   
n = 855 tumors  n 
    Chromogranin 563 521 92.5 
    Synaptophysin 427 409 95.8 
    Enolase 241 227 94.2 
    Insulin 128 35 27.3 
    Gastrin 121 31 25.6 
    Glucagon 125 42 33.6 
    Serotonin 51 19 37.3 
    Somatostatin 113 21 18.3 
Imaging studies   
n = 837 patients  n 
    Ultrasound 406 341 84.0 
    CT scan 720 644 89.4 
    MR 168 156 92.9 
    PET 29 24 82.8 
    Octreoscan® 418 342 81.8 
    Oral endoscopy 243 158 65.0 
    Colonoscopy 225 147 65.3 
    Echoendoscopy 65 58 89.2 
    Angiography 36 29 80.6 
    Exploratoy laparotomy 171 166 97.1 
    Intraoperative ultrasound 49 44 89.8 
    Bronchoscopy 19 42.1 
 Cases tested Elevated or positive tests
 
Biochemical tests 
n = 837 patients  n 
    5-hydroxyindole acetic acid 351 157 44.7 
    Chromogranin 234 156 66.7 
    Gastrin 183 73 39.9 
    Serotonin 112 67 59.8 
    Insulin 149 57 38.3 
    Glucagon 98 18 18.4 
    VIP 54 16 29.6 
    PP 52 11 21.2 
    ACTH 52 17.3 
    PTH-RP 24 29.2 
Immunohistochemistry   
n = 855 tumors  n 
    Chromogranin 563 521 92.5 
    Synaptophysin 427 409 95.8 
    Enolase 241 227 94.2 
    Insulin 128 35 27.3 
    Gastrin 121 31 25.6 
    Glucagon 125 42 33.6 
    Serotonin 51 19 37.3 
    Somatostatin 113 21 18.3 
Imaging studies   
n = 837 patients  n 
    Ultrasound 406 341 84.0 
    CT scan 720 644 89.4 
    MR 168 156 92.9 
    PET 29 24 82.8 
    Octreoscan® 418 342 81.8 
    Oral endoscopy 243 158 65.0 
    Colonoscopy 225 147 65.3 
    Echoendoscopy 65 58 89.2 
    Angiography 36 29 80.6 
    Exploratoy laparotomy 171 166 97.1 
    Intraoperative ultrasound 49 44 89.8 
    Bronchoscopy 19 42.1 

VIP, vasoactive intestinal peptide; PP, pancreatic polypeptide; ACTH, adrenal corticotrophin; PTH-RP, parathormone-related peptide; CT, computed tomography; MR, magnetic resonance; PET, positron emission tomography.

tumor characteristics

The most common tumor types were gastrointestinal carcinoids (55%), followed by pancreatic nonfunctional tumors (20%) and metastatic NETs of unknown primary (9%) (Table 3). Among functional tumors, enteric carcinoids (10%), insulinomas (8%) and gastrinomas (4%) were the most commonly encountered. Glucagonomas, vasoactive intestinal peptidomas (VIPomas) or somatostatinomas were found in <2% of the population. The gastrointestinal tract was the primary tumor site in 400 patients (47%), the pancreas in 288 patients (34%) and in 167 patients (20%), primary tumor site was unknown or not registered. Among enteric tumors, small intestine (16%), appendix (9%) and stomach (6%) were the most frequent sites of origin. Neither the distribution of tumor types nor primary tumor localizations varied significantly by gender, although there was a slightly higher incidence of insulinomas in women and of colon primary tumors in men (Table 3).

Table 3.

Tumor characteristics (N = 855 tumors)

