Adrenal Cancer Facts: What Adrenocortical Carcinoma Is and Why It Matters

Adrenal cancer is rare. Adrenocortical carcinoma (ACC), the cancer that starts in the outer layer of the adrenal gland, affects roughly 0.5 to 2 people per million each year worldwide. In the United States, the American Cancer Society says the exact number of new cases is not known and is probably around 200 per year. Other published reviews estimate 300 to 400 new cases per year. Either way, this is one of the least common cancers doctors see. If you feel like almost no one around you has heard of it, that is because very few people have.

The phrase "adrenal cancer" is an umbrella term. It covers more than one disease. These adrenal cancer facts center on adrenocortical carcinoma, because ACC is what most people mean when they say adrenal cancer, and it is what most people searching this term are trying to learn about. Throughout this guide, when you see "adrenal cancer" without any other label, it means ACC.

Three other things get confused with ACC, and it helps to sort them out right away.

• Pheochromocytoma is a tumor of the adrenal medulla, the inner core of the gland, and it behaves very differently from ACC.

• Adrenal metastases are cancers that started somewhere else, such as the lung or breast, and later spread to an adrenal gland. Those are not adrenal cancer, and they are treated as the original cancer. And most adrenal masses found on a scan are not cancer at all

• Benign (not cancer) growths called adenomas are far more common. Adrenal tumors show up in about 1 in every 10 people who have an imaging test of the adrenal gland, and most are harmless adenomas. If you are here because a scan picked up a spot on your adrenal gland by accident, that spot is called an incidentaloma, and the odds are strongly in your favor.

ACC has an unusual age pattern. It has two peaks instead of one. The first peak is in children younger than 5 years, and the second and larger peak is in adults in their forties and fifties. Children make up roughly 5% to 10% of all ACC diagnoses. If you are a parent reading this for your child, pediatric ACC behaves differently and is treated differently from adult ACC. ACC is also somewhat more common in women than in men, with reported ratios of about 2.5 to 1 or 3 to 1 among adults.

Two messages matter more than anything else in this guide, so we are putting them first.

• Get to a high-volume center with an adrenal specialist. Surgery done at centers that handle 15 or more ACC operations a year is linked to better recurrence-free survival and fewer local recurrences, and complete removal of the tumor with clean margins (called an R0 resection) is the single strongest thing that predicts adrenal cancer survival rates for any individual person.

• Second, ask about genetic counseling. Hereditary syndromes cause a meaningful share of ACC, and current European and American guidelines recommend that everyone diagnosed with ACC be offered genetic counseling and testing, no matter their age or family history. This is especially important for every child with ACC. Nothing in this guide replaces a conversation with your own care team, so bring your questions to them.

What Are the Adrenal Glands?

Source: Cancer.gov - Credit: Terese Winslow

You have two adrenal glands. One sits on top of each kidney, in the back of your upper belly. Each gland is small and shaped a bit like a triangle, roughly the size of a walnut or the tip of your thumb. They are hormone factories, and hormones are chemical messengers that travel in your blood and tell other parts of your body what to do.

Each adrenal gland has two parts that act almost like two separate organs. The outer layer is the adrenal cortex. The inner core is the adrenal medulla. This split matters for the rest of this guide, because ACC starts in the cortex and pheochromocytoma starts in the medulla.

The cortex is built in three layers, and each layer makes a different family of steroid hormones.

• The outermost layer makes aldosterone. Aldosterone tells your kidneys how much salt to hold onto and how much to let go, which is a big part of how your body sets your blood pressure and keeps your potassium level steady.

• The middle layer makes cortisol. Cortisol helps you handle stress, controls how your body uses protein, fat, and carbohydrates, and helps keep your blood sugar and blood pressure in a normal range.

• The innermost layer makes adrenal androgens, sometimes called DHEA. Adrenal androgens are converted in other parts of the body into the sex hormones testosterone and estrogen. In most adults, the testicles and ovaries make far more of those sex hormones than the adrenal glands do, so adrenal androgens usually stay in the background unless something goes wrong.

