John M. Lacy, MD, FACS
Stephen E. Strup, MD, FACS
BASICS
DESCRIPTION
Adrenal cortical carcinoma is a primary malignancy arising in the adrenal cortex
EPIDEMIOLOGY
Incidence
• Rare: 0.5–2 cases per million people per year
• Bimodal occurrence:
– Initial peak in children <5 yr old;
– 2nd peak in adults in 4th and 5th decades of life
• Female:male ratio ∼1.5:1
• ∼80–130 cases in USA annually
• <5% of all adrenal incidentalomas, with correlation between size of tumor and likelihood of ACC
– 2% of lesions <4 cm
– 6% of lesions 4–6 cm
– 25% of lesions >6 cm
Prevalence
Mirrors incidence, as prognosis is poor
RISK FACTORS
Genetic associations (see below)
Genetics
• Sporadic cases
– Inactivation of p53 on 17q13
– Alterations at 11p15 locus, site of IGF-2
– Activation of β-catenin gene
• Familial syndromes
– Li–Fraumeni syndrome
– Beckwith–Wiedemann syndrome
– Multiple endocrine neoplasia (MEN) 1
– Congenital adrenal hyperplasia
– Adenomatous polyposis coli
PATHOPHYSIOLOGY
• Difficult to distinguish benign from malignant adrenal tumors in absence of metastatic disease.
• Pathologic features such as mitotic activity, grade, vascular invasion, various architectural features, and tumor size have not consistently correlated with prognosis.
• Most (60–70%) ACCs are functioning, although this is related to the extent of workup.
ASSOCIATED CONDITIONS
• Cushing’s syndrome secondary to functional tumors
• Familial syndromes (see above)
GENERAL PREVENTION
No recommendations
DIAGNOSIS
HISTORY
• Most common symptoms are related to excess cortisol production (Cushing’s syndrome) in 50–60%, then virilization (20%), or mixed syndromes (20–30%)
• History of onset of symptoms <12 mo is suspicious for ACC
• Constitutional symptoms:
– Weight loss, malaise, weakness, nausea, or vomiting usually associated with poor prognosis
• In children, suggested by generalized weight gain and delayed linear growth
• Nonfunctional tumors may be larger and present with mass effect
– Painful or palpable mass
– Lower extremity edema
– Urinary obstruction
– Budd–Chiari syndrome
– GI symptoms
• Hyperaldosteronism (rare):
– Hypertension
– Hypokalemic alkalosis
• Feminization (rare)
• Incidental finding during imaging workup for other morbidities
PHYSICAL EXAM
• Palpable abdominal mass
• Signs of Cushing’s syndrome (functional ACCs): Violaceous striae, moon facies, truncal obesity, buffalo hump, glucose intolerance, hyperpigmentation
• Signs of virilization (oligomenorrhea, hirsutism, cystic acne, excessive muscle mass, voice deepening, temporal balding, clitoromegaly)
• Gynecomastia
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Tests for glucocorticoid excess (minimum 3 out of 4 tests)
– Dexamethasone suppression test
– 24-hr urinary free cortisol
– Basal cortisol (serum)
– Basal ACTH (plasma)
• Sexual steroids and steroid precursors
– DHEA-S (serum)
– 17-OH-progesterone (serum)
– Testosterone (serum)
– 17-β-estradiol
– 24-hr urine steroid metabolite exam
• Mineralocorticoid excess
– Potassium (serum)
– Aldosterone/renin ratio
Only used in patients with arterial hypertension and/or hypokalemia
• Catecholamine excess to exclude pheochromocytoma
– Meta- and normetanephrines (plasma)
– Catecholamines or metanephrine excretion (24-hr urine)
Imaging
• CT of abdomen is preferred initial study in patients adrenal lesion:
– Benign tumors
Homogeneous appearance with well-delineated margins
Generally <4–6 cm, smooth and round or oval contour
<10 HFU or rapid washout of contrast <15 min
– Primary ACCs:
Nonhomogeneous internal architecture
Irregular contour, invasion of surrounding structures
>10 HFU or delayed washout of contrast >15 min
• MRI not proven to be more sensitive in differentiating malignant from benign tumors:
– Preferred imaging modality for evaluation of vena caval involvement
– ACCs generally isodense to the liver on T1-weighted images; intermediate to high signal intensity (brighter white) on T2-weighted images (less bright than pheochromocytoma).
• FDG-PET potentially useful in radiologically indeterminate lesions.
• Bone scan if suspicious of skelet al metastases.
