Elizabeth Won, Diane Reidy-Lagunes, and Mabel Ryder
• Adrenal “incidentalomas” are adrenal nodules identified on imaging that is done for other reasons. Prevalence is 4% in abdominal imaging. Most are benign nonfunctional adenomas.
• ACC are extremely rare (incidence 1 to 2 per million), bimodal age distribution; peak incidence in early children & age 40–50
Etiology and Genetics of ACC
• RF are not understood due to rarity of adrenal carcinomas
• Majority are sporadic. Can be a/w hereditary syn: Li–Fraumeni, Beckwith–Wiedemann, MEN 1. High incidence in Southern Brazilian children, distinct germline TP53 Mt identified (R337H)
• Susceptibility genes: Sporadic tumors have been a/w Mt in TP53
• 60% ACC are hormone secreting & p/w signs & sx of hormone excess (see table). Cushing syn, virilization syn (or mixed) are most common in malignant ACC. Feminization & hyperaldosteronism is seen in <10% of malignant cases.
• Nonfunctional tumors p/w abdominal/back pain, early satiety, wt loss
Workup and Evaluation of Adrenal Nodule/Mass
• Is there a h/o prior malignancy? → Met adrenal masses are common in pts w/active 1° disease; it is typically not the 1st presentation of 1° CA elsewhere
• Morphologic evaluation: CT scan or MRI abdomen to determine size, heterogeneity, lipid content (MRI), Hounsfield units (HU), margin characteristics
• Imaging characteristics of adenomas vs. carcinomas
Adenomas: Often <4 cm, Hu < 10 precontrast, >50% Hu washout 15 min post-IV contrast, signal drop off on MRI chemical shift (Radiology 2002;222:629).
ACC: Size >4 cm (usu much larger), w/heterogenous, irregular margins, local invasion w/evidence of necrosis on CT
• Must r/o pheochromocytoma prior to bx or surgery! Sporadic pheochromocytomas can be found in adrenal cortex. Pheo typically have high HU on CT (>30 s) & bright on T2 MRI. Exclude pheo w/fractionated plasma metanephrines and/or 24 h urine metanephrines.
• Stage I: Tumor ≤5 cm
• Stage II: Tumor >5 cm, no extra-adrenal invasion
• Stage III: Any size w/local invasion or regional LN spread
• Stage IV: Invasion into adjacent organs or distant met
Management: Functional Adenomas
• Surgery: If unilateral adenoma → laparoscopic unilateral adrenalectomy
• Medical mgmt: If nonsurgical candidate or bilateral hormone production. Hyperaldosteronism: Control HTN, hypoK+ w/spironolactone or eplerenone. Cushing sy: Tx of choice adrenalectomy (rarely bilateral, then bilateral adrenalectomy)
Management: Localized Adrenal Carcinoma
• Surgery: Complete surgical resection is the only potentially curative tx for adrenal carcinoma. Open adrenalectomy w/lymphadenectomy should be performed at specialized referral center. Complete resection may require removal of adjacent structures (liver, kidney, pancreas, spleen). ↑ risk for local recurrence & peritoneal spread when done laparoscopically.
• Adjuvant chemotherapy: Adjuvant mitotane to be considered, esp in high-risk pts; improves DFS vs. observation alone in retrospective study (NEJM 2007;356:2372). Duration of adjuvant tx unknown.
• Adjuvant radiation: Controversial; consider external beam RT to tumor bed, esp if close margins or tumor spillage. Reduces local recurrence rate, no DFS, OS benefit (German ACC registry, J Clin Endocrinol Metab2006;91:4501)
• Surveillance: Imaging & hormone testing every 3–6 mos
Management: Metastatic Adrenal Carcinoma
• Clinical trials should be considered for all eligible pts
• Low grade tumor: Consider resection of 1° tumor & mets if >90% removable, particularly if functional. ↓ tumor burden, sx
EDP (etoposide, doxorubicin, cisplatin) + mitotane: ↑ RR (23% vs. 9.2%), PFS (5 mos vs. 2.1 mos), but no OS benefit vs. streptozocin + mitotane. Significant tox 58% AEs (FIRM-ACT, NEJM 2012;366:2189).
Mitotane monotherapy – only FDA approved drug, RR 10–30% (JCO 2009;27:4619). No standard optimal dose of mitotane; some institutions recommend target serum levels of 14–20 μg/mL if tolerated. Studies suggest therapeutic levels need to achieve benefit. Mitotane is adrenolytic → pts should be put on hydrocortisone Rx empirically to prevent the development of adrenal insufficiency; can also cause aldosterone deficiency.
Other options: Streptozocin ± mitotane, Cisplatin+etoposide ± doxorubicine or mitotane (NCCN compendium listing)
• Medical mgmt of Cushing syn 2° to unresectable, met ACC includes mitotane, ketoconazole, metyrapone, & mifepristone.
• Overall prognosis remains very poor. Stage, completeness of resection, pathologic grade are most important prognostic factors.