The medulla is different. It is really an extension of your nervous system. It makes adrenaline (also called epinephrine), noradrenaline (also called norepinephrine), and dopamine. These are the surge hormones. They speed up your heart, raise your blood pressure, and push sugar into your blood so your muscles have fuel. This is the "fight or flight" response you feel as a pounding heart and sweaty hands. Together, these are called catecholamines.

Put all of that together, and you can see why the adrenal glands matter so much. They help set your blood pressure, your blood sugar, your salt and water balance, your stress response, and some of your sex characteristics. When an adrenal tumor makes too much of one of these hormones, the effects show up all over the body, not just near the tumor.

One more thing worth knowing, because it comes up quickly after a diagnosis. Surgery for ACC usually removes the whole affected gland, an operation called an adrenalectomy. Most people can live a normal life with one adrenal gland, because a single healthy gland can generally do the work of two. Some people still need hormone medicine for a while afterward, and your care team will check for that.

How Does Adrenal Cancer Start?

Normal cells follow rules. A cell grows, copies its DNA, divides, and eventually wears out and is replaced. Checkpoints along the way stop a cell from dividing if its DNA is damaged. Cancer starts when changes in a cell's genes break those checkpoints, so the cell keeps dividing when it should stop. Over time, that cell and its copies form a lump, and some of them gain the ability to invade nearby tissue or travel elsewhere in the body.

Most ACC is sporadic. That means the gene changes were picked up during a person's life rather than inherited from a parent. These are called somatic changes, and they are not passed on to children. Nobody can point to a single trigger that caused them, which is one of the hardest parts of this diagnosis to sit with.

Researchers have mapped the main gene pathways involved.

• The TP53 gene, which normally acts as a brake on cell division and repairs DNA damage, is knocked out of action in more than half of ACC tumors.

• A second pathway, called Wnt/beta-catenin, is switched on in roughly 40% of cases.

  • That happens through changes in CTNNB1 (about 16% of tumors)

  • ZNRF3 (about 19% to 21% of tumors). ZNRF3 is now recognized as one of the most frequently altered genes in ACC.

  • A third change is overactivity of IGF2, a growth signal gene, which is present in 80% to 90% of ACC tumors and is thought to be one of the earliest steps in the process.

A meaningful share of ACC is not sporadic. Between about 5% and 15% of cases occur in people who carry an inherited gene change linked to a familial cancer syndrome. That share is far higher in children. Roughly 6% of adults with ACC carry an inherited TP53 change, compared with 50% to 80% of children with ACC. That single fact is why genetic counseling is recommended here rather than a footnote, and why it is offered to every child with ACC.

Unlike many cancers, ACC has no clear environmental cause. There is no established diet, chemical, or habit that reliably raises the risk. Prior radiation treatment to the head and neck has been reported as a risk factor, with a long gap of 15 to 30 years between exposure and tumor development. Some studies have suggested a link with cigarette smoking, but that association is weak and inconsistent and needs more study. ACC is largely not preventable, and if you are searching for something you did to cause this, the evidence says there almost certainly was nothing.

How Pheochromocytoma Starts Differently

Pheochromocytoma is a different adrenal cancer, and it works differently. It begins in the adrenal medulla, from chromaffin cells, the cells that make adrenaline and noradrenaline. Its biggest difference from ACC is genetic. More than 30% of people with pheochromocytoma or paraganglioma (PPGL) carry an inherited gene change, and up to 50% of those with metastatic disease do. At least 14 susceptibility genes have been described. The most important include the succinate dehydrogenase genes SDHB, SDHD, and SDHC, plus VHL (von Hippel-Lindau syndrome), RET (multiple endocrine neoplasia type 2), and NF1 (neurofibromatosis type 1). Because inherited causes are so common, the National Cancer Institute states that everyone diagnosed with pheochromocytoma or paraganglioma should have genetic counseling. Note how different that is from ACC, where most adult cases are sporadic. We come back to the PPGL genes in more detail later in this guide.

Where Does Adrenal Cancer Start?

