Neuroendocrine Tumor Basics
Neuroendocrine tumors (NETs) – first recognized by a German pathologist in 1907 – can arise in many different organs, including the organs of the gastrointestinal tract, lungs, head and neck, and genitourinary tract. These tumors derive from the neuroendocrine system, comprised of cells that have features of both nerve cells and endocrine cells (the cells that make hormones).
Neuroendocrine tumors range from extremely slow growing tumors such as carcinoid tumors (originating in the lungs and gastrointestinal tract) and pancreatic NETs, to rapidly growing, aggressive tumors such as high-grade neuroendocrine carcinomas (NECs). Other NETs include Merkel cell carcinoma (a rare type of skin cancer), adrenal cortical carcinoma (ACC), and paraganglioma – tumors that form near certain blood vessels and nerves, and in nerve tissue in the adrenal glands (pheochromocytoma).
A subset of NETs, called “functional tumors,” is associated with clinical symptoms stemming from hormone overproduction (e.g., low blood sugar from insulin excess, peptic ulcer disease, and diarrhea from gastrin excess). Approximately 30% of patients with advanced carcinoid tumor and pancreatic NETs experience carcinoid syndrome, characterized by symptoms such as flushing and diarrhea due to unregulated secretion of hormones.
FAQs
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What are Neuroendocrine tumors?
Neuroendocrine tumors (NETs) can form in nearly any organ in the body. Wherever the occur, all NETs originate in neuroendocrine cells, cells that are a combination of nerve cells and hormone-producing endocrine cells. NETs can produce hormones that may cause symptoms. NETs can be fast- or slow-growing, malignant (cancerous) or benign.
Pathologists grade NETs based on cellular features seen when biopsy tissue is examined under a microscope. These features include how closely the tumor cells resemble nearby normal cells and how fast the tumor cells are replicating.
Why is it sometimes hard to diagnose NETs?
The diagnosis of neuroendocrine tumors can be complex. With the exception of small cell lung cancer, individual tumor types are relatively rare and the disease course can vary widely from patient to patient. The tumor’s grade can even change over time, although this is uncommon, or the neuroendocrine component may emerge in the context of prior therapy.
A proper diagnosis requires bringing together many elements. Collecting a complete medical and family history is important, and can help identify hormone-mediated symptoms, where the tumor started and any underlying inherited syndrome. A physical examination and review of key imaging and laboratory studies are also essential. In particular, assessing the tumor’s growth over time is critical to determining the type and timing of therapy. Adequate biopsy material and interpretation by an experienced pathologist are also necessary. When this entire process is complete, most patients will receive an accurate diagnosis that includes identification of the site where the NET began.
Our goal is to optimize the experience and outcomes of all NET patients. We have assembled a large team of experienced providers from many different specialties who are passionate about caring for NET patients. As a result, our patients have access to experts in medical oncology, surgical oncology, nuclear medicine, endocrinology, symptom management, cardiology, nutrition and many other specialized areas.
We strive to individualize therapy for patients in concert with their local providers. Finally, we continually seek new opportunities for collaboration at UCSF, making the most of relevant disease sites and research endeavors.
Currently a patient? See how to make the most of your multidisciplinary team
Why is a multidisciplinary team important?
Knowing which treatment option to employ (and when) can be a challenge, as it depends on many factors including site of origin, grade and stage of the tumor, as well as individual preferences and symptoms, extent of disease, prior therapy, and medical history. Adding to the complexity, the need for intervention can be triggered by tumor growth, symptoms, or both, and depends on whether or not a hereditary cancer is present.
In most cases, a patient is likely to require input from many different members of the multidisciplinary care team throughout the continuum of care:
-Local provider (medical oncologist, primary care provider, surgery)
-NET specialists
-Medical oncologist
- Surgeon
- Radiologist
- Pathologist
- Interventional radiologist
- Nuclear medicine specialist
- Nurse
- Nurse practitioner (or physician assistant)
- Practice assistant
- As needed: Cardiologist, Endocrinologist, Gastroenterologist, Symptom Management Specialist, Genetic Counselor, Nutritionist, Therapist/psychiatrist, Social worker, Financial counselor
How can I make the most of my care team?
Communication is the key to success. NET treatment can be complicated and typically involves care from multiple providers, often across several institutions. Trying to coordinate care is challenging. The following tips may help:
> When seeing a new provider for a second opinion or consultation, bring the names and contact information for all the other members of your team. The more complete this information is, the more efficiently your providers can communicate.
