NEUROENDOCRINE & ENDOCRINE TUMOUR FACTS
Neuroendocrine and endocrine tumors (NETs & ETs) are a complex group of cancers that remain poorly understood despite decades of research. The lack of comprehensive data, heterogeneity, indolent biology, and nonspecific presentations has contributed to this gap. Although once considered rare, the incidence of NETs/ETs has risen dramatically, making them one of the fastest-growing tumor types worldwide. This surge is primarily attributed to advancements in diagnostic methods and molecular imaging technologies.
Globally, NET incidence has doubled from 4.90 per 100,000 in 2000 to 8.19 per 100,000 in 2018, with higher rates observed in Europe and North America compared to Asia . Most of these data represent gastro-entero-pancreatic NETs (GEP-NETs) and bronchial & thymic carcinoids, while other subgroups such as: thyroid cancers, adrenal carcinomas, malignant paragangliomas, pheochromocytomas, rare subtypes, are usually excluded and remain underrepresented.
Neuroendocrine tumors (NETs) are often inaccurately categorized based on their site of origin (e.g., pancreatic NETs grouped with pancreatic tumors, gastrointestinal NETs with colorectal tumors, etc.), rather than their biological characteristics. This misclassification significantly underrepresents the true NET population and can result in delayed or inappropriate workup and treatment of these patients. However, all these tumors share the same unique biology of neuroendocrine and endocrine differentiation, with the vast majority expressing SSTR receptors as another unifying feature.
What do you have to know
Neuroendocrine Tumours (NETs)
Neuroendocrine tumours (NETs) are abnormal growth of cells (neoplasms) that arise from cells of the diffuse neuroendocrine system. • NETs are considered complex tumours because both tumor growth & hormonal function must be addressed. • NETs are most common in the lung or gastrointestinal system, but they can also originate in other parts of the body such as the thyroid, thymus, pancreas, adrenals, paraganglia, ovaries & testes. • NETs are classified as functional (produce hormones that cause symptoms), or non-functional (may or may not produce hormones and do not cause hormonal symptoms). • The cause of NETs is currently unknown.
Tests for Diagnosis
Blood tests: chromogranin A, 5-HIAA, gastrin, somatostatin, pancreastatin, insulin, glucagon, ACTH and other hormones specific to the various NET cancers. Urine tests: 24 hour 5-HIAA - measures the metabolite of serotonin. Decreases may indicate a response to treatment. Scans: Many of the scans use markers (hormones labeled with radioactive isotopes) that bind to somatostatin receptors to show images of the tumours. Common scans include: Anatomic Imaging (CT, MRI), functional imaging (Octreotide scan, MIBG, PET Gallium 68, PET FDG scan) improved resolution and higher sensitivity. Endoscopies used for diagnosis include: bronchoscopy, EGD endoscopy, colonoscopy etc.
Symptoms and Diagnosis
NETs can be difficult to diagnose because symptoms are often vague including diarrhea, flushing and nausea, depending on the type of tumour. Symptoms are intermittent and fluctuate in intensity. • Patients commonly make many visits to the doctor over several years before an actual diagnosis is made; sometimes it takes 5-7 years from first symptoms to diagnosis. • Most symptoms mimic other conditions; therefore, NETs are often misdiagnosed as something else. • Because NETs are poorly diagnosed, often by the time of diagnosis, the tumour has spread to other parts of the body (metastasis). • Diagnosis of this type of cancer is complex and often requires sophisticated laboratory testing and scanning techniques.
Staging and Grading
The stage & grade of NETs depends on well-defined histological features: size, lymphovascular invasion, mitotic counts, Ki-67 labelling index, invasion of adjacent organs, presence of metastases & whether they produce hormones. • The grade includes looking at whether the tumor cells are well differentiated (look like normal cells) - grade 1 & 2, or poorly differentiated (abnormal looking cells) - grade 3. Additionally grade 3 tumors can be poorly differentiated called G3 NEC, or aggressive NEC. Staging is different from grading. While staging defines whether the tumors has spread to lymph nodes or other structures, grading distinguishes tumors by their proliferative index.
Treatment Options
NETs almost always become malignant. Surgical removal of very small, localized tumours is the only curative therapy. Regardless of therapy, disease recurs in 84% of patients after five years and 94% by 10 years. Treatment options include: SURGERY
Curative Surgery for early stage and Palliative Debulking Surgery for advanced stage. Even if not completely removed, this improves overall survival and quality of life. Having the liver resected increases the chances of living 5 years by 4 times and doubles the chances of living 10 years, after liver resection.
LOCAL THERAPIES
There are various Liver directed therapies, employed to target liver metastasis. Embolization techniques block or reduce blood flow to the tumour. Radiofrequency Ablative techniques emits energy to kills the cancer cells, while cryotherapy uses liquid nitrogen or liquid carbon to freeze abnormal cells.
RADIATION
External Radiation Therapy can be used post operatively to target positive margins for incomplete resection. RT is also widely used in metastatic setting to target specific metastatic that are more aggressive or poorly responding to systemic therapy (for instance bone metastasis, intracranial metastasis etc.)
THERANOSTICS
Theranostics is widely applied to both early and advanced NETs. Peptide receptor radionuclide therapy (PRRT): radiolabelled Lu177 that binds to SSTR receptor on the surface of NET cells can kill tumors cells with minimal to no damage to surrounding structures. Lutathera is both FDA (Jan 2018) and Health Canada (Feb 2019) approved for treatment of advanced GEP-NET post progression on SSA, and is soon coming as a standard of care in Alberta.
Lutathera approval based on the results of NETTER 1 Trial. Treatment with 177Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu-Dotatate group.
SSA
Somatostain analog therapy is the backbone of management of hormonal symptoms resulting from NETs: lanreotide (brand name: Somatuline) and octreotide (brand name: Sandostatin). In addition SSAs have an antiproliferative effect.
SYSTEMIC THERAPY
Molecular Agents. Biologically targeted therapies Attack cancer cells while limiting damage to normal cells. There are several approved agents for treatment of advanced NETs : everolimus, an mTORC 1 inhibitor; sunitinib, a tyrosine kinase inhibitor; cabozantinib, multi kinase inhibitor.
Chemotherapy. Several chemotherapies are used for treatment of metastatic advanced NETs and NECs. The most commonly used regiments are temozolomide-based therapies (CAPTEM), platinum-based therapies (CARBOPLATIN or CISPLATIN and ETOPOSIDE) etc.