Adrenal cortical carcinoma is a rare and aggressive cancer that arises in the outer layer of the adrenal glands, the small hormone-producing organs that sit atop each kidney. With roughly one to two cases per million people per year in the United States, most physicians will go an entire career without seeing one.1PubMed. Adrenocortical carcinoma: Diagnosis, prognostic classification and treatment of localized and advanced disease That rarity is part of what makes it dangerous: delayed recognition, limited treatment options, and a research landscape still catching up to more common cancers. Yet the science around ACC has sharpened considerably in the past two decades, and the picture that has emerged is more nuanced than the grim statistics alone suggest.
Who Develops ACC
ACC appears slightly more often in women than in men, with women accounting for about 59% of cases in large epidemiological studies.2Cancer. Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature The age distribution follows an unusual two-peak pattern: one peak in early childhood and another around the fifth decade of life. That childhood peak is closely linked to inherited genetic syndromes, which are discussed below. The adult peak, by contrast, is more often sporadic, meaning no clear hereditary cause is identified.
Because the adrenal cortex produces cortisol, aldosterone, and sex-hormone precursors, a tumor growing there can sometimes announce itself through hormone overproduction long before it would otherwise be detected. But roughly half of ACCs are non-functioning, meaning they do not secrete enough excess hormone to cause obvious symptoms. Those tumors tend to be found later, either because of vague complaints like abdominal pain and fatigue, or as an incidental finding on imaging done for an unrelated reason.3PubMed Central. Non-functioning adrenocortical carcinoma
Hormonal Symptoms and Why They Matter
When ACC does produce excess hormones, the most common pattern is cortisol overproduction, seen in up to half of all cases.4PubMed Central. Management of cushing’s syndrome in patients with adrenocortical cancer: state of the art and future perspectives That excess cortisol leads to Cushing’s syndrome, which can cause rapid weight gain concentrated in the trunk and face, thinning skin that bruises easily, high blood sugar, muscle weakness, and mood changes. In other cases the tumor produces androgens, leading to virilization in women (increased body hair, deepening voice, acne) or signs of feminization in men when estrogen precursors are overproduced. In children, the most common hormonal presentation is androgen excess, which can trigger premature puberty.
These hormonal symptoms are not just uncomfortable; they have real clinical consequences for treatment. Cortisol overproduction suppresses the immune system, which appears to reduce the effectiveness of immunotherapy. And because cortisol affects everything from bone density to wound healing, managing Cushing’s syndrome is a parallel treatment challenge running alongside the cancer itself.
Genetic Roots
ACC is one of those cancers where genetics plays a disproportionately large role, especially in children. The most commonly altered pathways involve TP53, the well-known tumor suppressor gene, and the Wnt/β-catenin signaling pathway.5PubMed Central. Genetics of Adrenocortical Development and Tumors TP53 mutations are found in about three-quarters of pediatric adrenal tumors, and loss of the normal copy of chromosome 17 (where TP53 lives) happens alongside it, suggesting this is one of the earliest events in tumor formation.6Nature Communications. Genomic landscape of paediatric adrenocortical tumours Meanwhile, nearly all pediatric cases show overexpression of IGF2, a growth factor gene on chromosome 11p, driven by selective loss of the maternal copy of that chromosome.
Several inherited syndromes dramatically raise the risk. Li-Fraumeni syndrome, caused by germline TP53 mutations, accounts for a large share of childhood ACC, with estimates ranging from 50% to 80% of pediatric cases.7PubMed. Diseases Predisposing to Adrenocortical Malignancy (Li-Fraumeni Syndrome, Beckwith-Wiedemann Syndrome, and Carney Complex) Beckwith-Wiedemann syndrome, an overgrowth condition tied to alterations at the same 11p15 chromosomal region where IGF2 sits, also includes childhood ACC in its tumor spectrum. Rarer associations include Carney complex and Multiple Endocrine Neoplasia type 1.8PubMed. Mutations in adrenocortical tumors This means that a child diagnosed with ACC should almost always be evaluated for an underlying genetic predisposition, because the implications extend to cancer surveillance for the child and their family members.
How ACC Is Detected and Diagnosed
Imaging is the first step in evaluating a suspicious adrenal mass. CT and MRI are the primary tools, and they can reveal several features that help distinguish ACC from benign adrenal adenomas, which are far more common. Characteristic signs that point toward malignancy include a mass larger than 4 cm, irregular shape, internal calcifications, areas of hemorrhage or necrosis producing a heterogeneous appearance, and a slow contrast washout on CT.9Applied Radiology. Adrenal Cortical Carcinoma A CT attenuation value above 10 Hounsfield units on an unenhanced scan is another red flag, since benign lipid-rich adenomas typically fall below that threshold.