ACC starts in the adrenal cortex, the outer layer of the gland. It grows from the same cells that normally make cortisol, aldosterone, and adrenal androgens, which is why so many of these tumors end up flooding the body with one of those hormones.

ACC almost always involves just one gland. Either the left or the right gland can be affected, and having tumors in both glands at once is uncommon. In one review of primary adrenal cancers, only about 1% of ACC cases involved both adrenal glands. If a scan shows masses on both sides, that pattern usually points your doctors toward something other than ACC, such as adrenal metastases or adrenal lymphoma.

ACC tumors are often large by the time they are found. The average tumor size at diagnosis is about 10 to 13 cm across, which is roughly the size of a grapefruit. Tumors that do not make hormones tend to be even larger, because nothing announces them early. This is not anyone's failure to notice. The adrenal glands sit deep in the back of the belly, where there is room for a tumor to grow quietly for a long time.

As an ACC tumor grows, it can push through the thin capsule around the gland and invade what is next to it. The fat around the adrenal gland is often the first tissue involved. From there, the tumor can grow into the kidney, into the liver, and into the inferior vena cava, the large vein that carries blood from the lower body back to the heart. Growth into that vein is one reason ACC surgery is complex and belongs in experienced hands.

ACC can also travel. Cancer cells can break away and move through the lymph system (the network of vessels and small glands that helps fight infection) or the bloodstream, and settle somewhere new. That is called metastasis. In ACC, the most common landing places are the lungs, reported in 40% to 80% of people with metastatic disease. The liver is reported in 40% to 90%, the bones in 5% to 20%, and nearby lymph nodes. Distant spread develops in more than half of people with ACC at some point. An important point about naming: if ACC spreads to the liver, the cells in the liver are still adrenocortical carcinoma cells. It is metastatic ACC, not liver cancer, and it is treated as ACC.

Where Pheochromocytoma and Paraganglioma Start

Pheochromocytoma starts in the adrenal medulla, the inner core of the gland, not in the cortex. Paraganglioma is its close cousin and starts outside the adrenal gland entirely, along the chains of nerve tissue that run through the body. Paragangliomas often form near the carotid artery in the neck, along nerve pathways in the head and neck, and in the chest, belly, and pelvis. About 80% to 85% of these chromaffin cell tumors are pheochromocytomas inside the adrenal gland, and 15% to 20% are paragangliomas outside it. Neuroblastoma, a childhood cancer, also starts in the medulla and is a separate disease.

Source: cancer.gov- Credit: Terese Winslow

How Does Adrenal Cancer Affect the Body?

ACC affects the body in two main ways. The first is hormone excess, when the tumor pours out far more of an adrenal hormone than you need. The second is mass effect, when the tumor grows large enough to press on things. Many people have both. Studies report that about 40% to 60% of ACC tumors make extra hormones, and the National Cancer Institute describes most adrenocortical tumors as hormone-making. In children, most ACC tumors make extra hormones. Most adrenal cancer symptoms come from hormones rather than from the tumor itself, which is why this section is the heart of the guide.

Too much cortisol causes a pattern called Cushing syndrome. Weight builds up in the face, neck, and trunk while the arms and legs stay thin or get thinner. The face becomes round, red, and full. A pad of fat can form at the base of the neck. Muscles weaken, especially in the thighs and shoulders, so stairs and getting out of a chair become hard. Blood sugar climbs, and blood pressure rises. Skin bruises easily and can develop purple stretch marks. Fine hair may grow on the face, upper back, or arms. When cortisol excess comes from ACC, it often builds fast and can come with a low potassium level and pronounced muscle weakness, which is one way doctors tell it apart from milder, benign causes. Cortisol also affects mood and sleep, so anxiety, low mood, and irritability are part of this picture, not a separate problem.

Too much aldosterone raises blood pressure and drives potassium out of the body. This is sometimes called Conn syndrome. Blood pressure can be high and hard to control even on several medicines. Low potassium causes muscle weakness and cramps. Many people also notice they are urinating often and feel thirsty much of the time. Aldosterone excess from ACC is less common than cortisol excess, but it is important because uncontrolled blood pressure carries its own risks.

