How to differentiate between functional and non-functional Neuroendocrine Tumors (NETs)?

From the Guidelines

Differentiating between functional and non-functional neuroendocrine tumors (NETs) primarily depends on the presence of clinical symptoms caused by hormone secretion, with functional NETs producing excess hormones leading to specific syndromes, and non-functional NETs either not secreting hormones or producing them in insufficient quantities to cause symptoms. According to the ESMO clinical practice guidelines for diagnosis, treatment, and follow-up of gastroenteropancreatic neuroendocrine neoplasms 1, the clinical classification of GEP-NETs by site of origin and by hormonal secretion is crucial for differentiation.

Key Differentiation Factors

• The presence of specific hormonal syndromes such as carcinoid syndrome (flushing, diarrhea, wheezing), insulinoma (hypoglycemia), gastrinoma (severe peptic ulcers), or other specific endocrine syndromes is indicative of functional NETs.
• Laboratory testing, including measurements of specific hormones like insulin, gastrin, glucagon, serotonin metabolites (5-HIAA), chromogranin A, and pancreatic polypeptide, is essential for differentiation.
• Imaging studies, including CT, MRI, somatostatin receptor scintigraphy (Octreoscan), or gallium-68 DOTATATE PET scans, help localize tumors and can aid in differentiation.

Diagnostic Approach

• The initial evaluation should focus on identifying characteristic hormonal syndromes and performing laboratory tests to confirm hormone secretion.
• Imaging studies should be used to localize the tumor and assess for potential metastases.
• The choice of imaging modality depends on the suspected location of the tumor and the availability of specific tests, with gallium-68 DOTATATE PET scans offering high sensitivity for most types of NET lesions 1.

Management Implications

• Functional NETs require both tumor-directed therapy and management of hormonal symptoms, which may include medications like octreotide or lanreotide.
• Non-functional NETs primarily require tumor control, with treatment focused on reducing tumor burden and managing symptoms related to tumor growth or metastasis.
• The distinction between functional and non-functional NETs is crucial because functional NETs may cause life-threatening hormonal crises requiring specific interventions, even when the tumor itself is small.

From the Research

Differentiation between Functional and Non-Functional Neuroendocrine Tumors

• The distinction between functioning and nonfunctioning neuroendocrine neoplasms is no longer clinically relevant, as both types are diagnosed and treated using the same principles 2.
• Nonfunctional tumors are usually diagnosed incidentally and at a later stage, as they do not secrete a bioactive product or do so in a form that is either inactive or in quantities that have no discernible effect 2.
• Functional neuroendocrine neoplasms are those associated with specific symptoms related to the hormonal secretion of the tumors, and management may involve tumor resection, reduction strategies, or specific therapies directed at decreasing hormonal synthesis, secretion, or end-organ effects 3.

Diagnosis and Management

• Diagnosis of neuroendocrine tumors relies on biochemical markers, computed tomography (CT), magnetic resonance imaging (MRI), and somatostatin-receptor based functional imaging 4.
• Treatment comprises surgery, somatostatin analogues, peptide receptor radionuclide therapy (PRRT), everolimus, sunitinib, liver-directed therapies, and sometimes chemotherapy 4.
• Somatostatin receptor scintigraphy (SRS) and positron emission tomography (PET) are useful in detecting and monitoring neuroendocrine tumors, especially in patients with well-differentiated tumors 5, 6.

Imaging Techniques

• Somatostatin receptor scintigraphy (SRS) using single photon emission tomography (SPECT) is a well-established standard in molecular imaging of neuroendocrine tumors 5.
• Positron emission tomography (PET) tracers, such as (68)Gallium-labeled somatostatin analogs, have demonstrated superiority compared to SRS in sensitivity and specificity 6.
• Hybrid imaging (SPECT/CT, PET/CT) increases sensitivity of examination, mainly resulting in better detection of small lesions 5.