 All patients Men, n (%) Women, n (%) 
 N 
Tumor type 
    Carcinoid enteric tumor 466 54.5 267 (57.1) 199 (51.4) 
    Pancreatic nonfunctional NET 171 20.0 95 (20.3) 76 (19.6) 
    Metastasis of unknown primary 78 9.1 40 (8.5) 38 (9.8) 
    Insulinoma 67 7.8 31 (6.6) 36 (9.3) 
    Gastrinoma 37 4.3 21 (4.5) 16 (4.1) 
    Glucagonoma 13 1.5 5 (1.1) 8 (2.1) 
    Pancreatic NET with ectopic HP 12 1.4 5 (1.1) 7 (1.8) 
    VIPoma 0.8 3 (0.6) 4 (1.0) 
    Pancreatic-mixed NET 0.4 1 (0.2) 2 (0.5) 
    Somatostatinoma 0.1 0 (0.0) 1 (0.3) 
Primary tumor site 
    Pancreas 288 33.7 147 (31.4) 141 (36.4) 
        Gastrointestinal tract 400 46.8 228 (48.7) 172 (44.4) 
        Stomach 51 6.0 29 (6.2) 22 (5.7) 
        Duodenum 30 3.5 17 (3.6) 13 (3.4) 
        Jejunum–ileum 133 15.6 71 (15.2) 62 (16.0) 
        Appendix 80 9.4 42 (9.0) 38 (9.8) 
        Colon 40 4.7 29 (6.2) 11 (2.8) 
        Rectum 50 5.8 29 (6.2) 21 (5.4) 
        Enteric NOS 16 1.9 11 (2.4) 5 (1.3) 
        Unknown or not registered 167 19.5 93 (19.9) 74 (19.1) 
Histopathological features 
    Ki-67 (%) 
        <2 135 15.8 70 (15.0) 65 (16.8) 
        3–20 115 13.5 59 (12.6) 56 (14.5) 
        >20 54 6.3 34 (7.3) 20 (5.2) 
        NR 551 64.4 305 (65.2) 246 (63.6) 
    Vascular invasion 
        Yes 171 20.0 91 (19.4) 80 (20.7) 
        No 236 27.6 120 (25.6) 116 (30.0) 
        NR 448 52.4 257 (54.9) 191 (49.4) 
    Lymphatic invasion 
        Yes 157 18.4 88 (18.8) 69 (17.8) 
        No 209 24.4 104 (22.2) 105 (27.1) 
        NR 489 57.2 276 (59.0) 213 (55.0) 
    Perineural invasion 
        Yes 106 12.4 65 (13.9) 41 (10.6) 
        No 247 28.9 118 (25.2) 129 (33.3) 
        NR 502 58.7 285 (60.9) 217 (56.1) 
 All patients Men, n (%) Women, n (%) 
 N 
Tumor type 
    Carcinoid enteric tumor 466 54.5 267 (57.1) 199 (51.4) 
    Pancreatic nonfunctional NET 171 20.0 95 (20.3) 76 (19.6) 
    Metastasis of unknown primary 78 9.1 40 (8.5) 38 (9.8) 
    Insulinoma 67 7.8 31 (6.6) 36 (9.3) 
    Gastrinoma 37 4.3 21 (4.5) 16 (4.1) 
    Glucagonoma 13 1.5 5 (1.1) 8 (2.1) 
    Pancreatic NET with ectopic HP 12 1.4 5 (1.1) 7 (1.8) 
    VIPoma 0.8 3 (0.6) 4 (1.0) 
    Pancreatic-mixed NET 0.4 1 (0.2) 2 (0.5) 
    Somatostatinoma 0.1 0 (0.0) 1 (0.3) 
Primary tumor site 
    Pancreas 288 33.7 147 (31.4) 141 (36.4) 
        Gastrointestinal tract 400 46.8 228 (48.7) 172 (44.4) 
        Stomach 51 6.0 29 (6.2) 22 (5.7) 
        Duodenum 30 3.5 17 (3.6) 13 (3.4) 
        Jejunum–ileum 133 15.6 71 (15.2) 62 (16.0) 
        Appendix 80 9.4 42 (9.0) 38 (9.8) 
        Colon 40 4.7 29 (6.2) 11 (2.8) 
        Rectum 50 5.8 29 (6.2) 21 (5.4) 
        Enteric NOS 16 1.9 11 (2.4) 5 (1.3) 
        Unknown or not registered 167 19.5 93 (19.9) 74 (19.1) 
Histopathological features 
    Ki-67 (%) 
        <2 135 15.8 70 (15.0) 65 (16.8) 
        3–20 115 13.5 59 (12.6) 56 (14.5) 
        >20 54 6.3 34 (7.3) 20 (5.2) 
        NR 551 64.4 305 (65.2) 246 (63.6) 
    Vascular invasion 
        Yes 171 20.0 91 (19.4) 80 (20.7) 
        No 236 27.6 120 (25.6) 116 (30.0) 
        NR 448 52.4 257 (54.9) 191 (49.4) 
    Lymphatic invasion 
        Yes 157 18.4 88 (18.8) 69 (17.8) 
        No 209 24.4 104 (22.2) 105 (27.1) 
        NR 489 57.2 276 (59.0) 213 (55.0) 
    Perineural invasion 
        Yes 106 12.4 65 (13.9) 41 (10.6) 
        No 247 28.9 118 (25.2) 129 (33.3) 
        NR 502 58.7 285 (60.9) 217 (56.1) 

NET, neuroendocrine tumors; HP, hormone production; VIPoma, vasoactive intestinal peptidoma; NOS, not otherwise specified; NR, not reported.

At diagnosis, tumors were localized in 36% of the patients, had regional spread in 14% and had distant metastases in 44%. Over one-third of them had tumors >2 cm (17% >4 cm). Fifty-six patients (7%) presented multiple primary tumors and 17 (2%) had several NET types. Ki-67 index was <2% in 44% of assessed tumors and >20% in 18%. The most common site of distant metastases was liver (42%), followed by distant lymph nodes (10%), peritoneum (7%), bone (5%) and lung (3%).

Women tended to have earlier tumor stages than men (42% versus 32% had localized disease). Stage at diagnosis was also significantly different depending upon localization of primary tumor, tumor type and grade (Table 4). The primary tumor sites that presented most frequently with distant disease at diagnosis included small intestine (65%), colon (48%), rectum (40%) and pancreas (38%), whereas it was most unusual in appendix primaries (1.3%). The tumor types most commonly associated with widespread disease were VIPomas (71%), pancreatic nonfunctioning tumors (44%) and bowel carcinoids (41%), as opposed to gastrinomas (22%), insulinomas or glucagonomas (15% each). As expected, poorly differentiated tumors were more prone to have distant metastasis at diagnosis (67%), although the proportion of patients with well-differentiated tumors and stage IV disease at presentation was also rather high (38%).

Table 4.