Too much androgen shows up most clearly in women and girls. Coarse hair grows on the face, chest, upper back, or arms. Acne appears or gets much worse. Hair thins at the temples and crown in a male pattern. The voice deepens. Periods become irregular or stop altogether. In girls, the outer genitals can enlarge. In boys, extra androgen can cause early growth of the penis and early puberty. Adult men with extra androgen alone often have no obvious signs at all, which means their tumors are found later. Too much estrogen does the opposite. In men, it causes breast tissue growth, lower sex drive, and trouble with erections. In women who have not gone through menopause, it causes irregular periods, and in women who have gone through menopause, it can cause vaginal bleeding. In boys, extra estrogen can cause breast tissue to grow.

Mass effect is the second mechanism, and it is what brings many people with hormone-quiet tumors to the doctor. Pain in the belly or the flank and lower back is the most common complaint. So is a feeling of fullness, pressure, or being bloated that does not go away after eating. Some people or their doctors can actually feel a firm lump in the upper belly. A large tumor can press on the stomach and cause early fullness and nausea, press on the kidney or its drainage, or press upward and make it harder to take a deep breath when lying flat. About 30% of people with ACC have symptoms from the mass itself, and about 15% to 20% have no symptoms at all and are found by accident on a scan done for another reason. Once the disease has spread, symptoms follow the new location: shortness of breath or cough from the lungs, belly pain or yellowing of the skin and eyes from the liver, and bone pain or a break with little injury from the bones. General cancer symptoms such as weight loss and loss of appetite are common too.

If you spent months or years being told your symptoms were something else, you are in very good company, and it was not your fault. The pieces of ACC look like ordinary problems taken one at a time. Weight gain, high blood pressure, high blood sugar, acne, irregular periods, thinning hair, low mood, and fatigue are all things a busy clinic sees every day. Even in a region where doctors actively watch for ACC in children, one study found a median gap of 15 weeks between the first symptoms and diagnosis in children who were not already being monitored, compared with 2 weeks in those who were. Rare diseases are recognized late almost by definition. Bring a written timeline of your changes and any photographs that show how your appearance shifted, because that record often does more to move a workup forward than any single test result.

Types of Adrenal Cancer

"Adrenal cancer" is not one disease, and knowing which type you have changes almost everything about testing and treatment. Adrenocortical carcinoma is the most common cancer that starts in the adrenal gland, making up about 40% of primary adrenal malignancies in one large series. Here are the types you are most likely to read about.

• Adrenocortical carcinoma (ACC): The main subject of this guide. ACC starts in the adrenal cortex. Under the microscope, pathologists grade it using the Weiss scoring system, which looks at nine features including how abnormal the nuclei look, how many cells are dividing, whether there is dead tissue inside the tumor, and whether the tumor has invaded veins, blood channels, or its own capsule. A score of 3 or higher indicates cancer. A protein marker called Ki-67 is also measured, and ACC usually shows a Ki-67 above 10% while benign adenomas are usually below 10%.

• Oncocytic, myxoid, and sarcomatoid ACC: The World Health Organization recognizes several ACC variants. Oncocytic ACC is packed with mitochondria, the tiny power plants inside cells, and is graded with a different system called Lin-Weiss-Bisceglia because the usual Weiss criteria overcall cancer in these tumors. Myxoid ACC contains a lot of gel-like material between the cells. Sarcomatoid ACC has lost its normal cortex-like appearance and looks more like a soft tissue cancer. These variants can change how a pathologist reads your slides, which is one reason a second opinion from an adrenal pathologist is often worth asking about.

• Functional and nonfunctional ACC: Functional means the tumor makes extra hormones. Reported rates run from about 40% to 60% of ACC tumors, and combined cortisol plus androgen excess accounts for roughly half of the functional ones. Nonfunctional tumors make no extra hormones, are usually found later, and tend to be larger at diagnosis.