Cross-sectional imaging is also essential for determining whether the tumor has invaded nearby structures or spread to distant sites, both of which shape surgical planning.10PubMed. Adrenocortical carcinoma: the range of appearances on CT and MRI The final diagnosis, however, comes from tissue. Pathologists use the Weiss scoring system, which evaluates nine features visible under a microscope, including mitotic rate, atypical cell division, and invasion into surrounding structures. A score of three or more out of nine indicates malignancy. This system has been in use for nearly three decades and remains the most widely employed standard, though it has known limitations: it performs less reliably in the hands of pathologists who do not regularly see adrenal tumors, and a gray zone exists for tumors scoring just one or two.11PubMed Central. The Weiss score and beyond–histopathology for adrenocortical carcinoma
Newer Diagnostic and Monitoring Tools
One of the trickiest problems in ACC management is monitoring for recurrence after surgery. Standard imaging can miss early recurrence, and there has been growing interest in biomarker-based surveillance. Urine steroid metabolomics is one promising approach. Because ACC cells often produce unusual patterns of steroid metabolites that healthy adrenal tissue does not, analyzing a urine sample can distinguish malignant from benign adrenal tumors with high sensitivity and specificity.12PubMed Central. Urine Steroid Metabolomics as a Biomarker Tool for Detecting Malignancy in Adrenal Tumors
Early work is also combining urine steroid profiles with circulating cell-free DNA, tiny fragments of tumor DNA that leak into the bloodstream. In a small study, integrating these two approaches detected disease recurrence in some patients months before it became visible on imaging.13Journal of the Endocrine Society. OR32-07 Integrated liquid biopsy by ccfDNA and urinary steroid metabolomics for longitudinal monitoring of adrenocortical carcinoma These tools are not yet standard of care, but they illustrate the direction the field is heading: less reliance on periodic scans alone and more use of molecular surveillance.
Staging and Prognosis
ACC is staged using the ENSAT system, which ranges from stage I (a small, localized tumor under 5 cm) to stage IV (distant metastases). The three factors most strongly linked to outcomes after surgery are stage at diagnosis, the completeness of surgical removal (whether any tumor was left behind at the margins), and the Ki-67 index, a measure of how rapidly the tumor cells are dividing.14BJS. European Society of Endocrine Surgeons (ESES) and European Network for the Study of Adrenal Tumours (ENSAT) recommendations for the surgical management of adrenocortical carcinoma Patients with early-stage disease and a complete resection have substantially better prospects than those with advanced disease, though ACC carries a high recurrence rate even after apparently successful surgery.
A newer scoring system called S-GRAS, which combines ENSAT stage with other clinical and pathological features, has shown improved ability to predict outcomes compared to stage or Ki-67 alone.15European Journal of Endocrinology. S-GRAS score for prognostic classification of adrenocortical carcinoma: an international, multicenter ENSAT study That kind of refined prognostic tool helps clinicians make better decisions about who needs aggressive adjuvant treatment and who may be safely monitored.
Surgery Is the Foundation
Complete surgical removal of the tumor remains the only potentially curative treatment for ACC. There has been ongoing debate about whether laparoscopic (minimally invasive) surgery is appropriate, given concerns that it might leave behind microscopic tumor cells or cause tumor spillage. A systematic review and meta-analysis comparing the two approaches found that open surgery led to lower rates of positive margins and better three-year survival and recurrence-free rates.16PubMed. Open Versus Laparoscopic Surgery in the Management of Adrenocortical Carcinoma: A Systematic Review and Meta-analysis Laparoscopic surgery did come with shorter hospital stays. This creates a genuine trade-off, and the picture may differ by tumor stage. One retrospective study of stage I–II tumors found that five-year overall survival was similar between the two approaches, though disease-free survival still favored open surgery.17PubMed Central. Laparoscopic or Open Adrenalectomy for Stage I–II Adrenocortical Carcinoma: A Retrospective Study The current consensus leans toward open surgery for most confirmed ACC cases, with laparoscopic techniques reserved for small, early-stage tumors where the diagnosis may not have been certain preoperatively.
Mitotane as Adjuvant Treatment
Mitotane is the only drug specifically approved for treating ACC, and it has been in use for over 60 years.18Drugs & Therapy Perspectives. Mitotane in adrenocortical carcinoma: a profile of its use It is a peculiar medication. Derived from the insecticide DDT, mitotane is directly toxic to adrenal cortex cells. It is used both as adjuvant therapy after surgery (to reduce recurrence) and as treatment for advanced disease.
