Adrenal glands

Adrenal glands are small, triangular-shaped glands located on top of both kidneys.

Adrenal glands are composed of two parts — the cortex and the medulla — which are each responsible for producing different hormones. These hormones help regulate your metabolism, immune system, blood pressure, response to stress and other essential functions.

Cancer of the adrenal glands

Cancers that form in the adrenal medulla are called phenochromocytoma (for more information click here).

Adrenocortical Carcinoma (ACC) are cancers that form in the adrenal cortex. They can be functioning - that is they produce higher levels of hormones than normal or non-functioning - they produce the normal level of hormones.

Adrenocortical Carcinoma (ACC)

Due to different presentation of ACC - functioning (60%) verses non-functioning (40%)- and the fact that the tumor mass may produce different hormones means that there may be different presentation of symptoms. This makes early diagnosis difficult.

A nonfunctioning adrenocortical tumor may not cause signs or symptoms in the early stages as it is not producing any hormones.

A functioning adrenocortical tumor makes too much of one of the following hormones:

• Cortisol - stress hormone

• Aldosterone - regulates water and salt balance. Too much aldosterne can cause high blood pressure.

• Testosterone - primary sex hormone in men.

• Estrogen - sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics.

Detection and Diagnosis

Diagnosis of ACC can be complicated as it presents differently in different patients. There are no key indicators of ACC that would flag to a general practitioner to test for ACC. Due to ACC being a rare cancer there are no early detection tests. ACC is often detected at a late stage (that is when it has spread to other organs). Spread to other organs is known as metastatic disease and can include the lymph nodes (25–46%), lungs (45–97%), liver (48–96%), and bone (11–33%).

ACC can be discovered incidentally (<25%) this is known as an adrenal incidentaloma - an unsuspected tumor in one or both of your adrenal glands. This type of tumor is usually found by chance during an imaging test, such as an ultrasound or CT scan, which is done for another condition.

·       Ultrasound - Adrenal cortical cancer can be diagnosed incidentally by ultrasound imaging. Certain imaging features have been established for the diagnoses of adrenal tumors (refer to https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4228948/)

·       CT scan – abdominal Computed Tomography (CT) with or without contrast dye may be used to detect cancerous masses in the abdomen. The CT may detect masses in the adrenal gland or may detect the masses in other organs (depending on the stage of the cancer). The reason that masses may be detected in other organs first is that ACC is difficult to diagnose and the physician may not be examining for adrenal cancers. Detection of adrenal masses by CT will not be able to determine if it is a primary adrenal cancer (that is the cancer originated in the adrenal gland or another organ) or if it originated in the adrenal medulla or cortex. The CT scan can help determine if surgery is a good treatment option.

·       MRI – Magnetic Resonance Imaging (MRI) may sometimes provide more information than CT scans because it can better distinguish adrenal cancers from benign tumors. MRI can also be useful to determine hepatic (liver) invasion if CT is inconclusive. MRI of the brain may be done to examine the pituitary gland, because tumors of the pituitary gland can cause symptoms similar to adrenal cancer.

·       PET scan - Positron Emission Tomography (PET) scan is used to stage the ACC as it looks for spread (metastasis) into other organs. During the PET scan you are injected with slightly radioactive glucose (sugar). As such, Type I and Type II diabetics need to have their blood glucose levels below 175 mg/dL.  

·       Biopsy – the removal of cells or tissues to be viewed under a microscope to determine if the mass is benign or malignant by a pathologist. A thin needle (fine-needle aspiration) or wider needle (core biopsy) may be used to take the sample. The biopsy may be taken under CT guidance. Depending on the stage of the cancer will determine if a biopsy is taken. Earlier stage ACC that are suitable for surgery, a biopsy is not done as the sample for microscopic examination will be collected from the resected mass that is taken during surgery. If the ACC has metastasized and is not a candidate for surgery, then if a biopsy is done then it is likely to be taken from another organ other than the adrenal gland. The reason for this is that doing a biopsy can increase the risk that an adrenal cancer will spread outside of the adrenal gland.

