Advances in Adrenocortical Carcinoma Diagnosis: From Radiology to Molecular Assays

Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy that poses significant diagnostic challenges due to its heterogeneous presentation and clinical behavior. This resource provides a comprehensive overview of the modern diagnostic landscape for ACC, detailing the integrated clinical pathway from initial imaging to definitive histopathological assessment and molecular profiling.

Introduction to Adrenocortical Carcinoma

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy originating from the adrenal cortex, characterized by heterogeneous clinical behavior ranging from indolent growth to rapid metastasis. It may present with hormonal hypersecretion syndromes (such as Cushing's syndrome or virilization) or as a non-functioning mass discovered incidentally. Diagnosis requires a multimodal approach integrating radiological imaging, detailed hormonal profiling, histopathological evaluation using established criteria like the Weiss system, and emerging molecular biomarkers to distinguish ACC from benign adenomas and guide therapeutic decisions.

Fig.1 Driver genes in adrenocortical carcinoma and their correlation with tumor pyruvate kinase M2 (PKM2). (Das R, et al., 2022)

Imaging Modalities for Adrenocortical Carcinoma Diagnostics

Imaging plays a pivotal role in the diagnosis, staging, and management of adrenocortical carcinoma (ACC), providing essential information about tumor characteristics, local invasion, and distant metastasis. These advanced modalities are crucial for differentiating ACC from benign adrenal lesions and guiding treatment decisions.

CT and MRI

Computed tomography (CT) and magnetic resonance imaging (MRI) serve as the primary imaging tools for initial characterization of adrenal masses. CT excells in demonstrating tumor size, density, and calcifications, while MRI provides superior soft tissue contrast for evaluating local invasion and detecting intracellular lipid content. Both modalities utilize contrast enhancement patterns, particularly the absolute and relative washout characteristics, to help distinguish ACC from adenomas.

PET-CT

Positron emission tomography-computed tomography (PET-CT) with 18F-FDG provides functional metabolic information that complements anatomical imaging. ACC typically demonstrates significantly increased FDG avidity due to its high glycolytic activity, making PET-CT particularly valuable for detecting distant metastases, evaluating treatment response, and monitoring disease recurrence. This modality enhances staging accuracy and helps identify occult metastatic disease not apparent on conventional imaging.

Histopathological Diagnosis and Grading of Adrenocortical Carcinoma

Histopathological examination is essential for confirming the diagnosis of adrenocortical carcinoma (ACC) and distinguishing it from benign adrenal tumors. This process involves meticulous microscopic evaluation using established criteria to assess malignant potential, complemented by immunohistochemical staining to support the diagnosis and provide prognostic information. Key diagnostic components include:

Weiss System

The most widely used diagnostic criteria, which evaluates nine histological features including high nuclear grade, mitotic rate, atypical mitoses, clear cells comprising ≤25% of the tumor, diffuse architecture, necrosis, venous invasion, sinusoidal invasion, and capsular invasion. The presence of three or more of these features indicates malignancy.

Ki-67 Proliferation Index

A critical biomarker for grading and prognosis, with higher proliferation indices (typically >10-20%) strongly associated with aggressive behavior and poor outcomes in ACC.

Immunohistochemistry

Utilizes a panel of markers including SF-1 (steroidogenic factor 1), Melan-A, Inhibin-alpha, and Synaptophysin to confirm adrenocortical origin and differentiate ACC from other malignancies such as renal cell carcinoma or pheochromocytoma.

Molecular Diagnostics and Biomarkers of Adrenocortical Carcinoma

Molecular diagnostics have revolutionized the understanding and management of adrenocortical carcinoma (ACC) by uncovering the genomic alterations driving tumorigenesis, enabling refined prognostic stratification, and identifying potential therapeutic targets beyond conventional histopathological assessment. Key biomarkers include:

• IGF-2 Overexpression: The most common molecular alteration, promoting tumor growth through aberrant insulin-like growth factor signaling.
• TP53 Mutations: Frequently observed in sporadic ACC, associated with aggressive tumor behavior and poor prognosis.
• β-Catenin (CTNNB1) Mutations: Lead to Wnt pathway activation, contributing to tumor proliferation and dedifferentiation.
• Steroidogenic Factor-1 (SF-1): Overexpression aids in confirming adrenocortical origin and correlates with poor outcomes.
• Circulating Tumor DNA (ctDNA): Enables non-invasive detection of tumor-specific mutations and monitoring of treatment response.

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