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Adrenocortical carcinoma represents a highly aggressive malignancy arising from the adrenal cortex, with an annual incidence of 0.5 to 2 cases per million and a bimodal age distribution affecting young children and adults in midlife. This course reviews this tumor, which, despite its rarity, carries a significant clinical impact due to frequent hormone hypersecretion, high metastatic potential, and substantial recurrence rates even after complete resection. Contemporary management of adrenocortical carcinoma, which incorporates systematic hormonal evaluation, advanced imaging, molecular characterization, and multimodal therapy, is also discussed, including surgery, mitotane-based adjuvant treatment, and palliative interventions for advanced disease. This activity explores the genetic predisposition to adrenocortical carcinoma, its early recognition, diagnostic evaluation, and evidence-informed management strategies. Participants will also gain a better understanding of the functional and nonfunctional presentations, biochemical and imaging findings, and current surgical and adjuvant treatment principles. This activity for healthcare professionals is designed to enhance the learner's competence in identifying adrenocortical carcinoma, performing the recommended evaluation, and implementing an appropriate interprofessional approach when managing this condition, ultimately strengthening clinical decision-making, supporting earlier detection, optimizing outcomes, and improving patient-centered care. Objectives: Identify key pathophysiologic features that contribute to adrenocortical carcinoma pathogenesis. Assess imaging findings across modalities to support accurate staging of adrenocortical carcinoma. Apply evidence-based surgical techniques and adjuvant treatment strategies to optimize disease-free and overall survival. Collaborate with interprofessional team members to provide coordinated care and improve patient outcomes. Access free multiple choice questions on this topic.

Adrenocortical carcinoma represents one of the most aggressive malignancies, with an estimated incidence of 0.5 to 2 cases per million population annually. This cancer ranks as the second most common malignancy in endocrinology after anaplastic thyroid cancer. The tumor arises from the adrenal cortex and accounts for approximately 0.02% to 0.2% of all cancer-related deaths. A bimodal age distribution is observed, with peaks in children younger than 5 years and in adults in their fourth to fifth decades, along with a female predominance reflected in a 2.5:1 to 3:1 ratio. Clinical significance extends far beyond rarity, driven by aggressive biological behavior, frequent late-stage presentation, and the complexity of management. Functional hormone production occurs in approximately 40% to 60% of cases and produces distinct endocrine syndromes, while the remaining cases involve nonfunctional tumors detected incidentally or through mass-effect symptoms. Early metastatic spread and high recurrence rates, even after complete surgical resection, demand intensive multimodal therapy. Current management focuses on early recognition supported by detailed hormonal evaluation, complete resection with negative margins, and appropriate adjuvant treatment. Molecular features, including frequent TP53 mutations, Wnt/β-catenin pathway activation, and IGF-II overexpression, offer valuable insight into pathogenesis and potential therapeutic targets. Despite meaningful advances in understanding, prognosis remains poor, particularly in advanced disease, underscoring the need for early detection and optimized treatment strategies.

Adrenocortical carcinoma development is unknown. Complex interactions among genetic predisposition, environmental factors, and acquired molecular alterations are known to contribute to adrenocortical carcinoma. Familial cancer syndromes account for approximately 10% to 15% of adrenocortical carcinoma cases, with Li-Fraumeni syndrome being the most significant hereditary cause. Li-Fraumeni syndrome results from germline TP53 mutations, particularly the p.R337H variant prevalent in Southern Brazil, where pediatric adrenocortical carcinoma incidence is 10 to 15 times higher than worldwide averages. The TP53 tumor suppressor gene regulates cell cycle control and apoptosis, and its loss of function promotes malignant transformation. Beckwith-Wiedemann syndrome is another important hereditary cause, characterized by dysregulation of the 11p15.5 chromosomal region, which contains the IGF-II, H19, and CDKN1C genes. This syndrome predisposes to embryonal malignancies, including adrenocortical carcinoma, with tumor development risk estimated at 7.5% in affected children. Familial adenomatous polyposis, caused by APC gene mutations, also increases adrenocortical carcinoma risk through activation of the Wnt/β-catenin signaling pathway. Carney complex is a rare hereditary disorder that has also been associated with adrenocortical carcinoma. Environmental risk factors include prior ionizing radiation exposure to the head and neck region, with latency periods of 15 to 30 years between exposure and tumor development. Occupational exposure to radioactive materials or therapeutic radiation treatments is an established risk factor. Some studies suggest associations with cigarette smoking, though these relationships require further validation. Acquired genetic alterations play crucial roles in sporadic adrenocortical carcinoma development. Somatic TP53 mutations occur in 16% to 70% of cases when comprehensive gene sequencing is performed, with loss of heterozygosity at 17p13 present in 85% of tumors. Wnt/β-catenin pathway activation occurs through CTNNB1 mutations (16%) or ZNRF3 alterations (19%-21%), collectively affecting approximately 40% of adrenocortical carcinoma cases. IGF-II overexpression, present in 80% to 90% of cases, results from loss of imprinting and represents one of the earliest molecular abnormalities in adrenocortical carcinoma development.

Adrenocortical carcinoma demonstrates distinct epidemiological patterns with significant geographic and demographic variations. The annual incidence ranges from 0.5 to 2.0 cases per million population worldwide, with approximately 300 to 400 new cases diagnosed annually in the United States. Notable geographic clustering occurs in Southern Brazil, where the incidence ranges from 10 to 15 cases per million children, driven by the prevalent TP53 p.R337H founder mutation. The age distribution shows a characteristic bimodal pattern, with the first peak in children younger than 5 years and a second, larger peak in adults during the fourth to fifth decades of life. Pediatric cases comprise approximately 5% to 10% of all adrenocortical carcinoma diagnoses, with most occurring before age 15. Adult cases demonstrate a consistent female predominance, with a female-to-male ratio of 2.5:1 to 3:1, which becomes more pronounced in younger adults. Racial and ethnic variations exist, with higher incidence rates reported in Caucasian populations compared to African American and Asian populations. However, these differences may reflect variations in diagnostic access and reporting rather than actual biological differences. Socioeconomic factors may influence presentation patterns, with lower-income populations more likely to present with advanced-stage disease due to delayed diagnosis. Temporal trends show relatively stable incidence rates over the past 3 decades, though improved imaging techniques have led to increased detection of smaller, potentially earlier-stage tumors. The proportion of incidentally discovered adrenal masses has increased substantially, though most incidental adrenocortical carcinoma cases still measure greater than 4 cm at diagnosis. Survival outcomes have improved modestly over time, primarily attributed to better surgical techniques, earlier detection, and improved supportive care rather than revolutionary therapeutic advances.

