Adrenal Cancer

What is Adrenal Cancer?

The adrenal gland is an important part of our body’s hormone system, with two main jobs. Its outer layer, the adrenal cortex, creates steroid hormones like cortisol and aldosterone. These hormones help manage how our body uses carbohydrates, proteins, and fats and assist in maintaining fluid balance by controlling sodium and potassium levels. The adrenal gland’s inner layer, the adrenal medulla, generates chemicals like dopamine, epinephrine, and norepinephrine. These hormones have a vital role in our bodies and are necessary for our survival.

During regular health examinations, doctors may occasionally discover adrenal mass or growths. These growths can either actively produce hormones (functional) or not produce hormones (silent), which could be benign (harmless) or malignant (cancerous). However, less than 1% of these tumors are cancerous.

In 2017, the World Health Organization (WHO) classified adrenal cancer into two groups: tumors of the adrenal cortex and tumors of the adrenal medulla. The WHO emphasizes the role genetics may play in these tumors, including a few rare malignancies of the adrenal cortex and medulla.

Certain tumors occur in the adrenal cortex, including cortical carcinoma, cortical adenoma, sex cord-stromal tumors, adenomatoid tumor, mesenchymal and stromal tumors, hematological tumors, and secondary tumors. Some of these are benign growths like Adrenocortical adenoma, Adrenal myelolipoma, and adrenal adenomatoid tumor. Cancerous secondary tumors generally occur due to cancer spreading from neighboring areas or distant sites. Such metastases are common in patients with advanced cancer situations.

Adrenocortical carcinomas, which are very aggressive tumors, are extremely rare. Even though they occur less frequently than other adrenal tumors, they still contribute to a small percentage of all cancer-related deaths. Some Adrenocortical carcinomas can produce hormones, leading to Cushing syndrome or masculinization, but most are non-functional and only show up as a mass in the abdomen or are found incidentally.

Whether an adrenal tumor is cancerous mainly depends on if it has spread locally or to distant parts of the body. No strict criteria exist to determine if an adrenal gland-confined lesion is malignant, but usually, a Weiss score of 3 or more, which is based on microscopic examination of the tissue, is an indicator of its cancerous nature.

What Causes Adrenal Cancer?

Adrenocortical carcinomas are a type of cancer that can develop either randomly or as part of a hereditary condition. Though we understand quite well how these carcinomas form in people with hereditary conditions, it’s less clear what happens at the molecular level when these cancers develop randomly – which is actually how they appear in most cases.

Studies have shown that most non-cancerous adrenocortical tumors exhibit multiple different cell lines; however, cancerous adrenocortical tumors tend to come from a single cell line. This suggests that specific genetic changes may be connected to their development. Notably, these genetic rearrangements also appear in benign (non-cancerous) and malignant (cancerous) tumors, resulting in altered pathways involved in cancer progression. They occur more frequently in malignant tumors.

Li-Fraumeni Syndrome is a familial cancer syndrome caused by a mutation in the TP53 gene. Patients carrying this gene mutation are susceptible to various forms of cancer, including breast cancer, sarcomas, brain tumors, and leukemia, as well as adrenocortical carcinoma. A specific mutation within this gene, called pR337H, is commonly detected in Southern Brazil and is linked to a high rate of pediatric adrenocortical carcinoma. Functionally, this mutation impairs the normal action of the protein at a physiological pH, or acidity level.

Patients with familial adenomatous polyposis, or Gardner syndrome, possess a mutated APC gene which increases the risk of early colon carcinomas and a range of other malignant tumors. Adrenocortical tumors occur in 7 to 13% of patients with this syndrome.

Beckwith-Wiedemann syndrome results from genetic changes in certain genes leading to growth disorders and risk of embryonal malignancies, including adrenocortical carcinoma. Overexpression of IGF-II has been reported in approximately 60% to 90% of adrenocortical carcinoma cases.

