Adrenocortical CarcinomaEdit

Adrenocortical carcinoma (ACC) is a rare, aggressive cancer that arises from the cortex of the adrenal gland. It sits at the intersection of endocrine physiology and solid tumor oncology, and its behavior ranges from hormonally active tumors that produce excess steroids to nonfunctioning masses that present as a growing abdominal lesion. Because ACC is uncommon, care is typically concentrated in specialized centers with multidisciplinary teams experienced in endocrine tumors and complex surgical resections. The disease tends to be advanced at diagnosis more often than not, which contributes to a challenging prognosis compared with many other cancers. Understanding ACC requires attention to both the biology of the adrenal cortex and the real-world issues that influence access to treatment and long-term follow-up in different healthcare systems. Adrenal cortex Adrenocortical carcinoma

ACC is linked to a spectrum of hereditary and sporadic factors. A subset of cases occurs in the setting of genetic syndromes such as Li-Fraumeni syndrome or Carney complex and occasionally in association with other conditions like Beckwith-Wiedemann syndrome. In certain populations, especially in southern Brazil, a founder TP53 mutation drives a higher incidence of ACC. Pediatric ACC is more likely to be hormonally active (often virilizing or manifesting Cushingoid features) than many adult cases, whereas adults may present with either excess hormone production or a palpable abdominal mass. The clinical course is frequently aggressive, with a substantial risk of recurrence after initial treatment. The management landscape reflects ongoing debates about optimal sequencing of surgery, drug therapy, and radiation in the context of patient priorities and healthcare resources. TP53 Beckwith-Wiedemann syndrome Carney complex Weiss criteria TNM staging

Presentation and diagnosis

Clinical presentation

Functional ACCs can secrete cortisol, androgens, or rarely estrogens, producing a range of signs from Cushing syndrome (weight gain, glucose intolerance, hypertension, “moon face”) to virilization (hirsutism, clitoromegaly, irregular menses). Nonfunctional tumors may grow silently until they cause abdominal pain, fullness, or are discovered incidentally on imaging performed for unrelated reasons. Because adrenal tumors can mimic other abdominal or retroperitoneal diseases, clinicians often pursue a combination of hormonal profiling and imaging to distinguish ACC from adenoma, pheochromocytoma, and metastatic lesions. Cushing syndrome Androgens Pheochromocytoma Adrenalectomy

Biochemical diagnosis

When ACC is suspected, biochemical testing typically includes measurements of serum cortisol and ACTH (to assess hypercortisolism), and androgen precursors such as DHEA-S, along with screening for signs of mineralocorticoid excess if relevant. In virilizing tumors, elevated androgens can be detected even in the absence of overt cortisol excess. In functional disease, biochemical data help guide urgency and perioperative planning and may affect decisions about adjuvant therapy. Cortisol ACTH DHEA-S Androgens

Imaging and histopathology

Cross-sectional imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is essential for characterizing tumor size, local invasion, and ring-fenced margins. ACCs are typically large at diagnosis and may invade adjacent organs or vessels. The Weiss criteria and related histopathologic scoring systems help pathologists distinguish malignant adrenal cortical tumors from adenomas, with features such as mitotic rate, nuclear grade, and necrosis informing prognosis. Immunohistochemical studies often demonstrate corticogenic markers (e.g., steroidogenic factor-1) and other lineage markers to support the adrenal cortical origin. In many cases, surgical pathology after adrenalectomy provides the definitive diagnosis. Weiss criteria Steroidogenic factor-1 Adrenalectomy TNM staging

Genetic predisposition and hereditary considerations

Germline testing for cancer susceptibility is increasingly incorporated into ACC care because of the potential implications for family members and surveillance strategies. Mutations linked to Li-Fraumeni syndrome, Carney complex, or Beckwith-Wiedemann syndrome can shape management decisions and counseling. Tumor boards facing ACC often discuss when to pursue genetic testing and how results might influence screening for other tumors. Li-Fraumeni syndrome Carney complex Beckwith-Wiedemann syndrome

Staging and prognosis

ACC is staged using a TNM framework that estimates tumor extent (T), regional lymph node involvement (N), and distant metastasis (M). Localized disease confined to the adrenal gland or with limited regional spread has a markedly better prognosis than disease with extensive invasion or distant metastases. Overall 5-year survival varies considerably by stage and resection outcome, with better results after complete surgical removal and negative margins, and worse outcomes with residual disease or distant spread. The prognosis also reflects tumor biology, hormonal activity, and the feasibility of delivering effective adjuvant therapy. TNM staging

