A Research Guide for
Adrenocortical Carcinoma

Cortisol excess is the most common hormonal presentation, occurring in roughly 30–40% of functional ACCs. Signs and symptoms develop over weeks to months and include:

• Rapid weight gain, especially in the face (moon face), abdomen, and upper back (buffalo hump)
• Thinning skin that bruises easily; purple stretch marks (striae) on the abdomen
• Muscle weakness, especially in the thighs and upper arms
• High blood sugar (often new diabetes) and high blood pressure
• Mood changes: anxiety, irritability, depression, insomnia
• Increased susceptibility to infections
• Bone thinning (osteoporosis)

Cushing syndrome from ACC tends to develop more rapidly and be more severe than Cushing syndrome from benign causes. The rapid onset of severe Cushing features should raise concern for a malignant adrenal tumor.

Excess male hormones (androgens, especially DHEA-S and testosterone) from ACC can cause virilization. In women, this may present as:

• New or rapidly worsening facial and body hair (hirsutism)
• Deepening of the voice
• Acne
• Male-pattern hair loss
• Menstrual irregularity or cessation
• Increased muscle mass

In children, androgen-producing ACC can cause precocious puberty (early puberty signs in young children). In men, androgen excess from ACC may go unnoticed or cause subtle changes. Androgen excess combined with cortisol excess is particularly suggestive of ACC rather than a benign adrenal adenoma.

Estrogen-producing ACC is rare. In men, it may cause breast enlargement (gynecomastia), testicular atrophy, and decreased libido. In pre-pubertal girls, it can cause early breast development and vaginal bleeding. An estrogen-producing adrenal mass in a male is strongly suspicious for ACC (benign adrenal adenomas very rarely produce estrogen).

Aldosterone-producing ACC is uncommon. When present, it causes high blood pressure that is difficult to control, low potassium levels (hypokalemia) with associated muscle weakness and cramping, and excessive urination. While benign aldosterone-producing adenomas (Conn syndrome) are relatively common, aldosterone-producing ACC is rare. However, a large adrenal mass with aldosterone excess should be evaluated carefully for malignancy.

ACC frequently produces more than one type of hormone. The combination of cortisol and androgen excess is particularly common and is itself a diagnostic clue — benign adrenal adenomas rarely produce multiple hormone types simultaneously. Any adrenal mass that produces excess hormones from more than one pathway should be evaluated with high suspicion for malignancy.

The primary imaging tools for ACC are:

• CT scan of the abdomen and pelvis — the workhorse study. ACC typically appears as a large (often >6 cm), heterogeneous mass with irregular borders, areas of necrosis or hemorrhage, and high density (>10 Hounsfield units on unenhanced CT, with delayed contrast washout). These imaging features help distinguish ACC from benign adrenal adenomas, which are typically smaller, homogeneous, and lipid-rich.
• MRI of the abdomen — useful when CT findings are equivocal, for evaluating invasion into adjacent structures (especially the inferior vena cava), and for patients who cannot receive CT contrast.
• CT scan of the chest — to evaluate for lung metastases, a common site of ACC spread.
• PET/CT (FDG-PET) — can help distinguish benign from malignant adrenal masses and assess for distant metastases. High FDG uptake in an adrenal mass is concerning for malignancy.
• Brain MRI — not routine, but considered if there are neurological symptoms.

Size matters in adrenal tumors. Adrenal masses larger than 4 cm have an increasing probability of malignancy. Masses larger than 6 cm have a substantial risk. However, size alone does not confirm or exclude cancer — the complete clinical picture (imaging characteristics, hormone profile, growth rate) determines management.

A comprehensive hormonal evaluation should be performed before surgery for any suspected ACC. The recommended panel includes:

• Cortisol: 24-hour urinary free cortisol, late-night salivary cortisol, 1 mg overnight dexamethasone suppression test, morning ACTH
• Androgens: DHEA-S, total testosterone, androstenedione, 17-hydroxyprogesterone
• Estrogens: Estradiol (especially in males and postmenopausal females)
• Mineralocorticoids: Aldosterone and renin (aldosterone-to-renin ratio), potassium
• Catecholamines: Plasma metanephrines or 24-hour urine metanephrines (to exclude pheochromocytoma, which requires different preoperative preparation)

This workup serves three purposes: it identifies hormone excess that must be managed before and during surgery, it provides baseline levels that serve as tumor markers after treatment, and it helps differentiate ACC from other adrenal masses.

