Neuroendocrine tumors (NETs) are a perplexing category of cancers that originate in specialized cells known as neuroendocrine cells. These unique cells share characteristics with both nerve cells and hormone-producing cells, making them a subject of intrigue in the world of oncology.
NETs are relatively rare and capable of manifesting anywhere within the body’s intricate web of tissues. However, they most commonly take root in the lungs, appendix, small intestine, rectum, and pancreas.
This diverse group of tumors comes in a variety of forms. Some evolve gradually, while others progress rapidly. Certain NETs are notorious for overproducing hormones, earning them the designation of “functional neuroendocrine tumors.” In contrast, there are nonfunctional neuroendocrine tumors that either release minimal hormones or none at all, often eluding detection due to their asymptomatic nature.
The diagnostic and treatment approach to NETs hinges on several factors, including the tumor’s specific type, its location within the body, hormone production, aggressiveness, and any indications of metastasis.
Neuroendocrine Tumors: Overview
Historically, NETs were considered rare and sometimes overlooked by healthcare providers. However, advancements in diagnostic techniques have expedited their detection. As a result, early diagnosis and treatment have ushered in a growing population of individuals living with NETs for extended periods of time.
In essence, NETs are tumors that originate within the specialized cells of the neuroendocrine system—a network comprising both nerve and gland cells responsible for producing and releasing hormones into the bloodstream, thereby regulating vital bodily functions such as digestion.
These neuroendocrine carcinoma cells are distributed throughout the body, with significant concentrations found in the gastrointestinal tract, including the large and small bowels, pancreas, and lung transplants.
NETs are characterized by their development in these neuroendocrine cells. Their malignancy status can vary, with some being cancerous (malignant) and others non-cancerous (benign). Typically, NETs exhibit slow growth, although exceptions exist. The specific cell type impacted defines the NET’s classification.
Functional NETs, which produce excess hormones, can trigger distinct symptoms. Conversely, nonfunctional NETs remain asymptomatic in terms of hormone release.
Some subtypes of NETs include:
- Gastrointestinal NETs: Arising in the large and small bowel
- Pancreatic NETs: Accounting for approximately 7% of all NETs
- Lung NETs: Manifesting within lung tissues
- Merkel Cell Carcinoma: Involving Merkel cells in the skin’s upper layer
- Neuroblastoma: Primarily affecting immature or developing nerve cells in children, often originating in the adrenal glands.
In 2022, over 5,400 individuals received a diagnosis of neuroendocrine cancer, with the average age at diagnosis being 64 years old. This highlights the importance of continued research and awareness in tackling this intricate and evolving field of oncology.
What is a neuroendocrine tumor (NET)?
Neuroendocrine tumors (NETs) represent an unusual category of tumors originating from specialized cells within your neuroendocrine system. These unique cells possess a blend of characteristics from both nerve cells and hormone-producing endocrine cells, forming a crucial link between your endocrine system, which is responsible for hormone regulation, and your nervous system. Remarkably, neuroendocrine cells are distributed throughout your body.
NETs exhibit a diverse array of types and subtypes, often presenting symptoms that may be initially mistaken for less severe conditions. While once considered a rare form of cancer, the landscape is changing as more individuals receive NET diagnoses, courtesy of enhanced diagnostic tests capable of swiftly identifying NETs. This shift toward earlier diagnosis and treatment is steadily expanding the population of long-term NET survivors.
Role of Neuroendocrine Cells
Neuroendocrine cells can be likened to diligent traffic officers overseeing bustling intersections and directing drivers on when to halt and when to proceed. In a similar vein, these specialized cells within your body act as vigilant sentinels, receiving signals from your nervous system.
Upon receiving these signals, these cells prompt your endocrine system to release hormones. These hormones serve as chemical messengers, orchestrating various bodily functions and conveying essential instructions to your body regarding when and how to execute them.
However, the responsibilities of neuroendocrine cells extend beyond merely monitoring signals and instigating hormone release. They also engage in the production and secretion of hormones that govern activities within the organs where they reside.
For instance, the neuroendocrine cells in your digestive system generate hormones that stimulate the production of digestive fluids and coordinate the muscular contractions responsible for propelling food through your intestines.
