Definition and epidemiology
Adrenocortical carcinoma is a rare malignant neoplasm originating from the adrenal cortex, accounting for approximately 0.02% of all cancers. The annual incidence is 1-2 cases per million population, with no significant geographic variation.
ACC demonstrates a bimodal age distribution, with peaks in children younger than 5 years and adults between 40-50 years. There is a slight female predominance (female-to-male ratio approximately 1.5:1). In pediatric cases, ACC is strongly associated with Li-Fraumeni syndrome and Beckwith-Wiedemann syndrome.
Approximately 50-60% of ACC cases are functional, producing excess hormones that lead to clinical syndromes. The remaining 40-50% are non-functional and present with mass effect symptoms or are discovered incidentally. The prognosis is generally poor, with 5-year survival rates ranging from 15-45% depending on stage at diagnosis.
- ACC presents with combined Cushing syndrome plus virilization in 25% of cases; this combination is highly specific for malignancy.
- DHEA-S >600 μg/dL strongly suggests ACC over benign adenoma.
- ACC tumors are typically >6 cm, have unenhanced CT density >10 HU, and show <50% contrast washout at 10 minutes.
- Open adrenalectomy is preferred over laparoscopy for suspected ACC to avoid tumor spillage and peritoneal seeding.
- Mitotane is the only FDA-approved drug for ACC; it requires monitoring of drug levels (target 14-20 mg/L) and causes adrenal insufficiency requiring steroid replacement.
- Complete surgical resection (R0) is the only potentially curative treatment; even stage III disease should be resected if technically feasible.
- ACC is associated with Li-Fraumeni syndrome (TP53 mutations), especially in children; Beckwith-Wiedemann syndrome also increases risk.
- Five-year survival for stage IV ACC is <15%; prognosis is primarily determined by resectability and completeness of surgical resection.
Etiology and risk factors
The exact etiology of most ACC cases remains unknown. Both sporadic and hereditary forms exist.
Genetic syndromes associated with ACC:
- Li-Fraumeni syndrome (TP53 germline mutations) – accounts for up to 50-80% of childhood ACC in southern Brazil
- Beckwith-Wiedemann syndrome (11p15 abnormalities, IGF2 overexpression)
- Multiple endocrine neoplasia type 1 (MEN1)
- Lynch syndrome (hereditary non-polyposis colorectal cancer)
- Familial adenomatous polyposis (FAP)
- Carney complex
Molecular alterations in sporadic ACC:
- TP53 mutations (25-30% of cases)
- IGF2 overexpression (90% of cases)
- Abnormalities in Wnt/β-catenin signaling pathway (CTNNB1 mutations in 15-30%)
- Alterations in chromosome 17p13
Risk factors:
- Family history of cancer predisposition syndromes
- Previous radiation exposure (weak association)
- Female sex (slight increase)
Most cases occur sporadically without identifiable risk factors. There is no established link with smoking, diet, or occupational exposures.
Pathophysiology
ACC arises from malignant transformation of adrenocortical cells. The tumor may originate from any of the three cortical zones (zona glomerulosa, fasciculata, or reticularis), though most are thought to arise from the zona fasciculata or reticularis.
Molecular pathogenesis:
Key pathways involved include dysregulation of the IGF2/IGF1R axis (insulin-like growth factor 2 is overexpressed in the majority of ACC), activation of Wnt/β-catenin signaling, and loss of tumor suppressor function (particularly TP53). These alterations lead to uncontrolled cell proliferation, resistance to apoptosis, and acquisition of invasive properties.
Hormonal hypersecretion:
Functional tumors produce excess steroid hormones due to upregulation of steroidogenic enzymes. The pattern depends on which enzymes are preferentially expressed:
- Cortisol excess leads to Cushing syndrome
- Androgen excess (DHEA, DHEA-S, androstenedione, testosterone) causes virilization in women and children, precocious puberty in boys
- Estrogen excess (rare) causes feminization in men, menstrual irregularities in women
- Aldosterone excess (very rare in pure ACC) causes primary hyperaldosteronism
- Mixed hormone production is common, with combined cortisol and androgen hypersecretion being typical
Tumor behavior:
ACC is characterized by aggressive local invasion into surrounding structures (kidney, liver, inferior vena cava), early vascular invasion, and hematogenous metastasis. Common metastatic sites include liver (40-75%), lung (35-60%), lymph nodes (25-40%), and bone (10-30%). The tumor often presents at an advanced stage due to its retroperitoneal location allowing significant growth before symptoms develop.
