Adrenal masses: Pathology review

Definitions & Key takeaways

Adrenal masses are abnormal growths or lumps on the adrenal glands. The most common type of adrenal mass is a non-cancerous (benign) tumor, but several types of cancer can occur in the adrenal glands.

The symptoms of an adrenal mass depend on its size and location. Smaller tumors may not cause any symptoms, while larger tumors can cause pain, pressure, or other problems depending on their location.

Chapters:

Watch video only

Case study0:00–0:56

While doing your rounds, you see two individuals. First is Jessica, who comes in with lumbar pain, anuria, and constipation.
Examination is unremarkable and she doesn’t have any history of kidney disease. The other person is 38-year-old Dan, who is obese and has an abnormally round face.
He is also hypertensive and hyperglycemic. Dan is not taking any medications but he’s complaining of severe lumbar pain on the left side.
Abdominal CT scans were obtained for both. In Jessica’s case, imaging detected a mass in the right adrenal cortex.
In Dan’s case, CT detected a mass in the left adrenal cortex.Ok, so both seem to have some type of adrenal masses. But first, a little bit of physiology.

Pathophysiology0:56–3:54

Each adrenal gland has two main components: the cortex and the medulla. For your exam, something high-yield to keep in mind is that the cortex is composed of 3 zones.
The zona glomerulosa, the outer zone, contains clustered cells that produce mineralocorticoids, mainly aldosterone, which regulates blood pressure and electrolyte balance.
The zona fasciculata, the middle zone, contains foamy-looking cells in columns that are responsible for the production of glucocorticoids, predominantly cortisol, which increases blood sugar levels via gluconeogenesis, suppresses the immune system, and aids in metabolism.
And the innermost zone is the zona reticularis, which has basophilic cells arranged in anastomosing cords that produce gonadocorticoids, especially androgens like dehydroepiandrosterone or DHEA.
The medulla is composed of special cells called chromaffin cells. These are modified postganglionic sympathetic neurons that originate from the neural crest.
Normally, when a fetus is in its 5th week of development, special cells called neural crest cells start migrating along the midline of the embryo.
In the thoracic region, neural crest cells differentiate into the neurons of the sympathetic chain on either side of the developing spinal cord.
In the lumbar region, neural crest cells differentiate into the cells of the adrenal medulla. Chromaffin cells are also responsible for the pulsatile production of catecholamines like epinephrine, also known as adrenaline; norepinephrine, or noradrenaline; and small amounts of dopamine.
These hormones prepare the body for the fight-or-flight response by increasing the heart and respiratory rate, constricting blood vessels, increasing the metabolic rate, and heightening cognitive awareness.
Another high-yield fact is that unlike postganglionic sympathetic neurons that release norepinephrine as a neurotransmitter, chromaffin cells release norepinephrine in the bloodstream as a hormone so it can act on various tissues far from the adrenal glands.
Ok, so adrenal masses and tumors can emerge from any cell of the adrenal cortex or medulla that over proliferates. The tumors can be benign or malignant, and, with regard to hormone secretion, these tumors can be non-functional, meaning they don’t secrete hormones, or functional, meaning they secrete hormones and cause hormone-specific symptoms.Now, when it comes to non-functional adrenal tumors, the ones in the cortex are typically benign and most are adenomas.

