Adrenocortical Carcinoma (ACC): Causes, Symptoms, Diagnosis and Treatment — Overview, Diagnosis & Treatment Options | MyMedicPlus

Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy arising from the epithelial cells of the adrenal cortex, with an annual incidence of approximately 1-2 cases per million population — corresponding to approximately 300-500 new US cases per year. ACC has a distinctive bimodal age distribution, with one peak in children under 5 years (often associated with Li-Fraumeni syndrome) and a second peak in adults in the 4th-5th decades (median age 47 years). Women are affected slightly more often than men (approximately 1.5:1 female-to-male ratio). Approximately 60% of ACCs are functionally active, secreting excess adrenal hormones — most commonly cortisol (causing Cushing syndrome), adrenal androgens (causing virilization in women), or combinations. The remaining 40% are non-functional and present with symptoms of local mass effect or are discovered incidentally. ACC carries a poor prognosis overall: 5-year survival ranges from approximately 40-60% for resected Stage I-II disease to below 15% for Stage IV metastatic disease. Resection is the only potentially curative treatment; mitotane is the only FDA-approved drug for ACC and remains the cornerstone of adjuvant and palliative systemic therapy per European Society of Endocrinology (ESE) guidelines.

The majority of ACC cases (approximately 95%) are sporadic, arising from sequential somatic mutations in adrenocortical progenitor cells without an identifiable germline predisposition. However, hereditary syndromes account for a disproportionately large share of pediatric ACC. Li-Fraumeni syndrome (germline TP53 mutation on chromosome 17p13.1) is the most important hereditary association — TP53 germline mutations are present in approximately 3-4% of adult ACC patients and in up to 50-80% of pediatric ACC cases, particularly in the Brazilian pediatric ACC cluster (TP53 R337H founder mutation). Other hereditary associations: MEN1 (multiple endocrine neoplasia type 1, menin gene mutation — adrenal adenomas and occasionally ACC); familial adenomatous polyposis (APC germline mutation — rare ACC risk); Beckwith-Wiedemann syndrome (BWS: chromosome 11p15.5 abnormalities causing IGF2 overexpression and CDKN1C loss — elevated pediatric ACC risk); Lynch syndrome (MMR gene mutations — low but recognized ACC risk). Somatic molecular alterations in sporadic ACC: IGF2 overexpression (90% of ACC), somatic TP53 mutations, CTNNB1 (Wnt/beta-catenin pathway activation — approximately 15%), CDKN2A loss, TERT promoter mutation, CDK4 amplification, and chromatin remodeling gene mutations (ATRX, DAXX). The Weiss histopathological score (defined by 9 criteria including mitotic rate, atypical mitoses, necrosis, vascular and capsular invasion) distinguishes ACC from adenoma — Weiss score of 3 or more establishes malignancy.

Clinical presentation of ACC reflects hormonal secretory status, tumor size, and extent of disease. Cortisol-secreting ACC (most common functional type): Cushing syndrome manifesting as rapid progressive onset central obesity with moon face, dorsocervical fat pad (buffalo hump), and peripheral muscle wasting; purple abdominal striae wider than 1 cm; thin fragile skin with easy bruising; severe proximal myopathy causing difficulty rising from a chair or climbing stairs; new-onset hypertension, diabetes, and osteoporosis; clinical depression, cognitive impairment, and insomnia; hypokalemia from mineralocorticoid excess of cortisol. Androgen-secreting ACC: rapid onset of virilization in women — hirsutism, clitoral enlargement, temporal hair recession, voice deepening, acne, and oligo- or amenorrhea; in men, feminization from co-secreted estrogens. Mixed cortisol plus androgen secretion: most common functional pattern in ACC (approximately 40% of functional tumors). Non-functional ACC: symptoms from tumor mass — dull or colicky unilateral abdominal or flank pain; palpable abdominal mass; weight loss, anorexia, and fatigue reflecting systemic malignancy; constitutional features including fever (paraneoplastic) and night sweats. Locally advanced ACC may present with symptoms of inferior vena cava (IVC) invasion — leg edema, abdominal distension — or hepatic invasion with jaundice.

Hormonal evaluation is mandatory for all suspected ACC to establish functional status and guide perioperative management. Cortisol excess: serum cortisol after 1 mg overnight dexamethasone (above 1.8 μg/dL indicates autonomous cortisol secretion); 24-hour urinary free cortisol; late-night salivary cortisol. Androgen excess: serum DHEA-S (markedly elevated in ACC), testosterone, and androstenedione. Aldosterone excess: plasma aldosterone-to-renin ratio. Pheochromocytoma exclusion: plasma fractionated metanephrines or 24-hour urine catecholamines and metanephrines — must be excluded before any surgical procedure. Adrenal CT protocol: ACC typically appears as a heterogeneous mass larger than 4 cm with unenhanced HU above 10, irregular margins, heterogeneous enhancement, and inadequate contrast washout (absolute washout below 60% at 15 minutes). MRI: T2-weighted hyperintensity, no chemical shift signal drop (distinguishing from lipid-rich adenoma). FDG-PET/CT: evaluates distant metastases and guides surgical resectability assessment. Biopsy: generally avoided for primary ACC due to tumor seeding risk; reserved for evaluation of suspected recurrence or equivocal metastases when surgery is not planned. Histopathology: Weiss score on resected tumor (3+ of 9 criteria = ACC); Ki-67 proliferation index above 10% indicates high-risk behavior requiring adjuvant mitotane. ENSAT staging (I-IV) guides prognosis and therapy.