> Whenever possible, bring printouts of all reports—imaging, pathology, laboratory studies, procedure notes—to your appointments. This may seem unnecessary in an age of electronic medical records, but these systems do not always communicate with each other. And while looking up information on your tablet or phone can be helpful, it doesn’t provide your caregiver with a permanent record. A printout can be scanned into the electronic record.
> When an outside laboratory is running tests, arrange for relevant providers to get copies of the results.
> Always ask for a disk with your radiographic images and bring it to your appointments, so team members can look at the actual images in addition to the report.
> If you have undergone or are undergoing treatment at another center, bring a copy of your treatment flow sheet to your appointments.
What hereditary cancer syndromes are associated with NET?
Neuroendocrine tumors may be caused by a mutation in one of several cancer susceptibility genes that have been found in families with these tumors. Features that suggest a hereditary cancer predisposition include young age at diagnosis, multiple primary tumors in the same individual, multiple affected family members on the same side of the family and rare tumor types associated with known hereditary syndromes. Some NET types seem to be particularly associated with hereditary syndromes. These include paraganglioma, pheochromocytoma and medullary thyroid carcinoma. In addition, patients with pancreatic NET may be at greater risk for inherited syndromes than previously thought, so we often refer them to the Cancer Risk Program for genetic counseling.
Additional information about cancer genetics can be found from the NCI and also via kintalk.org.
In detail: Types of neuroendocrine tumors
Neuroendocrine tumors (NETs) arise in nearly any organ site and are characterized by their grade and ability to make hormones that cause symptoms. They are classified based on cellular features under the microscope (e.g. differentiation, cell size) and markers of cell replication (mitotic rate, Ki67 proliferative index). They can arise in nearly any organ and can be well differentiated or poorly differentiated, the unifying feature being expression of markers of neuroendocrine differentiation (e.g. chromogranin, synaptophysin, CD56, neuron specific enolase). These makers can be identified by special tests performed on biopsy material by a pathologist.
Poorly differentiated (grade 3) neuroendocrine carcinomas (PD-NECs)
These consist of large and small cell neuroendocrine carcinomas. They have often spread to distant sites at the time of diagnosis and carry a relatively poor prognosis. The classic PD-NEC is small cell lung cancer (SCLC), which accounts for nearly 15% of all lung cancers. Outside the lungs, PD-NECs typically account for <5% of tumors of a given organ site and sometimes occur in the setting of an associated component of adenocarcinoma or squamous carcinoma (e.g. mixed tumor). Regardless of site of origin, PD-NECs are typically treated with platinum-based chemotherapy (with surgery and/or radiation therapy reserved for local disease). Additional chemotherapy can be used for resistant disease. Immunotherapy is approved for use in small cell lung cancer, but the role of immunotherapy in PD-NECs arising in other sites is uncertain unless the tumor is a microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumor (e.g. high tumor mutation burden).
In terms of imaging, PD-NEC often demonstrate robust tracer uptake on FDG-PET scans, but limited uptake on somatostatin scintigraphy or somatostatin receptor (SSTR)-PET imaging (e.g. Ga68 dotatate PET). In the lungs, PD-NECs appear to be smoking related. In other locations, their cause is unclear, although at least some may be therapy-related (e.g. hormone refractory prostate cancer).
Previously known as “carcinoid tumors” (if arising outside of the pancreas) and “islet cell tumors” (if arising in the pancreas), these tumors occur in many different organ sites. In the lungs, they are categorized as typical or atypical bronchial carcinoid tumors. In the gastrointestinal tract and pancreas, well differentiated gastroenteropancreatic NETs (GEP-NETs) consist of G1 and G2 NETs, which are defined morphologically and by proliferative markers (G1 having Ki67 <3% and mitotic rare <2 per 10 HPF; G2 Ki 67 3-20% and mitotic rate 2-20 per 10 HPF). In addition, a new category of NETs was identified in 2017 (pancreas) and 2019 (GI tract) called well differentiated grade 3 (G3) NETs (WD G3 NETs). These tumors look well differentiated under the microscope, but they have a Ki 67 (>20%) or mitotic rate (>20 per 10 HPF) in the grade 3 range and can demonstrate variable tumor behavior.
