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Adrenocortical carcinoma is a rare and aggressive malignancy arising from the adrenal cortex, with biological behavior characterized by infiltrative growth, vascular invasion and early metastatic potential. From a functional perspective, it may present as a functioning tumor, with autonomous production of steroid hormones, or as a nonfunctioning lesion detected incidentally or because of its mass effect. The secretory profile substantially influences the clinical presentation: cortisol hypersecretion frequently produces a phenotype of hypercortisolism, whereas the production of androgens or steroids with androgenic activity may cause virilization or reproductive disturbances. More rarely, manifestations attributable to mineralocorticoid excess or mixed secretion occur, consistently with the tumor’s cortical origin and the possibility that it may lose the physiological compartmentalization of steroidogenesis.

Clinical management requires specialist assessment because diagnosis does not depend solely on demonstrating the presence of an adrenal mass, but on integrating clinical and endocrine suspicion, advanced imaging and pathological confirmation in a setting in which treatment strategy and prognosis are strongly influenced by stage, surgical resectability and the degree of biological aggressiveness. In practical terms, adrenocortical carcinoma must be regarded as a disease in which the accuracy of the initial pathway, from hormonal characterization to staging, is essential to maximize the likelihood of disease control and reduce the risk of suboptimal procedures that could compromise surgical margins and subsequent treatment options.

The epidemiology of adrenocortical carcinoma is dominated by its rarity, with an annual incidence generally estimated at approximately 1-2 cases per million people and, consequently, limited clinical familiarity outside specialist centers. This low frequency means that the diagnostic pathway frequently begins in indirect scenarios, such as the identification of an adrenal mass during imaging performed for other reasons, or from clinical manifestations related to hormone overproduction. Demographically, many case series describe a distribution with a slight female predominance and a concentration of cases in adulthood, while also recognizing a second peak in childhood, particularly among forms associated with genetic predisposition. The clinical presentation is also influenced by the fact that functioning tumors become symptomatic earlier, whereas nonfunctioning tumors may reach a considerable size before being recognized.

From a clinical and epidemiological perspective, it is useful to distinguish adrenocortical carcinoma from the much broader group of adrenal masses, which are frequently benign and often nonfunctioning. In this setting, carcinoma represents a minority of cases but has a disproportionate impact because of its prognostic implications and management complexity. The pre-test probability of malignancy increases markedly in the presence of a large size, rapid growth, suspicious radiological features and signs of local invasion. However, the assessment must remain integrated with the hormonal profile because steroid hypersecretion, particularly of cortisol and androgens, is more common in malignant tumors than in nonfunctioning adenomas and may represent a biological marker of more aggressive behavior.

Among recognized risk factors, the most firmly established group consists of genetic predisposition syndromes, which are particularly relevant in pediatric disease and in a selected proportion of adults with early onset or a suggestive personal and family history. Li-Fraumeni syndrome, associated with germline pathogenic variants of TP53, is one of the most characteristic associations, with an increased risk of multiple tumors and particular relevance of adrenocortical carcinoma during childhood and early adolescence. Another important condition is Beckwith-Wiedemann syndrome, in which altered growth regulation and imprinting are associated with an increased risk of embryonal tumors, including adrenal neoplasms of cortical origin. In some patients, predisposition may also form part of broader multiple endocrine neoplasia syndromes, in which the adrenal gland is considered within a systemic susceptibility to endocrine tumorigenesis.

Alongside inherited predisposition, adrenocortical carcinoma is classified as sporadic in most cases, with development associated with the accumulation of molecular alterations involving proliferative control, genomic stability and growth signaling. In this context, the clinically relevant concept is not so much the identification of a single established environmental factor as the ability to recognize situations in which the probability of carcinoma increases: a very young age, a family history of early-onset tumors, adrenal masses showing rapid enlargement, or the coexistence of clinical signs of combined hormonal hypersecretion suggesting loss of normal cortical steroidogenic regulation. The rarity of the disease and the heterogeneity of its presentations explain why suspicion must arise primarily from the integration of clinical, endocrine and radiological findings rather than from population risk factors on which universal preventive strategies could be based.

Overall, adrenocortical carcinoma represents a model of a rare endocrine malignancy in which epidemiology does not support large-scale prevention, but makes the identification of high-risk subgroups and the correct interpretation of adrenal masses within their clinical context essential. Attention to syndromic conditions, signs of hypercortisolism or virilization and radiological features of aggressiveness forms the practical basis for reducing diagnostic delays and directing patients promptly toward appropriate specialist pathways.

There are no population screening programs for adrenocortical carcinoma, mainly because of the combination of its low incidence, the absence of a simple and sufficiently accurate test and the high risk of false-positive findings if a generalized imaging-based strategy were attempted. In clinical practice, most cases are identified in one of two ways: as an incidentally detected adrenal mass that is subsequently characterized, or as a suspected malignancy in the presence of clinical and endocrine signs of steroid hormone overproduction. In this context, “early diagnosis” does not result from systematic screening, but from the ability to correctly attribute clinical significance to findings and symptoms that, when interpreted separately, might be attributed to common non-oncological conditions.

