Adrenal Cancer Stages: What Stage I Through Stage IV Mean

Staging is the process your care team uses to measure how much cancer is in your body and where it is. For adrenal cancer, staging answers three questions.

1. How big is the tumor, and has it grown past the edge of the adrenal gland?

2. Has it reached the lymph nodes (small glands that help fight infection) near the gland?

3. Has it traveled to a distant organ such as the lung, liver, bone, or the lining of the abdomen?

Your doctors combine those answers into a single stage, numbered I through IV.

This guide is about adrenocortical carcinoma, usually shortened to ACC. That is cancer of the adrenal cortex, the outer layer of the adrenal gland, and it is what most people mean when they say adrenal cancer. Two other things get confused with it. Adrenal metastases are cancers that started somewhere else, such as the lung or the breast, and spread to the adrenal gland. Those are not adrenal cancer and are staged and treated as the original cancer. Benign adrenal tumors, including the adrenal incidentaloma (a mass found by accident on a scan done for another reason), are far more common than ACC and are not staged at all. If you just had a mass found on a CT scan, the odds are strongly in your favor that it is benign.

Here is the part that matters most about ACC staging. Stage by itself does not carry the whole story. Three things together drive treatment and outlook:

1. Your stage

2. Whether the surgeon was able to remove all of the tumor with a clear rim of normal tissue around it

3. The Ki-67 proliferation index, a laboratory measurement of how fast the tumor cells are dividing.

A person with a stage II tumor that was completely removed and has a low Ki-67 is in a very different situation from a person with a stage II tumor that was removed in pieces and has a high Ki-67, even though the stage number on the chart is identical.

It also helps to know that ACC is often found later than anyone would like. The StatPearls review of adrenocortical carcinoma describes frequent late-stage presentation as one of the defining problems of this disease. The reason is not carelessness. Most adrenal cancer symptoms come from hormone excess, and those symptoms look like ordinary things. Weight gain around the face and belly, high blood pressure, low potassium, acne, new body hair, a deepening voice, irregular periods, mood changes, and fatigue are all easy to attribute to stress, aging, or weight. Many patients spent months or years being told it was something else.

ACC is rare, on the order of 0.5 to 2 cases per million people each year, and it affects women somewhat more often than men. It also has two age peaks, one in children younger than about 5 years and one in adults in their forties and fifties. If you are the parent of a child with ACC, the staging language on this page will look familiar, but the details differ, and there is a section on that below. Whatever your situation, this guide explains staging in general terms only. Your own numbers, your own scans, and your own choices belong in a conversation with your care team.

How Doctors Stage Adrenal Cancer

Adrenal cancer is staged with the TNM system, the same framework used for most solid tumors. The three letters stand for three separate measurements that get combined at the end.

1. T describes the primary tumor, meaning the original growth in the adrenal gland.

2. N describes whether cancer has reached the regional lymph nodes, the node groups that sit near the adrenal gland and drain fluid away from it.

3. M describes whether cancer has spread to a distant site.

Higher numbers after each letter mean more extensive disease.

For adrenal cancer, T is built on two things: the size of the tumor measured in centimeters, and whether the tumor has grown outside the adrenal gland.

• Size of the tumor within the gland determines T1 from T2.

• Growth beyond the gland separates T3 and T4

This is different from other cancers, where T depends on how deeply the tumor has burrowed through layers of the wall. As you read this, keep in mind staging for other cancers does not apply to adrenal cancer.

There are two staging systems in active use, and both use the same TNM categories. The older one is the American Joint Committee on Cancer system, usually called AJCC. The newer one is the ENSAT system, developed by the European Network for the Study of Adrenal Tumors. The National Cancer Institute states that the ENSAT system is becoming the international standard because it lines up better with what actually happens to patients. In plain terms, ENSAT sorts people into groups whose outcomes really do differ from one another, which is the whole point of a staging system.

The two systems mostly agree; where they differ is in defining the difference between stage III and stage IV. The National Cancer Institute puts it simply: the ENSAT system is essentially the same as the AJCC system, but reserves stage IV only for tumors that have spread beyond the adrenal gland or for how far they have metastasized. The current AJCC 8th edition, which the American Cancer Society publishes, now matches ENSAT closely, so a tumor that grows into the fat around the gland or into a neighboring organ is stage III in both systems as long as there is no distant spread. Researchers have also proposed a modified ENSAT system that would move lymph node-positive disease from stage III up to stage IV, because survival data suggest node-positive tumors behave more like stage IV. That proposal is not the standard yet, but it explains why your team may treat node involvement as a serious finding even at stage III.