Clinical features
ACC presents with three main clinical patterns: hormone excess syndromes, abdominal mass effects, or incidental discovery.
Hormone-related manifestations (50-60% of cases):
Cushing syndrome (30-40% of ACC)
- Rapid onset and progression (weeks to months vs. years in benign disease)
- Central obesity, moon facies, buffalo hump
- Proximal muscle weakness, easy bruising
- Hypertension, hyperglycemia
- Purple striae, thin skin
- Severe hypercortisolism often with hypokalemic alkalosis
Virilization (20-30%, more common in women)
- Hirsutism, male-pattern baldness
- Acne, deepening voice
- Clitoral enlargement in women
- Increased muscle mass
- Often occurs together with Cushing syndrome (mixed syndrome in 25% of cases)
Feminization (rare, <10%)
- Gynecomastia in men
- Testicular atrophy, decreased libido
- Menstrual irregularities in women
Hyperaldosteronism (very rare in pure ACC)
- Hypertension with hypokalemia
- Usually occurs with other hormone excess
Mass effect symptoms (40-50% of cases):
- Abdominal or flank pain (most common presenting symptom)
- Palpable abdominal mass
- Early satiety, nausea
- Weight loss (often suggests advanced disease)
- Back pain
Constitutional symptoms:
- Fatigue, malaise
- Fever (uncommon)
- Night sweats
- Anorexia and cachexia in advanced disease
Typical presentation patterns:
- Children: usually functional tumors with virilization ± Cushing syndrome
- Women: combined Cushing syndrome and virilization is highly suggestive of ACC
- Men: often non-functional or present with mass effect
- Incidentalomas: 15-25% discovered on imaging for unrelated reasons
The rapid onset and severity of symptoms, particularly combined hormonal syndromes, should raise suspicion for malignancy over benign adenoma.
Diagnosis
Diagnosis requires integration of clinical presentation, hormonal evaluation, and imaging. The goals are to confirm adrenal origin, assess functionality, determine malignant features, and stage the disease.
Hormonal evaluation (perform in all patients):
Complete adrenal hormone workup includes:
- 24-hour urinary free cortisol and 17-ketosteroids
- 1 mg overnight dexamethasone suppression test (cortisol >5 μg/dL suggests autonomous production)
- DHEA-S, androstenedione, testosterone (in women and children)
- Plasma metanephrines (to exclude pheochromocytoma)
- If hypertensive: plasma aldosterone and renin
Key features suggesting ACC: markedly elevated DHEA-S (>600 μg/dL), combined hormone elevation, failure to suppress with dexamethasone.
Imaging:
CT or MRI of abdomen and pelvis
- ACC typically >6 cm at diagnosis (mean 10-13 cm)
- Heterogeneous appearance with necrosis, hemorrhage, and calcification
- Irregular borders, local invasion
- Unenhanced CT: density >10-20 Hounsfield units
- Contrast washout: <50% at 10 minutes (poor lipid content)
- Vascular invasion (IVC tumor thrombus)
- MRI: heterogeneous T2 signal, variable T1 signal, chemical shift imaging shows minimal signal dropout (unlike lipid-rich adenomas)
Chest CT
- Essential for staging (detect pulmonary metastases)
- Should be performed in all suspected ACC
FDG-PET/CT
- High FDG avidity in most ACC (SUVmax typically >10)
- Useful for detecting metastases and monitoring treatment response
- Cannot reliably distinguish ACC from pheochromocytoma or metastases
Weiss criteria (pathological diagnosis):
Used to distinguish ACC from adenoma in resected specimens. Score ≥3 indicates malignancy:
- High nuclear grade
- Mitotic rate >5 per 50 high-power fields
- Atypical mitoses
- Clear cells ≤25% of tumor
- Diffuse architecture (>33% of tumor)
- Necrosis
- Venous invasion
- Sinusoidal invasion
- Capsular invasion
Laboratory findings:
- Elevated cortisol with suppressed ACTH (in Cushing syndrome)
- Hypokalemia, metabolic alkalosis (severe cortisol or aldosterone excess)
- Hyperglycemia
- Anemia (chronic disease)
- Elevated liver enzymes (if hepatic metastases)
Biopsy:
Biopsy is generally contraindicated in potentially resectable adrenal masses due to risk of seeding and inability to reliably distinguish ACC from adenoma. It is only considered when:
- Metastatic disease is present and tissue diagnosis would change management
- Suspicion of metastasis from another primary tumor
- Lymphoma is suspected
Always exclude pheochromocytoma before any invasive procedure.
