Trends in Incidence of Neuroendocrine Neoplasms in Norway: A Report of 16,075 Cases from 1993 through 2010.

BACKGROUND: Epidemiological studies show an increasing trend in the incidence of neuroendocrine neoplasms (NENs). A significant number of NENs occur in less common primary sites, but they are often excluded from the population-based studies. We studied the incidence trends of all NENs in Norway according to different primary sites. MATERIALS AND METHODS: Our analyses were based on cancer cases diagnosed between 1993 and 2010 and reported to the national population-based Cancer Registry of Norway. A total of 65 morphological codes were identified as neuroendocrine and stratified into 3 different groups of aggressiveness: low, intermediate and high. RESULTS: We identified 16,075 NENs of which 49.5% were in women. The median age at diagnosis was 65 years. The most common primary sites were the lung (48.1%) and the gastroenteropancreatic system (18.0%). Stage at diagnosis was local in 40.4% of the cases, regional in 17.5% and distant in 42.1%. The stage distribution was stable throughout the study period. The age-standardized (European) incidence rate (per 100,000 person-years) increased from 13.3 in 1993 to 21.3 in 2010 with an estimated annual increase of 5.1% in women and 2.1% in men. The increase was most pronounced for tumors of intermediate aggressiveness from 3.3 in 1993 to 7.3 in 2010. The largest annual increases were estimated for the adrenal gland (8.8%), the pancreas (6.9%) and the lungs (6.1%). CONCLUSION: The incidence of NENs increased. Most primary tumors were found in the lungs or in the gastroenteropancreatic system. The increase in the incidence differed according to the primary site, gender and tumor aggressiveness.

Survival and prognostic factors in well-differentiated pancreatic neuroendocrine tumors.

OBJECTIVES: Pancreatic neuroendocrine tumors (P-NETs) account for 2-3% of all pancreatic neoplasms. The aim of our study was to investigate survival and prognostic factors in patients with P-NETs. MATERIAL AND METHODS: We retrospectively reviewed the medical records of 114 patients diagnosed with well-differentiated P-NETs from 1982 through 2010. We studied demographical, clinical, radiological, and histopathological characteristics. RESULTS: Median age at diagnosis was 57 years (range 32-83); 53% were men and 78% had nonfunctional tumors. The most common presenting symptoms were abdominal pain (41%), weight loss (36%), and diarrhea (25%); 19% of the tumors were incidental findings. Median duration of symptoms before diagnosis was 4 months, 3 months for nonfunctional, and 12 months for functional tumors (p < 0.001). At diagnosis, 32.5% patients had local, 22.8% had regional, and 44.7% had distant disease. Men had more often distant disease at diagnosis (p = 0.02). Median survival was 6.6 years (95% confidence interval [CI]: 4.0-9.2). Overall 5-year survival was 53.9% (95% CI: 43.4-63.3). For those with local disease and those with distant disease at diagnosis, the 5-year survivals were 70.2% (95% CI: 49.9-83.6) and 33.0% (95% CI: 19.7-46.7), respectively. Surgery with curative intent was performed on 46 patients. Newly detected liver metastases were diagnosed up to 10 years after surgery in this group. In patients with metastases, palliative surgery (debulking) did not have a significant effect on survival compared to those who had no surgery. CONCLUSION: Distant metastases, Ki-67 > 2%, nonfunctional tumors, elevated level of chromogranin A, and palliative treatment were associated with poor survival.

Combination of cross-sectional and molecular imaging studies in the localization of gastroenteropancreatic neuroendocrine tumors.

Molecular imaging modalities exploit aspects of neuroendocrine tumors (NET) pathophysiology for both diagnostic imaging and therapeutic purposes. The characteristic metabolic pathways of NET determine which tracers are useful for their visualization. In this review, we summarize the diagnostic value of all available molecular imaging studies, present data about their use in daily practice in NET centers globally, and finally make recommendations about the appropriate use of those modalities in specific clinical scenarios. Somatostatin receptor scintigraphy (SRS) continues to have a central role in the diagnostic workup of patients with NET, as it is also widely available. However, and despite the lack of prospective randomized studies, many NET experts predict that Gallium-68 ((68)Ga)-DOTA positron emission tomography (PET) techniques may replace SRS in the future, not only because of their technical advantages, but also because they are superior in patients with small-volume disease, in patients with skeletal metastases, and in those with occult primary tumors. Carbon-11 ((11)C)-5-hydroxy-L-tryptophan (5-HTP) PET and (18)F-dihydroxyphenylalanine ((18)F-DOPA) PET are new molecular imaging techniques of limited availability, and based on retrospective data, their sensitivities seem to be inferior to that of (68)Ga-DOTA PET. Glucagon-like-peptide-1 (GLP-1) receptor imaging seems promising for localization of the primary in benign insulinomas, but is currently available only in a few centers. Fluorine-18 ((18)F)-fluorodeoxyglucose ((18)F-FDG) PET was initially thought to be of limited value in NET, due to their usually slow-growing nature. However, according to subsequent data, (18)F-FDG PET is particularly helpful for visualizing the more aggressive NET, such as poorly differentiated neuroendocrine carcinomas, and well-differentiated tumors with Ki67 values >10%. According to limited data, (18)F-FDG-avid tumor lesions, even in slow-growing NET, may indicate a more aggressive disease course. When a secondary malignancy has already been established or is strongly suspected, combining molecular imaging techniques (e.g. (18)F-FDG PET and (68)Ga-DOTA PET) takes advantage of the diverse avidities of different tumor types to differentiate lesions of different origins. All the above-mentioned molecular imaging studies should always be reviewed and interpreted in a multidisciplinary (tumor board) meeting in combination with the conventional cross-sectional imaging, as the latter remains the imaging of choice for the evaluation of treatment response and disease follow-up.

