Multiple endocrine neoplasia syndromes (MENS) are a rare group of neuroendocrine tumours characterised by tumours that develop in two or more endocrine glands. Endocrine glands are responsible for the production and secretion of hormones, and help to control many vital bodily functions.
Neuroendocrine cancers are a complex group of tumours that develop in the neuroendocrine system, which is responsible for regulating important bodily functions such as heart rate, blood pressure and metabolism. They most commonly develop in the gastro-intestinal tract, pancreas, and the lungs; however, they can develop anywhere in the body. These tumours develop from neuroendocrine cells, which are responsible for receiving signals from the nervous system and producing hormones and peptides (small proteins) in response.
MENS are also classified as familial cancer syndromes. Familial cancer syndromes, also known as hereditary cancer syndromes, are rare conditions that cause an increased risk of cancer as the result of inherited genetic mutattions in certain cancer-related genes. They can affect both adults and children, however they generally develop in people at a younger age than normal. While familial cancer syndromes are not classified as cancer, they are equally as severe and can be life-threatening as they are associated with the development of various tumours throughout the body. Having a familial cancer syndrome does not guarantee the development of cancer, however the risk of developing cancer is higher than those who do not have a familial cancer syndrome.
MENS tumours can be inherited or sporadic (no family history). The average age and sex of people with these diseases usually vary by subtype.
Types of Multiple Endocrine Neoplasia Syndromes
MENS tumours are broadly grouped into two categories based on the endocrine glands that are affected.
MEN Type 1
MEN type 1 (MEN 1), also known as Wermer’s syndrome, causes tumours to develop in a combination of the parathyroid gland, pituitary gland, and/or the pancreas. This may include any combination of the following NETs:
In rare cases, they may also involve the following NETs:
MEN 1 generally affects men and women equally, and are diagnosed in both children and adults. This disease can have a good prognosis.
MEN Type 2
MEN type 2 (MEN 2) is a rare disease that causes tumours to develop in a combination of the thyroid gland, the parathyroid gland, and/or the adrenal glands. There are two distinct types of MEN 2.
MEN Type 2A
MEN type 2A is the most common subtype of MEN 2, and involves a medullary thyroid carcinoma in addition to one or both of the following NETs:
MEN type 2A can also be categorised into four subvariants, based on the presence or absence of other conditions:
- Classical MEN 2A (no associated condition present).
- MEN2A with cutaneous lichen amyloidosis.
- MEN2A with Hirschsprung disease.
- Familial medullary thyroid cancer (inherited form of medullary thyroid cancer that presents without any other conditions, including pheochromocytoma and parathyroid tumours).
MEN 2A is generally diagnosed equally between the sexes, and is often more prevalent in children. These tumours can have a good prognosis.
MEN Type 2B
MEN type 2B is the rarer subtype of MEN 2, and involves a more severe presentation of medullary thyroid carcinoma, in addition to pheochromocytomas. These tumours do not involve a parathyroid tumour, and are generally more aggressive.
MEN 2B is generally diagnosed equally between the sexes, and is often more prevalent between the ages of 5-18. The prognosis for this disease may not be as good as other MEN tumours due to the advanced stage of medullary thyroid carcinoma.
For more information on medullary thyroid carcinoma, please refer to the Rare Cancers Australia Thyroid Cancer page.
Treatment
If a MENS is detected, each individual tumour will be staged and graded based on size, metastasis (whether the cancer has spread to other parts of the body) and how the cancer cells look under the microscope. Staging and grading helps your doctors determine the best treatment for you.
Cancers can be staged using the TNM staging system:
- T (tumour) indicates the size and depth of the tumour.
- N (nodes) indicates whether the cancer has spread to nearby lymph nodes.
- M (metastasis) indicates whether the cancer has spread to other parts of the body.
This system can also be used in combination with a numerical value, from stage 0-IV:
- Stage 0: this stage describes cancer cells in the place of origin (or ‘in situ’) that have not spread to nearby tissue.