ACC is staged using the European Network for the Study of Adrenal Tumors (ENSAT) system, which is now the international standard:

• Stage I: Tumor ≤5 cm, confined to the adrenal gland, no local invasion, no lymph nodes, no distant spread.
• Stage II: Tumor >5 cm, confined to the adrenal gland, no local invasion, no lymph nodes, no distant spread.
• Stage III: Tumor of any size with local invasion into surrounding tissues (including tumor thrombus in the renal vein or inferior vena cava), positive regional lymph nodes, or infiltration of surrounding organs (kidney, diaphragm, pancreas, spleen, liver) without distant metastases.
• Stage IV: Distant metastases present (most commonly liver, lungs, bone, peritoneum).

The ENSAT stage at diagnosis is one of the strongest predictors of outcome. Stage I and II (localized) tumors have the best prognosis, especially when completely resected. Stage III and IV disease is more challenging but still treatable.

A substantial number of ACCs are discovered incidentally — on CT or MRI scans performed for unrelated reasons. Adrenal masses found incidentally (adrenal incidentalomas) are actually quite common, found in roughly 4–5% of abdominal CT scans. The vast majority are benign adenomas. However, when an adrenal incidentaloma has worrisome features — large size (>4 cm), heterogeneous appearance, high density on CT, rapid growth on follow-up imaging, or associated hormone excess — the workup for possible ACC should proceed promptly.

When evaluating any treatment claim for ACC, ask these questions:

• Has this treatment been studied specifically in ACC, in a published clinical trial? Given how rare ACC is, the trial will likely be small — but it should exist.
• Is this recommended in the NCCN or ESMO–EURACAN ACC guidelines?
• Does the treating team at a specialized ACC center use or recommend this?
• Could it interfere with mitotane or other standard treatment?
• Does the person recommending it have a financial interest in selling it?

Be especially cautious of “adrenal support” supplements, which are widely marketed but have no role in ACC treatment. Some may contain substances that interfere with mitotane metabolism or hormone measurements. Every supplement should be reviewed with the endocrine oncology team before use.

This is not optional advice. ACC outcomes are strongly correlated with center experience. A study from the German ACC Registry showed that patients treated at high-volume specialized centers had significantly better survival than those treated at community hospitals, even after adjusting for stage. The reasons are straightforward: specialized centers have surgeons who perform adrenalectomies regularly, endocrinologists familiar with ACC hormone management, pathologists experienced in the Weiss scoring system, and oncologists who know how to dose and monitor mitotane.

If you have been diagnosed at a community hospital, the single most impactful thing you can do is request an urgent referral to a center with dedicated endocrine oncology and adrenal surgery programs. A few days of delay for a proper referral is far better than proceeding with surgery at an inexperienced center.

• How many ACC cases has this center treated in the past five years?
• How many adrenalectomies does the surgeon perform per year? Has the surgeon operated on ACC specifically?
• Has a complete hormonal workup been done?
• Has pheochromocytoma been excluded?
• Has staging been completed with chest and abdominal imaging?
• Should I get a second opinion at a specialized center before proceeding?
• Will my case be discussed at a multidisciplinary tumor board that includes endocrine surgery, medical oncology, endocrinology, and pathology?

• ☐ Adrenal mass identified on imaging; ACC suspected or confirmed
• ☐ Complete hormonal workup ordered (cortisol, androgens, estrogens, aldosterone/renin, catecholamines)
• ☐ Pheochromocytoma excluded with catecholamine/metanephrine testing
• ☐ Staging completed: CT chest + CT or MRI abdomen/pelvis; PET/CT if needed
• ☐ Referral to specialized endocrine surgery center made or being arranged
• ☐ Records folder started: all imaging (with discs or digital access), labs, hormone results
• ☐ Second opinion at a high-volume ACC center considered
• ☐ Genetic counseling discussed (especially if age <40, childhood ACC, or family cancer history)
• ☐ Hormone excess being medically managed if symptomatic (blood pressure, blood sugar, potassium)
• ☐ Financial counselor contacted at the treating center

• A dedicated endocrine surgery program with surgeons who perform adrenalectomies regularly (ideally >20 per year)
• Endocrinologists experienced in managing cortisol excess, adrenal insufficiency, and mitotane monitoring
• Medical oncologists who have treated ACC (not just read about it)
• Pathologists experienced in the Weiss score and Ki-67 assessment for adrenal tumors
• An active clinical trials program with ACC-relevant studies
• A multidisciplinary tumor board that regularly reviews adrenal tumors

For a tumor this rare, a second opinion at a major ACC center is not a luxury — it is a standard recommendation. Even if the patient plans to receive most treatment closer to home, having the surgical and treatment plan reviewed by an ACC-experienced team can change the approach. Several major centers offer remote second-opinion programs. At minimum, the imaging and pathology should be reviewed by the second center.

