Adrenal carcinoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:  Sara Mohsin, M.D.[2]

Synonyms and keywords: Adrenocortical carcinoma, Adrenal cortical carcinoma, Adrenal cortical cancer, Adrenal cortex cancer, Adrenal cancer, Adrenal tumor, Neuroblastoma, Pheochromocytoma, Ganglioneuroma, Adrenocortical adenoma, Adenomatoid tumor, Myelolipoma, Schwannoma.

## Overview

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Adrenal carcinoma or adrenal tumor is an aggressive disease which can originate either in the cortex (steroid hormone-producing tissue) or medulla of the adrenal gland. According to the 2017 WHO classification of adrenal tumors, adrenal cortical tumors are subclassified into cortical adenoma, cortical carcinoma, sex cord stromal tumors, adenomatoid tumor, mesenchymal and stromal tumors (myelolipoma, schwannoma), hematological tumors and secondary tumors, whereas tumors of adrenal medulla are subclassified into pheochromocytoma, paraganglioma, neuroblastic tumors, composite pheochromocytoma, and composite paraganglioma. Pathogenesis includes many genetic pathways, most prominent being Wnt-Beta catenin pathway and also association with other diseases such as multiple endocrine neoplasia (MEN1 and MEN2), familial adenomatous polyposis, Beckwith-Wiedemann syndrome, Li-Fraumeni syndrome, Lynch syndrome,von Hippel-Lindau disease, carney Complex/Syndrome, neurofibromatosis type 1 and congenital adrenal hyperplasia. Adrenocortical carcinoma is remarkable for the many hormonal syndromes which can occur in patients with steroid hormone-producing ("functional") tumors, including Cushing's syndrome, Conn syndrome, virilization, and feminization. Adrenal carcinoma can be treated with both medical therapy and surgery depending upon the stage of the tumor.

## Historical perspective

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* In 1978, Sullivan devised a staging system for adrenocortical carcinoma based on modifying the original McFarlane staging system.
* In 2004, International Union Against Cancer (UICC) and World Health Organization (WHO) proposed a new staging system which was based on the modified original version of Sullivan-McFarlane staging criteria.
* In 2017, WHO presented an update on recent classification of adrenal tumors (in fourth edition of the World Health Organization classification of endocrine tumors).[1]

## Classification

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* Adrenal cancer is subclassified according to its activity into:[2]
* Functional
* Non-functional
* In 2017, WHO presented the following updated classification of adrenal tumors in fourth edition of the World Health Organization classification of endocrine tumors:[1][3][4][5][6][7][8]

Updated 2017 WHO classification of adrenal tumors  Tumors of adrenal gland

Tumors of adrenal cortex |

* Cortical carcinoma

* Cortical adenoma

* Sex cord stromal tumors

* Adenomatoid tumor

* Mesenchymal and stromal tumors:
* Myelolipoma
* Schwannoma

* Haematological tumors

* Secondary tumors

Tumors of the adrenal medulla

and extra-adrenal paraganglia

* Pheochromocytoma

* Paraganglioma:
* Head and neck paraganglioma
* Sympathetic paraganglioma

* Neuroblastic tumors:
* Neuroblastoma
* Nodular ganglioneuroblastoma
* Intermixed ganglioneuroblastoma
* Ganglioneuroma

* Composite pheochromocytoma

* Composite paraganglioma

## Pathophysiology

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### Normal anatomy and physiology of adrenal glands

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* Adrenal glands are the 2 small glands located above the kidneys on either side (that's why also known as suprarenal glands)
* Normal anatomy and physiology of adrenal glands are given in the table below:

Normal anatomy and function of Adrenal glands  Adrenal gland layers | Functions

|

Adrenal cortex (outer layer) |

* Zona glomerulosa (outermost layer)

* Produces mineralocorticoids especially aldosterone which has following functions:
* Increases urinary excretion of potassium ions
* Increases interstitial levels of sodium ions
* Increases blood volume by water retention

* Zona fasciculata (middle layer)

* Produces glucocorticoids including:
* 11-deoxycorticosterone
* Corticosterone
* Cortisol especially which has following functions:
* Enhances activity of other hormones such as glucagon and catecholamines
* Stimulates release of amino acids from body
* Stimulates gluconeogenesis (production of glucose from newly-released amino acids and lipids)
* Stimulates lipolysis (fat breakdown)
* Increases water retention
* Increases blood glucose levels in response to stress (inhibits glucose uptake into muscle and adipocytes)
* Anti-inflammatory
* Anti-allergic
* Strengthens cardiac muscle contractions

* Zona reticularis (innermost layer)

* Produces androgens including:
* DHEA mainly
* DHEA sulfate (DHEA-S)
* Androstenedione (precursor of testosterone)
* These hormones don't have any specific function and just act as metabolic intermediates to convert into other hormones

Adrenal medulla (Inner layer) |

* Neuroendocrine/chromaffin cells (modified post-synaptic sympathetic neurons) of adrenal medulla produce:
* Catecholamines (80% epinephrine and 20% norepinephrine) play an important role in fight-or-flight response which is characterized by:
* Increased heart rate
* Increased blood pressure
* Increased metabolism
* Vasoconstriction of skin blood vessels
* Constriction of blood vessels in GIT
* Smooth muscle dilation
* Dilation of bronchioles
* Dilation of capillaries
* Enkephalin & enkephalin-containing peptides (produce analgesic effects by binding to opioid receptors)

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, https://commons.wikimedia.org/w/index.php?curid=6355511 |