Adrenocortical carcinoma pathogenesis involves complex molecular mechanisms centered around key signaling pathways that regulate cellular proliferation, differentiation, and apoptosis. The TP53 pathway represents the most frequently altered mechanism, with functional inactivation occurring in over 50% of cases through mutations, loss of heterozygosity, or protein dysfunction. TP53 serves as a critical tumor suppressor controlling cell cycle checkpoints and DNA damage responses, with its loss promoting unchecked cellular proliferation and resistance to apoptosis. The Wnt/β-catenin signaling pathway activation occurs in approximately 40% of adrenocortical carcinoma cases through multiple mechanisms. CTNNB1 mutations lead to β-catenin stabilization and nuclear accumulation, promoting transcription of proliferation-associated genes. ZNRF3 mutations, recently identified as the most frequently altered gene in adrenocortical carcinoma, result in loss of negative regulation of Wnt signaling. APC mutations, though less common (2%-3%), also contribute to pathway activation. Notably, TP53 and β-catenin mutations tend to be mutually exclusive, suggesting distinct pathogenic mechanisms. IGF-II overexpression represents a hallmark molecular abnormality present in 80% to 90% of adrenocortical carcinoma cases, contrasting with rare occurrence in benign adrenal adenomas. This overexpression results from loss of imprinting at the 11p15.5 locus, leading to biallelic IGF-II expression rather than normal monoallelic expression. Concurrent downregulation of H19, a tumor suppressor long noncoding RNA, further promotes the malignant phenotype. IGF-II activates both MAPK and PI3K signaling pathways, promoting cellular proliferation and survival. Chromosomal instability represents another key pathogenic feature, with recurrent gains at chromosomes 5, 7, 12, 16, 19, and 20, and losses at chromosomes 1, 2, 13, 17, and 22. Loss of heterozygosity occurs frequently at 17p13, 11q15, and 2p16. These chromosomal alterations contribute to the inactivation of tumor suppressor genes and the activation of oncogenes.

Chromosomal instability represents another key pathogenic feature, with recurrent gains at chromosomes 5, 7, 12, 16, 19, and 20, and losses at chromosomes 1, 2, 13, 17, and 22. Loss of heterozygosity occurs frequently at 17p13, 11q15, and 2p16. These chromosomal alterations contribute to the inactivation of tumor suppressor genes and the activation of oncogenes. Epigenetic modifications play increasingly recognized roles in the pathogenesis of adrenocortical carcinoma. Global DNA methylation patterns differ significantly between adrenocortical carcinoma and benign adrenal tissue, with adrenocortical carcinoma demonstrating CpG island methylator phenotype (CIMP) in subsets of tumors. CIMP-high tumors show extensive promoter hypermethylation leading to tumor suppressor gene silencing and are associated with worse prognosis. Conversely, global hypomethylation of intergenic regions promotes chromosomal instability. MicroRNA dysregulation represents another key pathogenic mechanism in adrenocortical carcinoma development. MiR-483-5p, located within the IGF-II locus, becomes upregulated in correlation with IGF-II overexpression and serves as a biomarker for aggressive disease. Downregulation of tumor suppressor miRNAs, including miR-195, miR-99a, and miR-100, promotes cellular proliferation and resistance to apoptosis. The miRNA expression profile can distinguish adrenocortical carcinoma from benign adenomas and provides prognostic information regarding disease aggressiveness.

Weiss Scoring System Adrenocortical carcinoma demonstrates characteristic histopathological features that distinguish it from benign adrenal adenomas, though differentiation can be challenging in some cases. The Weiss scoring system, proposed in 1984 and adopted by the current WHO classification, represents the gold standard for histological diagnosis. This system evaluates 9 histological criteria, including nuclear grade III or IV, high mitotic rate (greater than 5 mitoses per 50 high-power fields), presence of atypical mitoses, percentage of clear cells (≤25% of tumor), diffuse architecture, microscopic necrosis, venous invasion, sinusoidal invasion, and capsular invasion. A Weiss score of 3 or higher indicates malignancy with high specificity. A Weiss score of 2 can be suggestive of malignancy. Gross and Microscopic Histological Features Adrenocortical carcinoma commonly appears as a large, irregular mass with distinctive gross features, including a variegated yellow-to-brown coloration influenced by lipid content, extensive necrosis and hemorrhage, irregular margins that often invade surrounding tissues, and an infiltrative growth pattern without a true capsule. Microscopic evaluation shows marked cellular pleomorphism, enlarged hyperchromatic nuclei with irregular contours, elevated mitotic activity that frequently includes atypical figures, disruption of the normal reticulin framework reflecting architectural loss, and invasive behavior involving both vascular and capsular structures. Immunohistochemical Analysis Assessment of the proliferative index through Ki-67 immunostaining adds important diagnostic and prognostic value. Typical adrenocortical carcinoma displays Ki-67 labeling indices above 10%, while benign adenomas generally fall below 10%. Overlap between these ranges occasionally occurs, so Ki-67 findings should be interpreted alongside morphological characteristics rather than used independently. Immunohistochemical analysis helps confirm adrenocortical origin and exclude mimics. Tumors usually express steroidogenic factor-1, alpha-inhibin, calretinin, and melan-A, but lack chromogranin A, a feature that helps distinguish them from pheochromocytoma. Synaptophysin may show focal positivity, which merits cautious interpretation. Cytokeratin staining varies, with most tumors showing negative or only focal expression of common epithelial markers.

