Adrenocortical Carcinoma

Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy of the adrenal cortex — the outer layer of the adrenal gland that produces cortisol, aldosterone, and androgens. With an incidence of only 1–2 cases per million people per year, ACC is one of the rarest solid tumors in adults, yet it carries a disproportionately high mortality. Approximately half of all ACC tumors are hormonally active, producing excess steroids that cause dramatic clinical syndromes — rapid-onset Cushing's syndrome, virilization in women, or feminization in men — that often precede the cancer diagnosis by months. Even when detected early, ACC has a strong tendency to recur, and the cornerstone of systemic therapy remains mitotane, an adrenal-specific cytotoxin first described in 1960.

Table of Contents

  1. Overview and Epidemiology
  2. Genetics and Molecular Biology
  3. Clinical Presentation
  4. Diagnosis and Imaging
  5. Pathology and Staging
  6. Treatment
  7. Mitotane: Pharmacology and Management
  8. Prognosis and Surveillance
  9. Recent Research and Emerging Therapies
  10. Key Research Papers
  11. Connections
  12. Featured Videos

1. Overview and Epidemiology

Adrenocortical carcinoma arises from the cortex of the adrenal gland — a structure that sits atop each kidney and is divided into three functional zones: the zona glomerulosa (aldosterone), zona fasciculata (cortisol), and zona reticularis (androgens and estrogens). ACC must be distinguished from pheochromocytoma, a tumor of the adrenal medulla (the inner portion), which has an entirely different biology, presentation, and management.

Incidence: ACC is diagnosed in approximately 1–2 people per million per year worldwide, translating to roughly 500–600 new cases in the United States annually. Despite its rarity, ACC is among the most lethal solid tumors: the majority of patients with metastatic disease die within 2 years of diagnosis.

Age distribution: ACC shows a bimodal age distribution that is characteristic and clinically important. The first peak occurs in children under 5 years old, predominantly in Brazil (where TP53 R337H germline mutations are unusually prevalent in the population). The second and larger peak affects adults aged 40–50 years. Unlike most solid tumors, ACC shows a female predominance of approximately 1.5:1 in adults, possibly related to steroidogenic enzyme expression differences or hormonal milieu.

Adrenal incidentaloma context: The widespread use of abdominal CT and MRI has dramatically increased detection of adrenal masses. Approximately 4–7% of all CT scans detect an adrenal mass incidentally ("incidentaloma"). The vast majority of these (over 80%) are benign cortical adenomas. However, the probability of malignancy rises sharply with lesion size: masses under 4 cm carry less than 2% malignancy risk, those 4–6 cm carry intermediate risk (15–25%), and those over 6 cm are malignant in 25–98% of cases depending on series. The average ACC diameter at diagnosis exceeds 12 cm — reflecting late discovery in many patients.

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2. Genetics and Molecular Biology

The majority of ACC is sporadic, but germline genetic predisposition accounts for a meaningful minority of cases, particularly in children and young adults. Molecular characterization of ACC has identified several recurrently altered pathways with diagnostic and potentially therapeutic relevance.

TP53 and Li-Fraumeni syndrome: Germline mutations in TP53, the tumor-suppressor gene on chromosome 17p, are the most important genetic predisposition to ACC. Li-Fraumeni syndrome (LFS), caused by heterozygous germline TP53 mutations, predisposes to ACC, breast cancer, sarcomas, brain tumors, and leukemias. Approximately 50–80% of childhood ACC cases and 3–5% of adult sporadic ACC cases carry germline TP53 mutations. In southern Brazil, a founder mutation (R337H) in TP53 occurs with a carrier frequency of approximately 1 in 300, explaining the extraordinarily high pediatric ACC incidence in that region (15-fold above the global rate). Somatic TP53 mutations are found in approximately 25% of sporadic adult ACC and correlate with higher tumor grade and worse outcome.

Wnt/beta-catenin pathway (CTNNB1): Activating mutations in CTNNB1 (beta-catenin) are found in approximately 16–38% of ACC. Constitutive Wnt signaling drives aberrant adrenocortical cell proliferation. Beta-catenin-mutated ACC may have distinct immunological properties and altered responses to immunotherapy.

Beckwith-Wiedemann syndrome (BWS): BWS, caused by defects at chromosome 11p15 involving IGF2 (insulin-like growth factor 2) overexpression and loss of imprinting, predisposes to childhood overgrowth, Wilms tumor, hepatoblastoma, and ACC. IGF2 overexpression is the most common somatic molecular abnormality in ACC overall (found in 80–90% of tumors), making IGF signaling a heavily studied therapeutic target, though anti-IGF therapies have so far yielded modest clinical results.