Laparoscopic or robotic adrenalectomy may be considered for small (≤6 cm), well-circumscribed tumors where there is genuine diagnostic uncertainty (an adrenal mass that might be a benign adenoma but is being removed because of size or imaging features). But when ACC is the likely diagnosis, open surgery at an experienced center is the safer approach.

The essential goal is an R0 resection — complete removal with microscopically clear margins. If the tumor invades adjacent structures (kidney, liver, diaphragm, vena cava), en bloc resection of those structures may be necessary. This requires a surgeon prepared and technically equipped for a complex operation.

If the tumor produces excess cortisol, the patient is at risk of adrenal crisis after surgery. When the overactive tumor is removed, the remaining adrenal gland (if it exists) is typically suppressed and cannot immediately compensate. Perioperative glucocorticoid coverage (stress-dose hydrocortisone) must be planned and administered. The endocrinology team should be involved in preoperative preparation.

For aldosterone-producing tumors, potassium should be corrected and blood pressure controlled before surgery. For tumors with severe Cushing syndrome, preoperative cortisol-lowering medication (metyrapone, ketoconazole) may be considered to reduce surgical risk, though this is a specialized decision.

Regional lymph node dissection during ACC surgery is a subject of ongoing discussion. Retrospective data suggest that removing regional lymph nodes during the primary surgery may improve staging accuracy and possibly outcomes. ESMO–EURACAN guidelines recommend routine regional lymphadenectomy when technically feasible. This is another reason to have the surgery performed at an experienced center where the surgeon routinely performs adrenalectomies with lymph node sampling.

The Weiss score is the standard histopathological system used to distinguish ACC from benign adrenal adenomas. It evaluates nine microscopic features:

1. High nuclear grade
2. Mitotic rate >5 per 50 high-power fields
3. Atypical mitotic figures
4. Clear cells comprising ≤25% of the tumor
5. Diffuse architecture
6. Necrosis
7. Venous invasion
8. Sinusoidal invasion
9. Capsular invasion

A Weiss score of 3 or higher (out of 9) is considered diagnostic of malignancy. Higher Weiss scores generally correlate with more aggressive behavior, though the score is not a perfect predictor of individual outcome. The pathologist evaluating the specimen should have experience with adrenal pathology — this is a specialized assessment.

Ki-67 is a marker of how actively tumor cells are dividing. In ACC, the Ki-67 index is one of the strongest prognostic markers:

• Ki-67 ≤10%: Lower proliferation; associated with better prognosis
• Ki-67 >10%: Higher proliferation; associated with more aggressive disease and higher recurrence risk
• Ki-67 >20%: High proliferation; aggressive biology

The Ki-67 index is increasingly used to guide adjuvant treatment decisions. Patients with completely resected ACC and a Ki-67 >10% are generally considered higher risk and more likely to benefit from adjuvant mitotane. This value should be confirmed in the pathology report.

• Diagnosis: Confirmed adrenocortical carcinoma (Weiss score ≥3)
• Weiss score: The specific score and which features were present
• Ki-67 index: The proliferation percentage
• Resection margins: R0 (microscopically clear), R1 (microscopically involved), or R2 (grossly incomplete)
• Tumor size
• Invasion: Capsular invasion, vascular invasion, invasion into adjacent organs
• Lymph nodes: Number examined and number positive (if lymphadenectomy was performed)
• ENSAT stage: Based on all pathologic and clinical findings

The decision to use adjuvant mitotane (after complete surgical resection) is based on risk of recurrence. The ADIUVO trial — the only prospective randomized trial of adjuvant mitotane — studied patients with low-intermediate risk ACC (R0 resection, Ki-67 ≤10%) and did not show a statistically significant benefit for adjuvant mitotane in that population. However, for higher-risk patients, retrospective data support adjuvant mitotane.

Current guidelines generally recommend adjuvant mitotane for:

• Stage III disease (locally advanced)
• R1 resection (positive microscopic margins)
• Ki-67 >10%
• High Weiss score
• Stage I–II with high-risk features (large tumor, vascular invasion, high mitotic rate)

For low-risk completely resected ACC (stage I–II, R0, Ki-67 ≤10%), the decision is more nuanced. The ADIUVO trial results suggest that careful surveillance without adjuvant mitotane may be a reasonable option for this group. This discussion should involve an endocrine oncologist with ACC experience.