Management

ACC management relies on a multidisciplinary approach that integrates surgery, endocrinology, medical oncology, radiology, and, when appropriate, radiation oncology. The therapeutic backbone emphasizes complete resection when feasible, followed by adjuvant therapies in higher-risk cases. The choice and sequencing of treatments are influenced by tumor stage, hormonal activity, patient fitness, and access to specialized care. Adrenalectomy Mitotane Radiation therapy Etoposide Doxorubicin Cisplatin

Local and regional disease: surgery and adjuvant therapy

Surgery: Open adrenalectomy with en bloc resection of adjacent involved organs is the preferred approach for most suspected ACCs to minimize rupture and local spillage, though carefully selected small tumors may be considered for minimally invasive removal in some centers. Achieving negative margins is a key determinant of outcome. Adrenalectomy
Adjuvant therapy: The role of adjuvant mitotane after complete resection remains a matter of debate. Some guidelines favor adjuvant mitotane for high-risk features (e.g., large tumor size, high-grade histology, positive margins) to reduce recurrence risk, while others prioritize individualized risk assessment and careful monitoring of drug toxicity. The decision often weighs potential survival benefit against notable adverse effects and treatment costs. Mitotane
Radiotherapy: The evidence for routine adjuvant radiotherapy is mixed; radiotherapy is more commonly considered for local control in cases with positive margins, invasion, or when surgical margins are uncertain. Radiation therapy

Advanced and recurrent disease: systemic therapy

Mitotane as a cornerstone: Mitotane remains the most specific pharmacologic agent for ACC, with a unique adrenolytic mechanism. It requires careful dose titration and frequent monitoring to maintain therapeutic blood levels while managing toxicity (fatigue, gastrointestinal upset, neurotoxicity, lipid abnormalities). Drug interactions and long-term endocrine effects are important considerations. Mitotane
Combination chemotherapy: For unresectable, recurrent, or metastatic ACC, systemic therapy with regimens such as EDP-M (etoposide, doxorubicin, cisplatin, plus mitotane) is commonly employed. The regimen aims to shrink tumors and prolong survival, albeit with substantial hematologic and non-hematologic toxicities. The individual drug components have their own well-established profiles: etoposide, doxorubicin, cisplatin, and Mitotane.
Other systemic options and trials: Immunotherapy and targeted approaches are under investigation in clinical trials. Early signals in some cases have been modest, and participation in trials is often encouraged for patients with advanced disease. Clinical trial
Supportive and palliative care: Given the aggressive nature of ACC and treatment-related side effects, integrating supportive care that addresses nutrition, metabolic complications, pain, and psychological well-being is an important complement to antitumor therapy. Palliative care

Controversies and debates

Adjuvant mitotane use: As noted, the decision to use mitotane after surgery is debated, balancing potential improvements in disease-free survival against toxicity and the burden of long-term monitoring. Clinicians often rely on tumor size, grade, margins, and patient preferences in shared decision-making. Mitotane
Surgical approach: While open surgery is typically recommended for suspected ACCs, some centers with surgical expertise explore minimally invasive approaches for selected small lesions. The consensus emphasizes minimizing tumor rupture and ensuring complete resection. Adrenalectomy
Role of radiotherapy: The benefit of routine adjuvant radiotherapy is not uniformly supported across guidelines, leading to differing practice patterns depending on institutional experience and patient risk profiles. Radiation therapy
Access and cost considerations: The high price of mitotane and limited access to specialized care can influence outcomes, particularly in healthcare systems with strong cost-controls or limited insurance coverage. Advocates of market-driven healthcare argue for transparency, competition, and patient choice to improve access to proven therapies, while critics worry about disparities in access. These policy debates intersect with clinical decisions in real-world practice. Mitotane Clinical trial

Prognosis and follow-up

Patients require long-term follow-up owing to the risk of late recurrence and the potential toxicities of therapy. Follow-up plans typically include periodic imaging to monitor for local and distant disease, hormonal assessments to track residual or recurrent functionality, and ongoing management of mitotane-related endocrine effects if therapy is continued. The frequency of surveillance is tailored to stage, treatment history, and the presence or absence of hormonal activity. Recurrence risk remains a central concern even after seemingly successful initial treatment. TNM staging Mitotane

Epidemiology and risk factors

ACC is a rare cancer, with incidence estimated in the low per-million range in most populations. It shows a bimodal pattern with pediatric cases presenting more often with hormonal syndromes and adults presenting with a mix of functional and nonfunctional tumors. A notable geographic pattern exists in southern Brazil due to the TP53 founder mutation, illustrating how inherited susceptibility shapes regional disease burden. Awareness of hereditary cancer risk can inform screening strategies for families and influence the care pathway for newly diagnosed patients. TP53 Beckwith-Wiedemann syndrome Carney complex Southern Brazil (founder mutation)

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