Adrenal Cancer: Symptoms, Types, Causes and Treatment

Adrenal cancer is a rare but serious disease that affects the adrenal glands, small organs located above each kidney. These glands produce essential hormones that regulate many of the body’s functions, such as metabolism, blood pressure, and stress response. While adrenal cancer can be aggressive, early detection and a clear understanding of its symptoms, types, causes, and treatments can greatly improve patient outcomes. In this article, we’ll break down the key facts, offer practical insights, and provide evidence-based guidance on what you need to know about adrenal cancer.

Symptoms of Adrenal Cancer

Adrenal cancer can be elusive, often presenting with a wide range of symptoms—or in some cases, none at all. Because adrenal tumors may produce excess hormones, the symptoms can vary significantly depending on which hormones are affected. Recognizing these signs is crucial for timely diagnosis and better prognosis.

Symptom	Description	Frequency/Indicators	Source
Abdominal Pain	Dull, non-specific pain	Common first symptom	1 2 6
Hormonal Excess	Symptoms from excess cortisol, androgens, or aldosterone	Cushingoid features, virilization, hypertension, hypokalemia	2 4 6 12 13
Non-specific Signs	Fatigue, weight loss, pale skin	May occur in advanced disease	1 6
Incidental Finding	No symptoms, discovered on imaging	~15% of cases	13

Table 1: Key Symptoms

Recognizing the Symptoms

Adrenal cancer symptoms can be divided into those caused by the tumor’s location or size, and those related to hormone overproduction.

• Abdominal Discomfort: Many patients experience vague abdominal pain or discomfort, often due to the tumor pressing on nearby organs. In some cases, rapid tumor growth can cause bleeding, leading to anemia and pale skin 1.
• Symptoms of Hormone Excess:
  • Cortisol Overproduction (Cushing's syndrome): Weight gain (especially in the trunk), round face, muscle weakness, high blood sugar, and easy bruising.
  • Androgen/Estrogen Excess: In women, excess androgens may cause facial hair growth, deep voice, or irregular periods. In men, estrogen excess may cause breast enlargement or impotence 2 13.
  • Aldosterone Overproduction: High blood pressure and low blood potassium levels (hypokalemia).
• Non-specific and Advanced Symptoms: Fatigue, unexplained weight loss, and general malaise can occur, especially in advanced stages 6.
• Incidental Discovery: In about 15% of cases, adrenal cancer is found “incidentally” during imaging for unrelated reasons, before any symptoms appear 13.

When to Seek Medical Advice

Because many symptoms overlap with more common health issues, adrenal cancer can be difficult to detect early. If you experience persistent abdominal pain, unexplained hormonal changes, or are found to have an adrenal mass on imaging, prompt evaluation by a specialist is recommended 2 12.

Types of Adrenal Cancer

The adrenal glands are made up of two distinct parts: the cortex and the medulla. Each part can give rise to unique types of cancer, each with its own characteristics and clinical behavior. Understanding these differences is essential for accurate diagnosis and treatment.

Type	Origin	Key Features	Source
Adrenocortical Carcinoma (ACC)	Adrenal cortex	Most common, often hormone-secreting, aggressive	2 3 4 6 12 13
Malignant Pheochromocytoma (PPGL)	Adrenal medulla (and extra-adrenal paraganglia)	Catecholamine-producing, hypertension, can metastasize	2 3 6
Other Rare Tumors	Mixed, stromal, haematological	Schwannoma, myelolipoma, neuroblastoma	3

Table 2: Main Types of Adrenal Cancer

Adrenocortical Carcinoma (ACC)

• Definition: ACC arises from the cortex—the outer layer of the adrenal gland. It is the most common primary adrenal cancer in adults.
• Incidence: Extremely rare, with only 0.5–2 cases per million people each year 2 4 6 13.
• Behavior: ACC is often aggressive, with a high risk of metastasis and a generally poor prognosis, especially if not caught early 6 12.
• Hormone Production: About 60% of ACCs produce excess hormones, most commonly cortisol and androgens, leading to Cushing’s syndrome or virilization. Some are non-functioning 2 12 13.