Immunohistochemical analysis helps confirm adrenocortical origin and exclude mimics. Tumors usually express steroidogenic factor-1, alpha-inhibin, calretinin, and melan-A, but lack chromogranin A, a feature that helps distinguish them from pheochromocytoma. Synaptophysin may show focal positivity, which merits cautious interpretation. Cytokeratin staining varies, with most tumors showing negative or only focal expression of common epithelial markers. Histological Variants WHO classification recognizes several histological variants, including oncocytic carcinoma marked by mitochondria-rich cytoplasm, myxoid carcinoma characterized by abundant extracellular mucin, and sarcomatoid carcinoma showing loss of cortical differentiation. Diagnosis of the oncocytic variant relies on the Lin-Weiss-Bisceglia system because traditional Weiss criteria tend to overestimate malignancy in oncocytic lesions.

Adrenocortical carcinoma exhibits a wide range of clinical manifestations influenced by tumor functionality, size, and stage at diagnosis. Functional tumors, accounting for approximately 40% to 60% of cases, produce hormonal excess that leads to distinct endocrine syndromes, while the remaining cases present as nonfunctional masses discovered incidentally or due to symptoms from mass effect. The clinical presentation significantly shapes diagnostic evaluation and guides treatment strategies. Clinical Features  of Functional Tumors Functional tumors most commonly secrete excess glucocorticoids, resulting in Cushing syndrome. Typical features include central obesity with moon facies and buffalo hump, purple striae most prominent on the abdomen, proximal muscle weakness and atrophy, insulin resistance or diabetes mellitus, severe or difficult-to-control hypertension, osteoporosis with increased fracture risk, and psychiatric manifestations, eg, depression and cognitive changes. Severe hypercortisolism often develops rapidly, with marked hypokalemia and pronounced muscle weakness distinguishing it from benign causes. Androgen excess occurs in 20% to 30% of functional tumors, producing virilization in females, including male-pattern baldness, deepened voice, hirsutism, clitoromegaly, and menstrual irregularities or amenorrhea. Males with isolated hyperandrogenism frequently remain underdiagnosed due to subtle clinical signs. Combined glucocorticoid and androgen excess occurs in about 50% of functional tumors, while rare cases of estrogen excess lead to feminization in males, including gynecomastia, decreased libido, and testicular atrophy. Clinical Features of Nonfunctional Tumors Nonfunctional tumors typically present as large abdominal masses causing abdominal pain or fullness, early satiety, weight loss, and a palpable mass on examination. Symptoms from mass effect on adjacent organs may also be present. Average tumor size at diagnosis ranges from 10 to 13 cm, with nonfunctional tumors generally larger than functional tumors. Systemic Clinical Features

Nonfunctional tumors typically present as large abdominal masses causing abdominal pain or fullness, early satiety, weight loss, and a palpable mass on examination. Symptoms from mass effect on adjacent organs may also be present. Average tumor size at diagnosis ranges from 10 to 13 cm, with nonfunctional tumors generally larger than functional tumors. Systemic Clinical Features Adrenocortical carcinoma can have many clinically evident systemic effects. Systemic manifestations include fatigue, weight loss, and fever. Paraneoplastic syndromes, eg, IGF-II-mediated hypoglycemia (Doege-Potter syndrome), and hypercoagulable states that increase thromboembolism risk, are also associated with adrenocortical carcinoma. Metastatic disease may produce bone pain, respiratory symptoms from pulmonary involvement, and jaundice from hepatic metastases. Physical examination should systematically evaluate blood pressure and orthostatic changes, assess endocrine signs of hormone excess, examine the abdomen for masses or organomegaly, evaluate for lymphadenopathy, particularly in cervical and axillary regions, check for signs of thromboembolism, including lower extremity edema, and perform a dermatological inspection for characteristic changes associated with hormonal abnormalities.

Comprehensive evaluation of suspected adrenocortical carcinoma requires a systematic integration of biochemical testing, imaging studies, and histopathological analysis to establish an accurate diagnosis and determine disease stage. Each component provides complementary information, guiding appropriate treatment planning and risk stratification. Laboratory Studies Laboratory assessment begins with a complete metabolic panel, including electrolytes, glucose, liver function tests, and renal function tests, to establish baseline status and identify complications of hormone excess. Complete blood count may reveal leukocytosis or polycythemia in advanced disease. Coagulation studies evaluate thrombotic risk, which is particularly relevant given the elevated incidence of venous thromboembolism in adrenocortical carcinoma patients. Hormonal Assessment Endocrine evaluation follows European Network for the Study of Adrenal Tumors (ENSAT) recommendations, incorporating 24-hour urinary free cortisol, late-night salivary cortisol, and the overnight 1-mg dexamethasone suppression test to assess cortisol excess. Baseline ACTH confirms ACTH-independent hypercortisolism, while DHEA-S, 17-hydroxyprogesterone, testosterone, androstenedione, and estradiol levels assess androgen and estrogen production. Advanced steroid metabolomics may detect subtle hormonal abnormalities in tumors previously considered nonfunctional. Exclusion of pheochromocytoma through plasma or 24-hour urinary metanephrines remains essential when catecholamine excess is suspected. Computed Tomography Computed tomography (CT) of the abdomen and pelvis with intravenous contrast serves as the primary imaging modality, revealing tumor size greater than 4 to 6 cm, heterogeneous enhancement from necrosis and hemorrhage, attenuation values above 10 Hounsfield units on unenhanced scans, and delayed washout patterns with relative washout below 58% suggesting malignancy. Tumors larger than 4 cm demonstrate 97% sensitivity and 52% specificity for malignancy, while tumors over 6 cm show 91% sensitivity and 80% specificity. Chest CT remains mandatory, used to evaluate for pulmonary metastases, which are present in 40% to 80% of metastatic cases. Magnetic Resonance Imaging