Non-functional tumors3:54–8:16

The ones in the medulla however, are more likely to be carcinomas. One of the main risk factors for adrenal carcinomas is mutations in the TP53 gene, which codes for a tumor suppressor protein.
Those with a mutated TP53 gene are at risk of developing Li Fraumeni syndrome, which is an autosomal dominant disorder that involves multiple malignancies at an early age.
The syndrome is also known as SBLA syndrome, which is an acronym given by the malignancies it is associated with: sarcoma, breast cancer, leukaemia, and adrenal gland carcinoma.
Additionally, adrenal carcinomas may not be primary, meaning they metastasized from elsewhere in the body. These most often come from the lungs, kidney, colon, lymphomas and skin melanomas.Because non-functional tumors don’t secrete any hormones, the symptoms they cause mostly depend on their size and the organs they compress.
Many individuals are initially asymptomatic, however, if the tumor involves both glands from the beginning, which is a rare occurrence, it can lead to adrenal insufficiency.
Symptoms of adrenal insufficiency can include weight loss, muscle weakness, fatigue, low blood pressure, and darkening of the skin.
In time, as the tumor grows, it can start pressing on the nearby structures. These can consist of lumbar pain when the tumor presses on nearby spinal nerves, anuria, or non passage of urine, when it compresses on the ureters, and even constipation if the tumor is large enough to block a part of the intestine.
One very high yield complication is rupture of a highly vascularized tumor, which can lead to adrenal hemorrhage. The major signs of adrenal hemorrhage are abdominal pain, falling hematocrit, and signs of an adrenal crisis, including hyponatremia, fever, hypoglycemia, and loss of consciousness.
Additionally, malignant tumors can also cause symptoms like persistent abdominal or flank pain, hematuria, as well as general symptoms like weight loss and anorexia.
Adrenal carcinoma can also metastasize to the liver, lungs, lymph nodes, the 3 L’s, as well as the bones, which means individuals might also present symptoms related to the affected organ.
Diagnosis of non-functional tumors begins with a CT scan, which can provide some clues regarding the benign vs. malignant nature of the tumor, like the size of the mass, its shape and borders.
In some cases, a biopsy should also be performed, especially if imaging cannot characterize the mass as benign and if pheochromocytoma is excluded.
Biopsy is also recommended if there’s suspicion that the tumors are actually metastases from other sites in the body. If metastases are suspected, CT imaging of the chest and liver, as well as a bone scan should be done to find the primary tumor.
Treatment of benign non-functional tumors depends on the size. A smaller tumor can be monitored regularly by CT or MRI.
A large or potentially malignant tumor should be removed via laparoscopic adrenalectomy. Chemotherapy and radiation therapy are used as needed.
Now, when it comes to functional benign and malignant tumors, these are diverse and the symptoms they cause depend on the type of adrenal cells they derive from.Starting with the outermost zone of the adrenal cortex, the zona glomerulosa , you need to know that tumors that secrete aldosterone usually originate from this zone and these tumors are usually benign.

Aldosterone-secreting tumors8:16–11:51

Remember that aldosterone release is increased whenever there’s a drop in blood pressure or sodium levels. This hormone increases the activity of the sodium/potassium ATPase ion pump on the surface of the cells that line the distal tubules and collecting ducts of the kidney.
The result is increased sodium and water reabsorption and increased potassium and hydrogen excretion through urine. When there’s a tumor that secretes too much aldosterone, we get Conn syndrome or primary aldosteronism.
The high levels of aldosterone will lead to hypokalemia, hypernatremia, and metabolic alkalosis. In addition, more water is reabsorbed by the kidneys along with the sodium, so there’s also an increase in plasma volume, leading to hypertension.
As a result, the main symptom of primary aldosteronism is treatment-resistant hypertension. Now, it might be helpful to know that because hyperaldosteronism also causes potassium loss, the affected individuals might come in with symptoms of hypokalemia muscular aches and weakness, muscle spasms, numbness, and heart palpitations.
Excessive water retention can also lead to increased urination while metabolic alkalosis, is usually associated with nausea, vomiting, and abdominal pain.
Something else that might help you is that Conn syndrome does not usually cause edema because of something called an aldosterone escape mechanism.
The mechanism is actually unknown but it is believed that in these individuals, the surge in blood volume stimulates the atria of the heart to release high levels of atrial natriuretic peptide which leads to compensatory diuresis and “escape” from edema and severe hypernatremia.
This is in contrast with secondary hyperaldosteronism like in heart failure, where the aldosterone escape mechanism is impaired, and edema does occur.Diagnosis is high-yield and it begins by measuring serum potassium levels, which should be low, aldosterone levels which should be high, and plasma renin activity, which should be low as well since high blood pressure decreases renin release.
Serum sodium can be mildly elevated or normal due to the aldosterone escape mechanism. Once primary aldosteronism is confirmed, an abdominal CT or MRI scan is needed to confirm and locate the aldosterone-producing tumor.
Some cases may be treated by removing the tumor with surgery. In case of bilateral tumors, treatment is typically with aldosterone antagonists such as spironolactone or eplerenone.
Other medications for high blood pressure, hypokalemia, and a low salt diet may also be needed, especially before surgery.Next, the tumors that secrete cortisol typically originate in the cells of the zona fasciculata.