{{#ev:youtube|https://www.youtube.com/watch?v=JlI5N2N4d-k}}

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### Epigenetics

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* Adrenal tumors are usually not biopsied prior to surgery, hence, the diagnosis is confirmed on examination of the surgical specimen by a pathologist.[9][10][11][12][13][5][14]
* Following genes are involved in the development of adrenal tumors:
* IGF2 gene (increased expression at 11p15 locus-adrenocortical carcinoma)[15]
* Steroidogenic genes (increased expression-adrenocortical adenoma)
* p53
* CTNNB1 (Wnt pathway)
* Beta-catenin
* ACTH receptor
* BUB1B
* PINK1
* DLG7
* MEN1
* IGF2R
* p16
* p16ink/ p14arf
* CDKN2A
* Fibroblast growth factor 4 (FGF4)
* Cyclin-dependent kinase 4 (CDK4)
* Cyclin E1 (CCNE1)
* H19 (11p15 locus)
* PLAGL1
* G0S2
* NDRG2
* IGF1R
* RPTOR
* FRAP1
* Alterations in the following chromosomal regions are associated with adrenal tumors:
* 11q13
* 12q
* 5q
* 1p
* 7p
* 13q
* 16q
* 22q
* 19
* 20
* Loss of heterozygosity (LOH) at the following loci is strongly associated with high malignant potential of adrenal tumors:
* 11p15 (maternal 11p15 LOH with duplication of the active IGF-II paternal allele results in strong overexpression of IGF-II gene)
* 17p13 LOH (10 , 11)
* 2p16 LOH (6)
* 11q13 LOH (6 , 12, 13, 14)
* miRNAs involved in the pathogenesis of adrenal tumors are as follows:
* miR-184 (upregulated)
* miR-210 (upregulated)
* miR-503 (upregulated)
* miR-214 (downregulated)
* miR-375 (downregulated)
* miR-511 (downregulated)
* miR-483 (significant upregulation in pediatric adrenocortical carcinoma)
* miR-99a
* miR-100

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 ResearchVEGF.com, retrieved on November, 13, 2009, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3475250 |  WNT pathwayssource: By Fred the OysteriThe source code of this SVG is valid.This vector graphics image was created with Adobe Illustrator., GFDL, https://commons.wikimedia.org/w/index.php?curid=36340188 |  microRNA function, source: By Kelvinsong - Own work, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=23311105 |

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### Gross pathology

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#### Adrenocortical carcinoma

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* Gross pathology of adrenocortical carcinomas shows often a large mass (>5 cm in largest diameter), with a tan-yellow cut surface and areas of hemorrhage and necrosis (always present).
* Cut surface ranges from brown to orange to yellow depending on the lipid content of the cells.
* Typical adrenocortical carcinoma consists of a hypercellular population of cells with the earliest form of tumor necrosis.
* Atypical adrenocortical carcinoma consists of a solid growth pattern and an abundant eosinophilic cytoplasm with focal clear areas, consistent with lipid.

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, https://commons.wikimedia.org/w/index.php?curid=6719487

#### Pheochromocytoma

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* Gross pathology of pheochromocytoma varies from small to large and usually associated with hemorrhage and necrosis.
* Pheochromocytoma is usually lobulated and small tumors have compressed adrenal gland.
* Familial tumors are bilateral.
* It may be associated with hyperplasia in the adjacent medulla.
* Shows Chromaffin reaction: fresh tumor's cut section turns dark brown on adding potassium dichromate at pH 5-6.

Bilateral pheochromocytoma in MEN2. Gross image. Source: https://upload.wikimedia.org/wikipedia/commons/5/5f/Bilateral_pheo_MEN2.jpg

### Microscopic pathology

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* Pheochromocytoma demonstrates a typical nesting (Zellballen) pattern on histopathological analysis which is composed of well-defined clusters of tumor cells containing eosinophilic cytoplasm separated by fibrovascular stroma.
* Histopathological criterias for the diagnosis of adrenocortical carcinoma are given below.

#### Pathologic criterias for adrenocortical carcinoma

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* Different pathological criterias for adrenocortical carcinoma are given in the table below:[16][17][18][19][20][21][22][23]

Pathologic criteria | Details | Age applicability

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Weiss criteria |

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

1. High nuclear grade (III or IV)
2. High mitotic rate i.e. presence of >5 mitotic figures/50 high-power fields, definition suffers from HPFitis (counting 10 random fields in area of greatest number of mitotic figures on 5 slides with the greatest number of mitosis)
3. Atypical mitoses (abnormal distribution of chromosomes or excessive number of mitotic spindles)
4. Cleared or vacuolated cytoplasm in >/= 25% of the tumor cells
5. Sheeting (diffuse architecture of patternless sheets of cells)) in >= 1/3 of tumor cells
6. Necrosis in nests (microscopic necrosis)
7. Venous invasion (veins must have smooth muscles in wall; tumor cell clusters or sheets forming polypoid projections into the vessel lumen or polypoid tumor thrombi covered by endothelial layer)
8. Adrenal sinusoid invasion (sinusoid is endothelial lined vessel in adrenal gland with little supportive tissue; consider only sinusoids within tumor)
9. Capsular invasion (nests or cords of tumor extending into or through capsule with a stromal reaction); either incomplete or complete)

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

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* Mitotic rate >5 per 50 high-power fields
* Cytoplasm (clear cells comprising 25% or less of the tumor)
* Abnormal mitoses
* Necrosis
* Capsular invasion

| Adults
Volante criteria |

Simplified criteria by Volante et al (not widely used) is as follows:

* Reticular network disruption (with reticulin staining)
* One of the three following:
1. Abundant mitoses >5/50 high-power fields \- definition suffers from HPFitis
2. Necrosis
3. Vascular invasion

Wieneke et al and Dehner & Hill |

Wieneke et al and Dehner & Hill proposed the following very simple system:

* "Low risk" < 200 g & confined to the adrenal
* "Intermediate risk" 200-400 g, no mets, +/-microscopic disease outside adrenal
* "High risk" >400 g, or mets, or gross invasion of adjacent structures

| Pediatrics
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: https://librepathology.org |  Micrograph of pheochromocytoma. Source: By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=5938524 |  Histopathology of adrenal pheochromocytoma. Adrenectomy specimen. Source: CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=535945 |  Micrograph of pheochromocytoma. Source: CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=535944 |

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## Epidemiology and demographics

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* Adrenal carcinoma is a relatively rare tumor.
* It accounts for only 0.02-0.2% of all the cancer-related deaths.[24]
* It has bimodal age distribution i.e. occurs in children or in adults round the age of 40-50 years.[25]
* Prevalence of adrenocortical carcinoma is estimated to be between 4 and 12 per million in adults.[26]
* There is an increased prevalence of adrenocortical carcinoma in female patients with Cushing syndrome diagnosed during pregnancy as compared to the non-pregnant patients.
* Incidence of adrenocortical carcinoma is estimated to be between 0.72/1 to 2 per million cases per year in adults in North America and Europe.[27]
* Incidence is ten times lower except in South Brazil having a higher incidence of pediatric adrenocortical carcinoma (due to a specific germline p53 mutation).
* Increased risk of adrenal carcinoma in females than males has been reported.
* Pheochromocytoma is mostly found in middle-aged adults.

## Risk factors

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* Risk factors for adrenal carcinoma include:[28][29]
* Genetic mutations
* Family history of adrenal carcinoma
* Having some genetic diseases increases the chance of getting adrenal carcinoma upto 15% and include:[30][31][32][33][34]
* Multiple endocrine neoplasia (MEN1 and MEN2)
* Familial adenomatous polyposis (FAP)
* Beckwith-Wiedemann syndrome
* Li-Fraumeni syndrome
* Lynch syndrome or Hereditary nonpolyposis colorectal cancer (HNPCC)
* Von Hippel-Lindau disease
* Carney Complex/Syndrome
* Neurofibromatosis type 1
* Congenital adrenal hyperplasia
* Cigarette smoking
* Oral contraceptives use (especially before 25 years of age)
* Exposure to carcinogens

## Natural History, Complications and Prognosis

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* Adrenocortical carcinoma generally carries a poor prognosis and is unlike most tumors of the adrenal cortex, which are benign (adenomas) and only occasionally cause Cushing's syndrome.
* Five-year disease-free survival for a complete resection of a stage I-III adrenocortical carcinoma is approximately <30%.[35][36][37][38]
* Metastatic adrenocortical carcinoma has an overall survival of less than one year.[27]
* Local adrenal tumors of McFarlane stages 1 and 2 have a better outcome and prognosis.[26]
* Invasive and metastatic adrenal tumors of McFarlane stages 3 and 4 have a poor outcome and prognosis.
* Weiss criteria has a really good prognostic value for adrenocortical tumors.[39][9][35]
* Limitations to Weiss criteria include:
* Difficult to apply to individual cases
* Requires trained pathologists
* Score is not totally reliable (may differ from one area to another in the same tumor)
* Tumor size and histological grade are strong predictors of recurrence (tumors >5 cm in diameter and a Weiss score of ≥4).
* Other diagnostic markers for malignancy are required due to limitations of Weiss criteria, three of the tested molecular markers which are strong predictors of disease-free survival include:
* 17p13 LOH
* 11p15 LOH caused by parental isodisomy (overexpression of IGF-II gene which leads to proliferation of malignant adrenal H295R cells)
* Overexpression of IGF-II gene

## Diagnosis

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### History and Symptoms

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* Adrenocortical carcinoma may present differently in children and adults[40][41][42][43]

#### Symptoms in children

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* Most tumors in children are functional, and present with:
* Virilization (most common presenting symptom)
* Cushing's syndrome (glucocorticoid excess):
* Weight gain
* Muscle wasting
* Purple striae/lines on the abdomen
* Fatty "buffalo hump" on the neck
* "Moonlike" face
* Thinning of skin
* Fragile skin
* Precocious puberty[44]

{{#ev:youtube|https://www.youtube.com/watch?v=ea1sXgd5ui8&t=697s}}

#### Symptoms in adults

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* Adults present with hormonal syndromes such as:
* Cushing's syndrome (most common)
* Mixed Cushing's syndrome and virilization (glucocorticoid and androgen overproduction), with virilization presenting most obviously in women as:
* Excess facial and body hair (hirsutism)
* Acne
* Enlargement of clitoris
* Deepening of voice
* Coarsening of facial features
* Cessation of menstruation (amenorrhea)
* Feminization (i.e. estrogen excess, most readily seen in men) presents as:
* Breast enlargement (gynecomastia)
* Decreased libido
* Impotence
* Conn syndrome (mineralcorticoid excess, <10% cases) with low plasma renin activity, and high serum aldosterone presents with:[45]
* High blood pressure causing:
* Headache
* Hypokalemia causing:
* Muscle weakness
* Confusion
* Palpitations
* Pheochromocytoma-like hypersecretion of catecholamines (rarely) causing the following symptoms:
* High blood pressure
* Cardiac arrythmias
* Headache
* Palpitations
* Anxiety attacks
* Sweating
* Weight loss
* Tremor