There is also a difference between clinical staging and pathologic staging. Clinical staging is based on what your doctors can learn before surgery: physical examination, blood and urine hormone testing, and imaging such as CT, MRI with gadolinium, PET, or ultrasound of the vena cava. Pathologic staging is assigned after the adrenal gland has been removed and a pathologist has examined the tissue under a microscope. The American Cancer Society notes that pathologic staging is likely to be more accurate, because it adds what surgery revealed to what the scans suggested. Your stage may therefore shift after surgery, which is normal and is not a sign that anyone made a mistake. Our guide on how adrenal cancer is diagnosed walks through these tests in more detail.

Finally, several things on your pathology report sit outside the staging system but matter just as much.

• Grade describes how abnormal the cancer cells look and how fast they are dividing, and for adrenal cancer it is based largely on mitotic activity, meaning how many cells are caught in the act of dividing.

• The Weiss score is a nine-part checklist a pathologist uses to decide whether an adrenal tumor is cancer at all, using features such as nuclear grade, number of mitoses, atypical mitoses, necrosis (areas of dead tissue), and invasion of veins or the tumor capsule.

  • A Weiss score of 3 or higher points to cancer.

• The Ki-67 proliferation index is reported as a percentage.

  • Benign adenomas usually show Ki-67 below 10%

  • Adrenocortical carcinoma usually shows Ki-67 above 10%

  • A Ki-67 above 20% is associated with worse outcomes.

• Resection margin status is reported as

  • R0 when no cancer is left behind

  • R1 when microscopic cancer remains at the edge

  • R2 when visible tumor remains.

Ask for all four of these in writing along with your stage.

Source: National Cancer Institute. Tumor Size shown next to everyday objects.

What Do the T, N, and M Categories Mean?

The categories below come from the AJCC TNM system as published by the American Cancer Society and the National Cancer Institute. The one-size cutoff you need is 5 centimeters, which is about 2 inches, roughly the width of a lime.

The T categories describe the primary tumor:

• T1: The tumor is 5 centimeters or smaller and has not grown into tissues outside the adrenal gland.

• T2: The tumor is larger than 5 centimeters and still has not grown into tissues outside the adrenal gland.

• T3: The tumor is any size and is growing into the fat that surrounds the adrenal gland.

• T4: The tumor is any size and is growing into a nearby organ, such as the kidney, pancreas, spleen, or liver, or into a large blood vessel, meaning the renal vein or the vena cava.

• TX: The primary tumor could not be assessed because there is not enough information. This usually means a test has not been done yet.

• T0: There is no evidence of a primary tumor.

The N categories describe the regional lymph nodes, meaning the nodes near the adrenal gland:

• N0: No cancer is found in the regional lymph nodes.

• N1: Cancer is found in one or more regional lymph nodes.

• NX: The regional lymph nodes could not be assessed because there is not enough information.

The M categories describe distant spread:

• M0: No distant spread has been found.

• M1: Cancer has spread to a distant site. For adrenal cancer, the common sites are the lung, the liver, bone, and the peritoneum, which is the lining of the abdominal cavity. Lymph nodes far away from the adrenal gland also count as M1.

A word about the vena cava and renal vein, since T4 mentions them. The vena cava is the large vein that carries blood from the lower body back to the heart, and the renal vein carries blood away from the kidney. The right adrenal gland sits very close to the vena cava, so a tumor there can reach that vein without being enormous. Surgery that involves these vessels is demanding and is one of the clearest reasons to be treated at a center that does a lot of adrenal operations.

One thing your surgeon may raise is lymph node removal. Retrospective studies summarized in the StatPearls review found lower recurrence rates and better survival in people who had a systematic lymph node dissection at the time of their adrenal surgery compared with people whose nodes were never examined. Removing nodes also makes the N category real rather than a guess. It is a fair question to ask before your operation.

The Stages of Adrenal Cancer

The stage descriptions below follow the National Cancer Institute and American Cancer Society summaries. Read them as a map of what your team is working with, not as a forecast about you. Treatment is described in general terms only; the specifics belong to you and your doctors, and our guide to adrenal cancer treatment goes into more depth.

Stage I

The tumor is 5 centimeters or smaller and is found in the adrenal gland only, with no lymph node involvement and no distant spread. This is T1, N0, M0, and it is the same in both the ENSAT and AJCC systems. Stage I is the most favorable situation in adrenal cancer, and the StatPearls review reports five-year overall survival of 66% to 82% for ENSAT stage I.