The major challenge with mitotane is its narrow therapeutic window. Blood levels need to reach above 14 mg/L to be effective, but above 20 mg/L the risk of serious toxicity rises sharply.19PubMed Central. Role of Mitotane in Adrenocortical Carcinoma – Review and State of the art Complicating matters, mitotane’s absorption varies widely between individuals, influenced in part by factors like blood triglyceride levels, which means regular blood monitoring is essential.20International Journal of Translational Medicine. Influence of Plasma Triglyceride Levels on Mitotane Therapeutic Drug Monitoring in Adrenocortical Carcinoma: Translational Implications from a Case Report Side effects include nausea, fatigue, neurological symptoms like dizziness and confusion, and, inevitably, adrenal insufficiency. Because mitotane destroys adrenal tissue, essentially every patient on it needs glucocorticoid replacement therapy. After mitotane is stopped, the adrenal glands take a long time to recover. In one study, the average interval between stopping mitotane and regaining normal adrenal function was about 2.7 years, and roughly one in five patients either could not tolerate glucocorticoid withdrawal or never fully recovered.21PubMed Central. Recovery of Adrenal Insufficiency Is Frequent After Adjuvant Mitotane Therapy in Patients with Adrenocortical Carcinoma
Chemotherapy for Advanced Disease
When ACC has spread beyond the reach of surgery, the standard first-line chemotherapy regimen combines etoposide, doxorubicin, and cisplatin with mitotane, commonly abbreviated EDP-M. The landmark FIRM-ACT trial, published in the New England Journal of Medicine, established this as the preferred approach. Patients receiving EDP-mitotane had a response rate of about 23% and a median progression-free survival of five months, compared to about 9% and just over two months for the alternative regimen of streptozocin-mitotane.22PubMed. Combination chemotherapy in advanced adrenocortical carcinoma Overall survival did not significantly differ between the two arms, landing around 12 to 15 months, but the clear advantage in response rate and disease control cemented EDP-mitotane as first-line therapy.
Earlier, a large prospective phase II trial of EDP-mitotane had reported a considerably higher overall response rate of about 49% in 72 patients, with a median overall survival of 28.5 months for the whole group and nearly four years for those who responded.23Endocrine-Related Cancer. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial The gap between these results and the FIRM-ACT findings likely reflects differences in patient selection and trial design, but the message is consistent: EDP-mitotane can produce meaningful responses, and those who respond tend to do substantially better.
Immunotherapy and Why ACC Is a Tough Target
Immune checkpoint inhibitors have transformed outcomes in several cancers, so their testing in ACC was a natural step. The most studied agent is pembrolizumab, a PD-1 inhibitor. In a key phase II trial, pembrolizumab produced an objective response in about 23% of patients with advanced ACC who had already been treated, and disease was controlled (either shrinkage or stabilization) in roughly half.24PubMed Central. PD-1 Blockade in Advanced Adrenocortical Carcinoma The median overall survival in that study was about 25 months, and for those who did respond, the duration of response had not been reached at the time of analysis, meaning some responses were quite durable.
But the responses are not evenly distributed, and ACC has some built-in defenses against immunotherapy. One likely explanation is the cortisol produced by functioning tumors: excess cortisol is a potent immunosuppressant, potentially blunting the very immune response that checkpoint inhibitors are trying to unleash. Analysis of tumor tissue in one study found no clear relationship between the presence of immune cells in the tumor and response to pembrolizumab, suggesting that even when immune cells are present, the tumor microenvironment may be suppressing them.25Journal for ImmunoTherapy of Cancer. Phase II clinical trial of pembrolizumab efficacy and safety in advanced adrenocortical carcinoma Figuring out which patients are most likely to benefit, and whether combining immunotherapy with cortisol-blocking drugs could improve results, is an active area of investigation.
Radiation Therapy’s Evolving Role
ACC was historically considered resistant to radiation, but that view has softened. The strongest evidence supports adjuvant radiation (given after surgery) to reduce the chance of the tumor coming back in the same location. One study found that local recurrence occurred in only 1 of the irradiated patients compared to 12 in the control group, a dramatic difference.26PubMed. Adjuvant radiation therapy improves local control after surgical resection in patients with localized adrenocortical carcinoma However, overall survival was not significantly different, likely because ACC tends to recur at distant sites even when the tumor bed is well controlled.