#### Presentation of non-functional adrenal carcinoma

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* Non-functional tumors (40%) usually present with:
* Abdominal or flank or back pain
* Lump in abdomen
* Feeling of fullness (might keeps patient from eating much)
* Asymptomatic
* Detected incidentally

### Physical Examination

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* All patients with suspected adrenocortical carcinoma should be carefully examined for the signs and symptoms of following hormonal syndromes as mentioned above:
* Cushing's syndrome
* Virilization
* Conn syndrome
* Feminization

### Laboratory findings

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* Hormonal syndromes should be confirmed with laboratory testing

Laboratory findings of different hormonal syndromes in adrenal carcinoma  Hormonal syndrome | Laboratory findings

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Cushing syndrome |

* Increased serum glucose
* Increased urinary cortisol levels checked via:
* Twenty-four-hour urine test
* Low-dose dexamethasone suppression test
* High-dose dexamethasone suppression test

Virilization |

* Increased serum androstenedione
* Increased serum dehydroepiandrosterone

Conn syndrome |

* Low serum potassium (hypokalemia) checked via blood chemistry study
* Low plasma renin activity
* High serum aldosterone

Feminization |

* Increased serum estrogen

### Imaging studies

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* Following table shows the list of different imaging tests that are helpful in diagnosing adrenal carcinoma:

Imaging studies for the diagnosis of adrenal carcinoma  Imaging study | Details

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CT[46] |

* Abdominal CT scan is useful for:
* Identifying the tumor site
* Differentiating adrenocortical carcinoma from adrenocortical adenoma
* Local tumor recurrence
* Determining the extent of tumor invasion into the surrounding organs and tissues and distant metastasis
* Chest CT scan is routinely performed to look for metastases to the lungs and is critical in determining whether or not the tumor can be surgically removed (the only potential cure after metastasis)
* CT scan of adrenocortical carcinoma shows:
* Central tumor necrosis
* Calcifications
* Larger and more heterogeneous tumor
* CT scan of pheochromocytoma shows hypervascularity and marked enhancement after IV contrast administration

MRI |

* MRI like CT scan helps to determine tumor site, extent of tumor invasion, distant metastasis, its differentiation from other tumors, and local tumor recurrence
* Adrenocortical carcinoma appears as a large heterogeneous mass with low fat content on MRI
* CT scan of pheochromocytoma shows hypervascularity and marked enhancement after IV contrast administration

Bone scan |

* Bone scan is performed routinely to look for bone metastasis

PET scan[47][48][49][50][51][52] |

* 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG) PET scan is helpful in differentiating benign from malignant tumors/lesions as there's increased FDG uptake by malignant lesions comparative to benign lesions.
* FDG PET scan is especially very useful in defining the distribution of those pheochromocytomas that fail to concentrate MIBG.
* FDG PET scan is important in making the surgical decision as unnecessary removal of benign adrenal lesions can be avoided in case of the absence of FDG uptake without any prior history of poorly FDG-avid cancer.

123I-metaiodobenzylguanidine SPECT[50] |

* 123I-metaiodobenzylguanidine SPECT (MIBG scintigraphy) shows greater accumulation in well-differentiated tumors than in less-well-differentiated tumors in case of pheochromocytoma.

Molecular imaging[53] |

* 123Iodometomidate (IMTO) is a highly specific radiotracer for imaging of adrenocortical tissue as it provides the molecular imaging of cytochrome P450 family of adrenal 11B (Cyp11B) enzymes.

Adrenal angiography |

* In adrenal angiography, a contrast dye is injected and a series of X-ray images are taken afterwards to look for any block in adrenal arteries.

Adrenal venography |

* In adrenal venography, a contrast dye is injected and a series of X-ray images are taken afterwards to look for any block in adrenal veins and to check for any abnormal hormonal levels (by inserting a catheter in adrenal veins).

Ultrasound exam |

* After surgery, ultrasound is done to look for any recurrence or involvement of the surrounding organs.

### Biopsy

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* Two types of biopsies can be done for confirming the diagnosis of adrenal carcinoma:
* FNAC
* Core biopsy

### Adrenalectomy

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* After surgery, a part of the adrenal gland is removed and viewed under microscope to look for any local recurrence or any metastasis to the surrounding organs or distally.

## Treatment

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### Medical Therapy

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* Different treatment options for the medical therapy of adrenal carcinoma are given in the table below:[54]

Different types of medical therapies for treatment of adrenal carcinoma  Type of medical therapy | Details

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Radiation therapy | There are following two types of radiation therapies that can be used for the treatment of adrenal carcinoma:

* External beam radiation therapy:
* It uses a machine outside the body which sends radiations towards the cancer cells.
* Internal beam radiation therapy:
* It uses a radioactive substance which is sealed in needles, wires, seeds, or catheters and are placed directly into or near the cancer cells.

Radiofrequency ablation |

* A localized treatment which uses high-energy radio waves to heat & destroy the cancer cells.
* May be used for palliation in patients who are not surgical candidates.

Chemotherapy (chemoembolization)[55][56][57][58] |

* Chemotherapy regimens typically include the drug mitotane, an inhibitor of steroid synthesis which is toxic to the cells of adrenal cortex, as well as standard cytotoxic drugs.
* One widely used regimen consists of cisplatin, doxorubicin, etoposide and mitotane.
* The endocrine cell toxin streptozotocin has also been included in some treatment protocols.
* Chemotherapy may be given to the patients with unresectable disease, to shrink the tumor prior to surgery (neoadjuvant chemotherapy), or in an attempt to eliminate microscopic residual disease after surgery (adjuvant chemotherapy).