Mitotane is taken orally, usually starting at a low dose and increasing gradually. The critical pharmacological fact about mitotane is its long half-life (roughly 18–159 days) and its therapeutic window:

• Target blood level: 14–20 mg/L. Levels below 14 mg/L are considered subtherapeutic. Levels above 20 mg/L increase toxicity without clear additional benefit.
• Blood levels should be measured regularly (typically every 2–4 weeks initially, then monthly once stable).
• It can take weeks to months to achieve therapeutic levels. Some centers use a “loading dose” strategy to reach the target range faster.
• Even after stopping mitotane, it persists in the body for months due to storage in fat tissue.

Because mitotane destroys adrenal tissue, essentially all patients on mitotane require glucocorticoid replacement (hydrocortisone). Many also require mineralocorticoid replacement (fludrocortisone). The doses of replacement steroids need to be higher than typical physiological replacement because mitotane increases cortisol metabolism.

Mitotane has significant side effects, and managing them well is essential for maintaining the drug at therapeutic levels. Common side effects include:

• Gastrointestinal: Nausea, vomiting, diarrhea, and loss of appetite are common, especially during dose escalation. Taking mitotane with fatty food improves absorption and may reduce GI symptoms.
• Neurological: Dizziness, confusion, difficulty concentrating, ataxia (unsteady gait), speech difficulty. These often correlate with blood levels and may require dose reduction.
• Hormonal: Adrenal insufficiency (managed with replacement steroids), elevated cholesterol (can be severe), thyroid hormone alterations.
• Hepatic: Liver enzyme elevations; monitoring required.
• Other: Fatigue, skin rash, gynecomastia in men.

Many of these side effects are manageable with dose adjustment, supportive medications, and close monitoring. The neurological side effects typically improve when the dose is reduced. The goal is to maintain the therapeutic window (14–20 mg/L) while keeping side effects tolerable — this requires an experienced mitotane prescriber.

The FIRM-ACT trial (First International Randomized trial in locally advanced and Metastatic Adrenocortical Carcinoma Treatment) compared two chemotherapy regimens, both combined with mitotane:

• EDP-M: Etoposide + doxorubicin + cisplatin + mitotane
• Sz-M: Streptozocin + mitotane

EDP-M produced a significantly higher response rate (23% vs. 9%) and longer progression-free survival. EDP-M plus mitotane is now the standard first-line chemotherapy for advanced ACC.

EDP-M is given in 4-week cycles, typically for 4–6 cycles depending on response and tolerance. It is a toxic regimen requiring careful monitoring of blood counts, kidney function (cisplatin is nephrotoxic), and heart function (doxorubicin is cardiotoxic). Treatment should be administered at a center experienced with this specific combination.

• Unresectable locally advanced ACC: EDP-M may shrink the tumor enough to enable surgery (conversion/neoadjuvant approach).
• Metastatic ACC: EDP-M is the first-line systemic treatment to control disease.
• Recurrent ACC: If recurrence is not surgically resectable, EDP-M is the standard option (if not previously used or if a sufficient interval has passed).

Mitotane is continued during chemotherapy in the EDP-M regimen. The CYP3A4 induction by mitotane can affect etoposide metabolism, so dosing adjustments may be needed. This pharmacological interaction is another reason to receive treatment at an ACC-experienced center.

If ACC progresses on EDP-M, standard options are limited. Gemcitabine plus capecitabine has shown modest activity in some retrospective series but has not been validated in a randomized trial. Streptozocin-based regimens can be considered if not previously used. This is the setting where clinical trials are most important — patients with ACC that has progressed on standard therapy should be actively seeking trial access.

Because mitotane increases the metabolic clearance of cortisol, patients on mitotane typically need higher doses of hydrocortisone replacement than patients with other causes of adrenal insufficiency. The dose is adjusted based on clinical assessment and cortisol levels. Underdosing leads to symptoms of adrenal insufficiency (fatigue, nausea, lightheadedness); overdosing can cause Cushingoid features. Finding the right balance requires ongoing collaboration with the endocrinology team.

Sick-day rules: During illness, stress, or minor procedures, the hydrocortisone dose should be doubled or tripled (the specific rule should be provided by the endocrinology team). For major illness, surgery, or if unable to keep oral medication down, the emergency injection must be used and the patient should go to the emergency department.

Fludrocortisone replaces aldosterone when adrenal function is lost. It helps maintain blood pressure and electrolyte balance. Signs that mineralocorticoid replacement may be needed or needs adjustment include low blood pressure, dizziness on standing, salt craving, and low potassium or high sodium levels. Not all patients on mitotane require fludrocortisone — it depends on the degree of adrenal suppression.