A distinct role is played by the surveillance of high-risk groups with genetic predisposition. In individuals with Li-Fraumeni syndrome, the aim of surveillance is to identify tumors at an early stage while minimizing exposure to ionizing radiation, in a setting in which susceptibility to radiation-induced tumors and the frequency of multiple malignancies make strategies based on regular clinical assessments and non-ionizing imaging preferable. These programs often include periodic whole-body magnetic resonance imaging and targeted examinations, while children commonly undergo additional approaches based on abdominal ultrasonography at short intervals, consistently with the need to detect abdominal and adrenal tumors early during childhood, when the relative risk of adrenocortical carcinoma is clinically more significant.

In Beckwith-Wiedemann syndrome, pediatric tumor surveillance protocols typically include structured follow-up with repeated abdominal ultrasonography during the first years of life, with visualization of the liver, kidneys and adrenal glands, because the risk of embryonal tumors also includes adrenocortical neoplasms. The rationale is practical: ultrasonography is repeatable, does not involve radiation exposure and can identify abdominal masses at an early stage, when timely surgery and appropriate endocrine characterization can significantly modify the clinical course. In this setting, surveillance is not directed exclusively toward adrenocortical carcinoma but forms part of a broader secondary prevention program for the tumors typically associated with the syndrome.

Even outside genetic syndromes, a key surveillance concept concerns the management of incidentally identified adrenal masses. This pathway is not screening, but rather structured clinical attention: every adrenal mass must be assessed for hormonal activity and imaging features suggestive of malignancy and must be monitored over time when required by its risk profile and the selected clinical strategy. In this context, surveillance is intended to detect growth, morphological changes and the onset or worsening of hormonal hypersecretion, all of which increase the probability of an aggressive lesion and require acceleration of the diagnostic and therapeutic pathway in a specialist setting.

In summary, the absence of population screening for adrenocortical carcinoma is offset by two pillars: structured surveillance of individuals with a genetic predisposition, in whom dedicated protocols include clinical assessments and repeated low-risk imaging, and rigorous management of adrenal masses and steroid hypersecretion in clinical practice, where prompt specialist evaluation is the principal determinant of identification at a potentially more treatable stage.

The biology of adrenocortical carcinoma can only be properly understood within the physiology of steroidogenesis and the zonal organization of the adrenal cortex, in which cells of the zona glomerulosa, zona fasciculata and zona reticularis finely regulate steroid production and responses to trophic signals. In malignant tumors, this functional architecture tends to lose coherence, with dysregulation of cortical differentiation programs and the possibility of mixed secretory patterns combining cortisol excess, androgen excess and, more rarely, steroids with mineralocorticoid activity. Adrenocortical carcinoma is therefore an endocrine malignancy in which biological aggressiveness and clinical presentation depend on the combination of proliferative capacity, local invasiveness and loss of control over steroid biosynthesis, resulting in autonomous production no longer constrained by normal feedback mechanisms.

Malignant transformation does not generally follow a single linear sequence, but is associated with complex molecular evolution in which genomic instability, alterations in growth pathways and disruption of adrenocortical transcriptional regulation contribute to different phenotypes. At the molecular level, one of the most recurrent signals is activation of the IGF program, often supported by overexpression of IGF2 and dysregulation of imprinting and locus-control mechanisms, resulting in increased pro-proliferative and pro-survival signaling. In parallel, alterations in the Wnt pathway with activation of β-catenin, frequently through events involving CTNNB1 or related regulatory components, promote proliferation and loss of orderly differentiation, contributing to more aggressive behavior and a greater capacity for invasion.

At the genetic level, vulnerability of the mechanisms controlling the genome and cell cycle is central. Alterations involving TP53 impair the response to DNA damage and the ability to eliminate unstable clones, whereas dysregulation of cell-cycle control and replication facilitates the accumulation of additional somatic events. In a proportion of cases, particularly in inherited predisposition or early-onset disease, the molecular profile reflects the presence of germline variants that lower the threshold for neoplastic transformation. However, the coexistence of multiple cooperating alterations is also typical of sporadic disease. A biologically relevant role is also attributed to adrenocortical transcriptional regulation, in which hyperactivity of factors governing adrenal-lineage identity and development may sustain growth and a hormonally active phenotype, while simultaneously promoting a more plastic tumor architecture capable of adaptation.

Alongside structural and signaling alterations, epigenetic modifications help define clinical behavior. Aberrant DNA methylation patterns and chromatin remodeling modulate the expression of genes involved in proliferation, angiogenesis and differentiation programs, favoring the selection of more invasive or resistant subpopulations. In a tumor in which steroid secretion may be preserved or altered, epigenetic regulation also acts as an interface between endocrine identity and aggressiveness, producing situations in which an apparently well-differentiated secretory phenotype may coexist with a high capacity for invasion and metastasis.

The adrenal and periadrenal microenvironment is an active component of tumor evolution. The rich vascular supply of the gland and its proximity to major venous structures facilitate vascular invasion and the formation of tumor thrombi, while angiogenesis supports the growth of masses that may become very large. Intratumoral hypoxia, which is common in large tumors with necrosis, selects more resistant cells and promotes adaptive metabolic programs. The adrenal capsule and surrounding adipose tissues represent anatomical barriers whose breach indicates a biologically significant transition toward more aggressive behavior, with direct implications for surgical margins and the risk of local recurrence.