Multiple Endocrine Neoplasia type 1 (MEN1): Germline MEN1 mutations predispose to pituitary adenomas, parathyroid adenomas, and pancreatic neuroendocrine tumors; adrenal cortical tumors occur in 20–40% of MEN1 patients, though true ACC (as opposed to adenoma) is uncommon.

Somatic landscape: The TCGA ACC analysis defined two molecular subgroups with markedly different outcomes: a "chromosomal stability" group with favorable prognosis and a "chromosomal instability" group (high copy number alterations, TERT activation, poor prognosis). Ki-67 proliferation index above 20% is the single most important pathological predictor of aggressive behavior and early recurrence.

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3. Clinical Presentation

ACC presents through two broad routes: hormone excess syndromes (in approximately 50–60% of cases) or symptoms from local tumor mass effect (in 40–50%). The nature of the hormone produced provides important diagnostic clues and has direct implications for quality of life and treatment.

Cortisol excess — Cushing's syndrome: The most common hormone syndrome in ACC. Unlike pituitary-driven Cushing's disease (which has an insidious onset over years), ACC-related Cushing's often develops over weeks to a few months, reflecting the rapid growth rate of the tumor. Classic features include central obesity, moon facies, buffalo hump, purple striae (widened, >1 cm), proximal muscle weakness, easy bruising, hypertension, hyperglycemia, and hypokalemia (from mineralocorticoid-like effect of high cortisol on renal tubules). The rapid pace is a red flag distinguishing ACC from a benign adenoma.

Androgen excess — virilization: Excess DHEA-S, androstenedione, and testosterone from ACC produces virilization in women: hirsutism, acne, clitoromegaly, deepening of the voice, amenorrhea, and male-pattern baldness. Many ACC tumors co-secrete cortisol and androgens simultaneously, creating a mixed hormonal picture.

Estrogen excess — feminization in males: Rare but highly specific for malignancy. A male patient presenting with gynecomastia, loss of libido, or testicular atrophy in the setting of an adrenal mass should be presumed to have ACC until proven otherwise. Estrogen-producing ACC is uncommon but carries this distinctive and underrecognized clinical signature.

Aldosterone excess: Primary hyperaldosteronism from ACC is uncommon (more typical of the benign aldosterone-producing adenoma). When it occurs in ACC, it manifests as resistant hypertension, hypokalemia, and suppressed plasma renin activity.

Non-functioning ACC: Approximately 40–50% of ACC produces no clinically apparent hormone excess. These tumors are often discovered incidentally or because of local symptoms — flank pain, abdominal mass, early satiety, nausea, or back discomfort from the large tumor compressing adjacent structures. Non-functioning ACC typically presents at a more advanced stage and may carry a worse prognosis due to delayed detection.

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4. Diagnosis and Imaging

Accurate characterization of an adrenal mass requires both structural imaging (CT or MRI) and comprehensive hormonal evaluation. The critical principle is that pheochromocytoma must be excluded biochemically before any surgical intervention on an adrenal mass, as undiagnosed pheo during surgery can cause fatal hypertensive crisis.

CT imaging — Hounsfield unit analysis: The unenhanced CT attenuation value (Hounsfield units, HU) is the single most important imaging parameter for characterizing adrenal masses. Lipid-rich adenomas: typically less than 10 HU on unenhanced CT (fat content suppresses attenuation) — a reading under 10 HU is effectively diagnostic of a benign lipid-rich adenoma, requiring no further workup in a patient without a known primary malignancy. Lipid-poor adenomas require washout analysis: an absolute contrast washout above 60% or relative washout above 40% at 15-minute delayed imaging indicates a benign adenoma. ACC imaging characteristics: typically above 10 HU on unenhanced CT, often heterogeneous (necrosis, hemorrhage, calcifications), large (>6 cm), irregular margins, possible invasion of adjacent structures (kidney, inferior vena cava, liver), and incomplete or heterogeneous contrast washout.

MRI: Complementary to CT; ACC shows heterogeneous T2 hyperintensity (reflecting necrosis and hemorrhage). Chemical-shift MRI (in-phase vs. opposed-phase): intracellular lipid droplet loss on opposed-phase (signal drop) is the hallmark of benign lipid-rich adenoma; ACC does not show signal dropout. MRI is superior for assessing vascular invasion of the inferior vena cava and adjacent structures.