Stage at diagnosis according to localization of primary tumor, tumor type and grade

 Stage at diagnosis 
 All patients, n Local, n (%) Regional, n (%) Distant, n (%) 
Tumor type 
    Carcinoid enteric tumor 466 177 (38.0) 71 (15.2) 192 (41.2) 
    Pancreatic nonfunctional NET 171 59 (34.5) 32 (18.7) 75 (43.9) 
    Metastasis of unknown primary 78 0 (0.0) 0 (0.0) 77 (98.7) 
    Insulinoma 67 49 (73.1) 4 (6.0) 10 (14.9) 
    Gastrinoma 37 14 (37.8) 12 (32.4) 8 (21.6) 
    Glucagonoma 13 7 (53.8) 2 (15.4) 2 (15.4) 
    Pancreatic NET with ectopic HP 12 4 (33.3) 0 (0.0) 6 (50.0) 
    VIPoma 1 (14.3) 0 (0.0) 5 (71.4) 
    Pancreatic-mixed NET 0 (0.0) 0 (0.0) 3 (100) 
    Somatostatinoma 0 (0.0) 0 (0.0) 0 (0.0) 
Primary tumor site 
    Pancreas 288 121 (42.0) 47 (16.3) 109 (37.8) 
    Gastrointestinal tract 400 167 (41.8) 68 (17.0) 148 (37.0) 
        Stomach 51 30 (58.8) 10 (19.6) 11 (21.6) 
        Duodenum 30 14 (46.7) 5 (16.7) 11 (36.7) 
        Jejunum–ileum 133 13 (9.8) 32 (24.1) 86 (64.7) 
        Appendix 80 69 (86.3) 6 (7.5) 1 (1.3) 
        Colon 40 9 (22.5) 12 (30.0) 19 (47.5) 
        Rectum 50 27 (54.0) 3 (6.0) 20 (40.0) 
        Enteric NOS 16 5 (31.3) 0 (0.0) 0 (0.0) 
    Unknown or not registered 167 23 (13.8) 6 (3.6) 121 (72.5) 
Histopathological features 
    Ki-67 (%) 
        <2 135 55 (40.7) 24 (17.8) 56 (41.5) 
        3–20 115 29 (25.2) 20 (17.4) 66 (57.4) 
        >20 54 9 (16.7) 13 (24.1) 32 (59.3) 
        NR 551 218 (39.6) 64 (11.6) 224 (40.7) 
    Tumor grade 
        Well differentiated 435 197 (45.3) 71 (16.3) 167 (38.4) 
        Poorly differentiated 94 13 (13.8) 17 (18.1) 63 (67.0) 
        NR 326 101 (31.0) 33 (10.1) 148 (45.4) 
 Stage at diagnosis 
 All patients, n Local, n (%) Regional, n (%) Distant, n (%) 
Tumor type 
    Carcinoid enteric tumor 466 177 (38.0) 71 (15.2) 192 (41.2) 
    Pancreatic nonfunctional NET 171 59 (34.5) 32 (18.7) 75 (43.9) 
    Metastasis of unknown primary 78 0 (0.0) 0 (0.0) 77 (98.7) 
    Insulinoma 67 49 (73.1) 4 (6.0) 10 (14.9) 
    Gastrinoma 37 14 (37.8) 12 (32.4) 8 (21.6) 
    Glucagonoma 13 7 (53.8) 2 (15.4) 2 (15.4) 
    Pancreatic NET with ectopic HP 12 4 (33.3) 0 (0.0) 6 (50.0) 
    VIPoma 1 (14.3) 0 (0.0) 5 (71.4) 
    Pancreatic-mixed NET 0 (0.0) 0 (0.0) 3 (100) 
    Somatostatinoma 0 (0.0) 0 (0.0) 0 (0.0) 
Primary tumor site 
    Pancreas 288 121 (42.0) 47 (16.3) 109 (37.8) 
    Gastrointestinal tract 400 167 (41.8) 68 (17.0) 148 (37.0) 
        Stomach 51 30 (58.8) 10 (19.6) 11 (21.6) 
        Duodenum 30 14 (46.7) 5 (16.7) 11 (36.7) 
        Jejunum–ileum 133 13 (9.8) 32 (24.1) 86 (64.7) 
        Appendix 80 69 (86.3) 6 (7.5) 1 (1.3) 
        Colon 40 9 (22.5) 12 (30.0) 19 (47.5) 
        Rectum 50 27 (54.0) 3 (6.0) 20 (40.0) 
        Enteric NOS 16 5 (31.3) 0 (0.0) 0 (0.0) 
    Unknown or not registered 167 23 (13.8) 6 (3.6) 121 (72.5) 
Histopathological features 
    Ki-67 (%) 
        <2 135 55 (40.7) 24 (17.8) 56 (41.5) 
        3–20 115 29 (25.2) 20 (17.4) 66 (57.4) 
        >20 54 9 (16.7) 13 (24.1) 32 (59.3) 
        NR 551 218 (39.6) 64 (11.6) 224 (40.7) 
    Tumor grade 
        Well differentiated 435 197 (45.3) 71 (16.3) 167 (38.4) 
        Poorly differentiated 94 13 (13.8) 17 (18.1) 63 (67.0) 
        NR 326 101 (31.0) 33 (10.1) 148 (45.4) 

NET, neuroendocrine tumors; HP, hormone production; VIPoma, vasoactive intestinal peptidoma; NOS, not otherwise specified; NR, not reported.

therapeutic interventions

Overall, about two-thirds of the patients underwent surgery, most of them with curative intent (65%) but also with palliative purposes (14%). The proportion was higher among patients with local (85%) or regional (95%) disease but still remarkable in patients with widespread tumors (48%). Surgical resection of the primary tumor was carried out in 84% and 45% of patients with local versus distant disease, respectively. One hundred and twenty-nine patients underwent resection of metastatic disease: 27 patients had surgery of metachronous and 92 of synchronous metastases (Table 5). Local–regional therapies such as embolization, chemoembolization, radiofrequency or other ablative techniques were uncommon (<5% of the population).