Staging:
ENSAT (European Network for the Study of Adrenal Tumors) staging system:
- Stage I: tumor ≤5 cm, no invasion or metastasis (T1 N0 M0)
- Stage II: tumor >5 cm, no invasion or metastasis (T2 N0 M0)
- Stage III: tumor any size with local invasion (T3-T4) or positive regional lymph nodes (N1), no distant metastasis (M0)
- Stage IV: distant metastases (M1), regardless of T or N status
Most patients present with stage III or IV disease.
Differential diagnosis
The differential diagnosis depends on presentation pattern and imaging characteristics.
For large adrenal masses:
- Adrenocortical adenoma – smaller (<4 cm typically), homogeneous, lipid-rich (low HU on CT, signal dropout on chemical shift MRI), smooth borders, slow growth. Functional adenomas typically produce one hormone only. Most common benign adrenal tumor.
- Pheochromocytoma – similar size range, but classically presents with paroxysmal hypertension, palpitations, and sweating. Elevated plasma or urinary metanephrines. Bright on T2-weighted MRI. Can be large and heterogeneous like ACC.
- Adrenal metastases – history of known primary malignancy (most commonly lung, breast, melanoma, renal cell carcinoma). Often bilateral. Cannot always be distinguished from primary ACC without biopsy.
- Adrenal lymphoma – typically bilateral, homogeneous masses. Systemic lymphoma usually evident. Rare as isolated finding.
- Renal cell carcinoma – may be difficult to distinguish from adrenal origin on imaging. Upper pole renal masses can mimic adrenal tumors.
- Retroperitoneal sarcoma – large heterogeneous mass, may displace adrenal gland rather than arising from it.
For patients with Cushing syndrome:
- Cushing disease (pituitary ACTH-secreting adenoma) – most common cause of endogenous Cushing syndrome. ACTH elevated or normal, gradual onset, bilateral adrenal hyperplasia on imaging.
- Ectopic ACTH syndrome – elevated ACTH, often from small cell lung cancer or carcinoid. Rapid onset, severe hypokalemia.
- Adrenocortical adenoma – accounts for 10-15% of Cushing syndrome. Suppressed ACTH, unilateral adrenal mass typically <4 cm.
For virilization:
- Polycystic ovary syndrome – most common cause of hyperandrogenism in women. Normal adrenal imaging, mild DHEA-S elevation.
- Ovarian tumor – check pelvic imaging. Testosterone elevation disproportionate to DHEA-S.
- Congenital adrenal hyperplasia – presents in childhood or adolescence, bilateral adrenal hyperplasia, 17-hydroxyprogesterone elevated in 21-hydroxylase deficiency.
Key distinguishing features of ACC:
- Large size (>6 cm)
- Heterogeneous appearance with necrosis
- Imaging features suggesting malignancy (high HU, poor washout, invasion)
- Combined or marked hormone elevation (especially DHEA-S >600 μg/dL)
- Rapid symptom onset
- High FDG avidity on PET
Management
Treatment depends on stage, resectability, and performance status. A multidisciplinary approach involving endocrinology, surgical oncology, and medical oncology is essential.
Surgical management:
Complete surgical resection
- Only potentially curative treatment for localized ACC
- Open adrenalectomy is preferred over laparoscopy due to risk of tumor capsule violation and peritoneal seeding
- En bloc resection of invaded adjacent organs (kidney, liver, IVC) if necessary for negative margins (R0 resection)
- Regional lymphadenectomy should be performed
- Conversion to R0 resection is associated with improved survival
- Surgical resection may be considered for isolated metastases (oligometastatic disease)
Medical management of hormone excess:
Preoperative control of hypercortisolism is crucial:
- Metyrapone or ketoconazole to inhibit cortisol synthesis
- Mitotane started preoperatively in some centers
- Correct hypokalemia and hyperglycemia
- Glucocorticoid replacement needed postoperatively due to suppression of contralateral adrenal
For virilization: anti-androgens (spironolactone) may provide symptomatic relief but do not affect tumor.