The development of neuroendocrine tumors occurs when your endocrine cells undergo uncontrolled division and proliferation, eventually forming tumors that can disrupt the normal functions of the organs where these cells are situated.
Types of Neuroendocrine Tumors
Neuroendocrine tumors are categorized into two primary groups: primary and secondary tumors. A primary tumor refers to cancer that has not yet spread to other regions of the body. In contrast, a secondary tumor is a neuroendocrine tumor that has metastasized, typically spreading to the lymph nodes in the lymphatic system, the liver, or the bones.
NETs are further classified based on their specific location within the body. For instance, a neuroendocrine tumor residing in the gastrointestinal tract is termed a neuroendocrine tumor of the gastrointestinal tract. Among the most prevalent primary neuroendocrine tumor types are:
- Gastrointestinal (GI) Tract: NETs most frequently originate within the GI tract, with notable occurrences in the large intestine (20%), small intestine (19%), and appendix (4%). The GI tract plays a pivotal role in the digestion of food and liquids, as well as the processing of waste. In the past, GI tract NETs were referred to as carcinoid tumors.
- Lung: The lung represents the second-most common site for NETs. Approximately 30% of NETs develop within the bronchial system, responsible for air transport to the lungs. These tumors were formerly known as carcinoid tumors.
- Pancreas: Around 7% of NETs can emerge in the pancreas, a gland resembling a pear in shape located in the abdominal region between the stomach and spine. These tumors, previously termed islet cell tumors, are now referred to as Pancreas NETs (PNETs) and constitute approximately 7% of all pancreatic cancers.
Demographics and Prevalence of Neuroendocrine Tumors
Neuroendocrine tumors can potentially afflict individuals across a broad age spectrum, encompassing children, although such cases are exceedingly rare in children, teenagers, and young adults. The typical age range for diagnosis falls between 50 and 60 years. It is noteworthy that there is a slightly higher incidence of neuroendocrine tumors among females compared to males.
In terms of prevalence, neuroendocrine tumors impact approximately 5 out of every 100,000 individuals. Annually, more than 12,000 new cases receive diagnoses, and presently, there are as many as 125,000 individuals in the United States living with these tumors.
Neuroendocrine Tumor Symptoms
The symptoms associated with neuroendocrine tumors can exhibit variations contingent upon the location of the cancerous cells. It’s essential to bear in mind that not all symptoms necessarily indicate the presence of cancer. If you observe changes in your body resembling the symptoms described below, it is advisable to consult your healthcare provider for a thorough evaluation.
The manifestation of symptoms in a neuroendocrine tumor hinges on its location within the body and the specific hormones it produces. A tumor within the digestive system might lead to symptoms such as diarrhoea, constipation, or abdominal discomfort.
Initially, neuroendocrine tumors may quietly develop without evident signs or symptoms. The nature of the symptoms experienced hinges on the tumor’s location within the body and its propensity to overproduce hormones. Broadly speaking, signs and symptoms associated with neuroendocrine tumors may encompass:
- Pain due to tumor growth.
- The emergence of a palpable lump beneath the skin.
- Unusual and persistent fatigue.
- Involuntary weight loss without apparent cause.
In the case of a lung tumor, you may experience wheezing or persistent coughing. Certain tumors, known as functioning tumors, possess the ability to release excessive quantities of hormones into the bloodstream. Neuroendocrine tumors categorized as functional tumors, which release excessive hormones, can introduce additional symptoms, such as:
- Diarrhoea
- Flushin
- Cramps
- Wheezing
- Low blood sugar (hypoglycaemia)
- Alterations in blood pressure
- Cardiac complications
If you encounter any of these symptoms, seeking prompt medical evaluation is crucial to determine the underlying cause and receive appropriate care.
Causes of Neuroendocrine Tumor
The precise origins of neuroendocrine tumors remain elusive, and our understanding of their underlying causes is still incomplete. However, the likelihood of developing a neuroendocrine tumor is heightened if you possess one of the following rare conditions or syndromes:
- Multiple Endocrine Neoplasia Type 1 (MEN 1): This is a rare hereditary condition characterized by the emergence of tumors in the endocrine system, most commonly affecting the parathyroid glands, pituitary gland, and pancreas.