·       Twenty-four-hour urine test – urine is collected for 24 hours to measure the amount of hormones in the urine including: Cortisol, Aldosterone, Testosterone, and Estrogen. A higher than normal amount of hormones indicates a functioning ACC.

·       Dexamethasone suppression test – done to check if adrenal gland is making too much cortisol. Low or high dose dexamethasone is given and a blood or urine sample is collected for three days to determine the cortisol level. The difference between the low and high dose dexamethasone suppression test is that the high does test can determine if the pituitary gland is telling the adrenal gland to make too much cortisol.

·       Low potassium - increased aldosterone secretion by a functioning adrenal mass can cause low potassium levels. This can be detected in a blood test. However, in isolation low blood potassium levels would not indicate ACC to a medical professional.

Presentation of symptoms

People with a non-functioning adrenal mass that is not producing excess hormones will not have any symptoms of ACC. This can make early diagnosis difficult.

If the mass is large, then it may press on organs next to the adrenal gland and cause pain in the abdomen or lower back.

For people who have a functioning adrenal mass the symptoms will depend on the hormones that the adrenal mass releases. The symptoms could include weight gain (especially in the face, neck, and trunk), high blood pressure, high blood sugar (could result in Type II diabetes), muscle weakness, trouble sleeping, deepening voice and increased hair growth, usually on the face (in women), early puberty in boys, breast enlargement in boys or men, weight loss or loss of appetite.

Cushing’s syndrome

Cushing’s syndrome is a rare syndrome that occurs when the body produces too much of the hormone cortisol (hypercortisolism). A functioning adrenal mass can produce too much cortisol. 30% of people with ACC present with Cushing syndrome. Rapid onset of Cushing’s syndrome is a characteristic in adults with ACC. If left untreated, Cushing’s syndrome can be fatal.

The symptoms of Cushing’s syndrome can include:

·       High blood pressure.

·       High blood sugar.

·       High cholesterol.

·       Weight gain in the face (“moon face”), back of the neck/shoulder blades (“buffalo hump”), and trunk.

·       Hair growth on your face and body.

·       Bolding.

·       Purple stretch marks over the abdomen.

·       Easy bruising on the arms and legs.

·       General weakness and tiredness (fatigue).

·       Blurry vision and dizziness.

·       Weak muscles and thinner arms and legs.

·       Libido changes (sex drive) and erectile dysfunction.

·       Stunted growth in children.

Health issues can include:

·       Blood clots, especially in the lungs and legs.

·       Depression.

·       Heart attack.

·       Memory problems or difficulty concentrating.

·       Broken bones.

·       Type 2 diabetes.

·       Wounds that heal poorly.

Conn’s syndrome

Conn’s syndrome (primary aldosteronism) occurs when the adrenal glands produce too much of the steroid hormone aldosterone, which helps control sodium and potassium excretion. In extremely rare cases a functioning ACC can result in Conn’s syndrome (about 2% of ACC cases), which can present with symptoms of high blood pressure and low potassium levels. This can lead to risk of heart attack, stroke, kidney failure, temporary paralysis, or the inability to move, and rhythm irregularities.

The symptoms of Conn’s syndrome include high blood pressure and low potassium levels, the other symptoms can include:

·       Excessive thirst.

·       Fatigue.

·       Frequent urination.

·       Headache.

·       Muscle cramps.

·       Visual disturbances.

·       Weakness or tingling.

Patients with primary aldosteronism can be managed with medications, such as spirinolacone (brand name Aldactone®) or eplerenone (Inspra®) which block the effects of aldosterone. If the aldosterone is coming from a tumor in one gland they can potentially be cured by surgery to remove adrenal gland tumors.

Excess sex hormones in woman

Too much testosterone in women can cause (occurs in about 20% of cases of ACC):

·       Hair growth on your face and body.

·       Balding.

·       Deepening voice.

·       Lack of menstrual periods.

10-20% of females will present with combination of Cushing syndrome and virilization (female develops characteristics associated with male hormones (androgens – testosterone).

Too much estrogen in women can cause:

·       Irregular periods.

·       Bleeding after menopause.

·       Weight gain.

Too much sex hormones in men

Too much estrogen in men can cause:

·       Low sex drive.

