ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Biochemical Markers

Abstract

Biomarkers have been the mainstay in the diagnosis and follow-up of patients with neuroendocrine tumors (NETs) over the last few decades. In the beginning, secretory products from a variety of subtypes of NETs were regarded as biomarkers to follow during diagnosis and treatment: serotonin for small intestinal (SI) NETs, and gastrin and insulin for pancreatic NETs. However, it became evident that a large number of NETs were so-called nonfunctioning tumors without secreting substances that caused hormone-related symptoms. Therefore, it was necessary to develop so-called “general tumor markers.” The most important ones so far have been chromogranin A and neuron-specific enolase (NSE). Chromogranin A is the most important general biomarker for most NETs with a sensitivity and specificity somewhere between 60 and 90%. NSE has been a relevant biomarker for patients with high-grade tumors, particularly lung and gastrointestinal tract tumors. Serotonin and the breakdown product urinary 5-hydroxyindoleacetic acid (U-5-HIAA) is still an important marker for diagnosing and follow-up of SI NETs. Recently, 5-HIAA in plasma has been analyzed by high-performance liquid chromatography and fluorometric detection and has shown good agreement with U-5-HIAA analysis. In the future, we will see new tests including circulating tumor cells, circulating DNA and mRNA. Recently, a NET test has been developed analyzing gene transcripts in circulating blood. Preliminary data indicate high sensitivity and specificity for NETs. However, its precise role has to be validated in prospective randomized controlled trials which are ongoing right now.

NETest Liquid Biopsy Is Diagnostic of Lung Neuroendocrine Tumors and Identifies Progressive Disease

“…This suggests that the NETest levels do not correlate with the reported tumor tissue pathology. It is well recognized that a percentage of histologically classified TC subsequently present with recurrent or metastatic disease [2, 5]. Furthermore, the classification of endocrine tumor disease as benign or malignant is recognized as difficult even amongst experts although ∼70% of cases are properly identified [25].…”

“…Similarly, disease status cannot be adequately assessed since the sensitivity of imaging has limitations in the identification of early progression [4]. Currently, no blood biomarker exists to monitor disease status other than chromogranin A, which is regarded as inadequate for accuracy and methodological reasons [2, 5]. A key unmet clinical need is a circulating biomarker for diagnosis and to monitor disease status [6].…”

The Evolution of Neuroendocrine Tumor Treatment Reflected by ENETS Guidelines

“…Especially patients with a small intestinal NET should be screened for serotonin secretion by determining 5-hydroxyindoleacetic acid levels in the urine or plasma. Patients with elevated levels of this serotonin breakdown product might require SSA therapy to prevent carcinoid crises during surgery or other invasive procedures [36, 37]. ENETS recently updated its recommendations in this field [38].…”

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors

“…The following 9 papers [3,4,5,6,7,8,9,10,11] are the result of an Advisory Board Consensus Conference meeting. These ENETS guidelines for the standards of care in NET provide a tool to accurately assess the diagnosis of NET and provide practical recommendations for the use of surgery, and the different systemic therapeutic options that are available for the management of NET.…”