Finally, individuals with Multiple Endocrine Neoplasia Type 1, due to a defective MEN1 gene, are predisposed to various tumors, including adrenocortical carcinoma. Further research is needed to fully understand the genetic and epigenetic changes implicated in these hereditary familial tumor syndromes and their role in sporadic tumor development.

Studies have also indicated potential connections between DNA methylation – a mechanism that regulates gene transcription, and patterns in certain small RNAs, or miRNAs, and the development of adrenocortical carcinomas. Future insights into these areas could potentially serve as diagnostic and/or prognosis markers, and open possibilities for new therapeutic approaches.

Risk Factors and Frequency for Adrenal Cancer

Adrenocortical carcinoma, a rare type of cancer, is not widespread in the United States or around the world. The National Institute of Health Office of Rare Diseases Research shows that there are fewer than 200,000 cases present in the United States. Globally, the rate is 0.5 to 2 per million people, and in the U.S., it’s 0.72 per million. It’s responsible for a small percentage (0.2%) of deaths each year in the U.S. It typically affects adults in their 40s and 50s, but there’s also a smaller number of cases in children younger than five. This disease occurs more often in women than men, with the ratio being between 2.5 and 3 women for every man. Certain risk factors exist for this disease, including cigarette smoking and using oral contraceptives.

• There are less than 200,000 cases of adrenocortical carcinoma in the U.S.
• The worldwide incidence rate is between 0.5 and 2 cases per million people.
• In the U.S., the incidence rate is 0.72 per million people.
• Adrenocortical carcinoma accounts for 0.2% of annual deaths in the U.S.
• It generally affects adults in their 40s and 50s, but some children under five also contract it.
• The disease is more common in women than in men, with a ratio of 2.5 to 3 women for every man.
• Cigarette smoking and use of oral contraceptives could increase the risk of developing adrenocortical carcinoma.

Signs and Symptoms of Adrenal Cancer

Adrenocortical carcinoma is a type of cancer that mainly affects the adrenal glands. About one-third of patients show symptoms due to hormonal imbalance, another third have non-specific symptoms, while the remaining are accidentally diagnosed during imaging tests for other medical problems.

Hormonal imbalance is often linked to an excess of cortisol or androgens, or both. An excess of cortisol can result in a rounded face, diabetes, bone weakness, purple stripes on the belly, muscular weakness, obesity, and muscle shrinking. In some severe cases, fast-developing weakness and notable muscle wasting is observed. Excess androgens can cause male-pattern hair loss, masculinization, excessive hair growth, and abnormal menstrual cycles. Around 1 to 3% of patients excessively produce estrogen. In men, this overproduction leads to feminization, characterised by low libido, erectile dysfunction, testicle shrinking, and gynecomastia. It is common for patients to have both an excess of cortisol and androgens. Isolated androgen excess in men can be often overlooked.

Spontaneous aldosterone secretion can lead to high blood pressure and too much potassium in the blood. Adrenocortical carcinoma is often functional in children, leading to early puberty and masculinization. Testicular pain and varicocele might also indicate an adrenal mass.

Adrenocortical carcinoma can also cause non-specific symptoms, such as the growth of a local tumor, pain in the abdomen or sides, feeling full quickly when eating, and a sensation of fullness in the abdomen. The tumor is usually between 10 to 13 cm in size at diagnosis, though it can be smaller or larger. Tumors that aren’t functional are typically bigger and often discovered accidentally during imaging for other matters. Patients with non-functional tumors might have no symptoms until the cancer spreads, causing symptoms like yellowing of the skin or eyes, or bone pain. The most common locations for tumor spread are the lungs and liver. Tumors can also grow in the secondary adrenal gland in about 5% of cases, but it’s challenging to differentiate if it’s a separate tumor or related to the first one.