·       Erectile dysfunction.

·       Breast growth

2% of ACC cases in men will present with feminization (presentation of female characteristics in men due to excess estrogen).

Genetic conditions that increase ACC risk

·       Li-Fraumeni syndrome – is a genetic condition resulting in a mutation (change) in a tumor suppressor gene known as TP53. This results in the protein p53 being damaged and unable to help prevent tumors from forming. People with Li-Fraumeni syndrome are more susceptible to developing multiple cancers, including adrenocortical carcinoma (ACC). Not everyone with the mutation in the TP53 gene will develop cancer but they will have an increased risk of developing cancer. A diagnosis of Li-Fraumeni is important for family members that could potentially carry the mutation so that they can seek genetic counselling and early detection of cancers such as ACC.

·       Genetic testing is the only way to determine if families have Li-Fraumeni. Families that have multiple childhood cancers, or rare cancers such as ACC, choroid plexus carcinoma, anaplastic rhabdomyosarcoma, sonic hedgehog medulloblastoma, or hypodipoid acute lymphoblastic leukemia could indicate that they have Li-Fraumeni in their family. These families should discuss the potential of hereditary Li-Fraumeni as not all physicians are aware of the diagnosis of Li-Fraumeni.

·       Individuals with Li-Fraumeni have:

•                     approximately 50% of developing cancer by age 40,

•                     up to a 90% percent chance by age 60.

•                     Females with Li-Fraumeni have as high as a 90% - increased risk of breast cancer.

•                     Roughly 50 % of very early onset ACCs occur in children with germline TP53 mutations.

•                     Many individuals with Li-Fraumeni develop two or more primary cancers over their lifetimes.

·       Multiple endocrine neoplasia (MEN1). – also referred to as Wermer's syndrome is a rare disorder that causes tumors in the endocrine glands (including adrenal glands) and parts of the small intestine, and stomach. MEN1 is an inherited genetic disorder. Over 90% of individuals who inherit the MEN1 mutation will develop one or more symptoms of MEN1. Genetic testing is available to determine if people carry the MEN1 mutation.

·       Lynch syndrome - often called hereditary nonpolyposis colorectal cancer (HNPCC), is an inherited disorder that increases the risk of many types of cancer, particularly cancers of the colon (large intestine) and rectum, which are collectively referred to as colorectal cancer. People with Lynch syndrome also have an increased risk of ACC as well as cancers of the stomach, small intestine, liver, gallbladder ducts, urinary tract, brain, and skin. Additionally, women with this disorder have a high risk of cancer of the ovaries and lining of the uterus (endometrial cancer). People with Lynch syndrome usually develop cancer in their forties or fifties.

·       Changes in the MLH1, MSH2, MSH6, PMS2, or EPCAM gene have been found in people with Lynch syndrome. These genes are associated with repairing errors with DNA replication, mutations in these genes prevent proper DNA repair and result in errors during DNA replication. These errors in replication can result in cancerous cell growth. Mutations in the MLH1 or MSH2 gene result in 70 to 80% risk of developing cancer in a person's lifetime. While mutations in the MSH6 or PMS2 genes result in a 25 to 60% risk of developing cancer. Although mutations in these genes predispose people to cancer it does not mean that people with these mutations will get cancer in their lifetime it only increases the risk that they will develop cancer.

·       Beckwith-Wiedemann syndrome - is a growth disorder that can affect several parts of the body. Babies and children are larger than normal usually until age 8, when growth slows down, resulting in an average height in adults. Affected children have an increased risk to develop tumors, including ACC.

·       Carney complex - rare genetic disorder characterized by multiple benign tumors (multiple neoplasia) most often affecting the heart, skin and endocrine system. Abnormalities in skin coloring (pigment) resulting in a spotty appearance to the skin of affected areas are present. Some cases of Carney complex occur due to mutations of the PRKAR1A gene, not all cases of Carney complex occur due to PRKAR1A gene mutation and it is thought that other, yet to be identified, gene mutations could be involved.

·       Familial adenomatous polyposis (FAP).

·       Neurofibromatosis Type 1 (NF1).

·       Von Hippel-Lindau (VHL) syndrome.