Table 5.

Therapeutic interventions (N = 837 patients)

 Stage at diagnosis 
 All patients, n (%) Local, n (%) Regional, n (%) Distant, n (%) 
Surgery 575 (68.7) 264 (84.9) 115 (95.0) 180 (47.62) 
    Primary tumor 559 (71.6) 262 (84.2) 115 (95.0) 169 (44.7) 
    Metastasis 129 (15.4) 12 (3.9) 15 (12.4) 92 (24.3) 
    Curative 545 (65.1) 263 (84.6) 112 (92.6) 155 (41) 
    Palliative/cytoreductive 118 (14.1) 5 (1.6) 5 (4.1) 103 (27.2) 
Embolization 10 (1.2) 0 (0.0) 2 (1.7) 7 (1.9) 
Chemoembolization 23 (2.7) 2 (0.6) 0 (0.0) 20 (5.3) 
Ablative therapies 20 (2.4) 2 (0.6) 1 (0.8) 17 (4.5) 
Radiotherapy 27 (3.2) 3 (1.0) 3 (2.5) 21 (5.6) 
Radionuclides 8 (1) 0 (0.0) 1 (0.8) 7 (1.9) 
Pharmacotherapy 372 (44.4) 42 (13.5) 39 (32.2) 279 (73.8) 
    Somatostatin analogues 243 (29) 22 (7.1) 22 (18.2) 193 (51.1) 
    Chemotherapy 209 (25) 24 (7.7) 24 (19.8) 155 (41) 
    Interferon 79 (9.4) 5 (1.6) 4 (3.3) 64 (16.9) 
 Stage at diagnosis 
 All patients, n (%) Local, n (%) Regional, n (%) Distant, n (%) 
Surgery 575 (68.7) 264 (84.9) 115 (95.0) 180 (47.62) 
    Primary tumor 559 (71.6) 262 (84.2) 115 (95.0) 169 (44.7) 
    Metastasis 129 (15.4) 12 (3.9) 15 (12.4) 92 (24.3) 
    Curative 545 (65.1) 263 (84.6) 112 (92.6) 155 (41) 
    Palliative/cytoreductive 118 (14.1) 5 (1.6) 5 (4.1) 103 (27.2) 
Embolization 10 (1.2) 0 (0.0) 2 (1.7) 7 (1.9) 
Chemoembolization 23 (2.7) 2 (0.6) 0 (0.0) 20 (5.3) 
Ablative therapies 20 (2.4) 2 (0.6) 1 (0.8) 17 (4.5) 
Radiotherapy 27 (3.2) 3 (1.0) 3 (2.5) 21 (5.6) 
Radionuclides 8 (1) 0 (0.0) 1 (0.8) 7 (1.9) 
Pharmacotherapy 372 (44.4) 42 (13.5) 39 (32.2) 279 (73.8) 
    Somatostatin analogues 243 (29) 22 (7.1) 22 (18.2) 193 (51.1) 
    Chemotherapy 209 (25) 24 (7.7) 24 (19.8) 155 (41) 
    Interferon 79 (9.4) 5 (1.6) 4 (3.3) 64 (16.9) 

Three hundred and seventy-two patients (44%) received some kind of systemic therapy at some point along the course of the disease: 29% received somatostatin analogues, 9% interferon and 25% chemotherapy. These percentages were substantially higher among patients that presented with advanced disease (51% somatostatin analogues, 17% interferon and 41% chemotherapy). The somatostatin analogue most commonly used was octreotide (30% of patients versus 14% lanreotide). The cytotoxic drugs most frequently employed were platinum compounds (113 patients, 18.1%), etoposide (99 patients, 15.8%), streptozotocin (91 patients, 14.6%), fluoropyrimidines (88 patients, 14.1%), anthracyclines (53 patients, 8.5%), taxanes (15 patients, 2.4%), gemcitabine (10 patients, 1.6%), topoisomerase I inhibitors (7 patients, 1.1%), dacarbazine–temozolomide (4 patients, 0.6%) and mTOR inhibitors and antiangiogenics (4 patients each, 0.6%). The most common chemotherapy combination regimens used as first-line therapy included platinum–etoposide (93 patients, 14.9%), streptozotocin–5-fluorouracil (5-FU) (50 patients, 8.0%), doxorubicin–streptozotocin (37 patients, 5.9%), doxorubicin/5-FU (2 patients, 0.3%), doxorubicin–streptozotocin–5-FU (3 patients, 0.5%), oxaliplatin–fluoropyrimidine (6 patients, 1.0%), paclitaxel–carboplatin (6 patients, 1.0%) and docetaxel–gemcitabine (4 patients, 0.6%).

