Addison’s disease, also known as primary adrenal insufficiency, is a rare endocrine disorder in which the adrenal glands do not produce enough steroid hormones, primarily cortisol and aldosterone. It can be caused by a number of conditions that damage or impair the adrenal glands, including certain cancers. In this article, we will discuss what types of cancers can lead to Addison’s disease and the mechanisms behind it.
Metastasis to the Adrenal Glands
One of the most common cancer-related causes of Addison’s disease is metastasis of other cancers to the adrenal glands. Metastasis is when cancer cells spread from the original tumor site to other parts of the body. The adrenal glands are a relatively common site for cancer metastases, most likely due to their rich blood supply.
Some of the most frequent cancers that metastasize to the adrenal glands include:
– Lung cancer
– Breast cancer
– Kidney cancer
– Stomach cancer
– Pancreatic cancer
– Ovarian cancer
– Colorectal cancer
When these cancer types spread to the adrenal glands, they can impair adrenal function and lead to Addison’s disease. The metastasis causes damage and disruption to adrenal tissue, ultimately hindering or halting cortisol and aldosterone production.
According to one study, around 25% of adrenal metastases were found to originate from lung cancer, making it the most common primary cancer site leading to adrenal impairments. Other studies have found that adrenal metastases are present in up to 10-15% of lung cancer patients.
Mechanism of Adrenal Metastasis
The adrenal glands are susceptible sites for cancer metastases through two primary mechanisms:
1. Hematogenous spread – Cancer cells detach from the primary tumor, enter the bloodstream, and travel through circulation until they become lodged in adrenal capillary networks. This is thought to be the most common route of adrenal metastasis.
2. Lymphatic spread – Cancer cells can spread through lymph channels, particularly the lymphatic networks around major organs like the lungs, kidneys, and pancreas. The lymphatic drainage from these organs leads directly to the adrenal glands.
Once cancer cells reach the adrenals through these routes, they can lodge and proliferate, forming metastatic tumors and impairing normal adrenal cortical cells. Gradual adrenal destruction ultimately diminishes hormone production.
Adrenal Cancers
While metastatic cancers account for most cases of Addison’s disease, in rare instances it can also be caused by primary adrenal cancers arising from adrenal tissue itself.
Some types of cancer that begin in the adrenal glands include:
Adrenocortical Carcinoma
This very rare cancer forms in the outer layer or cortex of the adrenal glands. It’s estimated that adrenocortical carcinoma affects around 0.7-2.0 people per million each year.
These tumors can lead to Addison’s disease by invading the adrenal cortex and damaging cell function, leading to impaired steroidogenesis. Adrenocortical cancer more commonly leads to excess hormone production early on, but can ultimately cause adrenal failure.
Neuroblastoma
Neuroblastoma is the most common type of cancer found in infants. It arises from immature nerve cells and can form anywhere along the sympathetic nervous system, including in the adrenal medulla. Around half of neuroblastoma cases present with tumors in the adrenal glands.
Neuroblastoma can compress or replace normal adrenal tissue, leading to adrenal insufficiency. According to studies, 8-10% of children with neuroblastoma will develop Addison’s disease.
Pheochromocytoma and Paraganglioma
These two rare tumors arise from the chromaffin cells of the adrenal medulla which produce adrenaline and noradrenaline. Although not technically malignant cancers in most cases, they can still impair adrenal function.
Most pheochromocytomas and paragangliomas occur sporadically, but some are associated with genetic syndromes like Von Hippel-Lindau disease and multiple endocrine neoplasia type 2.
These tumors primarily cause issues related to catecholamine excess, like high blood pressure. However, if the tumors become large enough they can compress adrenal cortical tissue and contribute to adrenal insufficiency in some cases.
Cancer Treatments that can Damage the Adrenal Glands
In addition to direct effects from metastases or adrenal tumors, some cancer treatments used in chemotherapy or radiation therapy can also damage the adrenal glands and lead to Addison’s disease.
Chemotherapy
Powerful chemotherapy drugs designed to kill cancer cells may inadvertently also damage healthy cells in the body, including the adrenal glands.
Some chemo agents associated with adrenal damage include:
– Mitotane – used to treat adrenocortical carcinoma. Mitotane selectively destroys adrenal cortical cells and can lead to permanent adrenal insufficiency.
– Streptozocin – an alkylating agent used to treat pancreatic cancer. It has been associated with decreased cortisol production.
– Cisplatin – a platinum-based drug used against many cancers. Around 20-36% of patients develop adrenal insufficiency after cisplatin therapy.
– Mitoxantrone – can cause adrenal hemorrhage and necrosis.
– Gemcitabine – may injure endothelial cells in adrenal capillaries.
The risk of adrenal damage is increased with higher cumulative doses of these chemotherapy drugs. Combination chemotherapy further enhances this risk.
Radiation Therapy
Radiation aimed at treating cancers near the adrenal glands can also cause collateral damage. Radiation deposits energy in cells which can destroy chromosomes and lead to cell death.
The adrenal glands are particularly susceptible to radiation. Doses of as little as 20 Gray are enough to cause adrenal insufficiency.
