Adrenocortical Carcinoma

A detailed Overview for Clinicians

General Overview

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy originating in the adrenal cortex. The disease is characterized by a high risk of recurrence after radical resection.

Despite the high prevalence of benign adrenal tumors in adults over 50, ACC’s incidence is approximately 1–2 cases per million annually, with a slight female predominance. ACC presents unique management challenges due to its biological heterogeneity, frequent hormone excess syndromes, scarcity of evidence-based treatment, and limited therapeutic options. The only approved drug to treat ACC is mitotane (Lysodren®; Esteve).

Risk Factors

  • Genetic Syndromes: ACC is associated with hereditary cancer syndromes such as Li-Fraumeni, Beckwith-Wiedemann syndrome, and Carney complex.
  • Sporadic Cases: Most adult ACCs are sporadic, but germline and somatic mutations (e.g., in TP53, IGF2) are increasingly recognized.
  • Age and Sex: More common in adults (median age ~46), with a higher incidence in women.

Clinical Presentation & Signs/Symptoms

  • Hormonal Excess: About 60% of patients have overt endocrine syndromes at diagnosis, most commonly hypercortisolism (Cushing’s syndrome), often with androgen excess (virilization). Rarely, feminization or hyperaldosteronism occurs.
  • Mass Effect: Abdominal mass, pain, or fullness is common. Up to 40% of tumors are discovered incidentally on imaging.
  • Non-Functional Tumors: May be clinically silent until advanced.

Diagnostic Workup

  • Biochemical Assessment:
    • Cortisol excess: 1 mg dexamethasone suppression, 24-hour urinary cortisol.
    • Androgen/estrogen excess: DHEAS, 17-hydroxyprogesterone, androstenedione, testosterone (in women), estradiol (in men and postmenopausal women).
    • Aldosterone excess: Aldosterone/renin ratio, if hypertension or hypokalemia.
    • Rule out pheochromocytoma as imaging may not distinguish.
  • Imaging:
    • CT/MRI abdomen and pelvis: Evaluate size, invasion, and density.
    • Chest CT: Assess for pulmonary metastases.
    • [18F]FDG PET/CT: Useful for staging and detecting metastases.
  • Histopathology:
    • Weiss Score: >3 favors malignancy.
    • Ki67 Index: Key for prognosis; >10% indicates poorer outcome.
    • Immunohistochemistry for SF-1 to confirm adrenocortical origin.
  • Staging: ENSAT system is preferred for clinical and research use.

Staging (ENSAT)

  • Stage I: Tumor ≤5 cm, no invasion/metastasis.
  • Stage II: Tumor >5 cm, no invasion/metastasis.
  • Stage III: Local invasion or regional lymph node involvement, no distant metastasis.
  • Stage IV: Distant metastasis present.

Treatment Options

  • Localized Disease (Stage I–III):
    • Surgical Resection (R0): Open adrenalectomy by experienced surgeons in high-volume centers is the standard. Lymphadenectomy is recommended.
    • <1>Adjuvant Therapy: Mitotane for most cases, except low-risk (Ki67 ≤10%, stage I–II, R0 resection). Consider adjuvant radiotherapy in R1 resections or after local recurrence.
    • Surveillance: Cross-sectional imaging and hormonal tests every 3 months for 2 years, then gradually extended.
  • Advanced/Metastatic Disease (Stage IV):
    • Systemic Therapy: EDP-M regimen (etoposide, doxorubicin, cisplatin plus mitotane) is first-line. Mitotane monotherapy may be considered for low-burden disease.
    • Second-Line Options: Streptozocin plus mitotane, gemcitabine/capecitabine, temozolomide, pembrolizumab, cabozantinib.
    • Local Therapies: Radiotherapy or ablation for palliation of symptoms or local control.
    • Clinical Trials: This option is strongly encouraged due to limited effective options.
  • Recurrent Disease: Radical resection where feasible; otherwise, systemic or local therapies per above.

Long-Term Outlook & Prognosis

  • Prognostic Factors: ENSAT stage, R0 resection, Ki67 index, and performance status.
  • Survival Rates: 5-year survival varies by stage: 65–82% (I), 58–68% (II), 41–55% (III), and 10–20% (IV).
  • Recurrence Risk: High, emphasizing the importance of long-term surveillance.
  • Quality of Life & Supportive Care: Manage mitotane toxicity, hormone replacement, and provide early psycho-oncological and palliative support when indicated.

Summary

  • Early diagnosis and referral to experienced centers are critical.
  • Surgical expertise is paramount for cure in localized disease.
  • Adjuvant mitotane is standard except in low-risk cases.
  • Systemic therapy options are limited; clinical trial enrollment should be considered.
  • Prognosis remains poor for advanced disease, but outcomes are improving with multidisciplinary care.