- Neurofibromatosis Type 1: This group of genetic conditions prompts the growth of tumors along nerve pathways.
- Von Hippel-Lindau Syndrome (VHL): VHL is an inherited condition that triggers abnormal blood vessel growth.
Additionally, research has indicated that your risk of developing a neuroendocrine tumor experiences a slight increase if one of your parents has a history of such tumors.
For most neuroendocrine tumors, their exact causative factors remain unidentified. Nevertheless, certain risk factors may contribute, including:
- Genetic Factors: Some individuals with rare inherited diseases are at a higher risk of neuroendocrine tumor development.
- Pre-existing Conditions: Conditions like peptic ulcers or diabetes may potentially elevate the risk of neuroendocrine tumor occurrence.
The Origins of Neuroendocrine Tumors
The precise catalysts for the cellular growth that leads to the development of neuroendocrine tumors (NETs) remain an enigma to researchers. Nevertheless, they have established connections between NETs and inherited syndromes, such as:
- Multiple Endocrine Neoplasia Type 1 (MEN1): This condition triggers the overactivity of or the formation of tumors in the thyroid, parathyroid, or adrenal glands.
- Multiple Endocrine Neoplasia Type 2 (MEN2): Individuals with MEN2 experience overactivity or tumor formation in the pancreas, pituitary gland, or parathyroid glands.
- Von Hippel-Lindau Syndrome: This rare syndrome leads to the growth of benign tumors in various regions of the body.
- Neurofibromatosis Type 1: People with this rare condition witness the growth of tumors on the skin and nerves, affecting areas such as the eyes and other bodily regions.
- Tuberous Sclerosis Complex: Symptoms of this condition encompass epilepsy, autism or developmental delays, and the emergence of skin birthmarks during early childhood.
The precise trigger for neuroendocrine tumors remains shrouded in mystery. These cancers originate in neuroendocrine cells, possessing characteristics akin to both nerve cells and hormone-producing cells, and are dispersed throughout the body.
The inception of neuroendocrine tumors transpires when alterations (mutations) transpire within the DNA of neuroendocrine cells. DNA within a cell houses the instructions governing its behavior. These mutations send signals to neuroendocrine cells to undergo rapid proliferation, culminating in the formation of a tumor.
Notably, the growth rate of neuroendocrine tumors varies widely. Some progress slowly, while others manifest as aggressive malignancies capable of infiltrating and damaging healthy tissues or disseminating (metastasizing) to other regions of the body.
Carcinoid Syndrome
Carcinoid syndrome arises when neuroendocrine tumors (NETs) excessively produce hormones, surpassing the body’s requirements. It’s important to note that carcinoid syndrome is relatively uncommon, affecting fewer than 10% of individuals with NETs. The most prevalent and early indicator of carcinoid syndrome is an uncomfortable flushing sensation in the head and neck. Additional symptoms may include:
- Abdominal cramps and diarrhoea.
- The presence of fatty, foul-smelling stools.
- Edema is characterized by swelling in the feet and legs, which can also be indicative of heart failure.
- Wheezing and breathlessness
- Reduced interest in sexual activity or erectile dysfunction.
- Jaundice is a condition marked by the yellowing of the skin and the whites of the eyes.
Diagnosing Neuroendocrine Tumors
The diagnosis of neuroendocrine tumors (NETs) is a multifaceted endeavor that relies on the specific type of NET suspected by healthcare providers. Various diagnostic methods are employed, and some of the most commonly used tests include:
- Biopsy: This involves the extraction of cells, fluids, tissues, or abnormal growths for microscopic examination.
- Core Needle Biopsy: Utilizing a fine needle and syringe, healthcare providers retrieve fluid and tissue from potentially abnormal lumps.
- Urinalysis: Screening urine for signs indicative of underlying medical conditions.
- Biochemical Tests: These tests measure the quantity or activity of particular enzymes or proteins in blood, urine, or tissue samples.
- Computed Tomography (CT) Scan: This diagnostic tool employs a series of X-rays and computer technology to generate three-dimensional images of soft tissues and bones.
- Magnetic Resonance Imaging (MRI) is a non-invasive procedure utilizing a strong magnet, radio waves, and a computer to produce precise images of internal organs and structures.