Cortisol-secreting tumors11:51–17:07

These are more often adenomas, but in rarer cases, carcinomas can also secrete cortisol. High cortisol level causes Cushing syndrome.
Now, Cushing syndrome can be caused by anything that leads to excess cortisol, not only by adrenal tumors. A high yield fact to keep in mind is that the majority of cases actually occur in individuals using exogenous cortisol, like prednisone, over a long period of time, often as a treatment for autoimmune and inflammatory conditions, like rheumatoid arthritis or poorly controlled asthma.
Whatever the cause, high cortisol levels trigger the negative feedback in the hypothalamus, which suppresses corticotropin-releasing hormone or CRH production.
This suppresses adrenocorticotropic hormone or ACTH production by the pituitary. Normally, at this point, with nothing to simulate them, the adrenal glands would stop producing cortisol.
However, tumors secreting cortisol are not regulated by ACTH, so they keep pumping out cortisol independently. In contrast, with no stimulation from ACTH, the normal tissue in the zona fasciculata of the uninvolved adrenal gland shrinks and atrophies.
The symptoms of Cushing syndrome are directly related to the effects of excess cortisol on its various target tissues. For example, excess cortisol leads to severe muscle and skin breakdown, which leads to muscle wasting, skin thinning, abdominal striae or lines and easy bruising.
The bones are also broken down so fractures can occur due to osteoporosis. Next, there’s elevated blood glucose level due to increased gluconeogenesis in the liver.
As a result, insulin level goes up, and eventually insulin resistance develops. Cortisol also increases appetite which can lead to weight gain, which can manifest as truncal obesity.
But there’s also fat redistribution to the cheeks, resulting in a round, moon-shaped face, and to the back of the neck causing buffalo hump.
Cushing syndrome can also lead to arterial hypertension. That’s because cortisol can amplify the effect of catecholamines on blood vessels.
Cortisol is also a weak agonist for mineralocorticoid receptors, so it can increase blood pressure by causing the kidneys to retain more fluid and sodium.
Remember for your exam that this is called pseudohyperaldosteronism. High levels of cortisol also inhibits the secretion of gonadotropin-releasing hormone from the hypothalamus, which messes up normal ovarian and testicular function.
In females, this leads to amenorrhea or absent menstruation.Diagnosis of Cushing syndrome caused by an adrenal tumor is a simple algorithm that’s very high yield.
It’s initially based on measuring the free cortisol in a 24-hour urine sample to confirm cortisol levels are high. Alternatively, blood or saliva tests at midnight can help check if there’s a normal daily rise and fall of cortisol levels.
Moving on, we need to test the ACTH plasma level. In adrenal tumors, it’s important to know that ACTH levels are usually low because high levels of cortisol inhibit the pituitary secretion of ACTH.
The next step is the overnight low-dose dexamethasone suppression test, which is when a person is given a low dose of dexamethasone, which is an exogenous steroid that suppresses ACTH production in the pituitary gland.
Normally that should cause a decrease in ACTH and serum cortisol levels by morning, but if Cushing syndrome is caused by endogenous cortisol production, then the serum cortisol levels should remain unchanged.
And finally, an abdominal CT or MRI, might help locate and differentiate a benign tumor from a malignant one.Treatment consists of removing the tumor surgically.
Sometimes, medication can be given before or after surgery, or as an alternative when surgery is not possible. The antifungal ketoconazole, which acts as an adrenal steroidogenesis inhibitor, is the most commonly used drug for Cushing Syndrome, mainly because of its rapid action.
The glucocorticoid receptor antagonist mifepristone is also effective in controlling clinical comorbidities, mainly glucose intolerance.Now let’s switch to tumors of the medulla.

Neuroendocrine tumors17:07–18:03

These are usually neuroendocrine tumors, which are a group of tumors that can occur in almost any endocrine or non-endocrine tissue, especially in the gut, pancreas, lungs, and adrenal glands.
In essence, they are made up of cells that have traits similar to those of nerve cells and hormone-producing cells, which is why they can produce pretty much any type of hormone.
Just like most tumors, they can be functional or non-functional, and, of course, benign or malignant. They are sporadic but can also be seen in several inherited familial syndromes, including multiple endocrine neoplasia type 1 and 2, von Hippel-Lindau disease, and neurofibromatosis type 1.One particular neuroendocrine tumor that’s most often found in the adrenal gland is pheochromocytoma, a tumor that is derived from chromaffin cells and secretes catecholamines like epinephrine and norepinephrine.