Complete surgical resection (R0) is the cornerstone of ACC management and the only treatment with curative potential. Open adrenalectomy is preferred for most ACC to minimize risk of surgical capsule disruption and local tumor seeding; laparoscopic approach may be considered for small (below 6 cm) Stage I ACC at centers with expertise, with careful patient selection. En bloc resection of locally invaded adjacent structures (kidney, liver segment, spleen) is performed when required to achieve R0 margins. Adjuvant mitotane: the ESE 2018 guidelines recommend adjuvant mitotane for all completely resected ACC patients, particularly those with Stage II-III disease, Ki-67 above 10%, or evidence of vascular or capsular invasion; target therapeutic serum levels 14-20 mg/L (requires gradual dose escalation over weeks); adrenal insufficiency replacement (hydrocortisone, fludrocortisone) is required due to mitotane's adrenolytic action. Adjuvant chemotherapy: cisplatin-based combination (EDP: etoposide 100 mg/m2 days 5-7, doxorubicin 40 mg/m2 day 1, cisplatin 40 mg/m2 days 3-4, every 4 weeks) is added to mitotane for high-risk resected ACC in some centers based on non-randomized data. Advanced/metastatic ACC: first-line EDP plus mitotane (FIRM-ACT trial: superior PFS and OS compared to streptozotocin plus mitotane — median OS 14.8 vs 12.0 months); second-line options include gemcitabine plus capecitabine plus mitotane, and pembrolizumab (limited activity, approximately 15% ORR). Loco-regional recurrence: repeat surgical resection where feasible; radiofrequency ablation or microwave ablation for liver metastases; adrenal arterial embolization for palliation.

Adrenocortical carcinoma carries a guarded to poor prognosis that depends primarily on disease stage and completeness of surgical resection. Stage I ACC (below 5 cm, organ-confined) with R0 resection has 5-year overall survival of approximately 60-80%. Stage II ACC (above 5 cm, organ-confined, R0 resected) has 5-year survival of approximately 40-60%. Stage III ACC with local invasion or regional lymph node involvement carries 5-year survival of approximately 20-40% even after complete resection. Stage IV metastatic ACC has a median overall survival of approximately 10-15 months; fewer than 15% of patients survive 5 years despite systemic therapy with EDP plus mitotane. Complete surgical resection achieving R0 margins is the single most critical prognostic factor — positive microscopic margins (R1) or macroscopic residual disease (R2) dramatically worsens prognosis and almost universally leads to rapid recurrence. Ki-67 proliferation index above 20% indicates aggressive high-risk disease with worse prognosis regardless of stage. Functional ACC secreting cortisol may impose additional morbidity from Cushing syndrome complications — osteoporotic fractures, diabetes, cardiovascular disease, and opportunistic infections — that further impact quality of life and survival. Recurrence occurs in approximately 50-80% of patients after apparently complete resection, most commonly in the liver, lungs, and retroperitoneum, predominantly within the first 2 years. Mitotane serum levels in the therapeutic range (14-20 mg/L) are associated with improved outcomes in the adjuvant setting. Germline TP53 mutation (Li-Fraumeni syndrome) and pediatric ACC generally carry distinct biological behavior and should be managed at specialized centers with genetic counseling.

ACC cannot be prevented in most cases. Individuals with Li-Fraumeni syndrome (TP53 germline mutation) require systematic cancer surveillance that includes annual adrenal imaging from childhood, as ACC is the dominant childhood cancer in this syndrome. Genetic testing should be offered to all patients with ACC diagnosed before age 40 and their first-degree relatives. Patients with MEN1, FAP, or Beckwith-Wiedemann syndrome should also have periodic adrenal imaging as part of their syndrome-specific surveillance programme. Incidentally discovered adrenal masses must receive prompt biochemical and imaging evaluation — early detection of ACC before local invasion significantly improves surgical resectability and survival.

Features of Cushing syndrome — including unexplained central weight gain, moon face, purple abdominal striae, easy bruising, new-onset diabetes, and hypertension — warrant endocrine evaluation. Women developing hirsutism, voice deepening, or menstrual irregularity rapidly should be assessed for androgen-secreting adrenal tumors. Any child with features of virilization or Cushing syndrome requires urgent paediatric endocrine evaluation, as ACC is relatively more common in children and is frequently associated with Li-Fraumeni syndrome. An adrenal mass discovered incidentally on imaging (adrenal incidentaloma) requires referral for hormonal workup and radiological characterisation even if the patient is asymptomatic, as some are functional or malignant.