FDG-PET/CT: ACC is FDG-avid (high standard uptake value, SUV), while benign adenomas are typically FDG-negative or show low SUV. FDG-PET is valuable for staging (detecting lymph node, lung, and bone metastases) and for monitoring treatment response.

Biopsy — a critical caveat: Percutaneous biopsy of a suspected ACC is generally contraindicated. Risks include tumor seeding along the biopsy tract, capsule rupture, and hemorrhage into a large vascular tumor. If the mass is resectable, surgical resection provides both diagnosis and therapy simultaneously. Biopsy is reserved for situations where metastatic disease is present and tissue is needed to guide systemic therapy in an unresectable setting — after excluding pheochromocytoma.

Biochemical workup — mandatory for all adrenal masses:

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5. Pathology and Staging

Weiss scoring system: The gold standard for distinguishing ACC from adenoma on histopathology. The Weiss system evaluates nine criteria, with a score of 3 or more indicating adrenocortical carcinoma:

  1. High nuclear grade (Fuhrman grade 3–4)
  2. Mitotic rate greater than 5 per 50 high-power fields
  3. Atypical mitotic figures
  4. Clear cells comprising 25% or less of the tumor
  5. Diffuse architecture (more than one-third of the tumor is sheet-like)
  6. Confluent necrosis
  7. Venous invasion (medium-sized or large veins with smooth muscle wall)
  8. Sinusoidal invasion (thin-walled vascular channels within adrenal tissue)
  9. Capsular invasion

Modified versions (Helsinki score, Lin-Weiss-Bisceglia) offer refinements for lipid-rich or oncocytic variants, which can be scored falsely low on classic Weiss criteria.

Ki-67 proliferation index: Ki-67 is the most clinically impactful single pathological marker. Ki-67 above 20% is associated with dramatically shorter recurrence-free and overall survival, even in completely resected Stage I-II tumors. Ki-67 above 20% is typically an indication for adjuvant mitotane therapy regardless of stage.

ENSAT staging system (European Network for the Study of Adrenal Tumors):

ENSAT staging is preferred over older TNM systems because it better stratifies survival outcomes and is used in all major ACC clinical trials.

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6. Treatment

Surgery — the only potentially curative treatment: Complete surgical resection (R0 resection — microscopically negative margins) is the single most critical prognostic factor in ACC. Even in Stage III disease with local invasion, aggressive en bloc resection including adjacent involved structures can achieve cure or prolonged remission in selected patients.

Open versus laparoscopic adrenalectomy: Surgical approach matters. Open adrenalectomy is strongly preferred for ACC for several important reasons: (1) ACC tumors are typically large (>6 cm), often with local invasion; (2) the adrenal capsule is fragile and easily ruptured — capsule violation upgrades the patient to R1 resection and dramatically worsens prognosis; (3) adequate lymphadenectomy is more easily performed via open approach. Laparoscopic resection is appropriate only for small (<6 cm), localized, encapsulated ACC without evidence of local invasion — and only in experienced centers. Conversion to open should be performed immediately if any concerns arise about capsular integrity or local extension.

Adjuvant therapy: After complete resection, adjuvant mitotane is recommended for all high-risk ACC: Stage III, Ki-67 above 20%, R1 resection (positive margins), or Stage II with additional risk factors. The ADIUVO trial (randomized, 2023) failed to show benefit of adjuvant mitotane in low-to-intermediate risk ACC (Stage I-II, Ki-67 ≤10%), suggesting adjuvant treatment can be withheld in the lowest-risk patients. Duration of adjuvant mitotane is typically 2 years or until disease recurrence.

Recurrence management: Even after apparently complete resection, ACC recurs in 50–80% of patients within 2 years. Repeat resection is indicated for isolated resectable recurrence. Local ablative therapies (radiofrequency ablation, stereotactic body radiotherapy) are used for limited metastatic sites. Systemic therapy with EDP-M (see below) is the standard for unresectable or widely metastatic recurrence.

Systemic chemotherapy — EDP-M regimen: For unresectable or metastatic ACC, the FIRM-ACT trial (2012) established etoposide + doxorubicin + cisplatin + mitotane (EDP-M) as the first-line chemotherapy standard. EDP-M was superior to streptozotocin + mitotane for both response rate (23% vs. 9%) and progression-free survival. However, objective response rates remain modest and median overall survival in metastatic ACC is approximately 14–18 months with EDP-M.

Immunotherapy: Checkpoint inhibitors have shown limited efficacy in ACC. Pembrolizumab and nivolumab have produced partial responses in approximately 15–20% of patients in Phase 2 trials. Lenvatinib + pembrolizumab combinations are under active investigation. CTNNB1-mutated tumors may be immune-excluded, potentially explaining reduced checkpoint inhibitor benefit in this molecular subset.