- Stage I: cancer cells have begun to spread to nearby tissue. It is not deeply embedded into nearby tissue and had not spread to lymph nodes. This stage is also known as early-stage cancer.
- Stage II: cancer cells have grown deeper into nearby tissue. Lymph nodes may or may not be affected. This is also known as localised cancer.
- Stage III: the cancer has become larger and has grown deeper into nearby tissue. Lymph nodes are generally affected at this stage. This is also known as localised cancer.
- Stage IV: the cancer has spread to other tissues and organs in the body. This is also known as advanced or metastatic cancer.
Cancers can also be graded based on the rate of growth and how likely they are to spread:
- Grade I: cancer cells present as slightly abnormal and are usually slow growing. This is also known as a low-grade tumour.
- Grade II: cancer cells present as abnormal and grow faster than grade-I tumours. This is also known as an intermediate-grade tumour.
- Grade III: cancer cells present as very abnormal and grow quickly. This is also known as a high-grade tumour.
Once your tumours have been staged and graded, your doctor may recommend genetic testing, which analyses your tumour DNA and can help determine which treatment has the greatest chance of success. They will then discuss the most appropriate treatment option for you.
Treatment is dependent on several factors, including location, age, stage of disease and overall health.
Treatment Options for MENS Type 1
Treatment for MENS 1 may include:
- Surgery, potentially including:
- Parathyroidectomy (partial or total removal of a parathyroid gland).
- Lymphadenectomy (removal of affected lymph nodes).
- Tumour debulking (removal of as much of the tumour as possible without risk of damage).
- Transsphenoidal surgery (removal of pituitary tumour through an incision in the nasal cavity).
- Craniotomy (removal of the tumour through an opening in the skull).
- Pancreaticoduodenectomy/Whipple procedure (removal of portions of the pancreas, bile duct, small intestine/duodenum, gallbladder and/or stomach).
- Total pancreatectomy (complete removal of the pancreas).
- Distal pancreatectomy (removal of the tail of the pancreas and part of the spleen).
- Splenectomy (partial or total removal of the spleen).
- Thymectomy (partial or total removal of the thymus gland).
- Endoscopic resection (removal of tumour via an endoscopy).
- Gastrectomy (partial or total removal of the stomach).
- Surgery to insert a feeding tube (often required after surgery on the stomach).
- Right or left hemicolectomy (removal of the right or left side of the colon).
- Sigmoid colectomy (removal of the sigmoid portion of the colon).
- Total colectomy (complete removal of the colon).
- Proctocolectomy (removal of the colon and rectum).
- High anterior resection (removal of the lower end of the colon and the upper end of the rectum).
- Abdominoperineal resection or excision (APR or APE) (removal of the sigmoid colon, rectum, and anus).
- Ultra-low anterior resection (removal of the lower end of the colon and all of the rectum).
- Colonic J-pouch (an internal pouch is created from the lining of the bowel, which acts as the rectum).
- Appendectomy (complete removal of the appendix).
- Adrenalectomy (partial or total removal of affected adrenal gland).
- Radiation therapy, potentially including:
- Peptide receptor radionuclide therapy (PRRT).
- Selective Internal radiation therapy (SIRT).
- Chemotherapy.
- Somatostatin analogues (SSAs).
- Targeted therapy, potentially including:
- Monoclonal antibodies.
- Small molecular inhibitors.
- Hormone therapy.
- Immunotherapy.
- Cryotherapy.
- Radiofrequency ablation (RFA).
- Watch and wait (generally only used for indolent tumours only).
- Clinical trials.
- Palliative care.
Treatment Options for MENS Type 2 (A & B)
Treatment for MENS 2 may include:
- Surgery, potentially including:
- Parathyroidectomy (partial or total removal of a parathyroid gland).
- Lymphadenectomy (removal of affected lymph nodes).
- Tumour debulking (removal of as much of the tumour as possible without risk of damage).
