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These cells were characterized by the expression of markers such as neuropeptides, chromogranins, neuropeptide processing enzymes subtilase-like pro-protein convertases SPC2 and SPC3 or dense core secretory granules.

What is a small bowel carcinoid or a small bowel neuroendocrine tumor?

In fact, seventeen different circulating biomarkers have been identified for gastroenteric neuroendocrine tumors and more than 30 gut peptide hormone genes are known, which express more than bioactive peptides. The cytoplasm of neuroendocrine cells is occupied by a large number of secretory granules of varying electron densities, size and shape, and is the storage site of secretory products [i. Upon specific stimulation, granules are translocated to the cell membrane and their content released by exocytosis. Granins are found as major, or principal, components of the soluble core of dense-core secretory granules in neuroendocrine cells and are secreted in a physiologically regulated manner.

There are 8 members in granin family and CgA and chromogranin B CgB are the most clinically interesting. A predictive and prognostic value was also demonstrated because pre- and post-surgical levels might better reflect neuroendocrine disease burden and outcome. Also for CgB and NSE, sensitivity and specificity performances were reported inadequate for diagnosis and prognostic universal use [ 12 ] according to the National Institutes of Health NIH biomarker classification system criteria.

Gastrin is a diagnostic marker for Zollinger Ellison syndrome characterized by recurrent peptic ulcers and secretory diarrhea. Gastrin levels higher than 10 fold upper limit of normal in the setting of high gastric acid output is suggestive of gastrinoma. Determination of gastrin levels after a secretin test increases sensitivity in case of borderline levels.

Neuroendocrine tumors may secrete urinary 5-hydroxyindoleacetic acid u-5HIAA , a metabolite of 5-HT but also vasoactive intestinal peptide VIP , glucagon and somatostatin with specific syndromes such as carcinoid syndrome, watery diarrhea, sweet syndrome or association of gallstones, diabetes and steatorrhea.

Calcitonin is a peptide hormone that is normally secreted by thyroid C cells, but may be rarely produced ectopically by neuroendocrine tumors especially pancreatic NETs usually in association with other ectopically produced peptides and frequently with AVP [ 24 ] along with typical clinical symptoms of diarrhea and electrolyte disturbance. During the natural course of disease, additional peptides could be secreted or co-secreted [ 28 ] resulting in different overlapping clinical manifestations with potential impacts on morbidity and mortality.

These possibilities further complicate the puzzle that is NET patient management. The spectrum of clinical presentation of NETs is highly variable. Many are incidental findings, whereas other patients present with mass effects of the primary tumour or metastases usually liver. Most NETs are nonfunctional or secrete peptides with low biological consequences. They include tumors that secrete insulin insulinoma and gastrin gastrinoma but more rarely also vasointestinal peptide VIPoma , glucagon glucagonoma , somatostatin somatostatinoma , antidiuretic hormone tumor responsible of SIAD adrenocorticotropic hormone ectopic ACTHoma , growth-hormone releasing hormone ectopic GHRHoma , calcitonin medullary thyroid carcinoma , parathyroid hormone ectopic secretion of PTH , vasoactive compounds, including biogenic amines tumor responsible of carcinoid syndrome and catecholamines pheochromocytoma.

In these cases, a range of specific peptide hormones may also be measured and are useful as diagnostic and prognostic biomarkers. Both functional and nonfunctional NETs produce CgA but this marker does not distinguish between functional and nonfunctional tumors.

Stress and hormones

Nonspecific circulating NET biomarkers do not have a crucial role in NET diagnosis and are not recommended for population screening in the absence of strong clinical or radiological evidence of tumor presence. CgA is correlated with tumor load and levels tend to be highest in metastatic cancer, particularly in the liver.

The significance of NSE is limited in guidelines to poorly differentiated tumors but recent reports pointed to a possible prognostic role for this marker on progression-free survival, overall survival, as a marker of treatment outcome in well differentiated, advanced pancreatic neuroendocrine tumors pNET during everolimus treatment [ 34 ] and more recently as a prognostic marker in gastroenteroNETs. Although there are no data showing an absolute relationship between biomarker level and the degree of disease burden, higher levels are frequent in patients with metastasis, particularly in the liver.

In other words, circulating biomarkers may reflect the tumor burden. Circulating markers are useful for monitoring specific tumors by providing a surrogate endpoint: CgA for the majority of cases, pancreastatin for hepatic tumor load, and neurokinin A for serotonin-secreting tumors of the small bowel. In addition, CgA levels are reduced after hepatic resection or transplantation. Despite the fact that gastrinomas show high circulating CgA values even in the absence of liver metastasis, gastrin levels are generally proportional to tumor burden and highest gastrin levels are present in patients with metastatic disease.

In addition, gastrin seems higher in pancreatic compared to duodenal primary tumors, with no discernible difference between sporadic and multiple endocrine neoplasia MEN1 or Zollinger Ellison syndrome patients. When specific circulating biomarkers are elevated at the diagnosis in a patient there is indication to follow these over time.