Malignant Pheochromocytoma and Paraganglioma (PPGL)

• Definition: These tumors originate from the adrenal medulla (pheochromocytoma) or from similar cells outside the adrenal gland (paraganglioma).
• Key Features: They secrete catecholamines (adrenaline/noradrenaline), causing episodic headaches, sweating, palpitations, and dangerous spikes in blood pressure 2 3 6.
• Malignancy: Defined by the presence of metastases. All PPGLs are considered to have malignant potential 2 3.

Other Rare Adrenal Tumors

• WHO Classification: Includes rare entities such as cortical adenoma, myelolipoma, schwannoma, neuroblastoma, and composite tumors. Some of these are newly classified or reclassified in recent WHO updates 3.
• Clinical Relevance: Most are benign, but certain subtypes (e.g., neuroblastoma in children) can be aggressive 3.

Why Classification Matters

Accurate classification influences:

• Treatment decisions (surgery, chemotherapy, targeted therapy)
• Prognosis and follow-up
• Genetic counseling, as some types have hereditary links 2 3 6

Causes of Adrenal Cancer

Adrenal cancer is a complex disease with multiple possible causes. While most cases occur randomly, research has identified certain genetic and environmental risk factors. Understanding these can help in risk assessment, early detection, and family counseling.

Cause/Factor	Description	Impact/Association	Source
Genetic Mutations	Inherited or acquired gene changes	TP53, CTNNB1, ZNRF3, IGF-II, SDHB, MEN1	5 7 9 12 13
Hereditary Syndromes	Familial cancer syndromes	Li-Fraumeni, MEN1, Carney complex, SDH mutations	5 9 12
Environmental/Risk Factors	Smoking, oral contraceptives (OCs)	Heavy smoking (men), OC use (women)	8
Unknown/Idiopathic	No clear cause identified	Most cases	6 8

Table 3: Key Causes and Risk Factors

Genetic and Molecular Causes

• Somatic Mutations: Most ACCs harbor mutations in genes regulating cell growth and hormone production, such as TP53, CTNNB1 (beta-catenin), and ZNRF3. Overexpression of IGF-II is common in ACC 5 7 13.
• Familial Syndromes:
  • Li-Fraumeni Syndrome (TP53 mutations): Increases lifetime risk of ACC and other cancers.
  • Multiple Endocrine Neoplasia type 1 (MEN1): Up to 40% of MEN1 patients develop adrenal lesions, but direct causal mutations in MEN1 gene are rare in sporadic ACC 9.
  • Carney Complex and PRKAR1A mutations: Associated with pigmented nodular adrenal disease 5 9.
  • SDH Mutations: Especially SDHB, increase risk for malignant PPGL, with high metastatic potential 2 3.
• Hereditary Risk: At least 35% of PPGLs are linked to inherited gene mutations 2 3.

Environmental and Lifestyle Factors

• Smoking: Heavy smoking (≥25 cigarettes/day) increases adrenal cancer risk in men 8.
• Oral Contraceptives: Use, especially before age 25, may increase risk in women 8.
• Other Factors: No clear link has been found with alcohol, diet, or body weight 8.

Other and Unknown Causes

• Idiopathic Cases: Most adrenal cancers arise without a known cause or risk factor 6 8.
• Geographical Variations: Certain regions, such as parts of Brazil, have a much higher incidence, suggesting possible environmental or genetic contributors 6.

Why Causes and Risk Factors Matter

• Risk Assessment: Identifying hereditary syndromes can prompt family screening.
• Prevention/Monitoring: High-risk individuals may benefit from regular surveillance.
• Personalized Medicine: Understanding the molecular drivers can pave the way for targeted therapies 13.

Treatment of Adrenal Cancer

Treatment for adrenal cancer is complex and must be tailored to the individual, depending on the cancer type, stage, hormone secretion, and overall health. Because these tumors are rare and aggressive, care at specialized centers and a multidisciplinary approach are strongly recommended.