For functional ACC, the hormones the tumor produced before treatment serve as valuable tumor markers during follow-up. If the tumor was producing excess cortisol, DHEA-S, or testosterone, a return of those elevated levels after surgery (or a rise during treatment) may signal recurrence or progression before imaging changes are visible. This is why the baseline hormonal workup is so important — it establishes what to monitor.

Patients and families should know which hormones their specific tumor produced and ensure these are tracked at regular follow-up visits.

Structured surveillance after ACC surgery is essential. The typical schedule includes:

• CT scans of chest, abdomen, and pelvis every 3 months for the first 2 years, then every 3–6 months through year 5, then annually
• Hormone panels at each visit (the same hormones that were elevated at diagnosis)
• Mitotane levels if on adjuvant therapy (targeting 14–20 mg/L)
• Electrolytes, liver function, thyroid function, cholesterol (monitoring for mitotane effects)

The intensive surveillance schedule reflects the high recurrence risk. Early detection of recurrence is important because surgically resectable recurrence has a better outlook than unresectable recurrence.

When ACC recurs, the most important question — just as at initial diagnosis — is whether the recurrence can be completely removed by surgery. Complete resection of a local recurrence or limited metastases (particularly in the lung or liver) can extend survival and in some cases lead to long-term disease control. Repeated resections, while more technically challenging, are part of the ACC treatment paradigm at specialized centers.

If surgery is not feasible, systemic therapy (EDP-M if not recently used, or clinical trial) is the next step.

Pembrolizumab (Keytruda), a PD-1 checkpoint inhibitor, has been studied in ACC in several settings:

• A phase II trial (NCT02673333) of pembrolizumab in 39 patients with previously treated advanced ACC showed an objective response rate of approximately 23% and a disease control rate of approximately 52%. Some responses were durable, lasting over a year.
• KEYNOTE-158 (NCT02628067) is the tumor-agnostic basket trial that supported pembrolizumab’s approval for MSI-H/dMMR tumors; it included only a few ACC patients (selected for the biomarker), so it is not a source of ACC-specific response rates. Pembrolizumab’s modest, non-durable activity in unselected ACC comes from dedicated studies such as NCT02673333.

The challenge with immunotherapy in ACC is that cortisol-producing tumors may suppress the immune system, potentially reducing immunotherapy efficacy. Some investigators are exploring whether controlling cortisol levels (with mitotane or other agents) before or during immunotherapy could improve responses. This remains an active research question.

Combinations of PD-1/PD-L1 inhibitors with CTLA-4 inhibitors (nivolumab plus ipilimumab) are being explored in ACC based on the rationale that dual checkpoint blockade may overcome the immunosuppressive tumor microenvironment. Early data from small series have shown responses in some patients. The CA209-538 basket trial (NCT02923934) included ACC patients treated with nivolumab plus ipilimumab and reported partial responses in a subset.

Combinations of immunotherapy with mitotane are also under investigation, with the hypothesis that mitotane’s destruction of adrenal tissue and reduction of cortisol production might enhance the immune response.

The ADIUVO-2 trial (NCT03583710) is a significant ongoing phase III randomized trial evaluating adjuvant mitotane with or without cisplatin and etoposide in high-risk resected ACC (stage I–III). This is one of the most important ongoing ACC trials because it tests whether adding cytotoxic chemotherapy to adjuvant mitotane reduces recurrence in high-risk patients. Patients with recently resected high-risk ACC should ask their medical team about ADIUVO-2 eligibility.

The PEMBR-01 trial (NCT05563467) is an ongoing phase II trial evaluating pembrolizumab in advanced, progressive ACC. This trial is actively recruiting and represents another avenue for patients with ACC that has progressed on standard treatment. Patients with advanced ACC who are seeking immunotherapy options should ask about this trial.

The insulin-like growth factor 1 receptor (IGF-1R) pathway is overexpressed in many ACCs. Linsitinib, an IGF-1R inhibitor, was studied in a phase III trial (NCT00924989) in advanced ACC. Unfortunately, the trial did not meet its primary endpoint — linsitinib did not significantly improve progression-free or overall survival compared to placebo. Despite the negative trial result, IGF-1R pathway targeting remains of interest in combination approaches.

Cabozantinib, a multi-kinase inhibitor targeting VEGFR, MET, and AXL, is being explored in ACC based on the rationale that these pathways contribute to ACC growth and metastasis. A phase II trial (NCT03612232) evaluated cabozantinib in ACC patients and reported disease stabilization in a meaningful proportion. While not producing dramatic responses, this class of drugs may contribute to disease control strategies.