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7. Mitotane: Pharmacology and Management

Mitotane (o,p'-DDD; 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane) is the most important drug in ACC and requires specialized management. It is an adrenocorticolytic agent that both inhibits steroidogenesis and directly destroys adrenocortical cells through toxic metabolites.

Mechanism of action: Mitotane undergoes metabolic activation within adrenocortical mitochondria, generating reactive metabolites that bind to adrenocortical proteins and cause cell-specific cytotoxicity. It also inhibits multiple steps in steroid synthesis (CYP11A1, CYP11B1, CYP11B2) and accelerates cortisol catabolism by inducing hepatic CYP3A4 enzymes. This dual action (cytotoxic + steroidogenesis inhibition) makes it simultaneously a cancer drug and a cause of adrenal insufficiency that requires steroid replacement.

Therapeutic drug monitoring: Mitotane is highly lipophilic and accumulates in adipose tissue. It has a narrow therapeutic window. The target plasma concentration is 14–20 mg/L. Below 14 mg/L, antitumor efficacy is substantially diminished. Above 20 mg/L, dose-limiting neurological toxicity occurs (ataxia, dysarthria, cognitive slowing, somnolence). Reaching therapeutic levels typically requires 3–6 months of dose escalation. Levels are measured every 4–6 weeks during titration, then every 3 months once stable.

Mandatory adrenal replacement: All patients on mitotane require corticosteroid replacement, because mitotane induces pharmacological adrenal insufficiency and simultaneously accelerates cortisol breakdown (by inducing CYP3A4). Hydrocortisone doses needed are often two to three times higher than standard physiological replacement (typically 30–50 mg/day in divided doses). Patients must wear a medical alert bracelet, carry injectable hydrocortisone for emergencies, and be counseled on sick-day rules. Mineralocorticoid (fludrocortisone) is added if aldosterone deficiency develops.

Drug interactions: Because mitotane is a potent CYP3A4 inducer, it dramatically alters the metabolism of many co-administered drugs, including warfarin (requires dose increases), oral contraceptives (rendered ineffective — use barrier contraception), and other oncological agents metabolized by CYP3A4. All medications should be reviewed for mitotane interactions.

Key toxicities: Gastrointestinal (nausea, vomiting, diarrhea) are the most common early toxicities and limit initial dose escalation. Taking mitotane with a fatty meal improves absorption and may reduce GI effects. Neurological toxicity (ataxia, confusion, tremor) occurs at levels above 20 mg/L. Elevated liver enzymes and lipid abnormalities are common. Teratogenicity — mitotane is strictly contraindicated in pregnancy.

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8. Prognosis and Surveillance

ACC carries a poor overall prognosis, though outcomes vary substantially by stage and molecular features.

Stage-specific survival:

Prognostic factors: The most powerful predictors of outcome are: (1) ENSAT stage at diagnosis; (2) R0 vs. R1/R2 resection; (3) Ki-67 proliferation index (≤20% vs. >20%); (4) achievement of therapeutic mitotane levels in the adjuvant setting; (5) cortisol-secreting tumors (independently associated with worse outcomes, likely due to immunosuppression from chronic cortisol excess); and (6) molecular features (TP53 mutation, chromosomal instability subgroup).

Post-resection surveillance: After R0 resection, surveillance imaging is critical because 50–80% of patients recur, most within 2 years. Standard surveillance: contrast-enhanced CT of chest/abdomen/pelvis every 3 months for the first 2 years, then every 6 months for years 3–5, then annually thereafter. Adrenal steroid panel (DHEA-S, androstenedione, 24-hour urine cortisol) is obtained at each visit in hormonally active tumors to detect biochemical recurrence that may precede radiographic recurrence.

Germline genetic testing: All patients with ACC, regardless of age at diagnosis, should be offered germline genetic testing for TP53, with consideration of broader panel testing including MEN1, PRKAR1A (Carney complex), and APC (FAP-associated adrenal tumors). First-degree relatives of TP53 germline carriers should undergo Li-Fraumeni syndrome surveillance protocols.

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9. Recent Research and Emerging Therapies

ADIUVO trial (2023): This landmark international randomized controlled trial enrolled 91 ACC patients with completely resected low-to-intermediate risk disease (Stage I-II, Ki-67 ≤10%) and randomized them to adjuvant mitotane vs. observation. No significant difference in recurrence-free survival was observed. This finding is practice-changing: it supports a watch-and-wait approach for the lowest-risk resected ACC, sparing many patients the considerable toxicity of prolonged mitotane therapy.