From an immunological perspective, adrenocortical carcinoma displays a heterogeneous landscape. Immune infiltrates may be present, but antitumor efficacy may be limited by local immunoregulatory mechanisms and by a microenvironment that, partly because of associated hypercortisolism, may favor a more tolerogenic setting. Some tumors show a predominance of macrophages and myeloid cells with modulatory functions, together with signs of reduced cytotoxic T-cell activity. This variability contributes to the difficulty of predicting responses to immunomodulatory strategies and emphasizes the importance of interpreting the tumor as a biologically heterogeneous entity.

Recurrent pathogenic mechanisms are often recognized in the biology of adrenocortical carcinoma:

• dysregulation of growth and survival pathways, with frequent hyperactivation of the IGF axis and alterations in the Wnt pathway supporting proliferation and loss of differentiation;
• impairment of genomic surveillance and cell-cycle checkpoints, with instability and progressive clonal selection driving invasion and resistance;
• interaction with the vascular and periadrenal microenvironment, with angiogenesis, capsular and vascular invasion and adaptations to hypoxia promoting clinical aggressiveness.

These elements combine unevenly among patients and within the same mass, explaining the clinical heterogeneity of adrenocortical carcinoma, variability in hormonal secretion and differences in aggressiveness, resectability and risk of recurrence.

From a histological perspective, adrenocortical carcinoma is a malignant cortical neoplasm whose architecture may range from trabecular and solid patterns to diffuse areas, with cells that are often eosinophilic or clear, variable cytological atypia, necrosis and sometimes numerous mitoses, including atypical mitotic figures. A crucial feature is evidence of invasive behavior, such as capsular and vascular invasion, which correlates with the risk of recurrence and metastasis. Histological assessment must consider that the distinction between adenoma and carcinoma does not depend on a single finding but on a combination of morphological and invasive characteristics integrated with clinical and radiological information, because some neoplasms may contain more differentiated areas adjacent to high-grade components.

When assessing histology, it is useful to distinguish broad morphological patterns while maintaining a focus on identifying cortical malignancy and invasiveness:

• conventional forms: solid or trabecular patterns with variable atypia, necrosis and increased mitotic activity, often accompanied by capsular and vascular invasion;
• variants with distinctive morphology: including oncocytic, myxoid or sarcomatoid forms, whose interpretation requires experience and integration with indicators of aggressiveness;
• pediatric presentations: often characterized by distinct biology and a predisposing background, in which clinicopathological correlation and assessment of invasiveness remain essential for risk stratification.

Immunohistochemistry provides essential support in confirming adrenocortical origin and excluding common mimics, although the overall diagnosis remains an integration of morphology, invasiveness and clinical context. Markers of cortical differentiation such as SF-1 are particularly useful in supporting an adrenal origin, while inhibin-α, Melan-A and calretinin may strengthen the diagnosis when used in appropriate panels. Conversely, markers typical of medullary and neuroendocrine tumors, such as chromogranin, support alternative diagnoses when consistently positive. A proliferative parameter such as Ki-67 contributes to biological stratification and estimation of aggressiveness, particularly when integrated with mitotic activity, necrosis and vascular invasion. Overall, adequate sampling is crucial because intratumoral heterogeneity may cause a biopsy to capture less representative areas and because treatment planning critically depends on correct tumor classification and attribution to the cortical lineage.

Experimental models have clarified important mechanisms of pathogenesis, showing how the combination of dysregulated growth pathways, genomic instability and altered steroidogenic identity generates phenotypes capable of rapid growth and invasion. Multi-omics approaches and single-cell analyses have demonstrated the presence of subpopulations with different transcriptional programs, including more dedifferentiated and invasive components and others with greater steroidogenic activity. These findings help explain why hormone secretion and aggressiveness do not always progress in parallel. Overall, adrenocortical carcinoma emerges as a malignancy in which endocrine and oncological biology are closely intertwined, with direct implications for diagnosis, prognostic stratification and treatment selection.

The clinical manifestations of adrenocortical carcinoma depend on the balance between hormonal secretion, mass effect and disease spread. A substantial proportion of tumors are functioning and present with signs of steroid excess that, compared with adenomas, more often evolve rapidly and may involve combined secretory patterns. Cortisol overproduction may cause hypercortisolism with centripetal weight gain, skin fragility, bruising, proximal myopathy, hypertension and disturbances of glucose metabolism. When the excess is sustained and continuous, loss of the normal physiological rhythm amplifies systemic effects on the bones, muscles and cardiovascular system. In some patients, hypercortisolism is associated with functional immunosuppression, increased susceptibility to infections and a reduced ability to respond to stress, making both the presentation and treatment pathway more complex.

A second typical scenario is excess production of androgens or steroids with predominantly androgenic activity, which is more apparent in women and causes rapidly progressive hirsutism, severe acne, seborrhea, menstrual irregularities and signs of virilization such as deepening of the voice, clitoromegaly and reduced breast volume. In adult men, androgen excess may be less clinically apparent but can be associated with reproductive and metabolic disturbances. In children, androgen secretion may cause precocious puberty or accelerated linear growth with advanced bone age. More rarely, the production of steroids with estrogenic activity may cause feminization in men, with gynecomastia and reduced libido, suggesting particularly disorganized tumor steroidogenesis.