A meta-analysis pooling data from multiple studies reinforced the local control benefit and found that overall survival was in fact significantly better in the radiation group, with more than double the odds of survival.27PubMed Central. Efficacy of adjuvant radiotherapy for treatment of adrenocortical carcinoma: a retrospective study and an updated meta-analysis This discrepancy between individual studies and the pooled analysis is not unusual in rare cancers, where any single institution’s experience involves small numbers. Current practice tends to consider adjuvant radiation for patients at high risk of local recurrence, such as those with close or positive surgical margins or high Ki-67 values.
Targeted Therapies and the Search for Better Drugs
Given the limited options for advanced ACC, there has been considerable interest in targeted agents, particularly drugs that block specific signaling pathways. The results, however, have been largely disappointing. Sorafenib, a multi-target kinase inhibitor, was tested in combination with low-dose paclitaxel in patients whose disease had progressed on standard therapy. The trial was stopped early after all nine evaluable patients progressed at their first assessment.28PubMed Central. Novel Targeted Therapies in Adrenocortical Carcinoma Sunitinib, another kinase inhibitor, fared slightly better in a phase II study of 35 patients but still produced disease stabilization in only about 14%, with a median progression-free survival under three months.
Despite these failures, the field has not given up. IGF2, the growth factor overexpressed in nearly all pediatric ACC, has been a logical target, and agents directed at the IGF signaling pathway have been explored, though without breakthrough success. Newer strategies focus on individualized tumor profiling to select treatments and on preclinical testing of novel drug classes. One example is TAK-243, a drug that blocks ubiquitin-activating enzyme, a protein cells need to tag and recycle other proteins. In laboratory models including patient-derived organoids (three-dimensional tumor cultures grown from patients’ own cancer cells), TAK-243 showed activity at very low concentrations.29Cancer Research Communications. Activity of the Ubiquitin-activating Enzyme Inhibitor TAK-243 in Adrenocortical Carcinoma Cell Lines, Patient-derived Organoids, and Murine Xenografts Whether that translates to effectiveness in patients remains to be seen, but it reflects the shift toward using better laboratory models to screen drugs before committing to expensive clinical trials.
ACC in Children
Pediatric ACC deserves its own discussion because it differs from the adult version in important ways. Children typically present with signs of androgen excess, such as premature development of pubic hair or rapid growth, rather than Cushing’s syndrome.30PubMed Central. Pediatric Adrenocortical Carcinoma: The Nuts and Bolts of Diagnosis and Treatment and Avenues for Future Discovery As noted earlier, the vast majority of childhood cases are linked to inherited TP53 mutations through Li-Fraumeni syndrome or to Beckwith-Wiedemann syndrome.31PubMed Central. Association of adrenocortical carcinoma with familial cancer susceptibility syndromes
Genomic studies have identified a particularly aggressive subtype in children: tumors that carry both a TP53 mutation and an additional mutation in a gene called ATRX, which is involved in maintaining chromosome stability. Children with both mutations had significantly larger tumors, more advanced disease at diagnosis, and markedly worse survival compared to those with TP53 mutations alone or those with neither mutation.32Nature Communications. Genomic landscape of paediatric adrenocortical tumours This molecular stratification is increasingly shaping how pediatric oncologists think about prognosis and treatment intensity. Children diagnosed at an early stage can often be cured with surgery alone, but those with advanced disease and adverse genetic features face a much harder road.
Living With Mitotane’s Aftermath
One aspect of ACC that patients ask about but that gets relatively little attention in clinical summaries is what happens after treatment. For patients who take mitotane, the drug’s destruction of adrenal tissue means they will be dependent on replacement steroids for months or years. In the study that tracked adrenal recovery after mitotane cessation, roughly 78% of patients eventually regained normal adrenal function, but the average wait was nearly three years.33PubMed Central. Recovery of Adrenal Insufficiency Is Frequent After Adjuvant Mitotane Therapy in Patients with Adrenocortical Carcinoma During that time, patients must carry emergency steroid kits and adjust their doses during illness or surgery, because adrenal insufficiency can become life-threatening during physical stress. A small proportion never recover and remain on replacement hormones indefinitely.
Mitotane also interacts with many other medications, alters thyroid hormone metabolism, and raises cholesterol levels, adding layers of complexity to survivorship care. ACC survivors need long-term follow-up not only for recurrence surveillance but for managing the endocrine fallout of the disease and its treatment. That follow-up ideally happens at specialized centers with experience in both endocrinology and oncology, since the overlap between the two fields is at the core of this disease.