- Positron Emission Testing (PET) Scan: This involves the injection of a radioactive tracer into the body to detect early signs of cancer.
Neuroendocrine tumor diagnoses often fall into one of two main categories:
- Symptom-Based Diagnosis: Some individuals seek medical attention due to symptoms, such as pain resulting from metastatic disease, most commonly affecting the liver. For instance, a patient initially presenting with symptoms resembling gallbladder issues may ultimately be diagnosed with a neuroendocrine tumor in the liver. In other cases, hormonal symptoms serve as a diagnostic clue for healthcare providers.
- Asymptomatic Discovery: In the second group, patients exhibit no discernible symptoms, and the cancer is serendipitously detected. It may be stumbled upon during unrelated procedures like a colonoscopy, or through imaging tests like X-rays or CT scans performed for different medical reasons.
Neuroendocrine tumors can be elusive, occasionally surfacing as unexpected findings during tests for unrelated conditions. When a doctor suspects the presence of a NET or one of the syndromes linked to neuroendocrine tumors, they typically gather a comprehensive medical history, conduct a physical examination, and administer specific tests to facilitate an accurate diagnosis.
Neuroendocrine Tumor Grades
Indeed, healthcare providers employ a grading system to formulate their tumor treatment strategy. This system takes into account variables like the pace at which your cancer cells proliferate and the degree to which these cells resemble healthy cells versus cancerous cells when examined under a microscope. Familiarizing yourself with the staging and grading process can serve as valuable information during discussions with your healthcare provider about treatment options.
What are Neuroendocrine tumors (NETs) grades?
Neuroendocrine tumors (NETs) are graded based on the following criteria:
- Grade 1 (Low-Grade Tumor): These cells have a low rate of division and exhibit slow growth.
- Grade 2 (Intermediate-Grade Tumor): Cells in this category divide at an intermediate rate.
- Grade 3 (High-Grade Tumor): Cells with a fast division rate, resulting in rapid growth.
- Additionally, NETs are evaluated according to their degrees of differentiation:
- Well-Differentiated Neuroendocrine Tumor: In this case, the cells closely resemble healthy cells rather than cancerous ones.
- Poorly-Differentiated Neuroendocrine Tumor: Cells in this category bear a closer resemblance to cancerous cells than healthy ones. Poorly-differentiated tumors are further classified into small-cell and large-cell tumor subtypes.
Risk Factors Associated with Neuroendocrine Tumors
The likelihood of developing neuroendocrine tumors is elevated in individuals who inherit genetic syndromes associated with increased cancer risk. Some examples of these syndromes include:
- Multiple endocrine neoplasia, type 1 (MEN 1)
- Multiple endocrine neoplasia, type 2 (MEN 2)
- Von Hippel-Lindau disease
- Tuberous sclerosis
- Neurofibromatosis
Treatment Approaches for Neuroendocrine Tumors
The primary treatment for neuroendocrine tumors (NETs) typically involves surgery, which is the most common approach. However, if the tumors are sizable or have metastasized, additional treatment options may be considered:
- Somatostatin Analogs: This treatment category comprises medications designed to potentially curb excessive hormone production in the body, thereby retarding tumor growth when cancer cells have disseminated to other regions of the body.
- Targeted Therapy: Targeted therapy employs drugs that specifically target certain genes or proteins implicated in cancer cell proliferation, to eradicate these cancerous cells.
- Chemotherapy: Chemotherapy employs various drug types to combat and destroy cancer cells. This treatment can be employed as part of the therapeutic regimen for NETs when deemed appropriate.
Treatment for Neuroendocrine Tumors
Your treatment plan for neuroendocrine tumors (NETs) will be determined through discussions with your doctor, taking into consideration various factors including the type of NET, your specific symptoms, its location in your body, the extent of its spread, your age, overall fitness, general health, and your personal preferences.
Key treatment modalities for neuroendocrine tumors encompass:
- Surgery: Surgical intervention remains a primary treatment option, involving the removal of tumors and sometimes performing biopsies.
- Chemotherapy: Medical oncologists may prescribe and oversee chemotherapy regimens as part of your treatment plan.
- Targeted Therapy: This approach employs drugs designed to specifically target genes or proteins linked to cancer cell growth.
