The 2022 W H O classification puts the adrenal cortical proliferative diseases into four major categories: namely, diffuse adrenal cortical hyperplasia, adrenal cortical nodular diseases, adrenal cortical adenomas, and adrenal cortical carcinomas. Steroidogenic factor-1, Melan-A, calretinin, alpha-inhibin, and synaptophysin are markers to identify cells of adrenocortical origin by immunohistochemistry. This synoptic review highlights the key update of each category.
Adrenal cortical hyperplasia:
The diagnosis of adrenal cortical hyperplasia is now restricted to bilateral diffuse adrenal cortical hyperplasia resulting from a pituitary tumor or other ectopic endocrine causes such as ACTH- or CRH-producing neuroendocrine neoplasm, paraganglioma, etc.
The adrenal cortical nodular diseases:
The adrenal cortical nodular disease now includes the following three subtypes.
1. Sporadic nodular adrenocortical disease
2. Bilateral micronodular adrenal cortical disease, and
3. Bilateral macronodular adrenal cortical disease (formerly known as primary bilateral macronodular adrenal cortical hyperplasia). Please note that sporadic nodular adrenocortical disease has replaced “nodular adrenal cortical hyperplasia” for incidentally discovered sporadic non-functional adrenal cortical nodules. Virtually all bilateral micronodular and a significant fraction of bilateral macronodular adrenal cortical diseases are caused by genetic susceptibility.
Adrenal cortical adenoma (ACA): ACA is defined as a neoplasm of adrenocortical cell derivation that lacks morphologic features of malignancy. ACAs may be hormonally active or inactive. Cortisol- and aldosterone-secreting ACAs are the most frequent functional variants. Non-tumorous cortical atrophy is a characteristic gross and microscopic feature of cortisol-secreting ACA. ACAs are often solitary nodules although multifocal lesions can occur. ACAs less than 1.0 cm in size are often indistinguishable from sporadic nodular adrenal cortical disease. The distinction of functional ACAs from sporadic nodular adrenocortical disease requires immunohistochemical stains for enzymes of hormone production, such as Cytochrome P (CYP)-11B1, CYP11B2, and CYP17. Non-functioning ACAs do not show characteristic histologic features, except for their relatively larger size as compared to functional ones.
Adrenal cortical carcinoma (ACC): ACCs are subtyped based on their morphological features to include conventional, oncocytic, myxoid, and sarcomatoid subtypes. Features suggestive or indicative of malignancy include vascular invasion, local invasion into adjacent structures, tumor necrosis, atypical mitotic figures, increased mitotic activity (more than 5 mitoses per 10 square millimeters), and a marked loss of reticulin framework. These features are not seen in adenomas. Weiss scoring system is used to grade the tumor. However, its value is limited for predicting the behavior of oncocytic subtype ACC and tumors with extensive myxoid changes. Immunohistochemistry can be very helpful in diagnosis. For example, juxtanuclear IGF-2 immunostaining and p53 overexpression or complete loss are features of ACCs. Hormonal functional status can also aid the diagnosis of ACCs. An adrenal cortical neoplasm associated with virilization or feminization is highly worrisome for malignancy while primary aldosteronism is extremely rare in ACCs. Expression of 2 or more hormones is seen more frequently in ACCs.
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Key References
Hodgson, Anjelica et al. “A Diagnostic Approach to Adrenocortical Tumors.” Surgical pathology clinics vol. 12,4 (2019): 967-995. doi:10.1016/j.path.2019.08.005
Mete, Ozgur et al. “Overview of the 2022 WHO Classification of Adrenal Cortical Tumors.” Endocrine pathology vol. 33,1 (2022): 155-196. doi:10.1007/s12022-022-09710-8
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