Computed tomography (CT) of the abdomen and pelvis with intravenous contrast serves as the primary imaging modality, revealing tumor size greater than 4 to 6 cm, heterogeneous enhancement from necrosis and hemorrhage, attenuation values above 10 Hounsfield units on unenhanced scans, and delayed washout patterns with relative washout below 58% suggesting malignancy. Tumors larger than 4 cm demonstrate 97% sensitivity and 52% specificity for malignancy, while tumors over 6 cm show 91% sensitivity and 80% specificity. Chest CT remains mandatory, used to evaluate for pulmonary metastases, which are present in 40% to 80% of metastatic cases. Magnetic Resonance Imaging Magnetic resonance imaging (MRI) offers superior soft-tissue characterization, showing T1-weighted hypointense to isointense signal, T2-weighted hyperintense signal, and heterogeneous signal drop on chemical-shift imaging. Three key MRI features support the diagnosis: isointense to hypointense signal on T1, hyperintense signal on T2, and heterogeneous chemical shift signal loss. 18F-Fludeoxyglucose–Positron Emission Tomography With Computed Tomography 18F-fludeoxyglucose–positron emission tomography with computed tomography (18FDG-PET/CT) demonstrates high diagnostic accuracy with a sensitivity of 97% and a specificity of 91% for distinguishing malignant from benign adrenal lesions (see Image. Adrenal Myelolipoma). Adrenocortical carcinoma typically shows intense 18FDG uptake with adrenal-to-liver maximum standardized uptake value (SUV) ratios greater than 1.45, indicating malignancy. With a cutoff value of 3.4 for maximum adrenal SUV, sensitivity is 100% and specificity is 70%. However, 18FDG-PET/CT cannot distinguish adrenocortical carcinoma from metastases, lymphoma, or pheochromocytoma, all of which exhibit high metabolic activity. 11C-Metomidate PET This specialized tracer specifically targets adrenocortical tissue through binding to CYP11B enzymes and aldosterone synthase enzymes, providing confirmation of cortical origin while distinguishing from metastatic disease and medullary tumors. 11C-metomidate PET is particularly useful to determine adrenocortical origin when the diagnosis is uncertain. Tissue Sampling

This specialized tracer specifically targets adrenocortical tissue through binding to CYP11B enzymes and aldosterone synthase enzymes, providing confirmation of cortical origin while distinguishing from metastatic disease and medullary tumors. 11C-metomidate PET is particularly useful to determine adrenocortical origin when the diagnosis is uncertain. Tissue Sampling Percutaneous biopsy remains controversial and generally discouraged due to risks of tumor seeding, limited diagnostic yield from small samples, and potential false-negative results. When necessary, core needle biopsy offers superior tissue architecture compared with fine-needle aspiration and should be performed only after pheochromocytoma has been excluded and after careful consideration of surgical resectability. Staging Workup Staging requires comprehensive imaging of the chest, abdomen, and pelvis to evaluate local extension and metastatic spread, including dedicated vascular imaging of the inferior vena cava and renal veins. Regional lymph nodes should be assessed, and bone scans or 18FDG-PET/CT may be considered when clinically indicated to detect skeletal metastases.

The management of adrenocortical carcinoma poses a unique challenge because of its multiple endocrine functions. Because of the rarity of adrenocortical carcinomas and the limited clinical series, no universal guidelines exist. Current practice is influenced by expert consensus based on data from medical centers that specialize in the treatment of adrenocortical carcinoma.[1] Currently, the most practical approach to adrenocortical carcinoma is complete tumor resection (R0). Adjuvant therapies aim to decrease the frequency of recurrence. For management of localized disease without evidence of metastasis, surgical resection is the only curative option. The natural history of recurrence after surgery remains uncertain, but even after complete resection, the local recurrence rate ranges from 19% to 34%, depending on tumor stage. For this reason, adjuvant therapy after surgery is standard and includes mitotane and tumor irradiation.[2] Neoadjuvant therapy with mitotane may be considered for patients with borderline resectable tumors. Treatment of advanced adrenocortical carcinoma must be considered palliative. This treatment includes improving the quality of life through necessary interventions (eg, pain control, prevention of fractures caused by bony metastasis, and adequate control of hormonal symptoms) as well as minimizing adverse effects from antineoplastic therapies.

Differential diagnoses that should be considered when evaluating patients presenting with clinical features of adrenocortical carcinoma include: Benign adrenocortical lesions: Adrenocortical adenoma typically demonstrates a smaller size (<4 cm), homogeneous enhancement on imaging, low attenuation values  (lipid rich, <10 HU), and rapid contrast relative washout (>58%). Other primary adrenal malignancies: Pheochromocytoma can be distinguished through catecholamine excess symptoms and elevated metanephrines; primary adrenal lymphoma presents with bilateral involvement and lacks hormonal production. Metastatic disease to adrenal glands: Lung cancer, renal cell carcinoma, melanoma, and breast cancer commonly metastasize to the adrenal gland; clinical history and imaging patterns aid differentiation. Functional endocrine disorders: Primary aldosteronism, ACTH-dependent Cushing syndrome, and myelipolmas due to congenital adrenal hyperplasia require biochemical differentiation through hormonal testing. Other retroperitoneal masses: Retroperitoneal sarcomas, lymphomas, and neurogenic tumors may present similarly but lack characteristic adrenal imaging features.