• Pediatric adrenocortical carcinoma: ACC in children is not simply adult ACC in a smaller body. Children account for about 5% to 10% of ACC cases, most childhood tumors appear in the first 5 years of life, and most of them make extra hormones, so signs of early puberty, body hair, acne, a deepening voice, or faster than expected growth are often the first clue. Inherited TP53 changes are found in 50% to 80% of children with ACC. Treatment is overseen by a pediatric oncologist working with a whole pediatric team, and surgery is the main treatment.

• Malignant pheochromocytoma and paraganglioma (PPGL): This is a different disease of the adrenal medulla, not of the cortex, and it must not be blended into ACC information. PPGL causes surges of adrenaline and noradrenaline, so the classic pattern is hard to control high blood pressure with headache, heavy sweating, a pounding or racing heartbeat, shakiness, and looking very pale, sometimes triggered by exercise, injury, emotional stress, childbirth, anesthesia, surgery, or foods high in tyramine such as red wine, chocolate, and aged cheese. Diagnosis uses metanephrine testing in blood or urine rather than cortisol testing, and imaging often includes an MIBG or DOTATATE type scan rather than the tests used for ACC. Since the fourth edition of the WHO classification, these tumors are no longer split into benign and malignant, because any of them can turn out to have metastatic potential and there is no clear feature that reliably predicts it. That is why "benign pheochromocytoma" has largely disappeared from pathology reports.

• Adrenal lymphoma: Primary adrenal lymphoma is a cancer of immune system cells that begins in the adrenal glands. It made up about 4% of primary adrenal cancers in one series and represents less than 1% of all non-Hodgkin lymphomas. The most common type is diffuse large B-cell lymphoma. It often involves both adrenal glands, does not make adrenal hormones, and can cause adrenal insufficiency, meaning too little hormone rather than too much. It is treated as a lymphoma, not as ACC.

• Adrenal sarcoma, including angiosarcoma: Sarcomas are cancers of connective tissue, and they very rarely start in the adrenal gland. Sarcoma accounted for about 1% of primary adrenal cancers in one series. Adrenal angiosarcoma, which arises from blood vessel lining cells, is exceptionally rare and is easy to mistake for ACC on imaging and even on biopsy.

• Adrenal metastases are NOT adrenal cancer: If a cancer that started in your lung, breast, kidney, or skin later shows up in an adrenal gland, that is a metastasis. The cells are lung cancer cells or breast cancer cells sitting in the adrenal gland, and the disease is treated as that original cancer. This is the single most common malignant finding in the adrenal gland, and it is the point readers most often get wrong.

If your pathology report does not clearly name which of these you have, that is a fair and important question to ask. It changes your staging system, the way adrenal cancer is diagnosed and staged, your adrenal cancer treatment options, and your genetic counseling referral.

Related Conditions to Adrenal Cancer

Most things found in an adrenal gland are not cancer. This section sorts out the conditions that sit near ACC in your search results and in your worry. Some are benign tumors. Some are hormone problems with no tumor at all. A few need watching over time.

• Adrenal adenoma: A benign tumor of the adrenal cortex that does not spread beyond the gland. Adenomas are by far the most common adrenal tumor. They are usually smaller than 4 cm, usually affect only one gland, and most people who have one never know it and never have symptoms. Most adenomas are nonfunctional. A small share do make hormones and can cause Cushing syndrome, primary aldosteronism, or androgen and estrogen excess. Adenomas that cause symptoms or that look concerning on a scan may be removed; small, quiet, reassuring ones are often simply watched or left alone.

• Adrenal incidentaloma: This is a mass larger than 1 cm found by accident when a CT or MRI was done for some other reason. It is a finding, not a diagnosis. Adrenal tumors turn up in about 1 in every 10 people who have adrenal imaging, and the overwhelming majority are benign adenomas. Around 80% of incidentalomas make no extra hormones, and more than 90% are benign. The workup is usually straightforward: blood and urine hormone tests to see whether it is making anything, and a careful look at its size, borders, fat content, and how it handles contrast dye on imaging. Size matters, and masses larger than 4 cm get a closer look. If you have a known cancer elsewhere, the odds shift, because 30% to 70% of incidental adrenal masses in people with a cancer history turn out to be metastases.