survival and prognostic factors

At the last follow-up, 157 patients had died (19%). The median overall survival for all registered patients was 12 years (range 0.1–24.8 years), with 75.5% of patients alive at 5 years (95% confidence interval 71.4% to 79.6%). The main causes of death were tumor related (77%), treatment related (7%), due to other neoplasia (3%) or due to medical complications unrelated to tumor or therapy (12%). Sixty-one patients (7%) developed other non-neuroendocrine malignant neoplasia, which included 28 gastrointestinal tumors (22 colorectal, 4 biliopancreatic and 1 gastric adenocarcinomas), 15 genitourinary malignancies (5 urothelial carcinomas, 4 prostate adenocarcinomas, 4 clear-cell renal carcinomas, 1 Sertoli cell testicular tumor and 1 penis carcinoma), 9 gynecological cancers (3 breast, 3 ovarian, 2 endometrial and 1 cervical carcinomas), 4 head and neck tumors (1 meningioma, 1 neurinoma, 1 laryngeal and 1 follicular thyroid carcinoma), 3 hematological malignancies (1 multiple myeloma, 1 lymphoma and 1 leukemia) and a liposarcoma. Overall survival was significantly greater in women, younger patients and patients with hormonal syndrome and in early stage or lower grade tumors (Table 6) (Figure 1). Prognosis also differed significantly according to tumor type (insulinoma/gastrinoma > glucagonoma/VIPoma > carcinoid/nonfunctional pancreatic tumor > metastasis of unknown primary) or to localization of primary tumor (appendix > duodenum > jejunum–ileum > pancreas > colon > rectum > stomach) (Table 6). Survival rates according to disease stage for different tumor types and primary tumor locations are provided in Table 7. Multivariate analysis confirmed stage and Ki-67 index as the only independent prognostic factors for survival (Table 8).

Table 6.

Overall survival

 Overall survival (years) 
 n Median % at 5 years 95% CI P 
All patients 766 12.1 75.5 71.4–79.6  
Sex     0.022 
    Men 415 11.7 74.4 67.9–79.9  
    Women 351 NR 76.9 70.8–83.0  
Age (years)     0.012 
    <30 33 NR 100 NC  
    31–60 331 NR 88.0 82.9–93.1  
    >60 325 NR 79.6 73.7–85.5  
Hormonal syndrome     0.007 
    Yes 176 12.1 87.1 81.0–93.1  
    No 590 13.8 71.2 66.1–76.3  
MEN syndrome     0.053 
    Yes 32 NR 100 NC  
    No 685 12.1 75.1 70.8–79.4  
    UK 49 9.2 65.4 47.8–83.0  
Stage at diagnosis     <0.001 
    Local 277 13.8 90.1 84.0–96.2  
    Regional 118 NR 82.9 73.9–91.9  
    Distant 344 6.5 60.4 53.3–67.5  
Tumor type     <0.001 
    Carcinoid enteric tumor 422 12.1 77.6 72.1–83.1  
    Pancreatic nonfunctional NET 162 NR 71.1 61.1–81.1  
    Metastasis of unknown primary 69 4.2 45.3 26.7–63.9  
    Insulinoma 55 NR 88.7 77.7–99.7  
    Gastrinoma 28 NR 96.2 88.8–100  
    Glucagonoma 11 6.9 80.0 55.3–100  
    Pancreatic NET with ectopic HP 8.3 75.0 45.0–100  
    VIPoma NR 75.0 32.5–100  
    Pancreatic-mixed NET 2.7 50 0.0–100  
    Somatostatinoma 9.6 100 NC  
Primary tumor site     <0.001 
    Pancreas 265 NR 78.1 71.2–85.0  
    Gastrointestinal tract 372 NR 80.4 74.9–85.9  
        Stomach 46 NR 61.4 38.5–84.3  
        Duodenum 25 NR 89.3 75.2–100  
        Jejunum–ileum 126 11.7 83.0 73.8–92.2  
        Appendix 73 NR 100 NC  
        Colon 39 NR 65.1 48.4–81.8  
        Rectum 48 12.1 64.1 45.1–83.1  
        Enteric NOS 15 9.2 83.6 62.4–100  
    UK or not registered 129 6.5 56.7 44.6–68.9  
Histopathological features 
    Ki-67 (%)     <0.001 
        <2 126 11.7 83.3 68.8–97.8  
        3–20 109 NR 77.1 64.0–90.2  
        >20 53 1.2 43.5 25.3–61.7  
        UK 478 12.1 75.8 71.1–80.5  
    Tumor grade     <0.001 
        Well differentiated 410 NR 83.3 78.2–88.4  
        Poorly differentiated 85 1.7 39.1 24.6–53.6  
        UK 271 11.9 74.2 67.3–81.1  
 Overall survival (years) 
 n Median % at 5 years 95% CI P 
All patients 766 12.1 75.5 71.4–79.6  
Sex     0.022 
    Men 415 11.7 74.4 67.9–79.9  
    Women 351 NR 76.9 70.8–83.0  
Age (years)     0.012 
    <30 33 NR 100 NC  
    31–60 331 NR 88.0 82.9–93.1  
    >60 325 NR 79.6 73.7–85.5  
Hormonal syndrome     0.007 
    Yes 176 12.1 87.1 81.0–93.1  
    No 590 13.8 71.2 66.1–76.3  
MEN syndrome     0.053 
    Yes 32 NR 100 NC  
    No 685 12.1 75.1 70.8–79.4  
    UK 49 9.2 65.4 47.8–83.0  
Stage at diagnosis     <0.001 
    Local 277 13.8 90.1 84.0–96.2  
    Regional 118 NR 82.9 73.9–91.9  
    Distant 344 6.5 60.4 53.3–67.5  
Tumor type     <0.001 
    Carcinoid enteric tumor 422 12.1 77.6 72.1–83.1  
    Pancreatic nonfunctional NET 162 NR 71.1 61.1–81.1  
    Metastasis of unknown primary 69 4.2 45.3 26.7–63.9  
    Insulinoma 55 NR 88.7 77.7–99.7  
    Gastrinoma 28 NR 96.2 88.8–100  
    Glucagonoma 11 6.9 80.0 55.3–100  
    Pancreatic NET with ectopic HP 8.3 75.0 45.0–100  
    VIPoma NR 75.0 32.5–100  
    Pancreatic-mixed NET 2.7 50 0.0–100  
    Somatostatinoma 9.6 100 NC  
Primary tumor site     <0.001 
    Pancreas 265 NR 78.1 71.2–85.0  
    Gastrointestinal tract 372 NR 80.4 74.9–85.9  
        Stomach 46 NR 61.4 38.5–84.3  
        Duodenum 25 NR 89.3 75.2–100  
        Jejunum–ileum 126 11.7 83.0 73.8–92.2  
        Appendix 73 NR 100 NC  
        Colon 39 NR 65.1 48.4–81.8  
        Rectum 48 12.1 64.1 45.1–83.1  
        Enteric NOS 15 9.2 83.6 62.4–100  
    UK or not registered 129 6.5 56.7 44.6–68.9  
Histopathological features 
    Ki-67 (%)     <0.001 
        <2 126 11.7 83.3 68.8–97.8  
        3–20 109 NR 77.1 64.0–90.2  
        >20 53 1.2 43.5 25.3–61.7  
        UK 478 12.1 75.8 71.1–80.5  
    Tumor grade     <0.001 
        Well differentiated 410 NR 83.3 78.2–88.4  
        Poorly differentiated 85 1.7 39.1 24.6–53.6  
        UK 271 11.9 74.2 67.3–81.1  