Testing for Adrenal Cancer

Patients should do essential blood and hormonal tests to help doctors understand their body biology better. Other tests that might be useful include an MRI or CT scan of the pelvis and chest, and more specific tests like bone scans if the doctor suspects something specific, like skeletal metastasis.

Biochemical tests need to be done to check the levels of different hormones like cortisol, mineralocorticoids, androgens, and estrogens in the blood and urine. Even non-secreting adrenal tumors can release some urine steroid metabolites. Interestingly, the hormone levels or hormonal symptoms don’t depend on the size of the tumor.

In terms of tests to rule out other conditions, for instance, pheochromocytoma (a certain type of tumor), a specialized test measuring substances called metanephrine and normetanephrine in your urine or blood is required.

If an adrenal mass appears unexpectedly on an imaging test done for some other reason, it might indicate adrenocortical carcinoma (ACC). Size does matter when it comes to tumors: larger ones (more than 6 cm) could be malignant, whereas smaller ones (less than 4 cm) could be benign, though exceptions do exist.

An ACC often has a varied appearance on imaging tests due to internal factors like hemorrhage, necrosis, and calcification. Additionally, lungs, lymph nodes, or liver metastases, as well as extension into other organs, might be visible on these tests.

No single imaging method provides a definitive diagnosis of an ACC from a localized adrenal mass. So, different techniques including CT scans, MRIs, and Positron emission tomography (PET) scans are used. They allow for a detailed analysis of the lesion and help differentiate between benign adrenal lesions and ACC. The CT scans and MRIs provide measures and visual cues, while the PET scans record the metabolic activity of the cells in the lesion.

Recently, a new tracer, metomidate, has been found useful as it binds to certain adrenal enzymes involved in the final steps of steroid synthesis. This can help determine the actual origin of the tumor, laying a path for more targeted treatment.

Treatment Options for Adrenal Cancer

Treating adrenocortical carcinoma, a rare cancer of the adrenal glands, can be challenging due to the complex hormonal functions these glands perform. Since this type of cancer is so rare, there currently aren’t any established universal treatment guidelines.

The common strategy, based on expert opinions from specialists in the treatment of this type of cancer, is to fully remove the tumor through surgery. Surgery is often followed by additional treatments aimed at reducing the chances of the cancer coming back. Even with complete removal of the tumor, there is a significant risk (between 19% and 34%, depending on the stage of the cancer) of the cancer recurring. Adjuvant therapy, additional treatment given after surgery, often involves the use of a drug called mitotane and the delivery of a targeted dose of radiation to the tumor.

For advanced cases of this cancer, treatment often focuses on palliative care – improving the patient’s quality of life rather than attempting to cure the disease. This can involve controlling pain, preventing fractures resulting from cancer spread to the bones, managing hormonal symptoms, and minimizing side effects from cancer treatment drugs.

What else can Adrenal Cancer be?

Excess hormones in the body can be linked to various health conditions. These could include:

• Adenomas that produce cortisol independently
• Overgrowth of the adrenal gland
• Autoimmune reactions towards the adrenal cortex
• Polycystic ovarian syndrome
• Excessive growth of the ovarian tissues
• An inborn overactive adrenal gland condition known as CAH

In situations where an adrenal mass is discovered by accident, the National Institutes of Health (NIH) suggests certain guidelines depending on the size of the mass. For masses larger than 4 cm, they could be due to various reasons like:

• Adrenal cortical carcinoma (a type of cancer)
• Myelolipoma (a usually noncancerous tumor)
• Metastasis from other tumors
• Pheochromocytoma (a rare, usually benign, tumor)
• Adrenal cyst
• Ganglioneuroma (a usually benign tumor)
• Sarcoma (a type of cancer)
• Lymphoma (a type of cancer)

Adrenal cysts can also be benign, originate from the bronchus, develop in the retroperitoneal space, or be a cystic pheochromocytoma. Adrenal pheochromocytoma can be identified by examining biochemical markers. Generally, large adrenal tumors, other than lymphomas, may require further investigation and possibly even surgical removal.