• Adrenal hyperplasia: This is enlargement of adrenal tissue rather than a single tumor, and it is not cancer. Congenital adrenal hyperplasia is an inherited condition in which the adrenal glands cannot make cortisol normally, so the pituitary gland pushes them harder with a hormone called ACTH and they grow. People with congenital adrenal hyperplasia have a much higher rate of adrenal myelolipomas, up to 36% in one report. Hyperplasia is treated as a hormone condition, with medicine, not as a cancer.

• Adrenal myelolipoma: A benign, usually hormone-quiet tumor made of mature fat mixed with bone marrow-type tissue. Myelolipomas make up 6% to 16% of all adrenal incidentalomas, which makes them the second most common adrenal lesion after adenomas. They are usually found in people aged 40 to 70. Because they are full of fat, CT identifies them well. They have no known ability to become cancer. Small, quiet ones are monitored. Surgery is considered for tumors that grow, cause pain, become hormonally active, look suspicious, or get large enough that bleeding becomes a concern.

• Adrenal cyst: An uncommon, usually benign fluid-filled sac in or on the adrenal gland. Most cause no symptoms and are found by accident. Large ones can cause pressure or pain, and imaging that looks unclear may prompt further testing.

• Pheochromocytoma and why the terminology changed: You may still see "benign pheochromocytoma" in older records or older websites. The current classification has dropped that label. Since the fourth edition of the WHO classification, pheochromocytomas and paragangliomas are no longer divided into benign and malignant, because any of them can develop metastases, sometimes 20 or more years after the original tumor was removed, and no reliable feature predicts which ones will. In practice, this means long-term follow-up rather than a single all-clear.

• Cushing syndrome and Cushing disease: Cushing syndrome is the whole picture caused by too much cortisol, whatever the source. That source can be an adrenal tumor, but it can also be steroid medicine taken for another illness, or a tumor in the pituitary gland at the base of the brain. When the cause is a pituitary tumor driving the adrenal glands to overproduce, it is called Cushing disease. Telling these apart is exactly what tests like the low-dose and high-dose dexamethasone suppression tests are for. Same symptoms, different origin, different treatment.

• Primary aldosteronism: A hormone condition in which the adrenal glands make too much aldosterone, causing high blood pressure and often a low potassium level. It is usually caused by a benign adenoma or by hyperplasia rather than by cancer. It is treated with surgery or with medicines that block aldosterone, such as spironolactone or eplerenone.

• Adrenal insufficiency: The opposite problem, too little adrenal hormone. It can happen when both adrenal glands are damaged, for example by lymphoma or by metastases affecting more than about 90% of both glands. It can also follow treatment. After surgery for ACC, and while taking mitotane, people often need cortisol replacement such as hydrocortisone. Symptoms include fatigue, weakness, low appetite, nausea, weight loss, and salt and electrolyte changes, and they can be mistaken for the cancer itself or for treatment side effects. This is treatable, but it needs to be recognized, and it is a reason to keep an endocrinologist on your team.

What Are the Genetic and Risk Factors?

Genetics matter more in adrenal cancer than in most cancers, and this is the section to read twice. Between about 5% and 15% of ACC cases occur in people who carry an inherited change in a cancer predisposition gene. That number climbs steeply in children. Understanding your risk factors for adrenal cancer is not only about you. It can change screening for your siblings, your parents, and your children.

Li-Fraumeni syndrome is the most important hereditary cause. It is caused by an inherited change in TP53, the gene that normally repairs DNA damage and stops damaged cells from dividing. Inherited TP53 changes are found in roughly 3% to 7% of adults with ACC and in 50% to 80% of children with ACC. There is also a striking geographic story here. In southern Brazil, a specific founder version of the gene called TP53 p.R337H is unusually common in the general population. Newborn screening studies found carrier rates of about 0.30% in Paraná state, 0.24% in Santa Catarina, and 0.21% in Campinas, São Paulo. Because so many people carry it, childhood adrenocortical tumors occur about 20 times more often in southern Brazil than elsewhere in the world. For children who carry R337H, the cumulative risk of an adrenocortical tumor in the first decade of life is roughly 4%. Newborn screening followed by surveillance in that region has caught these tumors at stage I, when surgery cures nearly all of them, which is one of the clearest demonstrations anywhere that finding ACC early changes outcomes.