Treatment at this stage centers on surgery to remove the affected adrenal gland completely, an operation called adrenalectomy. The goal is an R0 resection, meaning no cancer cells left at the edges and no spillage of tumor during the operation. Because the tumor is small, some centers may consider a minimally invasive approach, but an open operation is often preferred when there is any question about invasion, because it lowers the risk of the tumor capsule breaking open. After surgery, your team will decide whether to add adjuvant treatment, meaning treatment given after surgery to lower the chance of return. Mitotane, the only drug approved specifically for adrenal cancer, and radiation to the tumor bed are both discussed at this point, and the decision leans heavily on your Ki-67 and your margin status rather than on the stage number alone.

Stage II

The tumor is larger than 5 centimeters and is still found in the adrenal gland only, with clear nodes and no distant spread. This is T2, N0, M0, and again the two systems agree. Reported five-year overall survival for ENSAT stage II is 58% to 64%.

Surgery is still the main treatment, and the goal is still a complete removal with clear margins. A larger tumor is harder to take out in one piece, which is exactly why the experience of the surgeon matters so much here. An open operation is usually favored for large tumors. After surgery, the conversation about adjuvant mitotane and radiation is the same as in stage I. If your tumor was making hormones, your team will also manage the hormone side of things, since removing a cortisol-producing tumor can leave your remaining adrenal gland temporarily unable to keep up, and you may need steroid replacement for a while.

Stage III

The tumor is any size and has spread beyond the gland itself, but not to a distant site. Stage III covers several combinations: a T1 or T2 tumor that has reached nearby lymph nodes, a T3 tumor growing into the surrounding fat with or without node involvement, or a T4 tumor growing into a nearby organ such as the kidney, pancreas, spleen, or liver, or into the renal vein or vena cava, with or without node involvement. Reported five-year overall survival for ENSAT stage III spans a wide range, 24% to 50%, which tells you how varied this group is.

This is the stage where the difference between staging systems is worth understanding. In the current AJCC 8th edition and in ENSAT, all of the situations above are stage III as long as there is no distant metastasis. Some older systems classified tumors invading nearby organs, or node-positive tumors, as stage IV. And the proposed modified ENSAT system would move node-positive disease into stage IV. So if you find conflicting stage numbers for the same tumor, the system being used is usually the explanation, and your TNM is the more useful thing to discuss.

Treatment still aims at cure when the tumor can be removed. That may mean an extended operation that takes the adrenal gland along with part of a neighboring organ or a piece of a large vein, all in one piece rather than in fragments. This is major surgery, and it belongs in experienced hands. Adjuvant mitotane and radiation to the tumor bed are used more often at this stage. If the tumor cannot be safely removed, radiation may be given to a tumor that is localized but unresectable, and drug treatment may be used to try to shrink the tumor first. Stage III is also a good point to ask about joining a clinical trial.

Stage IV

The tumor is any size, the lymph nodes may or may not be involved, and cancer has spread to a distant part of the body such as the lung, bone, liver, or peritoneum. This is any T, any N, M1. In both ENSAT and the current AJCC system, distant spread is what defines stage IV. Reported five-year overall survival for ENSAT stage IV is 0% to 17%, and those are honest numbers that also hide real variation, since a person with a single removable lung nodule is in a different position from a person with disease in several organs.

Treatment at stage IV shifts toward systemic therapy, meaning drugs that travel through the whole body, along with careful control of hormone excess. Mitotane is used both for its effect on the tumor and for its effect on cortisol production. Combination chemotherapy with etoposide, doxorubicin, and cisplatin plus mitotane is the standard first-line regimen for advanced disease. Surgery and radiation still have roles, either to remove or shrink a limited number of metastases or to relieve symptoms such as pain. Because no option here is fully satisfying, the National Cancer Institute specifically encourages people with advanced adrenal cancer to consider a clinical trial.

A Note on Childhood Adrenocortical Carcinoma

Adrenal cancer in children is staged with the same idea, meaning tests are done to see whether cancer has spread near the adrenal gland or to distant sites, but the National Cancer Institute summary for childhood adrenocortical carcinoma does not lay out numbered TNM groupings the way the adult summary does. Instead, it emphasizes a list of prognostic factors: the size of the tumor, how fast the cancer is growing, whether there are changes in certain genes, whether the tumor has spread, the child's age, whether the tumor was completely removed, and whether the covering around the tumor broke open during surgery. Most childhood adrenocortical tumors occur in the first 5 years of life, most are hormone-producing, and a mutation in the TP53 gene, Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, and hemihyperplasia all raise the risk. If you are a parent reading this, ask specifically about genetic testing and counseling, and about treatment at a pediatric center that has seen this disease before.