Pheochromocytoma18:03–23:43

Pheochromocytomas are usually benign and it’s the most common tumor of the adult adrenal medulla. Something that can help you remember the high yield facts about this tumor is the “rule of ten,” which is called that because around 10% of pheochromocytomas are; malignant, bilateral, extra adrenal, most commonly in the bladder, calcify, and occur in kids.
Although they tend to arise sporadically, 10% of pheochromocytomas are associated with inherited syndromes. For example, there are two syndromes called multiple endocrine neoplasia type 2A and type 2B, where there are multiple tumors, including pheochromocytoma, usually caused by a mutation in the RET gene, which has a role in cell growth and division.
Another disease associated with pheochromocytomas is Von Hippel-Lindau disease, which develops when there’s a mutation in the VHL gene of the chromosome 3p, which codes for the von Hippel-Lindau tumor suppressor protein.
A third disease is neurofibromatosis type 1 or Recklinghausen disease, which is caused by a mutation in the gene NF1, located on chromosome 17, that encodes for another tumor suppressor protein called neurofibromin.
Regardless of its cause, remember that once pheochromocytomas develop, they cause symptoms by releasing too much epinephrine, norepinephrine, and, sometimes, dopamine into the blood, which triggers a “spell” or an episode of hyperadrenergic symptoms.
This often occurs in situations of stress and physical exertion, where the sympathetic nervous system increases the release of catecholamines.
It can also occur upon ingesting certain foods like chocolate, cheese, and wine which contain tyramine, a substance that triggers the release of catecholamines.
Once released into the bloodstream, catecholamines cause the smooth muscles around blood vessels to contract, raising the peripheral vascular resistance, resulting in hypertension that can’t be controlled with antihypertensive medication.
During a spell, the blood pressure can go over 180/120 millimeters of Mercury, and this is called hypertensive urgency. This can cause damage to the smaller vessels in organs, leading to hemorrhage and ischemia.
When there’s organ damage, it’s called malignant hypertension. Organs that are more sensitive to ischemia or require a larger blood supply are affected first.
So common complications include retinal damage, ischemic or hemorrhagic stroke, kidney failure, and myocardial infarction or heart failure.
Besides hypertension, the excess catecholamines can also cause sympathetic over activation, leading to symptoms like anxiety, pallor, tremors, headaches, tachycardia, sweating or diaphoresis, chest pain, and palpitations.
In some cases, individuals can also develop a paraneoplastic syndrome called secondary polycythemia, where the tumor also secretes erythropoietin.
Excess erythropoietin leads to red blood cell overproduction, which makes the blood thicker, harder to pump, and easier to clot.
Finally, in the rare case of malignant pheochromocytoma, the tumor can metastasize, most commonly to lymph nodes, liver, bones, and lungs, and cause organ-specific symptoms.
Diagnosis is made by CT and MRI, and by checking the levels of two hormones, metanephrine and normetanephrine, which are compounds that come from the degradation of catecholamines in the blood and in the urine.
This can be done by either a plasma free metanephrines test or by a 24-hour urinary metanephrines test. Catecholamine levels can also be measured in the urine and plasma, although these methods are less accurate.
Once we know there’s a pheochromocytoma, an ultrasound or a CT scan can be used to look for the location of the tumor. For treatment, the goal is to remove the tumor surgically.
However, you need to know that blood pressure needs to be lowered prior to surgery to prevent a hypertensive crisis. This is done by alpha-blockade, which is achieved by giving irreversible alpha-blockers such as phenoxybenzamine, and it should always be followed and not preceded by beta-blockade, which is achieved with beta-blockers such as propranolol.
Another important neuroendocrine tumor that often affects the adrenal glands is neuroblastoma. This is a type of cancer and it’s the most common adrenal medulla tumor in infants and children under 4.