Some well differentiated NETs make hormones. Pancreatic NETs sometimes make hormones such as gastrin, insulin, glucagon, and vasoactive intestinal peptide. In the GI tract, the most common site of origin is the small bowel (mid-gut) and the most common hormone that is produced is serotonin. The resultant clinical syndrome (“carcinoid syndrome”) classically consists of flushing, palpitations, and diarrhea, although other symptoms may occur (including right heart valve dysfunction). Lung NETs sometimes make serotonin or adrenocorticotropic hormone (ACTH). While there are a few exceptions, most hormone-mediated symptoms are treated with somatostatin analogs (SSA) such as lanreotide and octreotide, which also have proven antitumor activity in GEP-NETs. Telotristat (an oral tryptophan hydroxylase inhibitor) can be used to treat SSA-refractory diarrhea. Treating the underlying tumor can also lead to improvement of symptoms.
Sequence of therapy for well differentiated NETs depends on site of origin, extent of disease, rate of growth and symptoms—but may include surgery, targeted therapy like everolimus (GI track, pancreas, lung) or sunitinib (pancreas), chemotherapy (most commonly temozolomide-based therapy for pancreatic NET), and liver-directed therapies such as transarterial embolization (TAE), chemoembolization (TACE), ablation, or selective internal radiation therapy (SIRT). Lu177 dotatate peptide receptor radionuclide therapy (PRRT) is a form of targeted radiation therapy which is also widely used for GEPNETs. PRRT is only indicated in tumors that express somatostatin receptors (SSTR) by SSTR PET imaging (e.g. Ga68 dotatate PET CT or Cu64 dotatate PET imaging).
The treatment of WD G3 NETs has not been defined. They are variably treated with regimens used for G1 / G2 NETs or PD-NECs depending on the Ki67 index and tumor behavior.
The cause of most WD-NETs is unclear, although a subgroup (<20%) arises in the setting of inherited cancer syndromes such as MEN1 syndrome, von Hippel Lindau disease and neurofibromatosis. Recommendations regarding genetic testing for NETs are evolving.
>More information on Gastrointestinal Neuroendocrine (Carcinoid) Tumors from the NCI
Pheochromocytomas and paragangliomas (pheo/para)
These tumors, also classified as neuroendocrine, arise in and outside of the adrenal glands and are characterized by S100 expression, uptake on 131I/123 I-meta-iodobenzylguanidine (MIBG) scintigraphy or FDG-PET imaging, +/- hormone-production (e.g. catecholamines). More than 1/3 of PPGL patients develop pheo/para in the setting of a hereditary cancer syndrome, as such, genetic counseling is routine. In terms of treatment, therapeutic [131I]-MIBG or iobenguane I131 is used in selected patients. Chemotherapy with CVD (cyclophosphamide, vincristine, dacarbazine) or temozolomide has activity in some patients, but additional therapeutic strategies are needed. The role of Lu177 dotatate PRRT is investigational in PPGL.
>More information from the NCI
Medullary thyroid carcinomas
These represent <10% of all thyroid cancers and arise from the parafollicular cells (C-cells) of the thyroid (which make calcitonin). While most MTC are sporadic, up to 20% occur in the setting of an inherited genetic syndrome (MEN2a, MEN2b, or familial medullary thyroid cancer), so genetic testing is routine in this disease. MEN 2A includes medullary thyroid cancer, pheochromocytoma, and hyperparathyroidism. MEN 2B includes medullary thyroid cancer, pheochromocytoma, and multiple ganglioneuromas. Most patients are asymptomatic at diagnosis, but calcitonin and CEA blood levels are often elevated and can be followed over time. Surgery is the treatment of choice for local disease. While chemotherapy has limited activity for the treatment of advanced disease, receptor tyrosine kinase inhibitors appear efficacious (e.g. cabozantanib, vandetinib).
Adrenal cortical carcinoma (ACC)
ACC is a rare type of cancer that arises in the adrenal gland cortex. A subset of patients develops ACC in the setting of a hereditary cancer syndrome (e.g. Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, or Carney complex). Approximately 80% of tumors are functional (hormone-secreting) and about 30% are confined to the adrenal gland at diagnosis. Surgical resection is the treatment of choice for localized disease, and the role of adjuvant therapy (e.g. after surgery) remains controversial. In the setting of advanced disease, treatment options include surgery, adrenolytic therapy with mitotane, antihormonal drugs (i.e., ketoconazole and metyrapone), systemic chemotherapy (e.g. etoposide, doxorubicin, and cisplatin; EDP), and/or radiation therapy. The precise choice of therapy depends on the extent and location of tumor, rate of growth, and whether or not hormone excess is present.
> More information from the NCI
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