Hormonal therapy |

* Steroid synthesis inhibitors such as aminoglutethimide may be used in a palliative manner to reduce the symptoms of hormonal syndromes.

Biological therapy (immunotherapy)  |

* Biotherapy uses patient's own immune system to fight against the cancer.
* Substances made by the human body or made in the laboratory are used to boost, direct, or restore the body's natural defenses against cancer.

Targeted therapy |

* Uses drugs or other substances such as Steroidogenic factor (SF)-1 antagonist therapy in order to identify and attack specific cancer cells without providing any harm to the normal cells.

mTOR antagonists |

* Temsirolimus (second-generation mTOR inhibitor) in combination with cixutumumab (anti-IGF-1R antibody) can be used in treating adrenocortical carcinoma.

### Surgery

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* The only curative treatment is complete surgical excision of the tumor, which can be performed even in the case of invasion into large blood vessels, such as the renal vein or inferior vena cava.
* Goal of the surgery is R0 tumor resection and removal of any involved tissues or viscera in an en bloc fashion.
* Feasibility of the surgical resection in a newly diagnosed case of adrenocortical carcinoma is the most important contributor to the overall survival.
* Complete surgical resection of adrenocortical carcinoma is necessary, if possible for the patients presenting with stage I to stage III disease.
* Patients undergoing a successful resection have a five-year survival of 50%-60%, however, a large percentage of patients are not surgical candidates unfortunately
* Median survival of unresectable patients is less than one year
* 5-year disease-specific survival stratified according to the stage of the disease (ACC) at the time of diagnosis is given below:

5-year disease-specific survival rate stratification in relation to the disease stage at the time of ACC tumor resection  Stage of the disease at the time of tumor resection | 5-year disease-specific survival

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Stage I  | 82%
Stage II  | 58%
Stage III  | 55%
Stage IV  | 18%

* The 2004, International Union Against Cancer (UICC) and World Health Organization (WHO) proposed new staging system based on Sullivan-McFarlane criteria for adrenocortical carcinoma (ACC) is given in the table below and is used to make the surgical decision about the tumor resection:

Comparison of UICC and ENSAT staging systems for adrenocortical carcinoma  Stage | UICC/WHO 2004 | ENSAT 2008

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I  |

* T1, N0, M0

* T1, N0, M0

II  |

* T2, N0, M0

* T2, N0, M0

III  |

* T1-2, N1, M0
* T3, N0, M0

* T1-2, N1, M0
* T3-4, N0-1, M0

IV  |

* T1–4, N0-1, M1
* T3, N1, M0
* T4, N0-1, M0

* T1–4, N0-1, M1

T1: tumor 5 cm; T2: tumor 5 cm; T3: tumor infiltration in surrounding tissue; T4: tumor infiltration in adjacent organs [ENSAT additionally the presence of a tumor thrombus in the Vena Cava or Vena Renalis]; N0: absence of positive lymph nodes; N1: presence of positive lymph nodes; M0: absence of distant metastases; M1: presence of distant metastasis.

## Differentiating Adrenal carcinoma from other Diseases

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### Bilateral

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* ACTH-dependent Cushing's Syndrome
* Adrenal Hemorrhage
* Adrenal metastases
* Amyloidosis
* Congenital adrenal hyperplasia
* Conn syndrome
* Fungi
* Idiopathic bilateral adrenal hypertrophy
* Leukemia
* Lymphoma
* Micronodular Adrenal Disease
* Pheochromocytoma
* Tuberculosis

### Unilateral

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* Adrenal adenoma
* Adrenal metastases
* Adrenolipoma
* Ganglioneuroma
* Hematoma
* Myelolipoma
* Pheochromocytoma
* Primary aldosteronism