If new signs and symptoms emerge, it is necessary to test for new paraneoplastic syndromes according to clinical presentation. All guidelines [Table 1] recommend the use of CgA for follow up in all NETs even though there is an absence of prospective studies supporting its use. CgA has been used in gastroenteric NETs as a predictive biomarker to identify patients most likely to have durable responses to long acting somatostatin analogue therapy. For CgA there is no universally accepted CgA assay and the different methodologies can lead to confusing results. Many physiological conditions as stress, pregnancy or exercise can increase circulating CgA levels and the same is true for many drugs and non-neuroendocrine diseases.

U-5HIAA measurements also have inherent pitfalls since they require a 24 h urine collection and are subject to interference by dietary habits. Pitfalls and bottlenecks and possible remedies for circulating chromogranin A and gastrin interpretation.


The identification of effective biomarkers in patients with NETs is a high priority. Unfortunately current universal circulating biomarkers are not able to provide this standard and, in particular, the role of CgA in the diagnosis of neuroendocrine tumors is decreasing. The principal limitation in the measurement of circulating CgA is the absence of a gold standard assay and wide variability of results from different kits and laboratories.

In addition, false positive results are reported as a result of other neoplasia prostate and breast cancer and hepatocellular carcinoma and common conditions kidney, liver or heart failure, chronic gastritis, inflammatory bowel disease, PPI use, essential hypertension and physical stress. In addition, the current biomarkers used for gastroenteropancreatic NETs are inadequate for bronchopulmonary NETs and vice versa.

For these reasons, a multianalyte approach would likely be more effective compared to a monoanalyte circulating biomarker.

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NETest is a PCR-based, transcript signature that is based on correlating and normalizing multiple sets of variables that represent gene clusters specific to NETs and their biological behavior. The use of this blood-based test is proposed to facilitate early detection of disease recurrence and to predict therapeutic efficacy. MAAAs and NETest in particular may improve diagnostic accuracy and offer better interdisciplinary perspective than single analyte testing. Recently, several novel biomarkers for NETs have been developed using an integration of genomics and technology platforms.

Khan et al. Presence of CTC was clearly associated with increasing tumor burden and weakly with tumor grade. In a more recent, large prospective study, the same group demonstrated that changes in CTC were associated with response to treatment and overall survival in metastatic neuroendocrine tumors, suggesting CTC may be useful as a surrogate marker to direct clinical decision making.

There is also increasing interest in miRNAs as clinical biomarkers of tumorigenesis, treatment response and outcomes, but to date clinical data are scarce and clinical application challenging. Similarly, there are several novel monoanalyte assays i.

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To date, the identification of sensitive, specific and reproducible NET circulating biomarkers for the prediction, diagnosis, prognosis and classification of NETs and to evaluate changes during therapy has been limited [ 12 ] and remains an unfulfilled unmet medical need as defined by the National Cancer Institute NET meeting. The road is long and new, robust prospective studies in different neuroendocrine tumors settings are required before new accurate biomarkers are validated and implemented into routine clinical practice.

One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35, cases in the United States. J Clin Oncol Biochemical Testing for Neuroendocrine Tumors. Pancreas ; New and emerging syndromes due to neuroendocrine tumors. Endocrinol Metab Clin North Am ; A rationale for multidisciplinary care in treating neuroendocrine tumours.

Curr Opin Endocrinol Diabetes Obes ; Italian Association of Clinical Endocrinologists AME position statement: a stepwise clinical approach to the diagnosis of gastroenteropancreatic neuroendocrine neoplasms. J Endocrinol Invest ; Clinical presentation and diagnosis of neuroendocrine tumors. Hematol Oncol Clin N Am ; However, there are many studies which failed to show any relationship between stress and GD.

No significant difference was seen in the number and nature of stressful life events up to six months before the onset of thyrotoxicosis between patients with thyrotoxicosis and nontoxic goiters in the study by Gray and Hoffenberg. Severe stress may be a risk factor for diabetes.

Children aged five to nine years with stress were significantly more likely to be diabetic. In females stress can lead to anovulation, amennorhea and other menstrual irregularities.

In males, there can be decreased sperm count, motility and altered morphology. This is an extreme form of failure to thrive and may be associated with dramatic behavioral abnormalities. Defective GH secretion has been reported with stimulation test. Reversal of GH insufficiency within three weeks of removal from hostile environment has been reported. Mental stress leads to chronic activation of the neuroendocrine systems. Cortisol favors central fat deposition, a decrease in the adipostatic signal leptin and an increase in the orexogenic signal ghrelin, inducing increased appetite and food intake.

This phenomenon contributes to the current epidemic of obesity. In adults the relationship between stress and poor diabetic control is well established. Patients with adrenal insufficiency because of various etiologies may develop adrenal crisis on exposure to stress.

To prevent this, the replacement doses of steroid need to be doubled during the period of stress. Thyroid storm may be precipitated by physical stress. Acute emotional stress can also precipitate thyroid storm. They observed a higher frequency of relapse in those who had stress. In today's competitive modern world one encounters stress in various aspects of life.

As an adaptive response to stress, there is a change in the serum level of various hormones including CRH, cortisol, catecholamines and thyroid hormone. These changes may be required for the fight or flight response of the individual to stress. However, long-term exposure to stress may lead to many deleterious consequences leading to various endocrine disorders.

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Also, stress leads to change in the clinical course or status of many endocrine conditions. Source of Support: Nil. Conflict of Interest: None declared. National Center for Biotechnology Information , U.

Indian J Endocrinol Metab. Salam Ranabir and K.

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