Several other syndromes raise ACC risk, each with its own profile.

• Beckwith-Wiedemann syndrome comes from changes in the 11p15.5 region of chromosome 11, which contains IGF2, H19, and CDKN1C. Children with it may have a large tongue, overgrowth, low blood sugar as newborns, and abdominal wall differences, and their overall risk of developing an embryonal tumor is estimated at about 7.5%. ACC is a rare but real part of that spectrum.

• Lynch syndrome, caused by changes in the mismatch repair genes MLH1, MSH2, MSH6, PMS2, or EPCAM, accounts for about 3% of adult ACC. One study found Lynch syndrome in 3.2% of people with primary ACC compared with 0.2% of the general population, which is comparable to its rate in colorectal and endometrial cancer, and researchers have argued that ACC should be formally recognized as a Lynch associated cancer.

• Multiple endocrine neoplasia type 1 (MEN1), caused by changes in the MEN1 gene, accounts for about 1% to 2% of adult ACC; notably, one-third to one-half of people with MEN1 develop some kind of adrenal tumor, but most of those are benign adenomas rather than cancer.

• Familial adenomatous polyposis (FAP), caused by APC changes, accounts for less than 1% of ACC, and adrenal tumors in FAP are usually benign adenomas.

• Carney complex, a rare inherited disorder, has also been associated with ACC and is listed by the National Cancer Institute among the syndromes that raise risk.

• Neurofibromatosis type 1, caused by NF1 changes, accounts for less than 1% of ACC and is much more strongly tied to pheochromocytoma than to cortical cancer.

The Pheochromocytoma and Paraganglioma Genes

The genetics of PPGL are a separate story. More than 30% of people with PPGL carry an inherited gene change, and up to 50% of those with metastatic disease do. At least 14 susceptibility genes are known, and which gene is involved strongly affects the chance that the tumor will spread. In a study of 519 adults with PPGL, SDHB changes were found in 17% and carried a 69% risk of malignancy. SDHD in 11% with a 31% risk, SDHC in 1% with a 17% risk, VHL in 10% with a 6% risk, RET in 9% with a 4% risk, and NF1 in 4% with a 5% risk. Because the stakes are so different from ACC, the National Cancer Institute states that everyone diagnosed with pheochromocytoma or paraganglioma should have genetic counseling. Testing is especially recommended for people with tumors in both adrenal glands, more than one tumor in a gland, any paraganglioma, signs of catecholamine excess or metastatic disease, or a diagnosis before age 40. The 2022 WHO classification reinforces genetic screening for all PPGL patients.

There is essentially no established modifiable risk factor for ACC. Prior radiation to the head and neck region has been reported, with a long latency of 15 to 30 years, and occupational or therapeutic radiation exposure is described as a risk factor. Cigarette smoking has been suggested in some studies, but the association is weak and inconsistent and has not been confirmed. The American Cancer Society notes smoking has been suggested as a risk factor while listing it among factors that are not clearly established. No diet, supplement, exercise plan, or detox has been shown to prevent ACC. Please do not spend energy chasing unproven adrenal cancer prevention strategies. There is also no population screening for adrenal cancer; the screening that exists is surveillance for people with known hereditary syndromes, which we cover in the adrenal cancer screening guide.

So who should be offered genetic counseling? For ACC, current European guidelines from 2018 and American guidelines from 2020 recommend that all adults with ACC be offered clinical genetic counseling, and that genomic testing be offered to everyone diagnosed with ACC regardless of age, other cancers, or family history. Every child with ACC should be tested for TP53, given how often it is found. Anyone with a family history of early breast cancer, sarcoma, brain tumors, childhood cancers, colorectal or endometrial cancer, or endocrine tumors should raise that history with their team. If a gene change is found, testing is usually then offered to relatives who are at risk but have no symptoms, which is how a diagnosis in one person can protect a whole family. Ask your care team directly: "Should I see a genetic counselor?" It is a reasonable question, and the answer is very often yes.