Highlights of Prescribing Information

Mitotane (Lysodren®; Esteve)[Prescribing Information]

Reference

[1] Else T, Kim AC, Sabolch A, Raymond VM, Kandathil A, Caoili EM, Jolly S, Miller BS, Giordano TJ, Hammer GD. Adrenocortical carcinoma. Endocr Rev. 2014 Apr;35(2):282-326. doi: 10.1210/er.2013-1029. Epub 2013 Dec 20. PMID: 24423978; PMCID: PMC3963263.
[2] Fassnacht M, Puglisi S, Kimpel O, Terzolo M. Adrenocortical carcinoma: a practical guide for clinicians. Lancet Diabetes Endocrinol. 2025 May;13(5):438-452. doi: 10.1016/S2213-8587(24)00378-4. Epub 2025 Mar 11. PMID: 40086465.
[3] Weiss LM, Medeiros LJ, Vickery AL Jr. Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol. 1989 Mar;13(3):202-6. doi: 10.1097/00000478-198903000-00004. PMID: 2919718.
[4] Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton PA, Rossetto R, Buci L, Sperone P, Grossrubatscher E, Reimondo G, Bollito E, Papotti M, Saeger W, Hahner S, Koschker AC, Arvat E, Ambrosi B, Loli P, Lombardi G, Mannelli M, Bruzzi P, Mantero F, Allolio B, Dogliotti L, Berruti A. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med. 2007 Jun 7;356(23):2372-80. doi: 10.1056/NEJMoa063360. PMID: 17554118.
[5] Percarpio B, Knowlton AH. Radiation therapy of adrenal cortical carcinoma. Acta Radiol Ther Phys Biol. 1976 Aug;15(4):288-92. doi: 10.3109/02841867609131965. PMID: 62490.


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A Guide for Patients


What Is Adrenocortical Carcinoma?

Adrenocortical carcinoma (ACC) is a rare cancer that forms in the outer layer (cortex) of the adrenal glands. These glands sit above each kidney and make important hormones that help control things like blood pressure, body salt and water balance, how your body uses food, and some male and female body characteristics.

Who Is at Risk?

Most ACCs happen for unknown reasons, but some people have inherited conditions that raise the risk, such as:

  • Li-Fraumeni syndrome
  • Beckwith-Wiedemann syndrome
  • Carney complex

ACC can affect adults and children, but it is rare (about 1–2 new cases per million people each year). It is slightly more common in women.

What Are the Signs and Symptoms?

Symptoms depend on whether the tumor makes extra hormones (“functioning”) or not (“non-functioning”):

  • Hormone-related symptoms:
    • Weight gain (especially face, neck, trunk), round/red face, muscle weakness
    • High blood pressure and high blood sugar
    • More body hair, acne, deep voice (especially in women)
    • Irregular or absent periods in women; breast swelling and low sex drive in men
  • Tumor-related symptoms:
    • Lump or swelling in the abdomen
    • Abdominal or back pain
    • Feeling full quickly
  • Many tumors are found by accident during scans for other reasons.

How Is ACC Diagnosed?

Doctors use several tests to find out if you have ACC:

  • Hormone tests: Blood and urine tests to see if your adrenal gland is making too many hormones.
  • Imaging: CT scans or MRI of your abdomen and chest look for tumors and check if cancer has spread.
  • Other scans: Sometimes PET scans or special nuclear medicine scans are used.
  • Biopsy: A sample of the tumor may be taken in some cases to confirm it is cancer.

What Are the Stages of ACC?

Staging describes how far the cancer has spread:

  • Stage I: Small tumor (≤5 cm), only in the adrenal gland
  • Stage II: Larger tumor (>5 cm), still only in the adrenal gland
  • Stage III: Cancer has grown into nearby tissues or lymph nodes
  • Stage IV: Cancer has spread to distant parts of the body (like lungs or liver)

Knowing the stage helps doctors plan the best treatment.

How Is ACC Treated?

Treatment depends on the stage and your overall health:

  • Surgery: The main treatment for early ACC is surgery to remove the adrenal gland (This is called adrenalectomy), and sometimes nearby lymph nodes. Surgery should be done at specialized centers by experienced surgeons.
  • Drug Therapy: Mitotane (Lysodren®; Esteve) is often given after surgery to reduce the risk of cancer returning. It may also be used if surgery isn’t possible. Regular monitoring for side effects mitotane is required.
  • Chemotherapy: For advanced ACC (when cancer has spread), chemotherapy drugs may be used, sometimes in combination with mitotane.
  • Radiation therapy: May be used to treat cancer in certain places or to reduce pain and symptoms.
  • Clinical trials: These research studies test new treatments. Because ACC is rare and difficult to treat, participating in a trial may be recommended.
  • Supportive care: Managing symptoms, hormone replacement, and emotional support are important parts of care.

What Is the Long-Term Outlook?

  • Early-stage ACC: Can sometimes be cured with surgery, but cancer can come back, so regular follow-up is needed.
  • Advanced ACC: Is harder to cure, but treatments can help control symptoms and improve quality of life.
  • Survival: The outlook depends on the stage at diagnosis and if all the cancer can be removed. Some people live many years, especially if the cancer is found early.

What Should Patients and Families Know?

  • ACC is rare and complex disease. Treatment and follow-up at specialized centers with experienced teams are important.
  • Ask your doctor about the benefits and side effects of each treatment, and about clinical trial options.
  • Ongoing support, including counseling and hormone management, can help with quality of life during and after treatment.

Disclaimer: The information provided on this website is for educational and general informational purposes only. It is not intended to be, nor does it serve as, a substitute for professional medical advice, diagnosis, treatment. If you have questions regarding a health condition, always seek the advice of a qualified healthcare professional. Never delay seeking or disregard professional medical advice because of something you have read here.