Cancers in the abdomen or chest are most likely to require radiation therapy that exposes the adrenals, such as lymphomas, lung, esophageal or pancreatic cancers.
After radiation, adrenal insufficiency can set in rapidly or it may gradually develop over years as the irradiated glands atrophy.
Other Cancers Associated with Addison’s Disease
While metastasis, primary adrenal cancers, and cancer treatments are the most direct causes of cancer-related Addison’s disease, other cancer types have also been linked to increased risk of adrenal insufficiency.
Some of these cancers include:
– Lymphomas – Both Hodgkin’s and Non-Hodgkin’s lymphoma are linked to higher rates of Addison’s disease. The association is not fully understood, but may be related to immune dysregulation in lymphoma.
– Multiple Myeloma – Around 5% of myeloma patients develop Addison’s disease, again potentially due to disordered immunity. Rates are higher in more advanced myeloma.
– Leukemias – Particularly acute lymphoblastic leukemia has been associated with Addison’s disease. As with lymphomas, the mechanism is unclear but may involve the immune system.
– Thymomas – Tumors of the thymus gland have autoimmune links to Addison’s disease, as well as risk of metastases to the adrenals.
Summary of Cancer-Related Causes
In summary, the cancers most likely to cause Addison’s disease include:
– Cancers that commonly metastasize to the adrenals (lung, breast, kidney, colorectal, etc.)
– Rare primary adrenal tumors like adrenocortical carcinoma and neuroblastoma
– Cancers treated with cytotoxic chemotherapy or radiation near the adrenals
– Less common associations with blood cancers and thymomas, potentially through autoimmune mechanisms
Proper diagnosis and management of the underlying cancer along with steroid replacement therapy is crucial in any patient who develops Addison’s disease related to malignancy.
Diagnosis
If Addison’s disease is suspected, diagnostic testing can help confirm adrenal insufficiency and potentially identify an underlying cause:
Laboratory Testing
– Low serum cortisol and aldosterone
– High ACTH on blood tests due to loss of negative feedback
– Electrolyte imbalances like hyponatremia and hyperkalemia
– Anemia, eosinophilia, lymphocytosis may be present
Adrenal Imaging
– CT scan of adrenals may show small atrophied glands or tumors
– PET scan can detect cancer metastases
– MRI also useful in identifying adrenal abnormalities
Biopsy
– If imaging reveals masses or lesions, adrenal biopsy may be done
– Can help distinguish between metastatic cancer vs benign adenoma
– Biopsy of other suspected cancer sites can also look for malignancy
Treatment
The mainstay of treating Addison’s disease is replacing the hormones that the adrenal glands can no longer produce. This generally involves:
– Glucocorticoids like hydrocortisone to replace cortisol
– Mineralocorticoids like fludrocortisone to replace aldosterone
Treating the underlying cancer is also a key part of management which may involve surgery, chemotherapy, radiation, or other cancer therapies.
If adrenal insufficiency results from chemotherapy, it is sometimes reversible after stopping the drug. However, if the adrenals have sustained permanent damage, lifelong hormone replacement is required.
Patients require extra glucocorticoid doses during periods of stress, such as infections or surgery, to mimic the normal stress response.
With prompt diagnosis and hormone replacement therapy, the prognosis for Addison’s disease is generally good. However, untreated adrenal crisis can lead to severe outcomes.
Prevention
There are no definitive ways to prevent Addison’s disease caused by underlying cancers. However, the following measures may help reduce risk in some cases:
– Early detection and treatment of tumors before they metastasize or grow large enough to impair adrenals
– Using less toxic cancer drugs when possible
– Carefully targeting radiation therapy to avoid adrenals
– Mitotane adrenal-sparing regimens for adrenocortical carcinoma
– Screening for hereditary cancer syndromes like MEN-2
Coping and Support
Being diagnosed with cancer and Addison’s disease at the same time can be emotionally and physically difficult. Good coping strategies and support resources include:
– Joining a support group to share experiences and tips for living with Addison’s
– Seeing a therapist or counselor to process emotions
– Practicing stress management techniques like mindfulness or yoga
– Reaching out to friends and family for emotional support
– Maintaining a good treatment team including endocrinologists and oncologists
– Working with dietitians to optimize nutrition and medication dosage
– Carrying medical alert jewelry and medication
– Getting enough rest and physical activity
With proper treatment and support, patients can manage their dual diagnoses and maintain a good quality of life.
Conclusion
Addison’s disease is a rare but serious complication of certain cancers and cancer therapies. Metastases to the adrenals and chemotherapy drugs are the most common cancer-related causes, but others like primary adrenal malignancies can also impair adrenal function.
Diagnosis involves blood tests, imaging, and sometimes biopsy. Lifelong steroid replacement is the cornerstone of treatment, along with targeting the underlying cancer when possible. Supportive care and stress management are also important.
While no definitive prevention exists, early tumor detection and conservative treatment choices may help reduce Addison’s risk in some cases. Increasing awareness of this adrenal condition among oncologists could lead to better outcomes for patients.