Nonfunctioning or minimally functioning tumors may present predominantly through their mass effect. The tumor may reach a considerable size before being recognized, causing pain or a sensation of heaviness in the flank, abdominal discomfort, distension, nausea, early satiety and weight loss. In some cases, the diagnosis is made incidentally during imaging performed for other reasons, but a large size or aggressive radiological features require rapid investigation. Infiltrative growth and proximity to major vessels may cause compression or invasion, with possible thrombosis or a venous tumor thrombus. This is a clinically important scenario because it may present with lower-limb edema, pain, signs of thromboembolism and, in more complex cases, hemodynamic instability or complications related to inferior vena cava involvement.

Clinical presentations can be grouped into several main, frequently overlapping patterns that guide suspicion and accelerate the diagnostic pathway:

• hypercortisolism phenotype: hypertension, diabetes or impaired glucose tolerance, proximal myopathy, skin fragility and bruising, osteopenia or fragility fractures, with rapid progression and loss of the physiological cortisol rhythm;
• androgen-excess or mixed-secretion phenotype: rapidly progressive hirsutism and virilization in women, precocious puberty or accelerated growth in children, sometimes associated with hypercortisolism and other signs of disorganized steroidogenesis;
• mass-effect or advanced-disease phenotype: flank pain, abdominal distension and weight loss, signs of vascular invasion or compression, and possible presentation related to liver, lung or bone metastases.

Metastatic spread has a profound influence on symptoms and frequently involves the liver, lungs and bones. Liver metastases may cause right upper-quadrant pain, hepatomegaly and abnormal liver function. Lung metastases are sometimes asymptomatic and detected only on imaging, but may be associated with cough, dyspnea or chest pain. Bone involvement may cause persistent focal pain and a risk of pathological fractures. Advanced disease may cause severe fatigue, weight loss and signs of systemic inflammation, which add to the effects of any hormonal excess and contribute to rapid deterioration of the patient’s general condition.

Physical examination may reveal, in addition to signs of steroid hypersecretion, findings attributable to a palpable abdominal mass, flank tenderness, hypertension and, in cases of venous thrombosis, dependent edema or signs of venous insufficiency. Clinical assessment must always be integrated with blood-pressure measurements, electrolyte testing and evaluation for cardiometabolic complications because hypercortisolism and mixed secretory patterns increase the risk of infections, thromboembolism, metabolic decompensation and bone fragility. Overall, adrenocortical carcinoma may present as a rapidly progressive endocrine syndrome, a large abdominal mass or advanced disease. This variability makes early recognition of the clinical patterns distinguishing a potentially aggressive lesion from more common benign adrenal conditions essential.

The diagnostic assessment of adrenocortical carcinoma must be initiated when there is a well-founded clinical suspicion and should follow a logical sequence integrating endocrine assessment, radiological characterization of the adrenal mass, histological confirmation in appropriate cases and determination of disease extent. It is a rare but aggressive malignancy of the adrenal cortex that may present with signs of hormonal hypersecretion, symptoms caused by an abdominal mass or as an incidentaloma detected during investigations performed for other reasons. Clinical suspicion typically arises in the presence of rapidly progressive hypercortisolism, signs of virilization in women or feminization in men, atypical hyperaldosteronism, or a large adrenal mass with suspicious radiological features. The aim of the initial evaluation is to recognize the possibility of malignancy at an early stage and refer the patient to a highly specialized center, avoiding inappropriate biopsies or delays in staging.

The first level of assessment is endocrine and biochemical. Because a substantial proportion of adrenocortical carcinomas are functioning, a complete hormonal profile must be obtained regardless of the apparent symptoms. Testing should include 24-hour urinary free cortisol, a low-dose dexamethasone suppression test, plasma ACTH, adrenal androgens such as DHEA-S, testosterone and androstenedione, and, when appropriate, 17-hydroxyprogesterone, together with aldosterone and renin in patients with hypertension or hypokalemia. The identification of multiple autonomous secretions or a hormonal pattern inconsistent with a benign adenoma is highly suspicious. Even in the absence of overt symptoms, subclinical secretion should be investigated because hormone production may be partial but biologically significant.

Radiological assessment begins with a dedicated contrast-enhanced CT scan of the adrenal glands. Density measured in Hounsfield units, the presence of necrotic areas, irregular margins, invasion of adjacent structures and contrast washout are key parameters for distinguishing a potentially malignant lesion from a benign adenoma. High attenuation inconsistent with a lipid-rich adenoma, a diameter greater than 4-6 cm and marked heterogeneity significantly increase suspicion. Magnetic resonance imaging may complement CT by providing better assessment of vascular invasion, inferior vena cava involvement and the relationship with the liver, kidney and diaphragm. In selected cases, 18F-FDG PET-CT contributes to the assessment of the metabolic nature of the mass and the detection of metastases.

Biopsy is not routinely indicated when the lesion is potentially resectable and the diagnosis is strongly suspected on the basis of clinical and radiological findings. Percutaneous biopsy is reserved for selected situations, such as suspected metastasis from another primary tumor or unresectable disease in which histological confirmation would change the treatment strategy. It must be avoided when pheochromocytoma has not been biochemically excluded. When performed, the procedure must be planned in a multidisciplinary setting to minimize the risk of tumor dissemination.