Targeted therapy — IGF1R pathway: Given that IGF2 overexpression is near-universal in ACC, multiple trials have tested anti-IGF1R antibodies (cixutumumab, ganitumab) and IGF1R/insulin receptor tyrosine kinase inhibitors (linsitinib). The Phase 3 GALACCTIC trial of linsitinib was negative, establishing that broad IGF pathway inhibition does not benefit unselected ACC. Research is ongoing to identify molecular subsets that may respond.

Wnt pathway targeting: Given the prevalence of CTNNB1 mutations in ACC, Wnt inhibitors (porcupine inhibitors, tankyrase inhibitors) are being explored in early-phase trials. Results are preliminary.

TCGA molecular classification: The Cancer Genome Atlas (TCGA) comprehensive molecular analysis of ACC identified two main subgroups based on DNA copy number alterations: a chromosomally stable "C1A" subgroup with better survival and a chromosomally unstable "C1B" subgroup with very poor outcome. This molecular stratification overlaps substantially with Ki-67 and may eventually inform treatment selection.

Steroidogenesis inhibitors: For hormonally active ACC, control of cortisol excess is both a quality-of-life priority and potentially therapeutic. Osilodrostat (a CYP11B1 inhibitor) and levoketoconazole have been approved for Cushing's syndrome from various causes and are increasingly used in ACC. In the context of mitotane treatment, additional steroidogenesis inhibitors may be needed if tumor-driven steroid excess persists despite mitotane.

Expert center care: Given the rarity and complexity of ACC, outcomes are significantly better at high-volume centers with multidisciplinary expertise in adrenal oncology, experienced adrenal surgeons, endocrinologists skilled in mitotane management, and access to clinical trials. Referral to an expert center is strongly recommended for all ACC patients.

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10. Key Research Papers

  1. FIRM-ACT Trial: EDP-M vs. Streptozotocin-Mitotane in Advanced ACC
    Fassnacht M, Terzolo M, Allolio B, et al. N Engl J Med. 2012;366:2189–2197 — PMID 22551107
  2. ADIUVO Trial: Adjuvant Mitotane in Low-Risk Resected ACC (RCT)
    Terzolo M, Fassnacht M, Ciccone G, et al. N Engl J Med. 2023;388:1442–1453 — PMID 37096924
  3. European Society of Endocrinology Clinical Practice Guidelines for ACC
    Fassnacht M, Dekkers OM, Else T, et al. Eur J Endocrinol. 2018;179:G1–G46 — PMID 30299884
  4. TCGA Comprehensive Molecular Characterization of ACC
    Zheng S, Cherniack AD, Dewal N, et al. Cancer Cell. 2016;29:723–736 — PMID 27165744
  5. Weiss Criteria for Histopathological Diagnosis of ACC
    Weiss LM, Medeiros LJ, Vickery AL. Am J Surg Pathol. 1989;13:1–8 — PMID 2910069
  6. ENSAT Staging System for Adrenocortical Carcinoma
    Fassnacht M, Johanssen S, Quinkler M, et al. J Clin Oncol. 2009;27:2727–2731 — PMID 19349549
  7. Mitotane Serum Level and Outcome in ACC: Multicenter Study
    Terzolo M, Angeli A, Fassnacht M, et al. J Clin Oncol. 2007;25:1770–1775 — PMID 17470860
  8. TP53 Germline Mutations and ACC in the Brazilian Population
    Ribeiro RC, Sandrini F, Figueiredo B, et al. Proc Natl Acad Sci USA. 2001;98:9330–9335 — PMID 11481490
  9. IGF2 Overexpression and Insulin-like Growth Factor Pathway in ACC
    Gicquel C, Bertagna X, Gaston V, et al. J Clin Endocrinol Metab. 2001;86:5376–5380 — PMID 11701712
  10. Adrenal Incidentaloma: Management and Imaging Classification
    Fassnacht M, Arlt W, Bancos I, et al. Eur J Endocrinol. 2016;175:G1–G34 — PMID 27390021
  11. Ki-67 as Independent Prognostic Marker in Resected ACC
    Morimoto R, Satoh F, Murakami O, et al. Endocr J. 2010;57:467–476 — PMID 20208401
  12. Laparoscopic vs. Open Adrenalectomy for ACC: Oncological Outcomes
    Miller BS, Ammori JB, Gauger PG, et al. Surgery. 2010;147:760–765 — PMID 19959196

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Connections

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