What Are the Related Cancers to Adrenal Cancer?

The cancers most closely related to ACC are the other cancers that cluster in the same hereditary syndromes. If ACC turned up in your family because of an inherited gene change, these are the diseases your relatives may need to watch for, and they are the reason genetic counseling reaches beyond you.

• Li-Fraumeni syndrome, from inherited TP53 changes, carries a high lifetime risk of a wide spectrum of cancers.

• Adrenocortical carcinoma, can include sarcomas (cancers of bone and soft tissue), early-onset breast cancer, brain tumors including choroid plexus tumors, leukemia, and lymphoma.

• Lynch syndrome, from mismatch repair gene changes, mainly raises the risk of colorectal cancer and endometrial cancer, plus cancers of the urinary tract including the ureter and the lining of the kidney, and also ovarian, stomach, small bowel, biliary, pancreatic, and some brain tumors.

• MEN1 clusters tumors of the parathyroid glands, the pituitary gland, and pancreatic neuroendocrine tumors, along with adrenal tumors that are usually benign.

• Beckwith-Wiedemann syndrome raises the risk of childhood embryonal tumors, especially Wilms tumor of the kidney and hepatoblastoma of the liver, and also rhabdomyosarcoma and ACC.

• PPGL family of genes, SDHx changes cluster paraganglioma and pheochromocytoma with gastrointestinal stromal tumor (GIST) in patterns called the Carney-Stratakis dyad and the Carney triad

• Hereditary leiomyomatosis and renal cell cancer are among the syndromes that raise PPGL risk, which is why kidney cancer belongs on the radar for these families.

What does this mean practically? Three things. First, it may change your own follow-up, because some of these syndromes come with surveillance plans that look for other cancers early. Second, it may change care for your parents, siblings, and children, who each have a 50% chance of inheriting an autosomal dominant condition such as Li-Fraumeni syndrome, Lynch syndrome, or MEN1. Third, it can change your treatment. Lynch syndrome and mismatch repair deficiency in a tumor can make immunotherapy with checkpoint inhibitors more likely to help, so finding it is not only about prevention.

The practical difference is enormous. Adrenal metastases are usually treated by treating the original cancer, most often with systemic therapy or radiation, and surgery is reserved for situations where the adrenal gland is the only site of spread. Most people with adrenal metastases have no symptoms from them. When someone has a known cancer and a new adrenal mass appears, 30% to 70% of the time that mass is a metastasis, which is a very different starting point from someone with no cancer history whose incidental adrenal mass is almost always a benign adenoma. Doctors do still test for pheochromocytoma before any adrenal biopsy, because sampling a pheochromocytoma unprepared can cause a dangerous blood pressure crisis, and they avoid needle biopsy when ACC is suspected because it can spread tumor cells and take away the chance of a complete removal.

Sources:

• Adrenocortical Carcinoma, National Cancer Institute

• What Is Adrenocortical Carcinoma?, National Cancer Institute

• Childhood Adrenocortical Carcinoma, National Cancer Institute

• Pheochromocytoma and Paraganglioma Treatment (PDQ) Patient Version, National Cancer Institute

• What Is Adrenal Cancer?, American Cancer Society

• Adrenocortical Carcinoma, StatPearls, NCBI Bookshelf

• Adrenal Metastasis, StatPearls, NCBI Bookshelf

• Adrenal Myelolipoma, StatPearls, NCBI Bookshelf

• Familial Adrenocortical Carcinoma in Association With Lynch Syndrome, Journal of Clinical Endocrinology and Metabolism

• Newborn Screening for the Detection of the TP53 R337H Variant and Surveillance for Early Diagnosis of Pediatric Adrenocortical Tumors, Cancers, PubMed Central