## References

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1. ↑ 1.0 1.1 Lam AK (2017). "Update on Adrenal Tumours in 2017 World Health Organization (WHO) of Endocrine Tumours". Endocr Pathol. 28 (3): 213–227. doi:10.1007/s12022-017-9484-5. PMID 28477311.
2. ↑ "Adrenocortical Carcinoma Treatment - National Cancer Institute".
3. ↑ "WHO Classification of Tumours of Endocrine Organs. Fourth Edition - WHO - OMS -".
4. ↑ "Update on Adrenal Tumours in 2017 World Health Organization (WHO) of Endocrine Tumours - Semantic Scholar".
5. ↑ 5.0 5.1 Pinto EM, Chen X, Easton J, Finkelstein D, Liu Z, Pounds S; et al. (2015). "Genomic landscape of paediatric adrenocortical tumours". Nat Commun. 6: 6302. doi:10.1038/ncomms7302. PMC 4352712. PMID 25743702.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
6. ↑ Zheng S, Cherniack AD, Dewal N, Moffitt RA, Danilova L, Murray BA; et al. (2016). "Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma". Cancer Cell. 30 (2): 363. doi:10.1016/j.ccell.2016.07.013. PMID 27505681.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
7. ↑ Zheng S, Cherniack AD, Dewal N, Moffitt RA, Danilova L, Murray BA; et al. (2016). "Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma". Cancer Cell. 29 (5): 723–736. doi:10.1016/j.ccell.2016.04.002. PMC 4864952. PMID 27165744.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
8. ↑ Assié G, Letouzé E, Fassnacht M, Jouinot A, Luscap W, Barreau O; et al. (2014). "Integrated genomic characterization of adrenocortical carcinoma". Nat Genet. 46 (6): 607–12. doi:10.1038/ng.2953. PMID 24747642.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
9. ↑ 9.0 9.1 Weiss LM (1984). "Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors". Am J Surg Pathol. 8 (3): 163–9. PMID 6703192.
10. ↑ "Mechanism of abnormal production of adrenal androgens in patients with adrenocortical adenomas and carcinomas | The Journal of Clinical Endocrinology & Metabolism | Oxford Academic".
11. ↑ "Variable Expression of the Transcription Factors cAMP Response Element-Binding Protein and Inducible cAMP Early Repressor in the Normal Adrenal Cortex and in Adrenocortical Adenomas and Carcinomas | The Journal of Clinical Endocrinology & Metabolism | Oxford Academic".
12. ↑ Fassnacht M, Libé R, Kroiss M, Allolio B (2011). "Adrenocortical carcinoma: a clinician's update". Nat Rev Endocrinol. 7 (6): 323–35. doi:10.1038/nrendo.2010.235. PMID 21386792.CS1 maint: Multiple names: authors list (link)
13. ↑ Menon V, Krishnamurthy SV (2006). "Adrenocortical carcinomas: a 12-year clinicopathologic study of 15 cases". Indian J Pathol Microbiol. 49 (1): 7–11. PMID 16625963.
14. ↑ Libè R, Groussin L, Tissier F, Elie C, René-Corail F, Fratticci A; et al. (2007). "Somatic TP53 mutations are relatively rare among adrenocortical cancers with the frequent 17p13 loss of heterozygosity". Clin Cancer Res. 13 (3): 844–50. doi:10.1158/1078-0432.CCR-06-2085. PMID 17289876.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
15. ↑ McCabe MJ, Pinese M, Chan CL, Sheriff N, Thompson TJ, Grady J; et al. (2019). "Genomic stratification and liquid biopsy in a rare adrenocortical carcinoma (ACC) case, with dual lung metastases". Cold Spring Harb Mol Case Stud. 5 (2). doi:10.1101/mcs.a003764. PMC 6549567 Check `|pmc=` value (help). PMID 30936196.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
16. ↑ Magro G, Esposito G, Cecchetto G, Dall'Igna P, Marcato R, Gambini C; et al. (2012). "Pediatric adrenocortical tumors: morphological diagnostic criteria and immunohistochemical expression of matrix metalloproteinase type 2 and human leucocyte-associated antigen (HLA) class II antigens. Results from the Italian Pediatric Rare Tumor (TREP) Study project". Hum Pathol. 43 (1): 31–9. doi:10.1016/j.humpath.2011.04.016. PMID 21820153.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
17. ↑ Tischler AS, Kimura N, Mcnicol AM (2006). "Pathology of pheochromocytoma and extra-adrenal paraganglioma". Ann N Y Acad Sci. 1073: 557–70. doi:10.1196/annals.1353.059. PMID 17102124.CS1 maint: Multiple names: authors list (link)
18. ↑ Ragazzon B, Libé R, Gaujoux S, Assié G, Fratticci A, Launay P; et al. (2010). "Transcriptome analysis reveals that p53 and {beta}-catenin alterations occur in a group of aggressive adrenocortical cancers". Cancer Res. 70 (21): 8276–81. doi:10.1158/0008-5472.CAN-10-2014. PMID 20959480.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
19. ↑ Ragazzon B, Libé R, Assié G, Tissier F, Barreau O, Houdayer C; et al. (2014). "Mass-array screening of frequent mutations in cancers reveals RB1 alterations in aggressive adrenocortical carcinomas". Eur J Endocrinol. 170 (3): 385–91. doi:10.1530/EJE-13-0778. PMID 24347427.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
20. ↑ Tissier F (2008). "[Sporadic adrenocortical tumors: genetics and perspectives for the pathologist]". Ann Pathol. 28 (5): 409–16. doi:10.1016/j.annpat.2008.07.005. PMID 19068395.
21. ↑ Gicquel C, Bertagna X, Gaston V, Coste J, Louvel A, Baudin E; et al. (2001). "Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors". Cancer Res. 61 (18): 6762–7. PMID 11559548.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
22. ↑ Das S, Sengupta M, Islam N, Roy P, Datta C, Mishra PK; et al. (2016). "Weineke criteria, Ki-67 index and p53 status to study pediatric adrenocortical tumors: Is there a correlation?". J Pediatr Surg. 51 (11): 1795–1800. doi:10.1016/j.jpedsurg.2016.07.014. PMID 27567308.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
23. ↑ Chatterjee G, DasGupta S, Mukherjee G, Sengupta M, Roy P, Arun I; et al. (2015). "Usefulness of Wieneke criteria in assessing morphologic characteristics of adrenocortical tumors in children". Pediatr Surg Int. 31 (6): 563–71. doi:10.1007/s00383-015-3708-x. PMID 25895073.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
24. ↑ "Adrenal Carcinoma: Practice Essentials, Background, Pathophysiology".
25. ↑ "Adrenal Cancer Causes and Symptoms".
26. ↑ 26.0 26.1 Libè R, Fratticci A, Bertherat J (2007). "Adrenocortical cancer: pathophysiology and clinical management". Endocr Relat Cancer. 14 (1): 13–28. doi:10.1677/erc.1.01130. PMID 17395972.CS1 maint: Multiple names: authors list (link)
27. ↑ 27.0 27.1 Cabezon-Gutierrez L, Franco-Moreno AI, Khosravi-Shahi P, Custodio-Cabello S, Garcia-Navarro MJ, Martin-Diaz RM (2015). "Clinical Case of Metastatic Adrenocortical Carcinoma With Unusual Evolution: Review the Literature". World J Oncol. 6 (6): 485–490. doi:10.14740/wjon936w. PMC 5624676. PMID 28983351.CS1 maint: Multiple names: authors list (link)
28. ↑ Hsing AW, Nam JM, Co Chien HT, McLaughlin JK, Fraumeni JF (1996). "Risk factors for adrenal cancer: an exploratory study". Int J Cancer. 65 (4): 432–6. doi:10.1002/(SICI)1097-0215(19960208)65:4<432::AID-IJC6>3.0.CO;2-Y. PMID 8621222.CS1 maint: Multiple names: authors list (link)