Pathological analysis is decisive. Diagnosis is based on morphological criteria integrated with scoring systems, including the Weiss system, which assesses features such as a high mitotic rate, necrosis, marked nuclear atypia, vascular invasion and capsular invasion. A score above the established threshold supports a diagnosis of carcinoma. Immunohistochemistry helps distinguish the tumor from metastases and other adrenal neoplasms and may include markers such as SF-1, inhibin, Melan-A and Ki-67, the latter having prognostic value in relation to the proliferative index. Integration of the clinical presentation, imaging and morphology is essential before initiating systemic treatment or radical surgery.

According to the principal international guidelines for adrenal neoplasms, correct diagnosis and initial workup of adrenocortical carcinoma require a minimum set of information representing essential operational requirements:

Elements required to establish the diagnosis and plan the initial workup of adrenocortical carcinoma

• Complete endocrine assessment with systematic investigation of glucocorticoid, androgen, mineralocorticoid and, when indicated, estrogen hypersecretion.
• Dedicated imaging with contrast-enhanced CT and/or MRI to characterize the mass and assess its anatomical relationships and signs of invasion.
• Multidisciplinary discussion at an expert center before any biopsy or surgery.
• Histological confirmation using validated morphological criteria and assessment of the proliferative index.
• Initiation of systemic staging to distinguish localized from advanced or metastatic disease.

Once the diagnosis has been established, systemic staging includes chest CT to detect pulmonary metastases, extended abdominal imaging to assess the liver and lymph nodes, and further targeted investigations when clinically indicated. PET-CT may help identify secondary lesions not evident on conventional imaging. At the same time, before any treatment, a comprehensive functional evaluation is required, with particular attention to control of hormonal hypersecretion, nutritional status, cardiac function and metabolic status, because severe hypercortisolism may increase perioperative risk and complicate oncological management.

In summary, the diagnostic pathway for adrenocortical carcinoma follows a structured sequence: recognition of clinical, endocrine or radiological suspicion; complete biochemical characterization; dedicated imaging with CT and MRI; selective use of biopsy when appropriate; histological confirmation using validated morphological criteria; and systemic staging with chest CT and complementary techniques according to the clinical context.

The purpose of staging in adrenocortical carcinoma is to describe the anatomical extent of the disease in a standardized manner and guide the treatment strategy. The system most widely used in clinical practice is the ENSAT classification, which has progressively replaced previous classifications because of its superior prognostic performance. Staging is based on the local extent of the primary tumor, lymph-node involvement and the presence of distant metastases.

Assessment of local extension integrates radiological and surgical findings. Maximum tumor size, capsular invasion, infiltration of adjacent tissues or major vessels and regional lymph-node involvement are assigned to the relevant stage categories. The complete ENSAT classification distinguishes:

ENSAT staging of adrenocortical carcinoma

• Stage I: tumor confined to the adrenal gland and measuring 5 cm or less, without lymph-node involvement or distant metastases.
• Stage II: tumor confined to the adrenal gland but measuring more than 5 cm, without lymph-node involvement or metastases.
• Stage III: tumor with local infiltration of surrounding tissues or major vessels and/or regional lymph-node involvement, without distant metastases.
• Stage IV: presence of distant metastases, regardless of tumor size or lymph-node status.

In addition to anatomical stage, histopathological features such as the Ki-67 proliferative index, mitotic grade, the presence of necrosis and the completeness of surgical resection with negative margins significantly influence prognosis. Hormonal secretion, particularly hypercortisolism, has also been associated with poorer outcomes, probably because of its systemic immunometabolic effects and the increased risk of complications.

Prognosis primarily depends on the stage at diagnosis. Localized, resectable tumors have significantly better survival than metastatic disease. Complete surgical resection is the main determinant of outcome in stage I-III disease. In advanced cases, the disease tends to progress rapidly, frequently involving the liver, lungs and peritoneum. The response to systemic treatment and the ability to control hormonal hypersecretion also influence quality of life and survival.

In summary, staging of adrenocortical carcinoma must precisely document local extension according to ENSAT criteria, lymph-node involvement and the presence of distant metastases, integrating this information with histological and biological parameters. Stage assignment allows standardized communication and prognostic assessment, which must always be interpreted together with surgical resectability, endocrine profile and the patient’s general condition.

Treatment of adrenocortical carcinoma requires a multimodal pathway centralized in centers with specific expertise, because prognosis critically depends on the possibility of achieving complete resection, appropriate management of any hormonal hypersecretion and proper use of adjuvant and systemic therapies. In localized disease, the curative objective is based on two complementary pillars: oncological surgery capable of achieving negative margins and a postoperative strategy aimed at reducing the risk of recurrence, which remains high in adrenocortical carcinoma even after radical surgery. In advanced or metastatic disease, treatment instead combines disease control, management of endocrine hyperfunction and preservation of quality of life, with decisions individualized according to disease burden, growth rate, resectability and organ reserve.