- Theranostics – Peptide Receptor Radionuclide Therapy (PRRT): A specialized treatment method that combines diagnostic imaging and therapeutic radionuclide therapy.
- Drug Therapy: Administered to manage symptoms arising from excess hormone production.
In some instances, Merkel cell carcinoma may also be treated using radiotherapy. Treatments may be administered individually, in combination, or sequentially, known as a multi-modality treatment. For slow-growing NETs without symptoms, immediate treatment may not be necessary.
Palliative Care
In select cases of neuroendocrine tumors, your medical team may introduce the concept of palliative care. Palliative care aims to enhance your quality of life by alleviating cancer-related symptoms. Alongside slowing the tumor’s spread, palliative treatment can alleviate pain and manage other associated symptoms. Treatment modalities might encompass radiotherapy, chemotherapy, or other drug therapies.
Treatment Team
Depending on your treatment plan, your healthcare team may comprise various specialists, including:
- General Practitioner (GP): Oversees your overall health and collaborates with specialists to coordinate treatment.
- Surgeon: Conducts tumor removal surgeries and biopsies when necessary.
- Medical Oncologist: Prescribes and manages chemotherapy courses.
- Radiation Oncologist: Prescribes and oversees radiation therapy.
- Nuclear Medicine Specialist: Coordinates radioactive scans and treatments.
- Gastroenterologist: Specializes in digestive system disorders.
- Endocrinologist: Diagnoses, treats, and manages hormonal system disorders.
- Lung Physician: Specializes in lung disease treatment and management.
- Cancer Nurse: Assists with treatment and offers information and support throughout the process.
- Dietitian: Provides dietary recommendations during treatment and recovery.
- Physiotherapist/Occupational Therapist: Aids in addressing physical and practical issues, including post-treatment mobility and movement restoration.
- Other Allied Health Professionals: This category encompasses social workers, pharmacists, and counsellors, who contribute to comprehensive care.
Endocrine Tumor Program
The Endocrine Tumor Program provides diagnosis and treatment of patients with benign or malignant tumors originating in the thyroid, parathyroid and adrenal glands, as well as the pancreas and gastrointestinal tract.
Because many endocrine tumors require a multidisciplinary approach, patients are better served in an environment where there are experts from endocrinology, surgery, radiology, nuclear medicine, hematology/oncology, radiation oncology, pathology, and gastroenterology.
Diagnosis and Treatment of Endocrine Tumors
New imaging modalities available to locate endocrine tumors include radionucleide tests, endoscopic ultrasound, intraoperative ultrasound, and new laparoscopic surgical techniques. The latest technologies are being used for the diagnosis and treatment of endocrine tumors. For example, endoscopic ultrasound has been found to be the most sensitive and cost-effective technique to locate pancreatic islet cell tumors before surgery. Intraoperative ultrasound is also routinely used to locate and stage potentially malignant tumors.
Surgeons in the Endocrine Tumor Program are recognized for their pioneering efforts in a technologically advanced surgical procedure called laparoscopic adrenalectomy. This procedure, done with four tiny incisions to remove adrenal tumors, results in less post-operative pain, a faster recovery, and a shorter hospital stay than traditional adrenalectomy. Advances in laparoscopic surgical techniques, including laparoscopic ultrasonography, are incorporated into operative strategies that stage endocrine tumors.
Advanced Surgical Procedures
Nuclear medicine, radiation therapy and chemotherapy are also used to treat some endocrine tumors.
The Endocrine Case Conference and the Tumor Conference are held weekly to discuss cases. Attended by specialists from endocrinology, surgery, radiology, nuclear medicine, haematology/oncology, radiation oncology, pathology, and gastroenterology, the team works closely together to formulate an individualized treatment plan for each patient.
In 1974, Research centres initiated a screening program and patient registry to assess the risk of thyroid tumors in patients with a history of low-dose head and neck irradiation. Because of the risk of thyroid cancer, the program continues to follow patients every year.
Areas of Special Interest and Evaluation
Other areas of special interest and investigation by the Endocrine Tumor Program include:
- Multiple Endocrine Neoplasia Syndromes
- Pancreatic Endocrine Tumors
- Adrenal Neoplasms
The Endocrine Tumor Program functions within the Department of Surgery at most hospitals.