- Adrenalectomy (partial or total removal of affected adrenal gland).
- Thyroidectomy (partial or total removal of the thyroid gland).
- Radiation therapy.
- Chemotherapy.
- Immunotherapy, potentially including:
- Checkpoint inhibitors.
- Immune stimulants.
- CAR T-cell therapy.
- Oncolytic virus therapy.
- Hormone therapy.
- Targeted therapy.
- Clinical trials.
- Palliative care.
For more information on the treatment options, please refer to the Rare Cancers Australia treatment options page.
Risk factors
MENS types 1 and 2 are inherited autosomal disorders, which means that an affected parent has a 50% chance of passing the condition on to their children. However, some people may experience the disease without a family history.
The genetic mutations that cause MENS include:
- MEN1 gene (MEN 1).
- RET gene (MEN 2).
Not everyone with these risk factors will develop the disease, and some people who have the disease may have none of these risk factors. See your general practitioner (GP) if you are concerned.
Early symptoms
Many people with a MENS may appear asymptomatic in the early stages of disease. As the tumour progresses, some of the following symptoms may appear.
Symptoms of MENS Type 1
Symptoms of MENS 1 will vary, depending on the endocrine glands that have been affected. General symptoms of MENS 1 include:
- General weakness.
- Fatigue.
- Nausea and/or vomiting.
- Unexplained weight loss/loss of appetite.
- Diarrhoea.
- Persistent abdominal, side, and/or back pain.
Symptoms of a Parathyroid Adenoma
In addition to the general symptoms listed above, people with a MENS 1 tumour involving the parathyroid gland may also experience the following symptoms:
- Unusually increased thirst.
- Polyuria (frequent or excessive urination).
- Constipation.
- Difficulties concentrating.
- Bone pain.
- Easily broken bones.
- Lump in the neck.
- Changes in the voice, such as hoarseness.
- Difficulties swallowing.
Symptoms of a Pituitary Adenoma
In addition to the general symptoms listed above, people with a MENS 1 tumour involving the pituitary gland may also experience the following symptoms:
- Persistent headaches.
- Changes in vision, such as:
- Blurred vision.
- Double vision.
- Loss of peripheral vision.
- Blindness.
- Eye muscle weakness.
- Facial numbness and/or pain.
- Dizziness.
- Loss of consciousness.
- Loss of body hair.
- Changes in menstruation and milk production.
- Decreased sex drive.
- Delayed growth and sexual development (children).
- Seizures.
- Infertility.
- Osteoporosis.
- Erectile dysfunction.
- Breast growth (in men).
- Giantism (children).
- Acromegaly (adults).
- Cushing’s disease.
- Lowered testosterone levels (in men).
- Hyperthyroidism.
Symptoms of a Pancreatic Neuroendocrine Tumour
In addition to the general symptoms listed above, people with a MENS 1 tumour involving the pancreas may also experience the following symptoms:
- Chronic peptic/stomach ulcers.
- Gastro-oesophageal reflux.
- Oesophagitis.
- Skin rash on the face, stomach, and/or legs.
- High blood sugar (Glucagonoma and Somatostatinoma).
- Blood clots, which has varied symptoms depending on location:
- Lungs – shortness of breath, cough, pain in the chest.
- Arms and/or legs – pain, swelling, warmth redness of area.
- Sore tongue and/or mouth sores.
- Low blood sugar (Insulinoma).
- Accelerated heart rate.
- Gallstones.
- Jaundice (yellowing of the eyes and/or the skin).
- Steatorrhea (very foul-smelling stool).
- Anaemia.
- Dehydration.
- Low potassium levels.
- Indigestion.
Rare Symptoms of MEN Type 1
In addition to the general symptoms listed above, people with a MENS 1 tumour involving the thymus gland, gastrointestinal tract, and/or adrenal glands, may also experience the following symptoms:
- Shortness of breath.
- Persistent cough.
- Chest pain.
- Difficulty swallowing.
- Superior vena cava syndrome.
