Adrenocortical carcinoma
Introduction
Adrenocortical carcinoma (ACC) is a rare and aggressive cancer originating in the adrenal cortex, the outer layer of the adrenal glands. These glands are located on top of each kidney and are responsible for producing a variety of hormones, including cortisol, aldosterone, and androgens. ACC can occur at any age but is most commonly diagnosed in adults aged 40 to 50 years. The malignancy can be functional, producing excess hormones, or non-functional, where hormone production is not significantly altered.
Epidemiology
ACC is an uncommon malignancy, with an estimated annual incidence of 1 to 2 cases per million people worldwide. The condition exhibits no significant gender predilection, although some studies suggest a slight female predominance. ACC can occur sporadically or as part of hereditary syndromes such as Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, and MEN1.
Pathophysiology
The pathogenesis of ACC involves complex genetic and molecular alterations. Mutations in the TP53 gene, which plays a critical role in cell cycle regulation and apoptosis, are frequently observed in ACC cases. Other genetic alterations include mutations in the CTNNB1 gene, leading to aberrant activation of the Wnt/β-catenin signaling pathway, and alterations in the IGF2 gene, which is involved in cell growth and development.
ACC tumors can be classified based on their hormonal activity. Functional tumors produce excess hormones, leading to clinical syndromes such as Cushing's syndrome (excess cortisol), Conn's syndrome (excess aldosterone), or virilization (excess androgens). Non-functional tumors do not produce hormones but can cause symptoms due to mass effect.
Clinical Presentation
The clinical presentation of ACC varies depending on the tumor's hormonal activity. Functional tumors often present with symptoms related to hormone excess. For instance, patients with Cushing's syndrome may exhibit hypertension, hyperglycemia, obesity, and osteoporosis. Those with Conn's syndrome may present with hypertension and hypokalemia. Virilization can lead to hirsutism, acne, and menstrual irregularities in females.
Non-functional tumors typically present with symptoms related to the tumor's size and location, such as abdominal pain, a palpable mass, or weight loss. Due to the aggressive nature of ACC, many patients present with advanced disease at diagnosis.
Diagnosis
The diagnosis of ACC involves a combination of clinical evaluation, laboratory testing, and imaging studies. Hormonal assays are critical for assessing the functional status of the tumor. Elevated levels of cortisol, aldosterone, or androgens may indicate a functional tumor.
Imaging studies, including computed tomography (CT) and magnetic resonance imaging (MRI), are essential for evaluating the size, location, and extent of the tumor. These modalities can also help differentiate ACC from benign adrenal lesions such as adrenal adenoma.
Histopathological examination of the tumor is necessary for definitive diagnosis. The Weiss criteria, which assess features such as nuclear atypia, mitotic rate, and necrosis, are commonly used to distinguish ACC from benign adrenal tumors.
Staging
The staging of ACC is based on the European Network for the Study of Adrenal Tumors (ENSAT) classification, which considers tumor size, local invasion, lymph node involvement, and distant metastasis. Stages range from I (localized disease) to IV (distant metastasis). Accurate staging is crucial for determining prognosis and guiding treatment decisions.
Treatment
The primary treatment for ACC is surgical resection, which offers the best chance for cure in localized disease. Complete surgical removal of the tumor, along with any involved surrounding tissues, is essential for achieving optimal outcomes. In cases of advanced or metastatic disease, surgery may be combined with other therapeutic modalities.
Adjuvant therapies, including mitotane, a steroidogenesis inhibitor, are often used to manage residual disease and reduce the risk of recurrence. Mitotane can be administered alone or in combination with chemotherapy agents such as etoposide, doxorubicin, and cisplatin.
Radiation therapy may be considered for patients with incomplete surgical resection or for palliation in metastatic disease. However, its role in ACC is limited due to the tumor's relative radioresistance.
Prognosis
The prognosis of ACC is generally poor, with a five-year survival rate of approximately 20-35%. Prognostic factors include tumor stage, resection status, and hormonal activity. Early-stage tumors that are completely resected have a better prognosis compared to advanced-stage or unresectable tumors.
Research and Future Directions
Ongoing research in ACC is focused on understanding the molecular mechanisms underlying tumorigenesis and identifying novel therapeutic targets. Advances in genomics and proteomics have provided insights into potential biomarkers for early detection and treatment response.
Immunotherapy, which has revolutionized the treatment of several malignancies, is being explored as a potential option for ACC. Clinical trials investigating immune checkpoint inhibitors and other immunomodulatory agents are underway.