Genomic studies have identified several recurrently altered pathways in ACC, including TP53, Wnt/beta-catenin, mTOR, and chromatin remodeling pathways. Comprehensive molecular profiling (next-generation sequencing) of ACC tumors is increasingly performed at specialized centers to identify potentially actionable mutations and guide clinical trial enrollment. While no targeted therapy has yet become a standard ACC treatment based on molecular profiling, individual patients have benefited from molecularly matched therapies in case reports and basket trials.

The ENSAT molecular classification of ACC (based on gene expression profiling) identifies molecularly defined subgroups with distinct prognoses. While not yet routinely used for treatment selection, this classification is informing the design of future clinical trials.

ACC has traditionally been considered relatively radiation-resistant. However, adjuvant radiation therapy to the tumor bed is used at some centers for patients with positive margins (R1 resection) or locally advanced disease (stage III) to reduce local recurrence. This is not universally practiced and should be discussed with the multidisciplinary team. Stereotactic body radiation therapy (SBRT) may be considered for limited metastatic sites. Radiation can also play a palliative role for bone metastases or other symptomatic sites.

If the ACC produced excess cortisol before surgery, the effects of Cushing syndrome (weight gain, muscle weakness, thin skin, mood changes, high blood sugar) may persist for months after the tumor is removed as the body recovers. Recovery is gradual and can take 6–18 months. During this time:

• Physical therapy and graduated exercise can help rebuild muscle strength
• Blood sugar monitoring and management may be needed
• Mood changes, depression, and cognitive difficulty are common during recovery and should be addressed with the medical team
• Bone density testing should be performed, as prolonged cortisol excess causes bone thinning
• Skin fragility improves gradually but may take many months

Long-term mitotane therapy requires ongoing management of its side effects:

• GI symptoms: Taking mitotane with fatty food (peanut butter, avocado, cheese) improves absorption and may reduce nausea. Anti-nausea medications can be prescribed.
• Neurological effects: Report dizziness, difficulty concentrating, or unsteady gait promptly — dose adjustment may be needed.
• Cholesterol elevation: Mitotane frequently causes marked elevation in cholesterol. Statins may be needed, but note that mitotane interacts with many statins via CYP3A4.
• Thyroid function: Mitotane can alter thyroid hormone binding; thyroid function tests should be monitored.

Palliative care — specialized care focused on symptom relief and quality of life — should be integrated early in ACC treatment, not reserved for the end. It runs alongside active cancer treatment. For ACC patients, palliative care can help manage pain, hormone-related symptoms, chemotherapy side effects, and the psychological burden of a rare cancer diagnosis. Studies in other cancers have shown that early palliative care improves quality of life and, in some settings, survival.

Patients with rare cancers face challenges beyond the disease itself: fewer doctors who understand their condition, fewer patients to share experiences with, fewer clinical trials, and less public awareness. These realities can create a sense of isolation. Connecting with other ACC patients — even remotely — can be profoundly valuable. NORD and rare-cancer communities (including those reachable through NCI and the ENSAT network) can help facilitate these connections.

Caregiving for someone with ACC is demanding. The complexity of hormone management (emergency injection training, sick-day rules, medication schedules), the side effects of mitotane, and the emotional weight of a rare and serious diagnosis all contribute to caregiver stress. Key strategies:

• Learn the emergency protocols: how and when to administer hydrocortisone injection, what triggers adrenal crisis, when to call 911
• Keep medications organized and refills ahead of schedule (mitotane shortages have occurred)
• Build a support team — even one or two additional people who can share the load
• Use the ACC-specific support communities to connect with other caregivers who understand the disease
• Do not neglect your own health: caregiver burnout is real and harmful to both parties

Anxiety, fear, and depression are normal responses to an ACC diagnosis. The rarity of the disease can amplify these feelings — there is less public awareness, fewer survivor stories, and less reassurance from familiar narratives. Oncology social workers, psychologists, and psychiatrists experienced with cancer patients can help. Medication for anxiety or depression is reasonable and should be discussed without stigma. Support groups — even online ones specific to ACC — can reduce isolation.

• What is the exact diagnosis, and what ENSAT stage do you believe this is?
• Has a complete hormonal workup been done? Which hormones are elevated?
• Has pheochromocytoma been excluded?
• Has staging imaging been completed (CT chest and abdomen, possibly PET)?
• How many ACC cases has this center treated? How many adrenalectomies does the surgeon perform per year?
• Should I get a second opinion at a specialized center before surgery?
• Should I have genetic counseling or TP53 testing?

