Chromogranin A, NSE, and 5-hydroxyindolacetic acid measurements in patients with malignant carcinoids.

Background: Neuroendocrine tumors (NET) of the gastro-entero-pancreatic (GEP) system, which comprise nonfunctioning neuroendocrine pancreatic tumors, pancreatic islets tumors, and carcinoids, are a heterogeneous group of cancers more common in the small intestine. NET have extremely varying clinical pictures, and it has been estimated a global incidence between 2.5-5 cases/100,000 per year. Each NET, depending on its anatomical site, arises from a different neuroendocrine cell, exhibiting different functionality and biological behavior. The neuroendocrine system of the GEP has at least 16 different types of endocrine cells, that produce more than 50 amines or peptides, being the widest NET system of the whole body. The NET of the small intestine are rare, and usually asymptomatic. Gastric carcinoids accounts for 4-5% of all carcinoids, originate from enterochromaffin-like cells, which are the source of several hormonal substances, including histamine, serotonine, and chromogranin A (CgA). Because of widespread and long-term use of proton pump inhibitors, and subsequent chronic hypergastrinemia, in the last decades an increased risk of gastric carcinoids have been reported. Appendiceal endocrine tumors, found incidentally in about 0.1% of appendicectomies, are often very small and benign. Colorectal carcinoids are usually discovered on colonscopy in less than 0.1% of patients. In patients with malignant carcinoids a number of prognostic parameters have been considered, such as age, clinical symptoms related to the neoplasm, TNM staging, histological grade, as well as urinary 5-hydroxyindolacetic acid (5-HIAA), and CgA, and neuron-specific enolase (NSE) serum levels. 5-HIAA is a metabolite of serotonine, and thus it is a specific marker of carcinoids producing serotonine.With the aim of discriminating between well-differentiated and poorly differentiated malignant carcinoids, the immunohistochemical expression of Ki-67 proliferation index, which is associated with higher histologic grade and overall survival, should also be measured. Unfortunately, the sensitivity of each tumor marker (TM) largely depends on disease extent and the presence of functioning tumors, and thus their usefulness is still debated. The aim of this study was to found a relationship between TMs 5-HIAA, CgA, and NSE and survival in patients with gastrointestinal carcinoids. Patients and Methods: We retrospectively reviewed data regarding 14 patients (8 men, 6 women, median age 56 years, range 33-72) with histologically confirmed gastric (N=8), ileal (N=1), colorectal (N=4) and appendiceal (N=1) malignant carcinoids. All patients underwent surgery, and 4 had liver metastases at the time of diagnosis. Results: The specificity of TMs was 86%, 86%, and 93%, and the sensitivity was 64%, 36%, and 36% for CgA, NSE, and 5-HIAA, at a cut-off of 5 UI/L, 12lg/mL, and 50 lmol/24 h, respectively. In patients with liver metastases all TMs were above the cutoff. The overall survival was 35.5±41.4 months (median 18, range 4-132 months), while the 5-year survival was 28.6%. There was no relationship between survival and both CgA (R=0.22, p=0.21) and NSE (R=0.12, p=0.76) serum levels. Conclusions: The sensitivity of TMs is low, and they are not useful in predicting outcome of patients with gastrointestinal malignant carcinoids.