Source: National Cancer Institute

Recurrent Adrenal Cancer

Recurrent adrenal cancer means cancer that came back after treatment. The National Cancer Institute notes that adrenocortical carcinoma can recur in the adrenal cortex itself, meaning at or near the original site, or in other parts of the body. Doctors usually describe it as local recurrence when it returns in the same area, and distant recurrence or metastatic recurrence when it appears elsewhere.

Local recurrence is common in adrenal cancer, and it happens even after an operation that appeared to remove everything. The StatPearls review reports that recurrence rates range from 19% to 34% in localized disease even with complete resection. Those numbers are sobering, and they are also the reason your team will want to see you often after surgery rather than sending you off with a clean bill of health. A recurrence is not evidence that your surgery failed or that you did something wrong. It reflects the biology of this particular cancer.

Recurrence can still sometimes be treated with the intent to remove it. The National Cancer Institute states that local recurrence and selected sites of metastatic disease can sometimes be treated surgically or with radiation therapy, and that while recurrent adrenal cancer is generally not considered curable, control of hormone symptoms and occasional five-year survivals do happen. The same summary is honest that resection of recurrent tumors carries substantial risk of complications. Whether an operation makes sense depends on how much time has passed before the recurrence, how many spots there are, where they are, what treatment you had before, and how you are doing overall.

Because a recurrence that is small and in one place has more options than a recurrence that is widespread, catching it early genuinely matters. This is why imaging surveillance is scheduled tightly in the first years, when the risk is highest. The StatPearls review of adrenocortical carcinoma describes the follow-up pattern this way: every 3 months for the first 2 years, then every 6 months until year 5, then once a year after year 5. Visits typically pair imaging with hormone testing, since a functional tumor that returns often announces itself in the blood or urine before it is obvious on a scan. The European Society of Endocrinology and ENSAT clinical practice guideline for adrenocortical carcinoma is the document your endocrinologist is most likely to be following for these decisions.

Two practical things. First, keep the appointments even when you feel completely well, and especially then, since the whole purpose of surveillance is to find something before you can feel it. Second, tell your team about new symptoms between visits rather than waiting for the next scan. Returning hormone symptoms, new back or abdominal pain, unexplained weight change, or a return of the changes that first sent you to a doctor are all worth a phone call. You can read more about what happens after treatment in our guide to adrenal cancer survival rates.

Staging for Pheochromocytoma and Paraganglioma

Pheochromocytoma is a different adrenal cancer, and it works differently. Everything above this heading is about adrenocortical carcinoma, which begins in the adrenal cortex, the outer layer of the gland. Pheochromocytoma begins in the adrenal medulla, the inner core of the gland, and paraganglioma is the same kind of tumor arising outside the adrenal gland along nerve pathways. Together, they are often abbreviated as PPGL. They differ from adrenocortical carcinoma in their symptoms, which come from surges of catecholamines such as adrenaline and cause episodes of pounding headache, sweating, racing heart, and spikes in blood pressure. They differ in their testing, which relies on measuring metanephrines in blood or urine and on specialized scans such as MIBG or DOTATATE. They differ in their genetics, with the SDHx, VHL, RET, and NF1 genes carrying much of the hereditary risk. They differ in treatment and in outlook. And they are staged differently. Do not apply the ENSAT stages above to a pheochromocytoma.

The most important shift in how these tumors are classified is worth stating plainly. Doctors used to sort pheochromocytomas and paragangliomas into benign and malignant, as if they were two different diseases. Current classification does not do that. The World Health Organization classification now holds that all pheochromocytomas and paragangliomas carry metastatic potential, meaning any one of them could, in principle, spread, because these tumors have been documented to spread many years after a primary tumor was successfully removed, even when scans done shortly after surgery showed nothing left behind. The National Cancer Institute summary for health professionals reaches the same practical conclusion, stating that no combination of clinical, pathology, or laboratory features reliably predicts how one of these tumors will behave, that they cannot be considered benign by default, and that patients need continued lifelong surveillance.

What that means for you as a patient is a change in the question being asked. Instead of "is my tumor benign or malignant," the question becomes "has my tumor spread, and what is my long-term monitoring plan?" Under the current approach, disease is described as metastatic when tumor tissue turns up in places where this cell type does not normally live, most often bone and lymph nodes. If it has not spread, you are not handed a guarantee, but you are also not handed a cancer label you do not need. What you are handed is a follow-up schedule that does not end after five years, along with genetic testing, because these tumors are among the most heritable in all of medicine, and a result can change monitoring for you and for your relatives.