Diagnostic Procedures/Surgery
• Role of percutaneous biopsy limited
– Difficult to distinguish between benign and malignant tissue
– Concern for seeding biopsy tract
Pathologic Findings
• Macroscopic:
– Lobulated, orange tumor with necrotic areas, calcifications, intratumoral hemorrhages
• Microscopic:
– Weiss criteria for malignancy includes ≥3 of the following:
High nuclear grade
Mitotic rate > 5/50/hpf
Atypical mitotic fevers
Eosinophilic tumor cell cytoplasm
Diffuse architecture in >33% of tumor
Necrosis
Vascular invasion
Sinusoidal invasion
Capsular invasion
• Antigen Ki-67 is a promising new immunohistochemical marker
– Marker of proliferative activity
– Low-risk ACC – expressed in <10% of cells
– High-risk ACC – expressed in >10% of cells
DIFFERENTIAL DIAGNOSIS
• Functioning adrenal masses:
– Adenoma, aldosteronoma, pheochromocytoma
• Nonfunctioning adrenal masses:
– Hemorrhage, cyst, metastatic tumor, neuroblastoma
• Other: Renal cell carcinoma
TREATMENT
GENERAL MEASURES
Complete surgical excision is treatment of choice in resectable stage I or II tumors and children
MEDICATION
First Line
• Mitotane is the treatment of choice for metastatic ACC
– Objective regression in tumor size in 35%
– Dosage escalated to tolerance, which is limited
– Significant toxicity – GI, CNS, endocrine
– Must monitor serum levels closely
– Strong inhibitor of steroidogenesis
Both glucocorticoid and mineralocorticoid replacement necessary
• Mitotane monotherapy may be used in patients with low tumor burden or indolent disease
• Polychemotherapy indicated with high tumor burden or rapidly progressive disease
– Cytotoxic chemotherapy under investigation
Etoposide, doxorubicin, cisplatin, and mitotane
Streptozotocin and mitotane
Second Line
• If failed mitotane monotherapy, add cytotoxic chemotherapy
• If failed initial polychemotherapy regimen, may try whichever regimen was not used
• Clinical trials underway for targeted therapies
– IGF-1 receptor inhibitors
– Multi-tyrosine-kinase inhibitors
SURGERY/OTHER PROCEDURES
• Indications for surgery (1)
– Hormonally active mass
– Size >5–6 cm
• Open approaches
– Anterior approach (chevron or subcostal incision) for the rare low-stage ACC
– For more advanced ACCs, a thoracoabdominal incision provides optimal exposure
– Avoid risk of port side seeding associated with laparoscopy
• Laparoscopy
– Feasible in stage I and stage II tumors <10 cm in size
– Many studies report equivalent oncologic outcomes (1)
– Postoperative advantages
Less analgesic requirement
Lower blood loss
Shorter postop fasting period
Reduced length of hospital stay
• Advanced local disease may require resection of adjacent visceral organs, portions of vena cava and/or tumor thrombus
• Surgery may also play a role in the setting of metastatic disease
– Primary tumor represents the bulk of disease
– Complete resection is feasible
– Tumor objectively responds to medical treatment or stabilizes over period of 6 mo
• Lymphadenectomy provides improved staging and may lead to favorable oncologic outcomes (2)
ADDITIONAL TREATMENT
Radiation Therapy
• ACCs formerly considered radioresistant
• Now radiation used in 2 scenarios:
– Adjuvant therapy in patients with high risk for recurrence
– Palliative control of local symptomatic metastases to bone, brain, or vena cava obstruction (3)
Additional Therapies
• Inhibitors of steroid synthesis may be useful in controlling symptoms of glucocorticoid excess
– Metyrapone
– Aminoglutethimide
– Ketoconazole
– Etomidate
ALERT
Hydrocortisone must be administered during surgery and postoperatively if patients with glucocorticoid excess.
Complementary & Alternative Therapies
• Locoregional therapy may be indicated in cases of progression despite mitotane
– Arterial chemoembolization
– Radiofrequency ablation
ONGOING CARE
PROGNOSIS
• Overall prognosis is poor, with overall 5-yr survival ranging from 15–60% based on stage
• Overall recurrence rate 17–85%
– 23% in R0 patients
– 51% for R1 and R2 patients
• Stage at diagnosis is the most important prognostic variable
• ∼70% of patients present with advanced disease (stage III or IV)
COMPLICATIONS
• Fever due to tumor necrosis
• Anemia from hemorrhage into the tumor
• Adrenal crisis in patients who undergo surgery for functioning tumors without adequate steroid prep
FOLLOW-UP
Patient Monitoring
• Close follow-up is critical
• Abdominal CT or MRI and chest CT recommended every 3 mo for a minimum of 2 yr
• Serum and urinary steroid levels should also be monitored, though they are less sensitive for detection of recurrence than imaging
• Follow-up should be long-term, since late recurrence of ACC (after ≥10 yr) is not uncommon
Patient Resources
• www.adrenalcancerhope.org
• www.adrenocorticalcarcinoma.org
REFERENCES
1. Carnaille B. Adrenocortical Carcinoma: Which surgical approach? Langenbecks Arch Surg. 2012;397(2):195–199.
2. Reibenantz J, Jurowich C, Erdogan I, et al. Impact of lymphadenectomy on the oncologic outcome of patients with adrenocortical carcinoma. Ann Surg. 2012;255:363–369.
3. Polat B, Fassnacht M, Pfreunder L, et al. Radiotherapy in adrenocortical carcinoma. Cancer. 2009;115:2816–2823.
ADDITIONAL READING
• Baudin E, Leboulleux S, Al Ghuzlan A, et al. Therapeutic Management of advanced adrenocortical carcinoma: What do we know in 2011? Horm Cancer. 2011;6:363–371.
• Berruti A, Baudin E, Gelderblom H, et al. Adrenal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23(suppl 7):vii131–8.
• Carnaille B. Adrenocortical carcinoma: Which surgical approach? Langenbecks Arch Surg. 2012;397(2):195–199.
See Also (Topic, Algorithm, Media)
• Adrenal Adenoma
• Adrenal Cortical Carcinoma Image 
• Adrenal Mass
• Adrenal Mass Algorithm 
CODES
ICD9
• 194.0 Malignant neoplasm of adrenal gland
• V84.09 Genetic susceptibility to other malignant neoplasm
ICD10
• C74.00 Malignant neoplasm of cortex of unspecified adrenal gland
• C74.02 Malignant neoplasm of cortex of left adrenal gland
• Z15.09 Genetic susceptibility to other malignant neoplasm
CLINICAL/SURGICAL PEARLS
• Rapid development of symptoms is key to distinguishing ACC from Cushing’s syndrome.
• Lymphadenectomy provides improved staging and may lead to favorable oncologic outcomes.
• Radiation therapy useful as adjuvant therapy in high-risk patients and for local palliation.
• Laparoscopic adrenalectomy feasible in experienced surgeon’s hands if mass <8–10 cm.
• Close follow-up is critical, as late recurrence is reported.