• Will the surgery be open or laparoscopic? Why?
• Is the goal a complete (R0) resection? What structures might need to be removed en bloc?
• Will a lymph node dissection be performed?
• What is the plan for perioperative steroid coverage?
• After surgery: What is the Weiss score? What is the Ki-67 index? Were the margins clear (R0)?
• What is the ENSAT stage based on the pathology?
• Is adjuvant mitotane recommended? Why or why not?

• What is my current mitotane blood level? Is it in the therapeutic range (14–20 mg/L)?
• Am I on the right dose of hydrocortisone replacement? Do I have an emergency injection kit?
• Do I need fludrocortisone (mineralocorticoid replacement)?
• Have all my other medications been checked for interactions with mitotane?
• My side effects are [describe them] — should the dose be adjusted?
• How long should I continue mitotane?

• Can the recurrence or metastasis be surgically removed?
• Is EDP-M chemotherapy recommended? If I have already received it, what are the next options?
• Are there clinical trials I should consider? What about the ADIUVO-2 or PEMBR-01 trials?
• Has molecular profiling of my tumor been done? Are there any actionable findings?
• What is the realistic goal of treatment at this point — control, shrinkage, or symptom management?
• Should I be connected with palliative care for symptom management alongside treatment?

• Given my specific stage, Ki-67, and resection status, what is the realistic range of outcomes?
• What surveillance schedule will I be on? How often will I have scans and hormone checks?
• What signs of recurrence should I watch for?
• What signs of adrenal crisis should I and my family know?
• How do I reach the team between visits if something comes up?

• Genetic and Rare Diseases Information Center (GARD) — rarediseases.info.nih.gov. NIH information service for rare diseases including adrenocortical carcinoma.
• NCI / Cancer.gov — cancer.gov. Adrenocortical carcinoma treatment information and the NCI Contact Center (1-800-4-CANCER) for trial navigation.
• National Organization for Rare Disorders (NORD) — 203-744-0100, rarediseases.org. Medication assistance programs, rare disease information.

Mitotane (Lysodren) is a specialty drug that may not be stocked at regular pharmacies. It is typically dispensed through specialty pharmacy networks. Key points:

• Insurance coverage for mitotane varies. The oncology team’s financial counselor can help with pre-authorization.
• The manufacturer (HRA Pharma) may have patient assistance programs for uninsured or underinsured patients.
• Keep a buffer supply — mitotane shortages have occurred historically, and running out abruptly can cause problems.
• NORD and NeedyMeds (needymeds.org) maintain databases of medication assistance programs.

• Patient Advocate Foundation — case management and copay relief. 800-532-5274. patientadvocate.org
• CancerCare — financial-assistance grants, counseling. 800-813-4673. cancercare.org
• American Cancer Society — lodging (Hope Lodge), transportation. 800-227-2345. cancer.org
• Mercy Medical Angels — medical transportation assistance. mercymedical.org
• Social Security Disability Insurance (SSDI) — 800-772-1213. ACC may qualify for expedited disability review.

Mitotane (Lysodren) is FDA-approved for ACC. EDP-M chemotherapy uses individually approved agents in combination. Immunotherapy agents (pembrolizumab, nivolumab, ipilimumab) are FDA-approved for other indications and used in ACC through off-label use or clinical trials. NCCN guidelines for adrenal tumors are the primary clinical reference.

Mitotane is approved in Europe for ACC. The ESMO–EURACAN Clinical Practice Guidelines for ACC are the primary European reference and are considered among the most comprehensive ACC guidelines globally. The ENSAT network (ensat.org) coordinates European ACC research and clinical trials. Access to immunotherapy for ACC in Europe is generally through clinical trials or off-label use.

Mitotane availability varies by country. In Japan, mitotane is approved and marketed for ACC (sold as Opeprim). In Canada, mitotane (Lysodren) is approved by Health Canada for inoperable adrenal cortical carcinoma; provincial drug-plan coverage varies. In Australia, access is through the Therapeutic Goods Administration. For patients in countries where mitotane is not readily available, contact ENSAT or NORD for guidance on access programs.

• Linsitinib (IGF-1R inhibitor) FAILED
  Despite strong preclinical rationale targeting the IGF pathway in ACC, the phase III trial (NCT00924989) did not show a significant improvement in overall survival or progression-free survival versus placebo. IGF-1R inhibition alone is not an effective strategy for ACC.
• Sunitinib FAILED
  Several small studies and case series evaluated sunitinib in advanced ACC. Response rates were very low, and the drug did not demonstrate meaningful clinical activity as monotherapy in ACC.
• Gefitinib (EGFR inhibitor) FAILED
  Evaluated in a small ACC trial with no objective responses. EGFR inhibition is not effective in ACC.
• Streptozocin + mitotane (as first-line therapy) DE-ADOPTED
  Previously used as first-line treatment, streptozocin-based therapy was shown to be inferior to EDP-M in the FIRM-ACT trial. It is no longer recommended as first-line treatment but may still be considered in later lines.