CI, confidence interval; NR, not reached; NC, not computable; MEN, multiple endocrine neoplasia; UK, unknown; NET, neuroendocrine tumors; HP, hormone production; VIPoma, vasoactive intestinal peptidoma; NOS, not otherwise specified.

Table 7.

Survival according to primary tumor site, tumor type and stage

 Survival (% at 5 years) 
 All Local Regional Distant 
 n n n n 
Tumor type 
    Carcinoid enteric tumor 422 77.6 166 91.1 69 79.7 174 64.3 
    Pancreatic nonfunctional NET 162 71.1 54 85.3 31 83.7 72 56.4 
    Metastasis of unknown primary 69 45.3 – – 69 45.3 
    Insulinoma 55 88.7 39 88.4 100 75.0 
    Gastrinoma 28 96.2 100 12 100 83.3 
    Glucagonoma 11 80.0 100 50.0 50.0 
    Pancreatic NET with ectopic HP 75.0 – – 27.2 
    VIPoma 75.0 100 – 27.2 
    Pancreatic-mixed NET 50.0 – – 35.4 
    Somatostatinoma 100 – – – 
Primary tumor site 
    Pancreas 265 78.1 108 89.7 46 87.0 102 60.9 
    Gastrointestinal tract 372 80.4 155 91.5 66 78.9 137 68.1 
        Stomach 46 61.4 27 87.4 10 35.6 0.0 
        Duodenum 25 89.3 10 100 100 10 72.9 
        Jejunum–ileum 126 83.0 13 100 31 74.0 80 82.4 
        Appendix 73 100 65 100 100 100.0 
        Colon 39 65.1 71.1 12 91.7 18 42.9 
        Rectum 48 64.1 26 75.0 66.7 19 29.8 
        Enteric NOS 15 83.6 66.7 – – 
    Unknown or not registered 129 56.7 14 83.1 100 105 50.0 
 Survival (% at 5 years) 
 All Local Regional Distant 
 n n n n 
Tumor type 
    Carcinoid enteric tumor 422 77.6 166 91.1 69 79.7 174 64.3 
    Pancreatic nonfunctional NET 162 71.1 54 85.3 31 83.7 72 56.4 
    Metastasis of unknown primary 69 45.3 – – 69 45.3 
    Insulinoma 55 88.7 39 88.4 100 75.0 
    Gastrinoma 28 96.2 100 12 100 83.3 
    Glucagonoma 11 80.0 100 50.0 50.0 
    Pancreatic NET with ectopic HP 75.0 – – 27.2 
    VIPoma 75.0 100 – 27.2 
    Pancreatic-mixed NET 50.0 – – 35.4 
    Somatostatinoma 100 – – – 
Primary tumor site 
    Pancreas 265 78.1 108 89.7 46 87.0 102 60.9 
    Gastrointestinal tract 372 80.4 155 91.5 66 78.9 137 68.1 
        Stomach 46 61.4 27 87.4 10 35.6 0.0 
        Duodenum 25 89.3 10 100 100 10 72.9 
        Jejunum–ileum 126 83.0 13 100 31 74.0 80 82.4 
        Appendix 73 100 65 100 100 100.0 
        Colon 39 65.1 71.1 12 91.7 18 42.9 
        Rectum 48 64.1 26 75.0 66.7 19 29.8 
        Enteric NOS 15 83.6 66.7 – – 
    Unknown or not registered 129 56.7 14 83.1 100 105 50.0 

NET, neuroendocrine tumors; HP, hormone production; VIPoma, vasoactive intestinal peptidoma; NOS, not otherwise specified.

Table 8.