Comparison of 24-h and overnight samples of urinary 5-hydroxyindoleacetic acid in patients with intestinal neuroendocrine tumors.

Neuroendocrine tumors (NETs) arising in the small intestine are known to produce vasoactive substances, including serotonin, that may result in the carcinoid syndrome (flushing, diarrhea, bronchoconstriction, and carcinoid heart disease). Measurement of the serotonin breakdown product 5-hydroxyindoleacetic acid (5-HIAA) in urine is important in diagnosing and monitoring of patients with intestinal NETs. Our aim was to compare 5-HIAA measurement in 24-h urine sampling with overnight (∼8-h) sampling in patients with known NETs, or at follow-up of patients potentially cured for their NETs. Twenty-four-hour and overnight urine samples were collected from 34 patients and analyzed for urinary 5-HIAA (U5-HIAA) using HPLC. Comparison of the overnight sampling values with the 24-h values showed no difference, P=0.45, and there was a significant direct correlation between the two samples using linear regression (R=0.97, P<0.001). U5-HIAA sample collection during a nightly interval of ∼8 h appears to have the same accuracy as the 24-h collection in this group of patients.

Evaluation of right ventricular dysfunction by myocardial strain echocardiography in patients with intestinal carcinoid disease.

BACKGROUND: Cardiac fibrosis is an important complication of intestinal carcinoid disease, with resulting valvular and ventricular dysfunction due to endocardial fibrosis. Evaluation of right ventricular (RV) function in these patients has focused on valvular involvement. The aim of this study was to investigate whether myocardial strain by echocardiography can detect RV dysfunction in patients with carcinoid disease. METHODS: Eighty-nine patients with intestinal carcinoid and 50 healthy individuals were studied. Strain measurements were assessed by speckle-tracking echocardiography. The average of the three lateral RV segments was calculated as RV strain. Left ventricular global strain was calculated from a 16-segment model. RESULTS: Carcinoid heart disease was present in 15 of the 89 patients. RV strain was reduced in patients with carcinoid disease compared with healthy controls (-20.6 ± 5.0% vs -26.9 ± 4.4%, P < .001). RV function by strain was not significantly different in patients with and without carcinoid heart disease (-21.2 ± 5.7% vs -20.5 ± 4.8%, P = .59). Excluding patients with overt carcinoid heart disease, RV strain was reduced in patients with 5-hydroxyindoleacetic acid levels above the normal range compared with those with levels within the normal range (-19.4 ± 5.4 vs -21.6 ± 3.7%, P = .05). CONCLUSIONS: RV function by myocardial strain was reduced in patients with carcinoid disease independently of valvular involvement. This indicates that myocardial strain by echocardiography provides added information about RV function in patients with intestinal carcinoid disease.

Survival following resection of pancreatic endocrine tumors: importance of R-status and the WHO and TNM classification systems.

OBJECTIVE: The aim of this study was to delineate the clinical outcomes and pathological characteristics of surgically resected endocrine tumors of the pancreas and to determine the importance of the World Health Organization (WHO) and tumor-node metastasis (TNM) classifications, resection status, and Ki-67 expression for long-term survival. PATIENTS AND METHODS: Sixty-nine patients underwent surgical tumor resection with curative intent during 1990-2007. Hospital records were reviewed retrospectively for medical, surgical, pathological, and radiological data. RESULTS: Forty-one patients (59%) had non-functional tumors, 28 (41%) patients had functional tumors. Thirty-seven (54%) tumors were classified as WHO group 1 and the remaining 32 as WHO group 2. There were no poorly differentiated endocrine carcinomas. The overall R0-resection rate was 68%. Patients in whom all gross tumor was resected (R0/R1) had significantly better survival compared to patients with macroscopic residual disease (R2) (p < 0.001). There was no difference in survival between patients with R0 and R1 resections. Both the WHO (p < 0.001) and the TNM (p < 0.001) classifications significantly predicted five and 10-year survival after resection of the primary tumor. Survival analysis revealed significantly better outcome for patients with tumors with Ki-67 index < 2% (p = 0.003). CONCLUSIONS: Both WHO and TNM classifications reliably predict long-term survival in patients with resectable pancreatic endocrine tumors. R2 resection status predicted poor prognosis. R0 status did not improve prognosis relative to R1 status. Ki-67 index > 2% is a predictor of poor long-term survival.