My very first mentor was Dr Larry Kvols who I trained under at the Moffitt Cancer Center during my internal medicine residency. He would tell some good stories on some of the first patients he treated back in the day with a drug no one has ever heard using “octreotide” which today is the main first line therapy for most patients with NETs! Today, I have the privilege of caring for NET patients with a multidisciplinary team at the Orlando Health Cancer Institute. There are also great patient support groups such NCAN who are highly active with annual conferences for patients!
Neuroendocrine tumors (NETs) are an uncommon type of cancer that arise from cells of the endocrine and nervous systems. These tumors can develop in many different parts of the body, including the pancreas, lungs, stomach, intestines, and other organs. NETs are more often slow-growing tumors that can be difficult to diagnose and treat given the nonspecific symptoms that can occur and overlap with more benign diagnoses. Some NETs can act, grow, and spread aggressively. In this article, we will discuss the epidemiology, subtypes, diagnosis, prognostic factors, and general treatment options for neuroendocrine tumors.
Epidemiology
Neuroendocrine tumors are relatively rare, accounting for less than 2% of all cancers. However, their incidence has been increasing in recent years, possibly due to increased awareness and improved diagnostic techniques. The exact cause of NETs is unknown, but some risk factors include a family history of multiple endocrine neoplasia type 1 (MEN1) syndrome, exposure to certain chemicals, and genetic mutations. Most common NETs seem to occur in the more environmentally exposed organs such as the lung or intestines. NETs can occur at any age but are most diagnosed in individuals between the ages of 50 and 70. They are slightly more common in women than in men.
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Presentations
Most of the new diagnosis are often related to incidental findings from routine use of endoscopies or imaging studies. If you go to the ER with chest pain or abdominal pain, you may likely get a CT scan to rule out urgent etiologies however find an incidental “mesenteric adenopathy” or “metastatic liver disease”. I had one patient who presented to me an interesting story. For work, he is active in the field and had developed progressive shoulder pain issues that required elective orthopedic surgery. His orthopedic doctor referred him to cardiology for a preoperative clearance and as such had a positive stress test and catheterization that required surgical coronary bypass. Part of the cardiology workup and evaluation was to get a CT scan of the chest which included parts of the liver, which incidentally demonstrated “metastatic liver disease”. He had a biopsy done that showed a low grade well differentiated NET suggestive of a bowel primary. When he finally came to me, his first words were, “all I wanted to do was to fix my shoulder”! Come to find out he had a bowel surgery 10 years prior for a NET that likely had metastasized to the liver slowly over the years. We placed him on long acting SSA and eventually he underwent cardiac surgery and shoulder repair allowing him to get back to work and be happy again!
The 2nd common presentation are functional symptoms due to the release of specific peptides or hormones such as carcinoid syndrome with diarrhea, flushing, or abdominal pain. Sometimes patients can live decades long with metastatic NETs and it is no longer the disease process that’s problematic but the symptoms due to the copious amount of peptide or hormone being produced by the tumor. Patients and providers are more often focused on treating the symptoms with drug therapy. Although personally we like the two-for-one special with control of the tumors and improvement of the symptoms.
The other two presentations are uncommon and include mechanical symptoms due to the primary tumor causing a blockage of intestinal tract leading to nausea and emesis or systemic symptoms due widespread tumor or rapidly progressive symptoms with resultant weight loss, fatigue, failure to thrive symptoms. More often the symptoms of end stage cancer with most folks having hepatic involved disease developing hepatic failure and jaundice.
Subtypes of Neuroendocrine Tumors
Neuroendocrine tumors are a diverse group of tumors that can arise from many different parts of the body. There are several subtypes of NETs, including:
- Pancreatic Neuroendocrine Tumors: These tumors arise from the cells that produce hormones in the pancreas and make up only 3% of all pancreatic tumors as opposed to the more common and aggressive adenocarcinomas. They are typically slow-growing and can be either functional (producing hormones that cause symptoms) or non-functional (not producing hormones). These tend to be more chemo-sensitive subtypes compared to other types.
- Gastrointestinal Neuroendocrine Tumors: These tumors can arise from the cells in the stomach, small intestines, or rectum that produce hormones. They can be either functional or non-functional. Typical functional symptoms of carcinoid syndrome include copious amounts of serotonin being produced, causing significant diarrhea, abdominal pain, or flushing symptoms. These can be treated well with somatostatin analogs (SSA) or other supportive medications.
- Pulmonary Neuroendocrine Tumors: These tumors arise from the cells in the lungs that produce hormones. They are often classified into four subtypes: typical carcinoid, atypical carcinoid, small cell carcinoma, and large cell neuroendocrine carcinoma. The latter is best treated with platinum-based chemoimmunotherapy.
- Neuroendocrine Tumors of Unknown Primary: These tumors arise from neuroendocrine cells that cannot be traced to a specific location in the body. Although, most are probably related to a small bowel primary that cannot be detected on standard scans. Lately, super-sensitive dotatate PETs have been able to pick up some of these primary tumors.
Diagnosis
Diagnosing neuroendocrine tumors can be challenging, as they often grow slowly and do not cause symptoms until they have reached an advanced stage. Some of the common diagnostic tests for NETs include:
- Blood tests: Certain hormones and markers may be elevated in individuals with NETs.