Surgery is the decisive step in potentially curable disease. The standard procedure is adrenalectomy performed according to oncological principles, preferably through an open approach when malignancy is suspected, because this allows more reliable control of the dissection planes and reduces the risk of capsular rupture and dissemination. The priority is to achieve an R0 resection, avoiding fragmentation of the specimen and minimizing tumor manipulation, because peritoneal contamination and intraoperative rupture are associated with recurrence. When imaging suggests invasion of adjacent structures, surgery must be planned as an en bloc resection of the involved tissues, including, when necessary, portions of the kidney, liver, diaphragm or pancreas, with the aim of maintaining specimen integrity and adequate margins. Regional lymphadenectomy may be indicated in selected cases, particularly when suspicious lymph nodes are present, because lymph-node involvement has prognostic significance and affects staging.

A central and often underestimated aspect is the preoperative stabilization of patients with functioning disease. Severe hypercortisolism increases the risk of infections, thromboembolism, skin fragility, hyperglycemia and wound complications and may require pharmacological control before surgery. Similarly, hyperandrogenism or hyperaldosteronism, when present, must be managed to reduce metabolic and cardiovascular instability. Perioperative management of the risk of adrenal insufficiency must also be planned because removal of a cortisol-secreting mass frequently requires glucocorticoid coverage and subsequent reassessment of recovery of the hypothalamic-pituitary-adrenal axis.

After resection, the adjuvant strategy is based primarily on mitotane, an adrenolytic agent that represents the cornerstone of systemic treatment specifically directed against adrenocortical carcinoma. Adjuvant use is generally considered in patients at moderate or high risk of recurrence, taking into account stage, resection margins, proliferative index and histopathological features. The rationale is to maintain continuous therapeutic pressure on residual cells and reduce the probability of systemic recurrence. Because mitotane has complex pharmacokinetics and requires a target therapeutic concentration, treatment must be managed with periodic monitoring of plasma levels and careful prevention and management of adverse effects, including gastrointestinal symptoms, neurotoxicity, dyslipidemia and endocrine abnormalities. An essential practical point is that mitotane induces hepatic enzymes and accelerates glucocorticoid metabolism, often making higher doses of hydrocortisone replacement necessary, together with monitoring of thyroid and gonadal function when clinically indicated.

Radiotherapy is not a universal component of treatment but may have a role in selected settings, particularly to improve local control in patients with positive or uncertain surgical margins, microscopic residual disease or a high risk of local recurrence. Radiotherapy is also frequently relevant in the palliative setting to control pain or compressive symptoms from bone or other metastatic sites, with modern techniques allowing improved protection of critical organs. The decision must consider the site, treatable volumes, tissue tolerance and clinical objectives, avoiding treatments that could interfere with surgical pathways or compromise a potential salvage resection.

In unresectable locally advanced or metastatic disease, the standard systemic approach often combines multiagent chemotherapy with mitotane. The most widely used first-line regimen in eligible patients is etoposide, doxorubicin and cisplatin combined with mitotane, which has demonstrated better disease control than historical alternatives in clinical studies, although with substantial toxicity. Treatment selection requires careful assessment of cardiac and renal function, hematological status and frailty, together with a balance between the expected benefit and treatment burden. This is particularly important in patients with active hypercortisolism, which increases the risk of infection and metabolic complications. In later treatment lines or in patients unsuitable for intensive regimens, alternative options may be considered, including mitotane monotherapy or less aggressive chemotherapy combinations, always with realistic objectives of temporary disease control.

In a selected proportion of patients, surgery may retain a role even in advanced disease when substantial cytoreduction or complete resection of oligometastatic disease is feasible, particularly when tumor biology appears less aggressive and metastatic sites are limited and technically treatable. Selection must be rigorous and based on growth rate, response to systemic treatment, pattern of spread and the patient’s general condition. In this context, integrated management of endocrine symptoms remains essential because controlling hormonal excess may produce substantial clinical improvement even when the oncological objective is not curative.

The entire treatment pathway must be accompanied by structured management of toxicity and supportive needs. In addition to chemotherapy-related complications, mitotane requires proactive monitoring of neurological and gastrointestinal tolerability, lipid profile and endocrine balance, with prompt adjustment of replacement therapy. Thromboembolic prevention, blood-pressure and glucose control, nutritional support and attention to infection risk are essential components, particularly in patients with hypercortisolism, in whom systemic vulnerability is often an integral part of both the disease and its treatment.

Follow-up of adrenocortical carcinoma is a structured, high-intensity phase because the malignancy carries a substantial risk of recurrence even after complete resection and because management of endocrine sequelae and treatment toxicities is often complex. The principal objectives are to identify local or metastatic recurrence early, monitor the efficacy and tolerability of any adjuvant mitotane therapy, ensure metabolic safety in patients with previous hormonal hypersecretion and preserve the best possible long-term quality of life. Surveillance is not generic screening but a pathway tailored to the initial stage, resection margins, proliferative index, secretory profile and treatments received.

Oncological surveillance is based on serial imaging of the abdomen and chest. Because recurrence and metastases may appear early, particularly during the first years, the most cautious strategy involves close monitoring with abdominal CT or MRI to assess the adrenal bed, liver and lymph-node regions, together with thoracic imaging for the lungs. In many clinical pathways, examinations are more frequent during the first two or three years and are progressively spaced out when the patient remains disease-free. Prolonged surveillance must nevertheless be maintained because late recurrences, although less common, can occur. The choice between CT and MRI should consider cumulative radiation exposure, the need for tissue characterization and the quality of the available imaging windows, particularly in younger patients or those requiring numerous examinations over time.