Complete surgical resection is the only potentially curative treatment for adrenocortical carcinoma, with R0 resection being the primary therapeutic goal. Expected postoperative mortality for patients with adrenocortical carcinoma is less than 5%, though this varies significantly based on surgical expertise and patient selection. Redo surgery is recommended for R2 resection when technically feasible. Localized Disease Management For localized disease (stages I–II), surgeons should pursue en bloc adrenalectomy with wide margins using an open approach rather than laparoscopic techniques, given the substantially higher risk of tumor spillage and subsequent peritoneal carcinomatosis associated with minimally invasive procedures. Multiple reports have documented increased rates of peritoneal carcinomatosis among adrenocortical carcinoma patients treated with laparoscopic resection compared with those who underwent open adrenalectomy, underscoring the oncologic disadvantages of minimally invasive surgery. Although minimally invasive adrenalectomy can shorten hospital length of stay, this benefit does not offset its limitations in managing adrenocortical carcinoma. Laparoscopic access restricts the surgeon’s ability to perform a thorough regional lymph node dissection and reduces the likelihood of achieving R0 margins, both of which hold critical importance for long-term disease control. Consequently, open adrenalectomy remains the preferred standard for localized adrenocortical carcinoma due to superior oncologic safety and completeness of resection. Regional lymphadenectomy has become increasingly emphasized, with retrospective data demonstrating reduced recurrence rates and improved survival in patients undergoing systematic lymph node dissection compared to those without nodal evaluation. Standard oncologic resection practices must be followed, including en bloc adrenal gland resection, margin-free resection, no tumor spillage, and conversion to laparotomy in case of difficult dissection during attempted minimally invasive approaches. Tumors With Involvement of Adjacent Organs

Regional lymphadenectomy has become increasingly emphasized, with retrospective data demonstrating reduced recurrence rates and improved survival in patients undergoing systematic lymph node dissection compared to those without nodal evaluation. Standard oncologic resection practices must be followed, including en bloc adrenal gland resection, margin-free resection, no tumor spillage, and conversion to laparotomy in case of difficult dissection during attempted minimally invasive approaches. Tumors With Involvement of Adjacent Organs For tumors involving adjacent organs, en bloc multivisceral resection may be necessary to achieve negative margins. Imaging should be utilized before and during surgery because many aggressive adrenocortical carcinoma tumors grow large and involve adjacent structures. Intravascular ultrasound or venography may complement other imaging studies to estimate the extent of tumor involvement, particularly for inferior vena cava invasion. Surgical expertise significantly impacts outcomes, with high-volume centers (performing 15 or more adrenocortical carcinoma procedures annually) demonstrating superior recurrence-free survival and lower local recurrence rates than low-volume institutions, despite typically larger tumors in patients treated at high-volume centers. This emphasizes the importance of treatment at specialized centers with appropriate surgical experience. Preoperative considerations include management and optimization of patients with hormone excess, especially those with Cushing syndrome. A radical resection induces temporary cortisol deficiency in patients with cortisol-secreting adrenocortical carcinoma who will require glucocorticoid replacement postoperatively. Advanced Disease Management For advanced disease, the decision to resect the primary tumor in stage IV disease requires individualized attention. Generally, patients with multiple metastatic deposits in an organ system or widespread distant metastatic disease in multiple organs should not undergo adrenalectomy. Cytoreductive surgery may be considered in highly selected patients with minimal metastatic burden (limited number of tumoral organs ≤2), a resectable tumoral mass, minimal progression, good performance status, and when severe hormone excess is not medically manageable.

For advanced disease, the decision to resect the primary tumor in stage IV disease requires individualized attention. Generally, patients with multiple metastatic deposits in an organ system or widespread distant metastatic disease in multiple organs should not undergo adrenalectomy. Cytoreductive surgery may be considered in highly selected patients with minimal metastatic burden (limited number of tumoral organs ≤2), a resectable tumoral mass, minimal progression, good performance status, and when severe hormone excess is not medically manageable. Metastasectomy can provide a survival benefit in patients with oligometastatic disease, particularly when complete resection is achievable. Multiple groups have shown the benefit of metastasectomy in adrenocortical carcinoma with proper patient selection and surgical expertise required to minimize complications and improve outcomes. Common sites for metastasectomy include the liver, lung, and bone lesions. Recurrent Disease Management Repeat resection for recurrent disease may be beneficial in selected cases, especially when recurrence occurs more than 6 months after initial surgery. Late recurrences (>6 months after initial surgery) can occasionally be salvaged with resection of recurrent disease, and this approach correlates with improved survival compared with patients who experience early recurrences, which often indicate the need for systemic therapy. Multiple studies have shown that patients with a favorable prognosis and an achievable R0 resection benefit from repeat surgery for recurrent disease. Nonoperative Disease Management Loco-guided regional therapy, including interventional radiology techniques, is used to control tumor growth and improve secretory status when surgery is not feasible. Other therapies, including radiofrequency ablation and transarterial chemoembolization, are useful for treating small metastatic lesions in the liver, lungs, and bones. While neither of these methods has been subject to clinical trials, both serve as alternatives to surgery when surgery is not feasible.

In localized adrenocortical carcinoma, radiation therapy combined with surgery has been used in only a limited number of patients included in the National Cancer Data Base.[3] Prospective data defining the role of adjuvant radiation therapy remain unavailable, particularly since mitotane therapy has gained wider use. Some studies have shown reduced local recurrence rates following postoperative radiation therapy, although other investigations have not demonstrated the same effect.[4][5][6] No survival benefit has been demonstrated with adjuvant radiation therapy. These findings support the absence of a recommendation for routine adjuvant radiation therapy after initial surgical resection. However, patients who develop isolated local recurrence without distant disease may derive benefit from adjuvant radiation therapy following repeat surgery. In patients with advanced or metastatic adrenocortical carcinoma, palliative radiation therapy can provide symptom relief or local control when directed at selected sites of symptomatic or high-risk metastases.[7]