Neuroblastoma23:43–28:04

Neuroblastoma is composed of poorly differentiated “neuroblasts,” which also originate from the neural crest, and they can occur anywhere along the sympathetic chain and the adrenal glands.
And although the causes of neuroblastoma are unknown, the tumor is associated with amplification of N-myc oncogene. Now, just like pheochromocytoma, neuroblastomas produce catecholamines, especially norepinephrine and dopamine; however, they do not typically cause severe hypertension because these tumors do not usually secrete the more potent epinephrine.
Some of the symptoms of neuroblastoma can result from the tumor releasing inflammatory chemokines that cause fever, weight loss, sweating, and fatigue.
Other symptoms of neuroblastoma depend on where the tumor is located, and are usually a result of the tumor pressing up against surrounding organs.
For example, thoracic tumor that extends to the neck can compress the cervical ganglion, causing Horner syndrome. Horner syndrome involves miosis or constriction of the pupils, ptosis or drooping of the eyelid, and anhidrosis which is an inability to sweat.
Children with neuroblastoma of the adrenal medulla can have a large, painful abdominal mass that causes abdominal distention.
Now, a pediatric kidney cancer called Wilms tumor can also have a similar presentation. So remember that when a neuroblastoma grows large enough, it will often cross the midline, but a Wilms tumor typically won’t.
About half of all neuroblastomas spread to the bones, causing bone pain and small fractures. With the secretion of catecholamines, there might also be mild hypertension, although it is not nearly as severe as in pheochromocytoma.
Sometimes, there might be a paraneoplastic syndrome called the opsoclonus-myoclonus-ataxia syndrome or “dancing eye syndrome.” This is a serious, rare, and often chronic neurological disorder consisting of three main symptoms: opsoclonus, which are multidirectional, chaotic eye movements; myoclonus, which are nonepileptic limb jerkings that can also involve the head and face; and truncal ataxia, which causes gait imbalance.
This is another key clue that could help you differentiate neuroblastoma from Wilms tumor. Diagnosis of neuroblastoma usually starts with testing for epinephrine and norepinephrine metabolites like homovanillic acid or HVA, and vanillylmandelic acid, or VMA in the blood or urine.
An abdominal CT scan can be used to show the location and size of the tumor. Sometimes, a biopsy might be necessary, which typically shows dark tumor cells arranged in Homer-Wright rosettes, which are characteristic of neuroblastoma and medulloblastoma.
The rosettes are composed of a single layer of dark cells in a halo or spoken wheel arrangement, surrounding a pale core.
These cells also stain positive for bombesin, neurofilament, and neuron-specific enolase, which are markers associated with neuroendocrine tumors.Treatment largely depends on the size and staging of the neuroblastoma.
Early on, surgery can be used to remove the tumor, but once it starts to metastasize, it will require a combination of chemotherapy, radiotherapy, medication, and even a stem-cell or bone marrow transplantation.
All right, as a quick recap. Tumors in the adrenal glands can be functional or nonfunctional.
The functional tumors that secrete aldosterone originate from the cells of the zona glomerulosa and they cause Conn syndrome.

Review28:04–29:39

Excess aldosterone leads to hypokalemia, hypernatremia, metabolic alkalosis, and hypertension. When it comes to tumors that secrete cortisol, they typically originate in the cells of the zona fasciculata and they cause Cushing syndrome.
Common symptoms include weight gain, moon facies, buffalo hump, skin striae and thinning, and amenorrhea. Complications include osteoporosis, hypertension, and diabetes.
Common neuroendocrine tumors include pheochromocytoma, and neuroblastoma. Pheochromocytomas are typically benign and they release epinephrine and norepinephrine which leads to severe hypertension.
Neuroblastomas are a cancer of the adrenal medulla that’s mainly seen in children and infants. They secrete norepinephrine and dopamine, but not epinephrine.
So while they also cause hypertension, it’s not as severe as those seen in pheochromocytoma. They can grow very large, causing a palpable, painful abdominal mass, and even abdominal distention.
Going back to our cases, Jessica came in with lumbar pain, anuria, and constipation. Examination was unremarkable and she doesn’t have any history of kidney disease.

Summary29:39–30:59

Her symptoms are rather non-specific, which is why an abdominal CT was obtained. The CT scan showed a tumor in her right adrenal gland.
The tumor is also non-functional since Jessica doesn't appear to have any symptoms to suggest hormone excess. Dan, on the other hand is obese, has an abnormally round face, and he is hypertensive and hyperglycemic, which are symptoms consistent with Cushing syndrome.
The fact that Dan is not taking any medications but he’s complaining of severe lumbar pain on the left side makes us think the excess cortisol causing his symptoms is due to an adrenal tumor rather than exogenous cortisol ingestion.
This was actually confirmed by an abdominal CT, which showed a tumor in his left adrenal gland. To confirm the tumor is functional we need to measure the level of free cortisol in a 24-hour urine sample and perform a dexamethasone suppression test.