In parallel, follow-up must include repeated endocrine assessment. In functioning tumors, the hormonal profile that was abnormal at diagnosis becomes a useful marker of recurrence because an increase in cortisol, androgens or other steroids may precede radiological evidence. Periodic reassessment is also appropriate in tumors that were not clearly functioning initially because tumor biology may change and because treatments may cause endocrine disturbances requiring correction. Clinical vigilance must remain high for signs of recurrent hypercortisolism and its consequences, because renewed glucocorticoid excess may present with rapid worsening of blood pressure, glycemia, myopathy, skin fragility and susceptibility to infections.

When the patient is receiving mitotane, surveillance acquires an additional dimension because both efficacy and safety must be monitored. Mitotane requires periodic measurement of plasma levels to maintain the therapeutic range and reduce the risk of toxicity. At the same time, glucocorticoid replacement therapy is often essential, sometimes at higher-than-usual doses because of the increased metabolism induced by the drug. Thyroid and gonadal function may also need to be assessed in the presence of symptoms or laboratory abnormalities. Clinically, signs of neurotoxicity, impaired attention and balance, severe fatigue and gastrointestinal intolerance must be actively investigated because they may require dose adjustments or supportive strategies to preserve adherence and quality of life.

Follow-up must also include management of late complications and systemic risk factors, particularly in patients who experienced prolonged hypercortisolism or received chemotherapy. Cardiometabolic assessment, including monitoring of blood pressure, glycemia, lipid profile and bone health, is relevant because chronic exposure to endogenous or exogenous glucocorticoids may leave persistent effects on muscle mass, bone mineral density and cardiovascular risk. In patients treated with regimens containing anthracyclines or platinum compounds, surveillance of cardiac and renal function should be tailored to the cumulative dose and individual risk factors.

Psychosocial and functional dimensions are integral parts of surveillance. Adrenocortical carcinoma and its treatments may cause rapid changes in body weight, alterations in body image, mood disturbances and impaired sleep quality, as well as reduced ability to work. Fear of recurrence and depressive symptoms are common and must be recognized and managed in a structured manner, with psychological support when necessary. Patient education regarding warning signs, particularly those associated with adrenal insufficiency in individuals receiving replacement therapy, is also essential to prevent acute events and promote safe day-to-day management.

In summary, follow-up of adrenocortical carcinoma combines oncological surveillance with serial chest and abdominal imaging, targeted endocrine monitoring, assessment of mitotane levels and tolerability when the drug is used, and management of cardiometabolic and psychosocial sequelae. Its effectiveness depends on continuity of care, standardization of the pathway at the referral center and the ability to adapt the intensity and tools of surveillance to the individual patient’s risk profile, with the aim of detecting clinically treatable events early and preserving the best possible long-term quality of life.

Long-term quality-of-life considerations are an essential component of care in adrenocortical carcinoma because both the disease and its treatments may leave persistent somatic, psychological and social consequences. Even when prolonged oncological control is achieved, patients may live with endocrine and metabolic sequelae, functional limitations and support needs requiring systematic assessment and coordinated long-term management. In this malignancy, quality of life depends not only on disease control but also on the ability to re-establish stable hormonal balance and prevent late complications related to surgery, adjuvant therapy and previous exposure to steroid excess.

A central domain is the impact of endocrine dysregulation and its correction. In cortisol-secreting tumors, preoperative hypercortisolism may cause proximal myopathy, skin fragility, osteoporosis, hyperglycemia, hypertension and vulnerability to infection. Even after resection, clinical recovery may be slow and require metabolic and muscular rehabilitation. In many cases, suppression of the hypothalamic-pituitary-adrenal axis necessitates glucocorticoid replacement therapy for prolonged periods, with detailed education on dose adjustment during stress and recognition of the signs of adrenal insufficiency. In patients treated with mitotane, complexity increases because the drug alters steroid metabolism and may require higher replacement doses, with possible clinical fluctuations between symptoms of deficiency and relative excess that affect energy, sleep and daily functioning.

Fatigue and reduced physical capacity are common and may result from multiple factors, including previous exposure to hypercortisolism, deconditioning, loss of muscle mass, anemia or treatment adverse effects. Persistent fatigue affects occupational and social activities and requires integrated strategies including progressive rehabilitation, nutritional optimization, correction of endocrine deficiencies and assessment of cardiovascular and metabolic comorbidities. In patients with a history of hypercortisolism, recovery of strength may be particularly slow, and rehabilitation must progress gradually to avoid relapse or injury, especially when osteopenia or bone fragility is present.

Another important area is cardiometabolic health. Hypercortisolism, even when controlled, may leave persistent effects on blood pressure, glucose metabolism, thromboembolic risk and body composition. Patients who have received chemotherapy, particularly anthracyclines and platinum compounds, may also face long-term risks affecting cardiac and renal function, requiring periodic monitoring and structured cardiovascular prevention. Quality of life may also be affected by mitotane-induced dyslipidemia and the chronic pharmacological management of hypertension and diabetes, which may require frequent adjustments during periods of endocrine instability.

