Adrenocortical carcinoma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2] Shivali Marketkar, M.B.B.S. [3] Ahmad Al Maradni, M.D. [4] Mohammed Abdelwahed M.D[5]


ACCs are typically large tumors upon clinical presentation, often measuring more than 6 cm in diameter. They are bilateral in 2% to 10% of cases. Genetic basis of ACC depends on genomic aberrations that contribute to neoplastic transformation of adrenocortical cells such as gene mutations, chromosomal aberrations, and epigenetic changes. Intracellular signaling can occur via three pathways: IGF pathway, WNT signaling pathway, and Vascular endothelial growth factor pathway. On gross pathology, a large tan-yellow surface with areas of hemorrhage and necrosis is a characteristic finding of adrenocortical carcinoma. On microscopic histopathological analysis, sheets of atypical cells with some resemblance to the cells of the normal adrenal cortex are a characteristic finding of adrenocortical carcinoma. ACC may be associated with other neoplastic syndromes such as Lynch syndrome, Beckwith-Wiedemann syndrome (BWS), Carney complex, and Neurofibromatosis type1.


Spread can take several forms: [4]

ACCs can be graded into low and high-grade carcinoma groups based on their mitotic rates ( >20 mitoses per 50 high-power fields or <20 mitoses per 50 high-power fields)

  • The mitotic rate is closely associated with the patient outcome.
  • ACCs in children behave in a more indolent fashion compared with the adult, that is why there are so many pediatric ACCs but few pediatric deaths.[5]


The genetic dissection of ACC has revealed genomic aberrations that contribute to neoplastic transformation of the adrenocortical cells:

1. Clonality

2. Gene expression arrays

  • Expression levels of BUB1B, PINK1, and DLG7 are identified in ACC.[12]

3. MicroRNAs

microRNA function, source: By Kelvinsong - Own work, CC BY 3.0,

4. Gene mutations

  • TP53 located on 17p13 is the most commonly mutated gene in ACC, present in at least one-third of ACCs.[19]
  • LOH in the gene encoding p16ink/ p14arf, CDKN2A is observed in a subset of ACCs. The tumor suppressor function of this gene has been established in multiple cancers. LOH of 11q13 has been identified in 83% of samples.[20]
  • MEN1 somatic mutations are unusual in sporadic ACC.[21]
  • The canonical Wnt pathway, the catenin gene, and CTNNB1 have been identified as activating point mutations in over 25% of both ACAs and ACCs in children and adults.[22]
WNT pathwayssource: By Fred the OysteriThe source code of this SVG is valid.This vector graphics image was created with Adobe Illustrator., GFDL,

5. Chromosomal aberrations

  • ACCs showed complex chromosomal alterations.
  • ACCs contained multiple chromosomal gains or losses with a mean of 10 events.
  • The newest study confirmed increased alterations in ACC (44%) compared with ACAs (10%).
  • In ACCs, the frequently observed chromosomal gains at 5, 7, 12, 16, 19, and 20 and losses at 13 and 22 were confirmed.
  • The study confirmed the diagnostic utility of 6 loci (5q, 7p, 11p, 13q, 16q, and 22q) in the differentiation of ACA and ACC.

6. Epigenetic changes

Cellular signaling pathway

1. IGF pathway

2. WNT signaling pathway

  • Initial alterations of the WNT/ catenin system/pathway were identified in FAP.[34]
  • Both nuclear catenin accumulation and activating CTNNB1 mutations are present in ACCs suggesting WNT activation to be a part of ACA tumorigenesis.

3. Vascular endothelial growth factor

VEGF signaling, source: By Mikael Häggström.When using this image in external works, it may be cited as:Häggström, Mikael (2014). "Medical gallery of Mikael Häggström 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 2002-4436. Public Domain.orBy Mikael Häggström, used with permission. - [1]Interactions of VEGF ligands and VEGF receptors, retrieved on November, 13, 2009, Public Domain,

Hormones biosynthesis in adrenal cortex

source: By David Richfield (User:Slashme) and Mikael Häggström. Derived from previous version by Hoffmeier and Settersr.In external use, this diagram may be cited as:Häggström M, Richfield D (2014). "Diagram of the pathways of human steroidogenesis". Wikiversity Journal of Medicine 1 (1). DOI:10.15347/wjm/2014.005. ISSN 20018762. - Self-made using bkchem and inkscape, CC BY-SA 3.0,

Associated Conditions

Associated diseases with adrenocortical carcinoma are:

Gross Pathology

A large adrenal cortical carcinoma resected from a 27-year-old woman. The tumor measured 17 cm in diameter and invaded kidney and spleen which necessitated en bloc removal of these organs with the tumor. - By AFIP Atlas of Tumor Pathology - [1], Domena publiczna,

Shown above is a large adrenal cortical carcinoma resected from a 27-year-old woman. The tumor measured 17 cm in diameter and invaded kidney and spleen which necessitated en bloc removal of these organs with the tumor. The patient had evidence of virilization.

Microscopic Pathology

On microscopic examination, the tumor usually displays sheets of atypical cells with some resemblance to the cells of the normal adrenal cortex. The presence of invasion and mitotic activity helps differentiating benign tumors from adrenocortical adenomas.[42]

The Weiss criteria are the most reliable histopathological scoring system differentiating ACC from adrenocortical adenoma.

ACC can be diagnosed by the presence of at least 3 of the 9 Weiss criteria:

Modified Weiss criteria (score of 3 or more suggests malignancy):

Micrograph of an adrenocortical carcinoma (left of image - dark blue) and the adrenal cortex it arose from (right-top of image - pink/light blue). Benign adrenal medulla is present (right-middle of image - gray/blue). H&E stain. - Source:


Shown below is a video explaining the histology of adrenocortical carcinoma



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