For staging language itself, there are two versions you may encounter. The National Cancer Institute patient summary describes pheochromocytoma and paraganglioma as localized, meaning the tumor is in one or both adrenal glands or in one area only; regional, meaning it has spread to lymph nodes or other tissues near where it began; or metastatic, meaning it has spread to distant parts such as the liver, lungs, bone, or distant lymph nodes. Separately, the AJCC 8th edition did create a numbered TNM system for these tumors, with stage I for a pheochromocytoma under 5 centimeters with no spread, stage II for a pheochromocytoma 5 centimeters or larger or a functional paraganglioma of any size with no spread, stage III for regional lymph node involvement or invasion into surrounding tissues, and stage IV for distant metastasis. The National Cancer Institute notes candidly that this system does not capture the unique behavior of these tumors, though it may still help in understanding prognosis. Parasympathetic paragangliomas, the nonfunctional kind usually found in the head and neck, are not staged in this system.

Even after an apparently successful operation for a localized pheochromocytoma, follow-up continues. The National Cancer Institute reports that while people with localized disease can expect overall survival approaching that of people the same age without the disease, 6.5% to 16.5% of them will still develop a recurrence. That is the clearest argument for staying in touch with an endocrinologist for the long haul rather than considering the chapter closed.

What Your Stage Does and Does Not Tell You

Your stage is a planning tool and a shared language. It tells your surgeon how extensive the operation may need to be, tells your oncologist and endocrinologist whether to discuss adjuvant mitotane or radiation, tells everyone how closely to monitor you afterward, and determines which clinical trials you may be eligible for. It also gives a general sense of outlook at the population level. Those are real and useful things.

What your stage cannot do is predict what will happen to you. Stage is assigned once, based on the disease as it was found, and it does not change as you respond to treatment. The survival ranges attached to each stage are wide for a reason. Five-year overall survival of 24% to 50% for stage III is not one number with some noise around it; it is a group of people whose situations genuinely differed. Two people with the same stage can travel very different paths.

The single most important factor, and the one you have the most influence over, is complete surgical removal. The National Cancer Institute lists completeness of resection first among the prognostic factors for adrenal cancer, ahead of stage and grade. The StatPearls review states that R0 resection, meaning negative margins, is the most important prognostic factor, and that people who achieve it do significantly better than those left with microscopic disease at the margin or visible tumor behind. What follows from that is concrete: this operation should be done by a surgeon who performs adrenal cancer surgery regularly, at a high-volume center, before anyone operates rather than after a first attempt has already been made. If you are reading this before surgery, asking for a referral or a second opinion at an adrenal specialty center is the most useful thing you can do today.

Ki-67 adds information that stage does not carry. Adrenocortical carcinoma typically shows a Ki-67 above 10%, and a Ki-67 above 20% is associated with worse outcomes. The measurement is used directly in real decisions. The international ADIUVO trial, for example, defined low to intermediate risk after surgery as an R0 resection, no metastases, and a Ki-67 under 10%, and tested whether those patients need adjuvant mitotane at all or can be watched instead. Researchers have also grouped several factors together into what is called the GRAS criteria, standing for grade, resection status, age, and symptoms, to sharpen risk assessment within stages I through III. In other words, the field already accepts that stage alone is not enough.

Grade, hormone production, your age, your other health conditions, whether the tumor capsule stayed intact during surgery, whether you receive adjuvant treatment, and whether you are treated at a specialized center all shape outcome as well. Newer molecular tests, including gene expression subgroups and DNA methylation patterns, add prognostic information beyond conventional staging, though they are not yet part of routine care everywhere. All of this is a long way of saying that a stage number is a starting point for a conversation, not a conclusion.

A few practical steps. Ask for your full TNM and your stage in writing, along with your margin status, your Ki-67, and your grade, because other doctors will want all of it. Ask which staging system your report uses, ENSAT or AJCC. Ask how many adrenal cancer operations your surgeon does in a year. Ask what your follow-up imaging schedule will be and who is responsible for ordering it. Ask about genetic counseling, which matters more in adrenal cancer than in most cancers. And ask about clinical trials early rather than after other options are gone. Our guides to questions to ask about adrenal cancer, adrenal cancer treatment, and adrenal cancer survival rates can help you prepare.

Sources:

• Adrenocortical Carcinoma Stages, National Cancer Institute

• Childhood Adrenocortical Carcinoma, National Cancer Institute

• Adrenal Cancer Stages, American Cancer Society