Surgical Treatment of Adrenal Cancer

Adrenocortical carcinoma, a type of cancer that forms in the adrenal glands, is primarily treated through surgery. Patients in early stages of this disease (stage I or II) and most at stage III can undergo a comprehensive surgery to remove the cancer, which has the best chances for survival and cure. However, the unfortunate reality is that even after this type of surgery, the disease often comes back. Also, only half of these types of cancer are actually treatable through surgery.

The goal of the surgery is to remove all of the cancer, but due to the size of most adrenocortical carcinomas, this is often not possible. When all the cancer cannot be removed, there’s a higher risk that the disease will come back. Over the past few years, there’s been a movement towards also removing regional lymph nodes during the initial surgery. Data shows that this approach can reduce the chances of the disease coming back and reduce the death rate for patients.

As for surgical techniques, laparoscopic procedures, which are less invasive and require smaller incisions, have become more popular. However, this method carries a risk of spreading the cancer to the lining of the abdomen. While it may reduce the time spent in the hospital after surgery, many health professionals believe it is not as effective as an open procedure because it limits the surgeon’s ability to remove all the cancerous lymph nodes.

Having a highly experienced surgical team can improve the outcomes for patients. This is evidenced by patients treated at centers that perform more than 10 of these surgeries a year having a longer time before the disease comes back and lower rates of local recurrence, even when they have larger tumors.

Imaging should be used before and during surgery to assess the extent of the cancer. For patients who have excess hormones, especially those with Cushing syndrome, management and optimization are needed. A comprehensive removal induces a temporary cortisol deficiency in patients, hence they need glucocorticoid replacement after the procedure.

If the cancer comes back, surgery is again recommended if prognosis is good – considering that it could be completely resected. Predicted postoperative mortality for patients with ACC is less than 5%.

While surgery is the go-to treatment, the decision for tumor resection in stage IV disease requires special attention. Patients with cancer spread in multiple organs should not undergo adrenalectomy. For those with advanced disease who undergo complete surgical resection, recurrence is common both at the surgical site or distant organs. However, it has been observed that another resection of the recurrent disease can improve survival compared to those who experience early recurrences.

Additionally, other therapies including radiofrequency ablation and trans-arterial chemoembolization can be used to manage tumor growth, especially for small metastatic lesions in liver, lung, and bone. These methods provide an alternative to surgery when it is not possible. But it’s crucial to mention that these methods haven’t been the subject of clinical trials.

What to expect with Adrenal Cancer

The survival rate used to be really poor for people with adrenocortical carcinoma. On average, patients could only expect to live about 14.5 months after being diagnosed, and the 5-year death rate was incredibly high – about 75 to 90%. Those who have the disease spread throughout their body (known as stage IV) typically lived less than a year. However, it’s important to remember that those who got treatment had a better chance – about 30 to 60% were still alive five years later. Unfortunately, because this type of cancer is hard to cure even in its early stages, it was generally considered to have a poor prognosis.

Adrenocortical carcinoma has been known to spread to the liver, lungs, lymph nodes or bones. But everyone’s experience with this disease can be unique. Nowadays, it’s understood that survival rates can greatly differ, depending on individual circumstances. Because of this, two organizations – The Union for International Cancer Control (UICC) and the European Network Staging Study for Adrenal Tumors (ENSAT) – have come up with newer ways to stage the disease. The disease stage, the extent of tumor removal and the rate of tumor growth are all taken into account when predicting survival.

According to this new ENSAT staging system, the 5-year survival rates actually seem more optimistic than before. It’s reported to be 66 to 82% for stage I, 58 to 64% for stage II, between 24 to 50% for stage III, and anywhere between 0 to 17% for stage IV. Recent studies suggest that completely removing the tumor as well as its grade significantly influences the chances of the disease coming back. Older age, cancer spread, and not being able to remove the entire tumor are linked to a poorer survival rate.