- Carcinoid syndrome.
- Rectal bleeding.
- Bowel obstruction.
- Zollinger-Ellison syndrome.
- Hypertension (high blood pressure).
- Being very pale.
- Accelerated heart rate.
- Headaches.
- Unexplainable sweatiness.
- Anxiety.
- An adrenal mass.
- Orthostatic hypotension).
- Blurred vision.
- Polyuria (frequent or excessive urination).
- Constipation.
- Cardiomyopathy.
- Hyperglycaemia.
Symptoms of MEN Type 2
Symptoms of MENS 2 will vary, depending on the endocrine glands that have been affected.
Symptoms of a Medullary Thyroid Carcinoma
All people with a MEN 2 may experience some of the symptoms of a medullary thyroid carcinoma, which include:
- A painless lump in the neck.
- Difficulty swallowing.
- Difficulty breathing.
- Changes in the voice, such as hoarseness.
- Swollen lymph nodes in the neck.
Symptoms of Pheochromocytoma
In addition to the symptoms of the medullary thyroid carcinoma listed above, people with a MENS 2 tumour involving the adrenal glands may also experience the following symptoms:
- Hypertension (high blood pressure).
- Headaches.
- Unexplainable sweatiness.
- Accelerated heart rate.
- Shakiness.
- Anxiety.
- An adrenal mass.
- Orthostatic hypotension).
- Blurred vision.
- Polyuria (frequent or excessive urination).
- Constipation.
- Cardiomyopathy.
- Hyperglycaemia.
Symptoms of a Parathyroid Adenoma
In addition to the symptoms of the medullary thyroid cancer listed above, people with a MENS 2 tumour involving the parathyroid gland may also experience the following symptoms:
- Unusually increased thirst.
- Polyuria (frequent or excessive urination).
- Constipation.
- Difficulties concentrating.
- Bone pain.
- Easily broken bones.
Not everyone with the symptoms above will have cancer, but see your GP if you are concerned.
Diagnosis/diagnosing
If your doctor suspects you have a type of MEN, they may order the following tests to confirm the diagnosis and refer you to a specialist for treatment.
Physical Examination
Your doctor will collect your overall medical history, as well as your current symptoms. Following this, they may examine your body to check for any abnormalities.
Blood & Urine Tests
Blood and urine tests are used to assess overall health and detect any abnormalities. Some of these tests may include:
- General blood test to assess overall health.
- Full blood count, which measure the levels of red blood cells, white blood cells and platelets.
- Blood chemistry and/or blood hormone studies, which analyse the levels of certain hormones and other substances in the blood.
- Urinalysis, which analyses the colour of your urine and its contents (e.g., sugar, protein, red and/or white blood cells etc.).
- 24-hour urine test, which measures levels of catecholamine levels in your urine.
Imaging Tests
The doctor will take images of your body using magnetic resonance imaging (MRI), a computed tomography scan (CT scan), ultrasound, MIBG scan, octreotide scan, and/or positron emission tomography (PET scan), depending on where it is suspected the cancer is. The doctor may also look at other parts of the body and look for signs of metastasis.
Biopsy
Once the location(s) of the cancer has been identified, the doctor will perform a biopsy to remove a section of tissue using a needle. The tissue sample will then be analysed for cancer cells. This can be done by a fine needle aspiration (FNA), a core needle biopsy (CNB), or during a surgical procedure.
Prognosis (Certain factors affect the prognosis and treatment options)
While it is not possible to predict the exact course of the disease, your doctor may be able to give you a general idea based on the rate and depth of tumour growth, susceptibility to treatment, age, overall fitness, and medical history. Generally, early-stage MENS have a better prognosis and survival rates. However, if the cancer is advanced and has spread, the prognosis may not be as good and there may be a higher risk of cancer recurrence. It is very important to discuss your individual circumstances with your doctor to better understand your prognosis.
References
Some references are to overseas websites. There may be references to drugs and clinical trials that are not available here in Australia.