29. ↑ "Adrenal Gland Cancer (Adrenocortical Carcinoma) | Cleveland Clinic: Health Library".
30. ↑ "Top Adrenal Cancer Causes & Factors That Put You at Risk | CTCA".
31. ↑ "Adrenal Cancer Risk Factors".
32. ↑ "Adrenal Cancer Risk Factors | Roswell Park Comprehensive Cancer Center".
33. ↑ "Adrenal Cancer: Causes, Symptoms, and Diagnosis".
34. ↑ "Adrenal cancer - Symptoms and causes - Mayo Clinic".
35. ↑ 35.0 35.1 Weiss LM, Medeiros LJ, Vickery AL (1989). "Pathologic features of prognostic significance in adrenocortical carcinoma". Am J Surg Pathol. 13 (3): 202–6. PMID 2919718.CS1 maint: Multiple names: authors list (link)
36. ↑ Moreno S, Montoya G, Armstrong J, Leteurtre E, Aubert S, Vantyghem MC; et al. (2004). "Profile and outcome of pure androgen-secreting adrenal tumors in women: experience of 21 cases". Surgery. 136 (6): 1192–8. doi:10.1016/j.surg.2004.06.046. PMID 15657575.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
37. ↑ Wagner M, Walter PR, Ghnassia JP, Gasser B (1993). "[Adrenocortical tumors. I. Prognostic evaluation of a series of 17 cases using the Weiss criteria]". Ann Pathol. 13 (5): 306–11. PMID 8311856.CS1 maint: Multiple names: authors list (link)
38. ↑ Gandour MJ, Grizzle WE (1986). "A small adrenocortical carcinoma with aggressive behavior. An evaluation of criteria for malignancy". Arch Pathol Lab Med. 110 (11): 1076–9. PMID 3778125.
39. ↑ Jain M, Kapoor S, Mishra A, Gupta S, Agarwal A (2010). "Weiss criteria in large adrenocortical tumors: a validation study". Indian J Pathol Microbiol. 53 (2): 222–6. doi:10.4103/0377-4929.64325. PMID 20551521.CS1 maint: Multiple names: authors list (link)
40. ↑ "Hypoaldosteronism accompanied by normal or elevated mineralocorticosteroid pathway steroid: a marker of adrenal carcinoma. | The Journal of Clinical Endocrinology & Metabolism | Oxford Academic".
41. ↑ "ADRENAL CORTICAL CARCINOMA IN A MALE WITH EXCESS GONADOTROPIN IN THE URINE | The Journal of Clinical Endocrinology & Metabolism | Oxford Academic".
42. ↑ "UpToDate".
43. ↑ Allolio B, Fassnacht M (2006). "Clinical review: Adrenocortical carcinoma: clinical update". J Clin Endocrinol Metab. 91 (6): 2027–37. doi:10.1210/jc.2005-2639. PMID 16551738.
44. ↑ Sandrini R, Ribeiro RC, DeLacerda L (1997). "Childhood adrenocortical tumors". J Clin Endocrinol Metab. 82 (7): 2027–31. doi:10.1210/jcem.82.7.4057. PMID 9215267.CS1 maint: Multiple names: authors list (link)
45. ↑ Moreno S, Guillermo M, Decoulx M, Dewailly D, Bresson R, Proye Ch (2006). "Feminizing adreno-cortical carcinomas in male adults. A dire prognosis. Three cases in a series of 801 adrenalectomies and review of the literature". Ann Endocrinol (Paris). 67 (1): 32–8. PMID 16596055.CS1 maint: Multiple names: authors list (link)
46. ↑ Szolar DH, Korobkin M, Reittner P, Berghold A, Bauernhofer T, Trummer H; et al. (2005). "Adrenocortical carcinomas and adrenal pheochromocytomas: mass and enhancement loss evaluation at delayed contrast-enhanced CT". Radiology. 234 (2): 479–85. doi:10.1148/radiol.2342031876. PMID 15671003.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
47. ↑ Groussin L, Bonardel G, Silvéra S, Tissier F, Coste J, Abiven G; et al. (2009). "18F-Fluorodeoxyglucose positron emission tomography for the diagnosis of adrenocortical tumors: a prospective study in 77 operated patients". J Clin Endocrinol Metab. 94 (5): 1713–22. doi:10.1210/jc.2008-2302. PMID 19190108.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
48. ↑ Khan TS, Sundin A, Juhlin C, Långström B, Bergström M, Eriksson B (2003). "11C-metomidate PET imaging of adrenocortical cancer". Eur J Nucl Med Mol Imaging. 30 (3): 403–10. doi:10.1007/s00259-002-1025-9. PMID 12634969.CS1 maint: Multiple names: authors list (link)
49. ↑ Dong, Aisheng; Cui, Yong; Wang, Yang; Zuo, Changjing; Bai, Yushu (2014). "18F-FDG PET/CT of Adrenal Lesions". American Journal of Roentgenology. 203 (2): 245–252. doi:10.2214/AJR.13.11793. ISSN 0361-803X.
50. ↑ 50.0 50.1 Shulkin BL, Thompson NW, Shapiro B, Francis IR, Sisson JC (1999). "Pheochromocytomas: imaging with 2-[fluorine-18]fluoro-2-deoxy-D-glucose PET". Radiology. 212 (1): 35–41. doi:10.1148/radiology.212.1.r99jl3035. PMID 10405717.CS1 maint: Multiple names: authors list (link)
51. ↑ Ansquer C, Scigliano S, Mirallié E, Taïeb D, Brunaud L, Sebag F; et al. (2010). "18F-FDG PET/CT in the characterization and surgical decision concerning adrenal masses: a prospective multicentre evaluation". Eur J Nucl Med Mol Imaging. 37 (9): 1669–78. doi:10.1007/s00259-010-1471-8. PMID 20490488.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
52. ↑ Blake MA, Slattery JM, Kalra MK, Halpern EF, Fischman AJ, Mueller PR; et al. (2006). "Adrenal lesions: characterization with fused PET/CT image in patients with proved or suspected malignancy--initial experience". Radiology. 238 (3): 970–7. doi:10.1148/radiol.2383042164. PMID 16505394.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
53. ↑ Hahner S, Stuermer A, Kreissl M, Reiners C, Fassnacht M, Haenscheid H; et al. (2008). "[123 I]Iodometomidate for molecular imaging of adrenocortical cytochrome P450 family 11B enzymes". J Clin Endocrinol Metab. 93 (6): 2358–65. doi:10.1210/jc.2008-0050. PMID 18397978.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
54. ↑ "Adrenocortical Carcinoma Treatment (PDQ®)–Patient Version - National Cancer Institute".
55. ↑ Kwok GTY, Zhao JT, Glover AR, Gill AJ, Clifton-Bligh R, Robinson BG; et al. (2019). "microRNA-431 as a Chemosensitizer and Potentiator of Drug Activity in Adrenocortical Carcinoma". Oncologist. 24 (6): e241–e250. doi:10.1634/theoncologist.2018-0849. PMC 6656493 Check `|pmc=` value (help). PMID 30918109.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
56. ↑ Abraham J, Bakke S, Rutt A, Meadows B, Merino M, Alexander R; et al. (2002). "A phase II trial of combination chemotherapy and surgical resection for the treatment of metastatic adrenocortical carcinoma: continuous infusion doxorubicin, vincristine, and etoposide with daily mitotane as a P-glycoprotein antagonist". Cancer. 94 (9): 2333–43. doi:10.1002/cncr.10487. PMID 12015757.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
57. ↑ Berruti A, Terzolo M, Pia A, Angeli A, Dogliotti L (1998). "Mitotane associated with etoposide, doxorubicin, and cisplatin in the treatment of advanced adrenocortical carcinoma. Italian Group for the Study of Adrenal Cancer". Cancer. 83 (10): 2194–200. PMID 9827725.CS1 maint: Multiple names: authors list (link)
58. ↑ Williamson SK, Lew D, Miller GJ, Balcerzak SP, Baker LH, Crawford ED (2000). "Phase II evaluation of cisplatin and etoposide followed by mitotane at disease progression in patients with locally advanced or metastatic adrenocortical carcinoma: a Southwest Oncology Group Study". Cancer. 88 (5): 1159–65. PMID 10699907.CS1 maint: Multiple names: authors list (link)