Adjuvant Therapy Localized adrenocortical carcinoma encompasses stages I and II disease and most patients with stage III disease. Stage I is relatively uncommon, accounting for only 3% of all adrenocortical carcinoma cases, whereas stages II and III account for 37% and 34%, respectively. Surgery is usually the mainstay of therapy in these patients, but unfortunately, many experience disease recurrence. Even with complete resections, rates of local recurrence have typically ranged from 19% to 34% in those patients with no residual disease after surgery. Mitotane is the standard adjuvant treatment for patients with completely resected adrenocortical carcinoma due to high recurrence risk even after R0 resections. Mitotane exerts its effects by selectively destroying adrenocortical tissue, particularly the zona fasciculata and zona reticularis, while also inhibiting steroidogenic enzymes, including 11β-hydroxylase (cytochrome P450 11B1) and cholesterol side-chain cleavage by inhibiting CYP11A1 in the adrenal cortex. In the periphery, mitotane increases glucocorticoid clearance. The pharmacological mechanism is not fully understood, but studies using dog adrenal glands showed that mitotane selectively destroys the inner zones of the adrenal cortex and induces cell death via necrosis. Adjuvant treatment generally starts within 3 months of surgery, according to animal studies. Mitotane plasma monitoring is recommended for adrenocortical carcinoma management as this agent has a high volume of distribution and low clearance; mitotane is lipophilic and tends to accumulate in adipose tissue. Adaptive dosing based on age, sex, body mass index, lean body mass, and renal function is recommended with therapeutic levels of 14 to 20 mg/L associated with improved outcomes. Concurrent glucocorticoid replacement is mandatory to prevent adrenal insufficiency and minimize gastrointestinal toxicity. Adverse effects of mitotane include gastrointestinal and neurologic abnormalities. Contraception, vitamin K antagonist supplementation, and combined antitumor therapies are recommended during mitotane treatment.

Adjuvant treatment generally starts within 3 months of surgery, according to animal studies. Mitotane plasma monitoring is recommended for adrenocortical carcinoma management as this agent has a high volume of distribution and low clearance; mitotane is lipophilic and tends to accumulate in adipose tissue. Adaptive dosing based on age, sex, body mass index, lean body mass, and renal function is recommended with therapeutic levels of 14 to 20 mg/L associated with improved outcomes. Concurrent glucocorticoid replacement is mandatory to prevent adrenal insufficiency and minimize gastrointestinal toxicity. Adverse effects of mitotane include gastrointestinal and neurologic abnormalities. Contraception, vitamin K antagonist supplementation, and combined antitumor therapies are recommended during mitotane treatment. Mitotane has shown significant improvements in recurrence-free survival in some studies but not others. The ongoing international, prospective, randomized clinical trial (ADIUVO) is evaluating the efficacy of adjuvant mitotane in patients with adrenocortical carcinoma deemed to have low/intermediate risk of recurrence after radical surgical resection, defined as R0 resection, absence of metastases, and Ki67 less than 10%. This study compares mitotane treatment with a "watch and see" strategy. Neoadjuvant Therapy The use of neoadjuvant systemic chemotherapy as a bridge to surgery correlated with favorable outcomes in a small study with borderline resectable adrenocortical carcinoma (BRACC), defined as having oligometastases, needing multiorgan or vascular resection, or having poor performance status preventing surgery. Twelve patients (80%) received combination therapy with mitotane and etoposide/cisplatin-based chemotherapy, 2 patients (13%) received mitotane alone, and 1 patient (7%) received chemotherapy alone. Median disease-free survival for resected BRACC patients was 28 months, compared with 13 months for patients undergoing initial surgery. Five-year overall survival rates were also similar, demonstrating 65% for resected BRACC versus 50% for initial surgery. Management of Advanced Disease

The use of neoadjuvant systemic chemotherapy as a bridge to surgery correlated with favorable outcomes in a small study with borderline resectable adrenocortical carcinoma (BRACC), defined as having oligometastases, needing multiorgan or vascular resection, or having poor performance status preventing surgery. Twelve patients (80%) received combination therapy with mitotane and etoposide/cisplatin-based chemotherapy, 2 patients (13%) received mitotane alone, and 1 patient (7%) received chemotherapy alone. Median disease-free survival for resected BRACC patients was 28 months, compared with 13 months for patients undergoing initial surgery. Five-year overall survival rates were also similar, demonstrating 65% for resected BRACC versus 50% for initial surgery. Management of Advanced Disease More than half of adrenocortical carcinoma patients present with locally advanced or metastatic disease (stage III or IV). The advanced stage carries a poor prognosis and only a limited response to any single treatment modality. Thus, the use of an interprofessional approach and different treatment methods, when feasible, offers the best hope of improving outcomes in these patients. In metastatic disease, different parameters merit consideration, including tumoral volume, number of metastatic organs, and progression rates. Debulking surgery only benefits adrenocortical carcinoma patients with a limited number of tumoral organs (≤2), a resectable tumoral mass, light progression, and when severe hormone excess is not manageable medically. However, most patients require medical therapy. Mitotane remains the only medication approved by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) for the treatment of metastatic adrenocortical carcinoma. An overview of collected studies showed that the objective response rate is at best 24%. First-line treatment typically consists of mitotane alone or combination chemotherapy with etoposide, doxorubicin, and cisplatin plus mitotane (EDP-M), based on the FIRM-ACT trial, which demonstrated superior response rates and progression-free survival with combination therapy. Second-line options include streptozocin plus mitotane for patients progressing on first-line therapy. Targeted Therapy

