Adrenal tumors

Overview

• Malignant adrenal tumors are extremely rare, with limited data to guide treatment. The two principal malignancies are adrenocortical carcinoma (from the cortex) and malignant pheochromocytoma (from the medulla).

Adrenocortical carcinoma (ACC)

• Epidemiology: rare (~1 to 2 per million/yr). Bimodal age peaks. Aggressive; prognosis is poor, particularly with larger tumors (>5 cm) and/or local invasion.
• Hereditary: Li-Fraumeni (TP53), Beckwith-Wiedemann, MEN1, Lynch.
• Functional in ~60%: hypercortisolism (Cushing), virilization (DHEA-S), hyperaldosteronism (mineralocorticoid excess), or mixed secretion.
• Workup: hormonal evaluation (cortisol, DHEA-S, aldosterone, renin, plasma metanephrines to rule out pheo), CT/MRI adrenal protocol, urinary steroid profile.
• Imaging clues: size >4 to 6 cm, irregular margins, heterogeneous, calcifications, necrosis, unenhanced CT attenuation >10 HU (excludes lipid-rich adenoma but is indeterminate; >20 HU is suspicious).
• Staging (ENSAT): stage I (≤5 cm) through IV (mets).
• Treatment:
  • Surgery (open en bloc resection at an expert center). Avoid laparoscopic resection for known ACC (capsule rupture risk).
  • Mitotane (adrenocorticolytic agent) adjuvant for high-risk ACC: target serum 14 to 20 mg/L. Use for ≥2 yrs.
  • ADIUVO trial (Terzolo Lancet Diabetes Endocrinol 2023): adjuvant mitotane vs observation in low/intermediate-risk resected ACC (R0, Ki-67 ≤10%), negative for RFS (HR 0.74, not significant); supports avoiding routine adjuvant mitotane in completely resected low/intermediate-risk ACC (ADIUVO underpowered, n=91, stopped early, RFS HR 0.74, 95% CI 0.30 to 1.85; benefit not excluded).
  • Adjuvant RT for positive margins or stage III.
  • Metastatic (EDP-M): mitotane + EDP (etoposide, doxorubicin, cisplatin). Per the FIRM-ACT trial, EDP + mitotane (q4wk) vs streptozocin + mitotane (q3wk) improved response rate and PFS, with no OS difference (built-in crossover design). EDP-M is the standard first-line regimen in advanced disease.
  • Immunotherapy: pembrolizumab has modest activity in TMB-high or MSI-H tumors. A phase Ib study of the PD-L1 inhibitor avelumab in previously treated ACC showed limited ORR but a disease control rate of ~50%.
  • Cabozantinib in refractory ACC (phase 2, Campbell Lancet Oncol 2024): n=18, 4-mo PFS 72.2%, mPFS 6.0 mo; retrospective-series disease-control estimates (e.g. Grisanti) reported separately, not as the trial DCR; an option in EDP/mitotane-refractory metastatic disease.
  • Relacorilant (GRACE/GRADIENT program), a selective glucocorticoid receptor antagonist studied in endogenous Cushing syndrome (GRACE: mixed etiologies; GRADIENT: adrenal adenoma or hyperplasia), not ACC-specific; relevant to ACC only for endocrine control of hypercortisolism, not anti-tumor; not FDA-approved for hypercortisolism (NDA resubmitted Jun 2026 after an FDA complete response letter). ROSELLA is the separate ovarian cancer trial (relacorilant + nab-paclitaxel, FDA-approved Mar 25, 2026 for platinum-resistant ovarian cancer).

Malignant pheochromocytoma / paraganglioma

• Origin: pheochromocytomas arise from adrenal-medullary chromaffin cells; paragangliomas are extra-adrenal (sympathetic or parasympathetic paraganglia); metastatic disease develops in ~10% of pheochromocytomas (higher in paragangliomas and SDHB carriers); WHO 2022 regards all PPGLs as having metastatic potential and uses "metastatic" rather than "malignant". (See also NETs section.)
• Presentation: functional tumors secrete catecholamines, causing the classic triad of headache, diaphoresis, and tachycardia, plus episodic hypertension.
• Diagnosis: 24-hour urine for fractionated metanephrines and catecholamines, or plasma-fractionated metanephrines (drawn through an IV catheter placed 20 to 30 min beforehand with the patient supine). Do not routinely stop all adrenergic blockers (risky in catecholamine excess); review assay-specific interference and consider supervised withdrawal or substitution of interfering drugs (e.g., TCAs) only when necessary. If abnormal, localize with dedicated adrenal imaging.
• Treatment: no curative systemic therapy for malignant disease; mainstay is surgical resection with preoperative α blockade (essential); add a β blocker only for tachycardia, and only after adequate α blockade. Close collaboration with endocrinology is essential. Systemic data are limited; the VHL association has led to use of VEGFR-targeted agents.
• Belzutifan (HIF-2α inhibitor): FDA May 14, 2025 for locally advanced or metastatic pheochromocytoma/paraganglioma not amenable to surgery (LITESPARK-015, Jimenez NEJM 2025): ORR 26%, DCR 85%, mPFS 22.3 mo; grade 3 anemia 22%.

Adrenal incidentaloma

• Definition: adrenal mass found incidentally on imaging.
• Workup:
  • Hormonal eval (cortisol after 1 mg dexamethasone suppression, aldosterone/renin if HTN, DHEA-S if virilization; plasma or urinary metanephrines unless homogeneous ≤10 HU on unenhanced CT with no clinical suspicion of pheochromocytoma).
  • Imaging characterization: benign adenoma = homogeneous mass with ≤10 HU on unenhanced CT.
  • Surgical resection for: clinically significant hormone excess, or indeterminate/suspicious imaging (heterogeneous, unenhanced attenuation >20 HU), especially if ≥4 cm or interval growth. A nonfunctioning, unequivocally benign (homogeneous, ≤10 HU) mass generally does not need surgery regardless of size; mild autonomous cortisol secretion is individualized.

High-yield adrenal pearls

• ALWAYS rule out pheo before any adrenal surgery (catastrophic crisis risk); block α before β.
• Mitotane adjuvant for high-risk ACC (ADIUVO negative in low/intermediate risk).
• EDP-M (EDP + mitotane) for advanced ACC; improves response/PFS but not OS (FIRM-ACT).
• Avoid laparoscopic surgery for ACC.
• Hereditary screening for ACC (Li-Fraumeni, MEN1).