- Imaging studies: These may include CT scans, MRI scans, Dotatate or FDG PET scans, or ultrasound to visualize the tumor and assess its location and size. MRI multiphase liver scan with Eovist would be the most sensitive test to evaluate the liver.
- Endoscopy: EGD, colonoscopy with intubation of the ileum, and/or endoscopic ultrasound of the pancreas are super sensitive than evening imaging to detect small tumors. Although uncommon to use today, double balloon push enteroscopy can potentially visualized the entire bowel from the mouth to the anus then back again!
- Biopsy: A sample of the tumor may be taken for laboratory analysis to confirm the diagnosis and determine the tumor grade.
Prognostic Factors
The prognosis for neuroendocrine tumors depends on several factors, including the location and size of the primary tumor, whether the tumor has spread to nearby lymph nodes or other organs, the grade of the tumor based on the ki67 and/or mitosis, hepatic dominant or extrahepatic disease, hepatic burden, and the presence or absence of somatostatin receptors. Tumor grade is determined by the appearance of the tumor cells under a microscope and ranges from well-differentiated grade 1 (low-grade, slow-growing tumors) to grade 3 (high-grade, fast-growing tumors) to poorly differentiated high-grade aggressive neuroendocrine carcinomas (NECs).
Treatment Options
The treatment options for neuroendocrine tumors depend on several factors, including the location and size of the tumor, the grade of the tumor, and whether it has spread to other organs. In general, treatment options for NETs may include:
- Surgery: This is often the primary treatment for localized NETs and involves removing the tumor and surrounding tissue. Cytoreductive surgery of the metastatic disease makes sense for some patients with the intention of “resetting the clock” as it may take a long while for smaller tumors to grow back. This does not make sense for most patients with fast-growing tumors or those with significant extra-hepatic disease.
- Chemotherapy: This involves using drugs to kill cancer cells and is often used for NETs that have spread to other organs. The best regimen uses a temozolomide-based option in well-differentiated NETs, whereas chemotherapy with platinum-based therapy works best in high-grade poorly differentiated NECs.
- Somatostatin analogs (SSA): These drugs mimic the hormone somatostatin, which helps regulate the release of hormones. They can be used to treat NETs that produce hormones, as well as to control symptoms such as flushing and diarrhea. These are also used to help control tumors. The main question is when to start therapy? For older patients with small volume asymptomatic disease, it may be best to observe alone and start if significant changes occur. If symptoms are present or there is a high tumor burden, starting treatment with an SSA may be appropriate.
- Targeted therapy: These drugs work by targeting specific proteins or enzymes that cancer cells need to grow and spread. Examples include everolimus, which targets the mTOR pathway, and sunitinib, which targets multiple receptor tyrosine kinases (TKI). Cabozantinib is another up and coming promising TKI option. These options may be used for advanced or metastatic NETs that have progressed to other treatments.
- Peptide Receptor Radionuclide Therapy (PRRT): This innovative therapy involves using a radioactive substance bound to a molecule that specifically targets neuroendocrine tumor cells. The most common type is Lutathera, which uses the radioactive isotope lutetium-177 bound to a somatostatin analog. PRRT has shown promising results in clinical trials, with improved progression-free survival and reduced symptoms in patients with advanced NETs.
- Liver directed therapies: chemoembolization and bland embolization, are minimally invasive procedures performed by interventional radiologists to treat liver tumors. These therapies involve blocking the blood supply to the tumor, leading to its shrinkage and eventual death. In chemoembolization, a combination of chemotherapy drugs and embolic agents is delivered directly into the tumor’s blood vessels, maximizing drug delivery while minimizing systemic side effects. Bland embolization, on the other hand, utilizes only embolic agents to obstruct the tumor’s blood supply, without the addition of chemotherapy drugs. Both techniques are effective in controlling tumor growth and alleviating symptoms, particularly in patients with liver-dominant metastatic disease or those who are not candidates for surgery.
- Immunotherapy: Although still in the early stages of research, immunotherapy options such as checkpoint inhibitors may have potential for some patients with neuroendocrine tumors, particularly those with high-grade, poorly differentiated NECs. Newer clinical trials are needed to find alternate strategies to harness the immune response against low and intermediate grade NETs.
- Supportive care: Managing symptoms and side effects is an important part of cancer treatment. Supportive care may include medications to control symptoms, such as octreotide or lanreotide for flushing and diarrhea, or palliative treatments to improve quality of life. Palliative radiotherapy to painful bone metastasis, bone-building agents such as bisphosphanates, calcium, vitamin D.
Neuroendocrine tumors are a rare but increasingly recognized type of cancer that can arise from many different parts of the body. Diagnosing and treating NETs can be challenging, and treatment options depend on several factors, including the location and size of the tumor, the grade of the tumor, and whether it has spread to other organs. With advances in diagnosis and treatment, the prognosis for individuals with NETs has improved in recent years, and ongoing research continues to identify new treatment options for these complex tumors. It is best that these patients are evaluated and treated at centers with multidisciplinary teams.