Mitotane remains the only medication approved by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) for the treatment of metastatic adrenocortical carcinoma. An overview of collected studies showed that the objective response rate is at best 24%. First-line treatment typically consists of mitotane alone or combination chemotherapy with etoposide, doxorubicin, and cisplatin plus mitotane (EDP-M), based on the FIRM-ACT trial, which demonstrated superior response rates and progression-free survival with combination therapy. Second-line options include streptozocin plus mitotane for patients progressing on first-line therapy. Targeted Therapy Targeted therapy approaches remain investigational despite promising preclinical data. The first trials targeted the epidermal growth factor receptor (EGFR) with gefitinib and with erlotinib and gemcitabine combinations. Among vascular endothelial growth factor inhibitors, sunitinib demonstrated modest antitumor activity in phase 2 trials and can be administered to patients without mitotane treatment. Recently, drugs targeting IGF-II seemed very promising, as IGF-II is the most upregulated gene in adrenocortical carcinoma (present in 80% of cases). Preclinical studies using pharmacological agents to antagonize this pathway showed growth inhibition in vitro and in vivo. This inhibition was more potent than that observed with mitotane alone in decreasing xenograft growth, and the combination of IGF inhibition with mitotane resulted in greater antiproliferative effects than single-agent treatment. However, a phase 2 study of IMCA12 (cixutumumab), a fully humanized IGF-1R antibody, showed no efficacy in a cohort of 19 patients. Results of the large phase 3 trial "GALACTIC" with the highly specific IGF-1R inhibitor linsitinib (OSI-906) in 138 patients with metastatic adrenocortical carcinoma showed that progression-free and overall survival did not differ between the linsitinib and placebo groups. In another study, 26 heavily pretreated adrenocortical carcinoma patients received cixutumumab with temsirolimus, an mTOR inhibitor, weekly with restaging at 8 weeks. Of these 26 patients, 11 (42%) had stable disease for greater than 6 months. Because of disease heterogeneity, a single agent appears insufficient to induce objective responses. Trials with new targeted substances are ongoing.

In another study, 26 heavily pretreated adrenocortical carcinoma patients received cixutumumab with temsirolimus, an mTOR inhibitor, weekly with restaging at 8 weeks. Of these 26 patients, 11 (42%) had stable disease for greater than 6 months. Because of disease heterogeneity, a single agent appears insufficient to induce objective responses. Trials with new targeted substances are ongoing. Immunotherapy with PD-1 inhibitors, mainly nivolumab or pembrolizumab, has demonstrated limited activity in small studies, with response rates typically below 10% in unselected populations. Clinical trials investigating novel targeted agents, combination therapies, and immunotherapy approaches continue to be developed. Hormonal Therapy The combination of cancer burden and hormonal excess occurs in almost 50% of adrenocortical carcinoma patients. Control of hormone excess is a critical component of adrenocortical carcinoma management, significantly impacting quality of life and potentially survival outcomes. Because elevated cortisol levels are an adverse prognostic factor, every attempt should be made to normalize hormone levels, as this affects both survival and quality of life. In Cushing syndrome management, levoketoconazole inhibits CYP17A1 and CYP11A1, and to a lesser extent, CYP11B1. The starting dose is 300 mg twice daily, which can be increased to 1200 mg/day. During treatment, liver enzymes should be monitored for potential hepatotoxicity. Because ketoconazole is an inhibitor of several hepatic metabolizing enzymes, a potential for serious drug interactions is present. Metyrapone is an inhibitor of steroidogenesis at the level of CYP11B1 and generally is started at 250 mg twice daily and can be elevated to 2 to 3 g daily in 250-mg intervals. Inhibition of CYP11B1 may increase adrenal androgens, leading to or worsening hyperandrogenemia. Mifepristone is a direct glucocorticoid receptor antagonist that is highly effective in controlling clinical comorbidities, mainly glucose intolerance, making it particularly useful for Cushing syndrome associated with diabetes mellitus. Treatment is initiated at 300 mg daily and titrated up to 1200 mg daily. Adrenal insufficiency is a rare adverse effect of mifepristone.

Mifepristone is a direct glucocorticoid receptor antagonist that is highly effective in controlling clinical comorbidities, mainly glucose intolerance, making it particularly useful for Cushing syndrome associated with diabetes mellitus. Treatment is initiated at 300 mg daily and titrated up to 1200 mg daily. Adrenal insufficiency is a rare adverse effect of mifepristone. Spironolactone and eplerenone are mineralocorticoid receptor antagonists that can be used to counteract edema and hypertension associated with cortisol or aldosterone overproduction. Spironolactone can be used to manage androgen effects in female patients with androgen-secreting tumors as well as mineralocorticoid effects in those patients with mineralocorticoid-secreting tumors. Dosing may need to be as high as 200 to 400 mg daily. In males with gynecomastia, aromatase inhibitors (anastrozole and letrozole) and estrogen receptor antagonists (tamoxifen and raloxifene) can be used. The success of hormonal control is contingent on a synchronized approach that reduces hormonal production, counteracts the effects of hormonal overproduction, and reduces disease burden through surgery or systemic chemotherapy.

The ENSAT staging system serves as the internationally accepted standard for adrenocortical carcinoma staging due to its strong correlation with clinical outcomes. Stage I includes tumors smaller than 5 cm without local invasion or metastases, while stage II includes tumors larger than 5 cm without local invasion or metastases. Stage III encompasses tumors with local invasion or regional lymph node involvement, and stage IV includes tumors with distant metastases. The ENSAT model offers superior prognostic discrimination compared with earlier staging systems. Recent modifications have been proposed to address limitations of this staging system, eg, inadequate accounting for severe inferior vena cava invasion and lymph node involvement. The modified ENSAT system reclassifies lymph node–positive disease from stage III to stage IV based on survival data showing stage IV-like behavior in node-positive patients. Additional prognostic refinements arise from the GRAS criteria (Grade, Resection status, Age, Symptoms), which enhance risk stratification for stages I through III disease. Molecular staging continues to gain importance as a prognostic framework. Transcriptomic analyses identify distinct subgroups, including C1A tumors with aggressive biology and poor prognosis and C1B tumors with less aggressive behavior and more favorable outcomes. DNA methylation profiling further distinguishes CIMP-high tumors, associated with worse survival, from non-CIMP tumors with better prognosis. These molecular features contribute independent prognostic value beyond conventional staging parameters.