Cox multivariate analysis for overall survival (N = 659 patients)

Variable Hazard risk 95% CI P 
Stage at diagnosis 3.96 1.97–7.96 0.0001 
Ki-67 6.69 1.96–22.88 0.008 
Variable Hazard risk 95% CI P 
Stage at diagnosis 3.96 1.97–7.96 0.0001 
Ki-67 6.69 1.96–22.88 0.008 

Variables included in the regression model: gender (men versus women), age (<30 versus 31–60 versus >60 years), hormonal syndrome (yes versus no), MEN syndrome (yes versus no versus unknown), stage at diagnosis (distant versus localized), tumor type (enteric carcinoids, pancreatic nonfunctional NET, metastasis of unknown primary, insulinomas, gastrinomas, glucagonoma, pancreatic NET with ectopic HP, VIPoma, pancreatic-mixed NET and somatostatinoma), primary tumor site (pancreas versus stomach versus duodenum versus jejunum–ileum versus appendix versus colon versus rectum versus enteric NOS), tumor grade (well versus poorly differentiated) and Ki-67 (>20% versus ≤2%). Only significant variables are given in the table.

CI, confidence interval; MEN, multiple endocrine neoplasia; NET, neuroendocrine tumors; HP, hormone production; VIPoma, vasoactive intestinal polypeptidoma; NOS, not otherwise specified.

Figure 1.

(A) Overall survival in all patients. (B) Overall survival by gender. (C) Overall survival by age. (D) Overall survival by hormonal syndrome. (E) Overall survival by stage of disease. (F) Overall survival by Ki-67 index. (G) Overall survival by histological grade. (H) Overall survival by tumor type.

Figure 1.

(A) Overall survival in all patients. (B) Overall survival by gender. (C) Overall survival by age. (D) Overall survival by hormonal syndrome. (E) Overall survival by stage of disease. (F) Overall survival by Ki-67 index. (G) Overall survival by histological grade. (H) Overall survival by tumor type.

discussion

This study is relevant as it is to our knowledge the first providing comprehensive information on the incidence, management and outcome of this type of tumors from a Southern European country. Indeed, most reported data to date refer to the USA population and some Northern or Central European countries. As racial composition and other genetic and environmental factors, as well as availability of health care resources and institutional and registration biases may greatly differ among different patient populations, the present study may provide valuable insights which may help understand regional disparities in epidemiology, patterns of care and survival of NETs across different continents and countries.

This study confirms that NETs are a broad family of tumors with a wide range of clinical presentations and outcomes. Although more indolent than carcinomas, indeed the overall survival of our series was 75% at 5 years, the prognosis was highly variable from 100% for appendix primaries to <30% for poorly differentiated tumors. There was a slight preponderance of males in our series (versus a slight women preponderance in other series) [7, 8], although sex ratio was close to 1. As expected, the gastrointestinal tract was the primary tumor site in 400 patients (47%), the pancreas in 288 patients (34%) and in 167 patients (20%), primary tumor site was unknown or not registered. However, among enteric carcinoids, primary tumor site distribution in our series significantly differed with that observed in the Surveillance, Epidemiology and End Results (SEER) Program tumor registry. While the rectum was the most common gastrointestinal tumor primary in the USA population, particularly in Asian/Pacific Islander, American Indian/Alaskan Native and African-American patients, in our cohort, the most frequent sites of origin were the small intestine followed by the appendix and stomach, whereas the rectum only accounted for 6% of tumor cases [7]. Registries from Northern European countries, which as Spain have predominantly white Caucasian population, also find small intestine as the most common primary site of intestinal NETs [8].

A significant proportion of patients (44%) in our national registry presented with widespread disease at diagnosis compared with other series (21% in SEER database). Several potential explanations may justify this difference. First of all, the fact that the great majority of GETNE Society members (77%) are medical oncologists may introduce some registration bias as they generally deal with more advanced cases than endocrinologists, gastroenterologists or surgeons. On the other hand, a notably high proportion of patients in the SEER Registry had unknown stage (20%) versus only 5% in our series [7]. Nevertheless, a later diagnosis in our country possibly caused by poorer availability of health care resources cannot be excluded and is of concern particularly in this disease where surgery is the primary means of cure. However, this hypothesis is not consistent with the fact that despite more advanced disease, the overall survival of our cohort is in the upper range of that previously reported in other series. Stage migration due to improved diagnostic techniques, which would be expected in a more recent series like ours, could potentially explain these observations.

A strong correlation was observed, as in the SEER Registry, between primary tumor site and disease stage. However, some discrepancies in this association between both series shall be remarked. Whereas in our cohort, the most common primary tumor sites associated with widespread disease at diagnosis were jejunum/ileum (65%), colon (48%) and rectum (40%); in the SEER Registry, these included pancreas (64%), cecum/colon (44%/32%) and jejunum/ileum (30%). Early-stage gastric and rectal tumors are likely underrepresented in the Spanish registry as there is a low participation of gastroenterologists in the National Scientific Society of Neuroendocrine Tumors (GETNE). Tumor type was also significantly associated with stage at diagnosis: a higher proportion of VIPomas (71%), pancreatic nonfunctional tumors (44%) and enteric carcinoids (41%) presented with stage IV disease, compared with gastrinomas (22%), insulinomas or glucagonomas (15% each). As expected, poorly differentiated tumors were more prone to have distant metastases at diagnosis (67%), although the proportion of patients with well-differentiated tumors and stage IV disease at presentation was also rather high (38%). Finally, a trend toward a more localized disease and improved survival was observed in women.