Adjuvant therapy:
Mitotane
- Adrenolytic agent, only approved drug for ACC
- Recommended for all patients with high-risk features (stage III-IV, R1 resection, Ki-67 >10%)
- Target plasma level 14-20 mg/L
- Started postoperatively and continued for 2-5 years
- Requires glucocorticoid and often mineralocorticoid replacement
- Poorly tolerated (GI toxicity, neurological effects)
- Survival benefit demonstrated in some studies
Adjuvant chemotherapy
- Role less established than mitotane
- May be considered for high-risk patients
- Typically mitotane combined with cytotoxic chemotherapy
Treatment of advanced/metastatic disease:
First-line systemic therapy
- Mitotane plus EDP-M regimen: etoposide, doxorubicin, cisplatin, plus mitotane
- Demonstrated superior response rate and progression-free survival in FIRM-ACT trial
- Alternative: mitotane plus streptozocin (for patients unsuitable for EDP-M)
- Mitotane monotherapy for patients unable to tolerate chemotherapy
Second-line therapy
- Gemcitabine plus capecitabine
- Other platinum-based regimens
- No standard regimen; clinical trial enrollment encouraged
- Immunotherapy (checkpoint inhibitors) under investigation; limited efficacy to date
Radiation therapy:
- Adjuvant radiotherapy to tumor bed may reduce local recurrence risk after R1 resection or tumor spillage (controversial)
- Palliative radiation for painful bone metastases or symptomatic brain metastases
- Stereotactic body radiotherapy (SBRT) for oligometastatic disease
Monitoring and follow-up:
After complete resection:
- History, physical examination, hormonal markers every 3 months for 2 years, then every 6 months
- CT chest/abdomen/pelvis every 3 months for 2 years, then every 6 months for 3 years
- Monitor mitotane levels if on treatment
- High recurrence rate (50-85% of patients)
Supportive care:
- Glucocorticoid replacement (all patients on mitotane or after bilateral adrenalectomy)
- Mineralocorticoid replacement if needed
- Management of treatment toxicities
- Nutritional support
- Psychosocial support
Complications and prognosis
Complications:
Disease-related
- Severe hypercortisolism with metabolic derangements (hyperglycemia, hypokalemia)
- Thromboembolic events (hypercoagulable state from cortisol excess)
- Opportunistic infections (immunosuppression from hypercortisolism)
- Tumor hemorrhage or rupture (rare)
- IVC tumor thrombus with risk of pulmonary embolism
- Compression of adjacent organs
- Pathological fractures from bone metastases
Treatment-related
- Postoperative adrenal insufficiency (requires lifelong replacement if bilateral disease or mitotane therapy)
- Surgical complications (bleeding, infection, damage to adjacent organs)
- Mitotane toxicity (GI disturbance, neurological effects, hepatotoxicity, hyperlipidemia)
- Chemotherapy complications (myelosuppression, neuropathy, cardiotoxicity from doxorubicin)
Prognosis:
ACC has a poor overall prognosis due to aggressive biology and frequent advanced stage at presentation.
5-year survival rates by stage:
- Stage I: 60-80%
- Stage II: 50-60%
- Stage III: 20-35%
- Stage IV: 0-15%
- Overall 5-year survival: 35-45% (all stages combined)
Prognostic factors:
Favorable:
- Early stage (I-II) at diagnosis
- Complete surgical resection (R0)
- Low Ki-67 proliferative index (<10%)
- Low mitotic rate
- Younger age
- Absence of necrosis
Unfavorable:
- Advanced stage (III-IV)
- Incomplete resection (R1-R2)
- High Ki-67 (>20%)
- Venous invasion
- Non-functional tumors (paradoxically worse prognosis, likely due to delayed diagnosis)
- Metastatic disease at presentation
- High tumor grade
Recurrence:
Recurrence occurs in 50-85% of patients after complete resection, typically within 2 years. Local recurrence, liver metastases, and lung metastases are most common.
Molecular prognostic markers under investigation:
Molecular subtyping based on transcriptome and methylome profiles may predict prognosis and treatment response, but not yet in routine clinical use.
Despite poor overall survival, long-term survivors exist, particularly among patients with complete resection of localized disease. Aggressive surgical management of oligometastatic recurrence can occasionally achieve prolonged disease-free intervals.