Adrenocortical carcinoma remains challenging with significant variation based on stage at presentation, completeness of resection, and tumor biology. Overall survival has improved modestly over recent decades due to earlier detection, improved surgical techniques, and better supportive care, though outcomes remain suboptimal compared to many other malignancies. Stage-specific survival rates using the ENSAT staging system demonstrate 5-year overall survival of 66% to 82% for stage I, 58% to 64% for stage II, 24% to 50% for stage III, and 0% to 17% for Stage IV disease. Complete surgical resection (R0) represents the most important prognostic factor, with patients achieving negative margins demonstrating significantly superior outcomes compared to those with positive microscopic (R1) or macroscopic (R2) margins. Even with complete resection, recurrence rates range from 19% to 34% in localized disease, emphasizing the aggressive nature of this malignancy. Multiple factors influence prognosis, including tumor-related factors (eg, size, stage, Ki-67 proliferation index, and hormone production status), patient-related factors, including age, performance status, and presence of hereditary syndromes, and treatment-related factors (eg, completeness of resection, use of adjuvant mitotane, and treatment at specialized centers). Molecular markers increasingly provide prognostic information, with TP53 mutations, high Ki-67 indices (>20%), and CIMP-high methylation status associated with worse outcomes. Patients should have follow-up every 3 months for the first 2 years, then every 6 months until year 5. After year 5, follow-up can be once a year.

Complications specific to adrenocortical carcinoma primarily relate to hormone excess and tumor progression rather than treatment-related morbidity. Uncontrolled hypercortisolism is the most serious functional complication, occurring in 50% to 80% of hormone-secreting tumors and causing severe diabetes mellitus with poor glycemic control, profound muscle weakness progressing to myopathy, severe osteoporosis with pathological fractures, psychiatric complications including psychosis and severe depression, and life-threatening hypertensive crisis with hypokalemic paralysis. Androgen excess complications include severe virilization in females with irreversible voice changes and male-pattern baldness, menstrual dysfunction and infertility, and psychological distress from cosmetic changes. Disease progression complications include local recurrence occurring in 19% to 34% of completely resected cases, typically manifesting as retroperitoneal masses causing pain and organ compression. Distant metastases develop in over 50% of patients, most commonly affecting lungs (40%-80%), liver (40%-90%), and bones (5%-20%), leading to respiratory compromise, hepatic dysfunction, and pathological fractures, respectively. Tumor-related complications include spontaneous tumor hemorrhage causing acute abdominal pain and hemodynamic instability, inferior vena cava thrombosis from tumor compression or invasion, and paraneoplastic syndromes including IGF-II-mediated hypoglycemia and hypercoagulable states predisposing to thromboembolism.

Consultations play a central role in the management of adrenocortical carcinoma due to the tumor’s rarity, biological aggressiveness, and complex endocrine manifestations. Early involvement of endocrinologists supports accurate hormonal evaluation, stabilization of cortisol or androgen excess, and exclusion of alternative adrenal pathologies. Surgical oncology consultation remains essential, as complete resection with negative margins offers the only curative option for localized disease and requires expertise in complex retroperitoneal anatomy, vascular involvement, and adjacent organ relationships. Radiology consultations guide imaging selection and interpretation, integrating CT, MRI, and PET findings to refine staging, assess resectability, and monitor treatment response. Pathology consultation ensures accurate histologic diagnosis, grading, and identification of molecular features with prognostic and therapeutic relevance. Medical oncology consultation becomes crucial for determining the appropriateness of adjuvant mitotane therapy, systemic treatment for advanced disease, and enrollment in clinical trials targeting molecular pathways, eg, TP53 and Wnt/β-catenin. Additional consultations may include genetics specialists for patients with suspected hereditary syndromes, palliative care experts for symptom management in advanced stages, and specialized nursing teams for treatment education, toxicity monitoring, and long-term follow-up. Coordinated consultation among these disciplines enhances diagnostic precision, supports timely treatment decisions, reduces complications, and strengthens continuity of care throughout the patient’s clinical course.

Patient education regarding adrenocortical carcinoma focuses on understanding the aggressive nature of this rare malignancy while emphasizing the importance of early recognition and comprehensive interprofessional care. Patients should understand that adrenocortical carcinoma represents a serious cancer requiring immediate evaluation and treatment, though outcomes vary significantly based on stage at diagnosis and completeness of treatment. Critical educational points include recognition of hormone excess symptoms requiring prompt medical attention, eg, rapid weight gain with characteristic fat redistribution, severe muscle weakness, uncontrolled diabetes, or virilization in females. Patients must understand the importance of adherence to mitotane therapy when prescribed, including the need for regular blood level monitoring and concurrent glucocorticoid replacement. Long-term surveillance remains essential due to high recurrence risk, requiring lifelong follow-up with imaging studies and hormonal assessments. Patients should be counseled regarding the importance of treatment at specialized centers with interprofessional expertise in adrenal malignancies, as surgical volume and experience significantly impact outcomes.

Adrenocortical carcinoma represents a rare but highly aggressive endocrine malignancy marked by frequent hormone hypersecretion, early metastatic spread, and substantial recurrence risk despite complete resection. Diagnosis relies on integrated biochemical testing, cross-sectional and functional imaging, and expert pathological evaluation. Management incorporates surgical resection with negative margins, mitotane-based adjuvant therapy, and coordinated long-term surveillance. Because of its complexity and low incidence, optimal outcomes depend on evaluation and treatment at experienced, high-volume centers. Interprofessional care requires advanced skills in early recognition, management of hormone excess, interpretation of imaging, surgical planning, and longitudinal monitoring. Physicians, general practitioners, advanced practitioners, nurses, pharmacists, and allied health professionals strengthen patient-centered care by coordinating diagnostic steps, managing perioperative endocrine complications, optimizing mitotane dosing and toxicity monitoring, and ensuring consistent follow-up. Patient education and psychosocial support should be reinforced by multiple team members, given the significant impact of diagnosis and treatment on quality of life. Communication through tumor boards, shared documentation, and standardized protocols supports cohesive decision-making and safe transitions across care settings. Long-term follow-up requires coordinated scheduling between multiple subspecialists and clear communication regarding concerning findings. The interprofessional team should implement quality improvement initiatives, including outcome tracking, standardized treatment protocols, and participation in national registries, to advance knowledge in this rare malignancy. Collaborative planning, proactive surveillance, and integrated psychosocial support improve patient safety, treatment effectiveness, and overall quality of life for individuals facing this complex malignancy.