The neurocognitive and psychological domains may be significantly affected. Sleep disturbances, irritability, impaired concentration and mood changes are common in patients who have experienced hypercortisolism and may persist after treatment, affecting relationships and occupational performance. Fear of recurrence, the perception of physical vulnerability and the need for frequent examinations also contribute to anxiety and chronic stress. In patients receiving mitotane, possible neurological and cognitive symptoms may interfere with autonomy and safety in everyday activities, requiring active clinical monitoring and, when necessary, psychological and neuropsychological support.

The reproductive and sexual domains are additional factors that may affect quality of life. Androgen- or estrogen-secreting tumors may cause physical changes and sexual dysfunction that take time to regress and may leave a significant psychological burden. Systemic therapies and the need for prolonged treatment may interfere with reproductive plans, making dedicated counseling and targeted endocrine assessment important when menstrual irregularities, reduced libido or symptoms of functional hypogonadism develop. Management of osteoporosis and bone health, which are frequently compromised by hypercortisolism, is also essential to preserve independence and prevent fractures that would have a major impact on daily life.

Overall, long-term quality of life in adrenocortical carcinoma depends on the ability to provide multidimensional care in which oncological surveillance, endocrine follow-up, cardiovascular prevention, rehabilitation and psychological support are integrated into a single pathway. In this context, quality of life is a primary clinical outcome because disease control is truly meaningful only when accompanied by functional recovery and endocrine and metabolic stability that allow the patient to resume a life that is as independent and fulfilling as possible.

Complications of adrenocortical carcinoma result from the interaction between the tumor’s biological aggressiveness, any associated hormonal hypersecretion and complex treatments including major surgery, adrenolytic therapy and, in many cases, systemic chemotherapy. The clinical impact concerns not only oncological progression but also the systemic consequences of steroid excess and the metabolic vulnerability that may persist over time. From the earliest stages, a large adrenal mass may cause abdominal pain, a sensation of heaviness or compressive symptoms, while cortisol-secreting tumors may present with recurrent infections, rapidly worsening diabetes and hypertension, skin fragility and myopathy, increasing the risk of perioperative and treatment-related complications.

Local progression may involve infiltration of adjacent structures, including the kidney, liver, pancreas or diaphragm and, in more advanced cases, vascular invasion involving the renal vein or inferior vena cava. This may cause complications such as venous thrombosis, lower-limb edema, persistent pain and major technical difficulties during surgery, as well as an increased risk of local recurrence. Metastatic spread, frequently involving the liver, lungs, peritoneum and bones, is one of the main causes of clinical deterioration and poorer prognosis, with possible respiratory complications, bone pain, pathological fractures and ascites caused by peritoneal carcinomatosis.

Endocrine complications are particularly important. Sustained hypercortisolism increases the risk of thromboembolism, cardiovascular events, glycemic decompensation and severe infections, which may present as pneumonia, sepsis or opportunistic infections. Glucocorticoid-induced myopathy and bone fragility increase the risk of falls and fractures and may prolong postoperative recovery. After resection of a cortisol-secreting tumor, a critical complication is adrenal insufficiency, which may present with severe fatigue, hypotension, nausea and hypoglycemia and may progress to an adrenal crisis during intercurrent stress if glucocorticoid coverage is inadequate. Even in tumors that were not clearly functioning, mitotane therapy may induce functional adrenal insufficiency requiring replacement therapy and patient education on stress-dose management.

Surgery is associated with specific complications because oncological adrenalectomy may be a complex procedure, particularly for large or infiltrative tumors. Hemorrhage, injury to adjacent organs, thromboembolic complications and wound infections are significant risks and are amplified in patients with hypercortisolism, in whom tissue healing is impaired. Capsular rupture or peritoneal dissemination is a particularly unfavorable event because it increases the risk of recurrence. In cases of vascular invasion, surgical management of the tumor thrombus may carry a risk of embolism or major vascular complications and requires highly specialized teams.

Complications related to mitotane and systemic therapies represent an important area. Mitotane may cause persistent gastrointestinal symptoms, weight loss, fatigue and neurological manifestations, affecting the ability to work and personal independence. Metabolic abnormalities such as dyslipidemia and alterations in thyroid or gonadal function contribute to the chronic burden of disease. When combination chemotherapy is used, additional complications include myelotoxicity with febrile neutropenia, an increased risk of infection, nausea and vomiting, platinum-induced nephrotoxicity and ototoxicity and possible anthracycline-induced cardiotoxicity, requiring dedicated monitoring and preventive strategies.

At a systemic level, chronic fatigue, muscle decline and cardiovascular and thromboembolic complications may persist even when the disease is controlled, particularly in patients with a history of prolonged hypercortisolism. In advanced disease, cachexia, persistent pain and symptoms caused by progression require early integration of supportive interventions and palliative care, with attention to pain management, nutrition and psychological well-being.

Management of complications is based on structured prevention, including early control of hormonal hypersecretion, surgical planning at expert centers, close monitoring of mitotane and chemotherapy toxicities, surveillance of organ function and patient education regarding adrenal insufficiency and stress management. A multidisciplinary approach reduces the impact of adverse events, preserves independence and improves the overall quality of life of patients with adrenocortical carcinoma.