C-CANCER for features suggesting ACC over adenoma: Combined hormones, Abrupt onset, Necrosis on imaging, Colossal size (>6 cm), Elevated DHEA-S (>600), Rapid growth/symptom progression
Practice questions
1. A 45-year-old woman presents with a 3-month history of rapid weight gain, facial swelling, and new-onset diabetes. She also reports increased facial hair growth and deepening of her voice. Physical examination reveals central obesity, moon facies, multiple purple striae, and hirsutism. Blood pressure is 165/95 mmHg. Laboratory studies show: Serum potassium 2.8 mEq/L, Random glucose 245 mg/dL, 24-hour urinary free cortisol 850 μg (normal <50), DHEA-S 800 μg/dL (normal 35-430). CT abdomen shows a 9 cm heterogeneous left adrenal mass with areas of necrosis. What is the most likely diagnosis?
2. A 52-year-old man undergoes staging CT for newly diagnosed lung adenocarcinoma and is found to have a 7 cm left adrenal mass. The mass is heterogeneous with unenhanced density of 35 Hounsfield units and shows 30% contrast washout at 10 minutes. He has no symptoms of hormone excess. Plasma metanephrines and 24-hour urinary cortisol are normal. What is the next best step in management?
3. A 38-year-old woman undergoes successful open left adrenalectomy for a 10 cm adrenal mass. Pathology confirms adrenocortical carcinoma, Weiss score 6, Ki-67 index 15%, with negative surgical margins (R0 resection). Staging CT shows no evidence of metastatic disease (stage II). What is the most appropriate next step in management?
Frequently asked questions
What causes adrenocortical carcinoma?
The exact cause of most adrenocortical carcinomas is unknown. Genetic syndromes like Li-Fraumeni syndrome (TP53 mutations), Beckwith-Wiedemann syndrome, and Lynch syndrome increase risk, but most cases are sporadic without identifiable cause. Molecular studies show frequent IGF2 overexpression, TP53 mutations, and abnormalities in the Wnt signaling pathway in tumor cells. Unlike many cancers, ACC has no established links to lifestyle factors like smoking or diet.
What are the first symptoms of adrenocortical carcinoma?
Initial symptoms depend on whether the tumor produces hormones. Functional tumors often present with rapid-onset Cushing syndrome (weight gain, moon facies, weakness) combined with virilization in women (excess body hair, voice deepening, acne). Non-functional tumors typically present with abdominal or flank pain from mass effect. Constitutional symptoms like fatigue and weight loss may occur. In women, the combination of Cushing features plus virilization developing over weeks to months is particularly suspicious for ACC.
How is adrenocortical carcinoma diagnosed?
Diagnosis combines hormonal testing, imaging, and ultimately pathology. All patients need complete hormone workup including 24-hour urinary cortisol, DHEA-S, and other adrenal steroids. CT or MRI shows a large heterogeneous adrenal mass, typically over 6 cm with irregular borders, high density on unenhanced CT (>10 HU), and poor contrast washout. Chest CT is required for staging. Final diagnosis requires surgical resection with pathological examination using Weiss criteria (score ≥3 indicates malignancy). Biopsy is generally avoided for potentially resectable masses.
Is adrenocortical carcinoma curable?
ACC can be cured with complete surgical resection if caught at an early stage. Patients with stage I or II disease who undergo R0 resection (complete removal with negative margins) have 5-year survival rates of 50-80%. However, most patients present with advanced disease, and even after successful surgery, recurrence occurs in 50-85% of cases. Stage IV disease is rarely curable with 5-year survival under 15%. The key to cure is early detection and complete surgical removal before metastatic spread.
Adrenocortical carcinoma vs adenoma — what is the difference?
Adenomas are benign, typically small (<4 cm), homogeneous, lipid-rich tumors that grow slowly. ACC is malignant, typically large (>6 cm), heterogeneous with necrosis, and grows rapidly. On imaging, adenomas have low density (<10 HU unenhanced) and rapid contrast washout (>50% at 10 minutes), while ACC has higher density and poor washout. Hormonally, adenomas produce one hormone, while ACC often produces multiple hormones; combined Cushing syndrome and virilization strongly suggests cancer. Adenomas have excellent prognosis after resection, while ACC has poor prognosis with frequent metastases.
Key drugs
Related conditions and differentials
Sources and further reading
StatPearls (NCBI Bookshelf)MedlinePlusWHO ICD-10: C74.0
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.