On a genetic level, researchers have managed to identify a couple of distinct types of the disease. One type grows rapidly and leads to a poor outcome, while the other type grows more slowly and is typically less serious. Also, the level of certain genes like H19 can tell doctors a lot about the potential course of the disease. Interestingly, those with an elevated level of methylation – when a specific kind of chemical group is added to a molecule – have a worse survival rate.

Finally, certain molecules called miRNA can serve as markers of an aggressive form of the disease, particularly miR-195 and miR483-5p. Research has shown that high levels of mir-483-5p and low levels of mir-195 are associated with a worse prognosis. With all these multifaceted analyses and advanced tools, predicting the course and survival of patients with adrenocortical carcinoma has become a bit clearer and hopefully also more accurate.

Possible Complications When Diagnosed with Adrenal Cancer

Adrenocortical carcinoma, or ACC, can lead to issues because it can make the body produce too much hormones. This happens in about 40% to 60% of people with ACC. The main issue is hypercortisolism, which happens in about half to 80% of ACCs that produce hormones. This can lead to symptoms such as diabetes, fatigue, high blood pressure, obesity in the belly area, weak or shrinking muscles, and bone loss.

There are other complications too:

• Between 19% and 34% of patients who had surgery and were left with no residual disease (R0) might experience the return of the disease locally or regionally.
• More than half of ACC patients are diagnosed when the disease is already advanced or has spread to other parts of the body.

Recovery from Adrenal Cancer

While there’s no exact guideline for how to monitor patients after treatment for adrenocortical carcinomas, it’s generally recommended that check-ups should occur every three months due to the cancer’s aggressive nature. If the patient doesn’t experience a recurrence for 2 to 3 years, these check-ups can be extended to every six months for up to five years. After five years without the disease, patients can reduce their check-ups to once every 1 to 2 years. It’s important to note that some patients can experience a late relapse, even though it’s quite rare. During the check-ups, patients should undergo a hormone test, comprehensive imaging studies including CT scans of the chest and abdomen, and a complete physical exam. Even though it’s not always required, an [18F]FDG-PET (a type of imaging test) can be considered for follow-up care of patients with adrenocortical carcinomas.

Preventing Adrenal Cancer

Adrenal cancer occurs when cells in the adrenal gland start to grow out of control. Some people may not notice any symptoms, while others may find out they have the cancer when undergoing imaging tests for something else.

When this type of cancer causes symptoms, it’s usually because it’s producing hormones. The exact symptoms can depend on which hormones are being produced. These could include:

* Feeling weak in the muscles
* Putting on weight
* Growing more hair, especially on the face for women, and having a deeper voice
* Feeling tired
* Having trouble sleeping
* Having purple-colored skin
* High blood pressure

Adrenal tumors might also cause other symptoms not related to hormone levels. These could include:

* Weight loss or not feeling hungry
* Pain in the belly or lower back

Now, these symptoms could be caused by many other health issues, so it’s essential to have an in-depth check-up to find out what’s happening. But if anyone notices these symptoms, they should tell their doctor or nurse right away.

Tests for adrenal cancer typically include:

* Blood samples and urine tests to check hormone levels
* CT or MRI scan

The treatment plan will depend on the stage of the cancer. Most people with this illness will have surgery to remove the tumor. But after surgery, some may need extra treatments such as:

* Drug therapy (chemotherapy)
* Radiation therapy

After the initial treatment, regular follow-ups with the doctor are crucial to see if the cancer has been fully treated or if it’s come back. These check-ups might involve blood tests and imaging tests. If anyone notices symptoms, it could mean the adrenal tumor has returned, so they should let their doctor or nurse know. In the long term, medication to adjust hormone levels might be needed.

What happens if the adrenal cancer returns or becomes more widespread? If the adrenal tumor comes back or spreads, additional treatments like chemotherapy, surgery, or radiation therapy might be required.