• ACC — adrenocortical carcinoma; cancer of the outer layer (cortex) of the adrenal gland.
• Adenoma — a benign (non-cancerous) adrenal tumor; the most common type of adrenal mass.
• Adjuvant therapy — treatment given after surgery to reduce recurrence risk.
• Adrenal cortex — the outer layer of the adrenal gland that produces cortisol, aldosterone, and sex hormones.
• Adrenal crisis — a life-threatening emergency caused by insufficient cortisol; can be triggered by illness, injury, or missing steroid medication.
• Adrenalectomy — surgical removal of one or both adrenal glands.
• Aldosterone — a hormone produced by the adrenal cortex that regulates blood pressure and salt/potassium balance.
• Cortisol — the primary stress hormone produced by the adrenal cortex; essential for life.
• Cushing syndrome — the collection of signs and symptoms caused by prolonged cortisol excess.
• CYP3A4 — a liver enzyme that metabolizes many drugs; strongly induced by mitotane, causing drug interactions.
• DHEA-S — dehydroepiandrosterone sulfate; an androgen precursor produced by the adrenal cortex; often elevated in ACC.
• EDP-M — the standard chemotherapy regimen for advanced ACC: etoposide, doxorubicin, cisplatin, plus mitotane.
• En bloc resection — surgical removal of the tumor together with adjacent invaded structures in a single piece.
• ENSAT — European Network for the Study of Adrenal Tumors; the international collaborative ACC research network and staging system.

• Fludrocortisone — a synthetic mineralocorticoid used to replace aldosterone when the adrenal glands are not functioning.
• Functional tumor — a tumor that produces excess hormones, causing symptoms.
• Hydrocortisone — a synthetic form of cortisol used as replacement therapy when the adrenal glands cannot produce enough.
• Hyperaldosteronism — excess aldosterone production, causing high blood pressure and low potassium.
• Immunotherapy — checkpoint inhibitor drugs (pembrolizumab, nivolumab, ipilimumab) that activate the immune system against cancer.
• Incidentaloma — an adrenal mass discovered incidentally on imaging done for another reason.
• Ki-67 — a protein marker of cell proliferation; Ki-67 index reflects how actively tumor cells are dividing.
• Li-Fraumeni syndrome — inherited TP53 mutation causing predisposition to multiple cancers including ACC.
• Mitotane (Lysodren) — the only FDA-approved drug for ACC; selectively destroys adrenal cortical cells.

• Non-functional tumor — a tumor that does not produce clinically significant hormone excess.
• Pheochromocytoma — a tumor of the adrenal medulla (inner part); a different disease from ACC that must be excluded before surgery.
• R0 resection — complete surgical removal with microscopically clear margins; the goal in ACC surgery.
• R1 resection — surgical removal with microscopically positive margins (cancer cells at the edge of the removed tissue).
• R2 resection — grossly incomplete surgical removal (visible tumor left behind).
• Virilization — the development of male physical characteristics (facial hair, deep voice, muscle mass) in females, caused by excess androgen production.
• Weiss score — a histopathological scoring system (0–9) used to distinguish ACC from benign adrenal adenomas; a score of 3 or higher indicates malignancy.

Guidelines:

• NCCN Clinical Practice Guidelines — Adrenal Gland Tumors (current version)
• ESMO–EURACAN Clinical Practice Guidelines for Adrenocortical Carcinoma
• Endocrine Society Clinical Practice Guideline on Adrenal Incidentalomas

Landmark trials referenced in this guide:

• NIH GARD (rarediseases.info.nih.gov) — rare-disease information for adrenocortical carcinoma
• ENSAT (ensat.org) — European Network for the Study of Adrenal Tumors
• National Organization for Rare Disorders (NORD) (rarediseases.org) — Rare disease information and assistance
• ClinicalTrials.gov (clinicaltrials.gov) — Official U.S. registry of clinical trials
• National Cancer Institute (cancer.gov) — Comprehensive information and trial search (1-800-4-CANCER)
• PubMed (pubmed.ncbi.nlm.nih.gov) — Free public database of medical research
• American Cancer Society (cancer.org) — 800-227-2345