Treatment	Best Used For	Key Points	Source
Surgery	Localized tumors, some metastases	Complete en-bloc resection is goal, requires expertise	2 4 12 13
Mitotane Therapy	Adjuvant (after surgery), metastatic ACC	Main drug for ACC, may be combined with chemo	12 13
Chemotherapy	Advanced/Metastatic disease	EDP (etoposide, doxorubicin, cisplatin) + mitotane standard	12 13
Other Local Therapies	Recurrent/oligometastatic disease	Radiation, ablation, embolization	12
Experimental/Targeted	Selected cases	IGF-1R inhibitors, immunotherapy, gene therapy	10 11 13

Table 4: Main Treatment Approaches

Surgical Treatment

• Surgery is the cornerstone for potentially curative treatment of ACC and localized PPGL. Complete removal (en-bloc resection) is critical because incomplete surgery is linked to poor outcomes 2 4 12 13.
• Who Should Operate?: Only surgeons with adrenal and oncologic experience should perform these operations due to the risk of tumor spillage and spread 12.
• Metastatic Disease: Surgery may be considered for isolated metastases or after good response to systemic therapy 12 13.

Medical Therapy

Mitotane

• What is Mitotane?: A unique adrenolytic drug that specifically targets adrenal cortex cells.
• Use:
  • As adjuvant therapy after surgery for high-risk ACC (e.g., stage III, positive margins, high Ki67 index).
  • As first-line for metastatic or unresectable ACC, alone or with chemotherapy 12 13.
• Monitoring: Requires careful dose adjustments and hormone replacement support 12.

Chemotherapy

• Standard Regimen: Combination of etoposide, doxorubicin, and cisplatin (EDP) with mitotane is the gold standard for advanced ACC based on recent trial data 13.
• Other Options: Less commonly, other drugs or regimens may be used if EDP/mitotane is not tolerated 13.

Other Systemic and Local Therapies

• Radiation, Ablation, Embolization: For specific metastatic or recurrent lesions, especially if surgery is not feasible 12.
• Gossypol: An investigational plant-derived agent showed partial responses in some patients with metastatic ACC, but larger trials are needed 10.

Targeted and Experimental Therapies

• Targeted Therapies: IGF-1 receptor inhibitors and other molecular agents are under investigation, but so far, results are limited 13.
• Immunotherapy and Gene Therapy: Early-stage research includes dendritic cell therapy, DNA vaccines, and gene transfer approaches 11 13.
• Clinical Trials: Ongoing trials and “omics” research may soon yield new treatment options 13.

Multidisciplinary Care and Follow-up

• Expert Team: All cases should be reviewed by a multidisciplinary team, including endocrinologists, surgeons, oncologists, and pathologists 2 12.
• Pathology Review: Weiss score and Ki67 index guide risk stratification and treatment planning 12 13.
• Long-term Monitoring: Regular imaging and hormone tests are essential for early detection of recurrence or metastasis 2 12.

Prognosis

• Localized ACC: If completely resected at an early stage, 5-year survival can approach 90% 2.
• Advanced Disease: Median survival drops to 15–30 months for metastatic cases 6 12.
• PPGL: Prognosis depends on metastatic spread and genetic factors (e.g., SDHB mutations) 2 3.

Conclusion

Adrenal cancer is a rare and challenging disease, but advances in diagnosis and treatment are improving patient outcomes. Here’s what you need to remember:

• Early Recognition is Key: Be alert to symptoms of hormone excess or abdominal pain, and investigate incidental adrenal masses thoroughly.
• Know the Types: Adrenocortical carcinoma and malignant pheochromocytoma/paraganglioma are the main forms, each requiring specialized management.
• Understand the Causes: Genetic mutations and hereditary syndromes play an important role, but most cases are sporadic.
• Treatment is Multimodal: Surgery is the mainstay, but mitotane, chemotherapy, and emerging therapies are vital for advanced disease.
• Multidisciplinary Care Matters: Patients benefit from specialized centers and coordinated expert teams for optimal outcomes.

Staying informed and proactive can make a significant difference for those facing adrenal cancer. If you or a loved one is affected, seek care at a dedicated center, ask about genetic counseling, and discuss all available treatment options with your healthcare team.