The present study also provides one of the most comprehensive reports on diagnostic and therapeutic procedures used in current clinical practice in this patient population. Of note, specific biochemical tests or immunohistochemical stainings were greatly infra-utilized. Although the high rate of incidental diagnosis (22%) may partially explain why only 41% and 27% of patients had serum chromogranin A or urinary 5-HIAA levels tested at diagnosis, a low use of immunohistochemical staining for chromogranin, synaptophysin and Ki-67 index, which were only carried out in 66%, 50% and 36% of tumors, respectively, was also observed. These figures probably reflect the low referral rate of patients to specialized centers in our country. Regarding therapeutic interventions, however, there was an extensive and appropriate use of surgery and systemic therapies in all disease stages, although a low use of local–regional ablative approaches again most likely reflecting a low number of referrals. The nonavailability of radionuclide therapy in Spain justifies the fact that only 1% of the patients received this therapeutic modality.

Overall prognosis was favorable, with a 5-year survival rate of 75%. This figure, however, may be somewhat overestimated due to insufficient follow-up in the context of a slow growing disease with a high rate of late events. Indeed, despite the relatively indolent nature of these tumors, as compared with gastrointestinal carcinomas, once the tumor has progressed beyond surgical resectability, the disease is eminently incurable. In this regard, it is remarkable that 77% of deaths in our cohort were due to tumor progression and an additional 7% were due to treatment-related issues (drug toxicity, surgical complications). Survival was significantly greater in women, younger patients and patients with hormonal syndrome and in early stage or lower grade tumors. As observed by others, prognosis also differed significantly according to tumor type or to primary tumor site, although with some striking differences compared with other geographical regions (i.e. poorer survival for gastric or rectal primaries in our country). However, stage and grade remained the only independent predictors for outcome in multivariate analysis, which underscores the need for earlier diagnosis and for improved systemic therapies for advanced disease.

This national database reveals relevant information regarding current clinical practices and provides valuable insights into the epidemiology and outcome of this heterogeneous and not so uncommon disease. Indeed, GEP-NETs are more prevalent and lethal than previously thought. Despite some recent progress [17–22], patient survival has not significantly changed over the last 30 years. Improving our understanding of the molecular basis of this disease, as well as the mechanisms involved in response and resistance to therapy, will be essential tools that will help us develop early diagnosis tools and newer more rationally designed treatment strategies that will potentially change the natural history of malignant NETs. Finally, encouraging physicians to refer these patients to specialized centers and patients to participate in clinical trials is of utmost importance.

funding

Novartis Oncology (Spain); Ipsen Pharma (Spain).

disclosure

The authors state no conflict of interest.

We are most grateful to all participating physicians that generously contributed with their patients to this registry (Appendix 1).

list of participating centers and physicians in order of contribution (after authors of this paper)

Marrupe González D. (Hospital General de Móstoles, Madrid); Fraile López-Amor M. (Hospital Ramón y Cajal, Madrid); Fuster Salvá J. A. (Hospital Son Dureta, Mallorca); Giménez Pérez G. (Hospital de Sabadell, Corporación Parc Taulí, Barcelona); La Casta Muñoa A. (Hospital Donostia, San Sebastian); Biarnés Costa J. (Hospital Dr Josep Trueta, Gerona); Abad Esteve A. (Hospital Universitario Germans Trias i Pujol, Barcelona); Aller J. (Hospital Puerta de Hierro, Madrid); Alarcó Hernández A. (Hospital Universitario de Canarias); Blanco Carrera C. (Hospital Central Universitario de Asturias); Cano J. M. (Complejo Hospitalario Torrecárdenas, Almería); Molina Garrido M. J. (Hospital General Universitario de Elche); Tomé Martinez de Rituerto M. A. (Hospital de Conxo, Complejo Hospitalario Universitario de Santiago (CHUS), Santiago de Compostela); Lomas Garrido M. (Hospital Universitario Infanta Cristina, Badajoz); Serrano Blanch R. (Hospital Reina Sofia, Córdoba); Cordido Carballido F. (Hospital Juan Canalejo, La Coruña); Del Pozo Pico C. (Hospital Mutua de Terrassa, Barcelona); Etxeberria Larrea A. (Instituto Oncologico, Guipuzcoa); Moneva Arce A. (Hospital Nuestra Señora de la Candelaria, Santa Cruz de Tenerife); Afonso Gómez R. (Hospital Insular de las Palmas de Gran Canaria); Arribas Palomar L. (Hospital Marina Alta, Valencia); Carabantes Ocon F. J. (Hospital Regional Carlos Haya; Malaga); Catot Tort S. (Hospital Althaia Manresa, Barcelona); García Fernández H. (Hospital Son Dureta, Mallorca); Leon Carbonero A. (Fundación Jiménez Díaz, Madrid); Marco Martinez A. (Hospital Virgen de la Salud, Toledo); Martínez Olmos A. (Complejo Hospitalario Universitario de Santiago); Reina Zoilo J. J. (Hospital SAS Juan Ramón Jiménez, Huelva); Segura Huerta A. (Hospital Universitario La Fe, Valencia); Vicente Delgado A. (Hospital Virgen de la Salud, Toledo); Aguilar Bujanda D. (Hospital Doctor Negrin, Gran Canaria); Baena Cañada J. M. (Hospital Universitario Puerta del Mar, Barcelona); Carmona Bayonas A. (Hospital Morales Messeguer, Murcia); Jiménez Orozco E. (Hospital de Jerez, Jerez); Losa Gaspa F. (Hospital General de L'Hospitalet, Barcelona); Manzano Monzo J. L. (Hospital Universitario Germans Trias i Pujol, Barcelona); Tofé Povedano S. (Hospital Reina Sofia, Cordoba); Wagner Fahlin A. M. (Hospital San Pau, Barcelona, Spain).

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