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Endocrine pathology: endocrine diseases (E00-35, 240-259)

Thyroid|

Hypothyroidism (Iodine deficiency, Cretinism, Congenital hypothyroidism, Goitre, Myxedema) - Hyperthyroidism (Graves disease, Toxic multinodular goitre, Teratoma with thyroid tissue or Struma ovarii) - Thyroiditis (De Quervain's thyroiditis, Hashimoto's thyroiditis, Riedel's thyroiditis) - Euthyroid sick syndrome

Pancreas|

Diabetes mellitus (type 1, type 2, coma, angiopathy, ketoacidosis, nephropathy, neuropathy, retinopathy) - Hypoglycemia \- Hyperinsulinism \- Zollinger-Ellison syndrome \- insulin receptor (Rabson-Mendenhall syndrome)

Parathyroid|

Hypoparathyroidism (Pseudohypoparathyroidism) - Hyperparathyroidism (Primary, Secondary, Tertiary)

Pituitary|

Hyperpituitarism (Acromegaly, Hyperprolactinaemia, SIADH) - Hypopituitarism (Simmonds' disease / Sheehan's syndrome, Kallmann syndrome, Growth hormone deficiency, Diabetes insipidus) - Adiposogenital dystrophy \- Empty sella syndrome \- Hypophysitis

Adrenal|

Cushing's syndrome (Nelson's syndrome, Pseudo-Cushing's syndrome) - CAH (Lipoid, 3β, 11β, 17α, 21α) - Hyperaldosteronism (Conn syndrome, Bartter syndrome) - Adrenal insufficiency (Addison's disease) - Hypoaldosteronism

Gonads|

Ovarian dysfunction (Polycystic ovary syndrome, Premature ovarian failure) - Testicular dysfunction (5-alpha-reductase deficiency) - Testosterone biosynthesis (17-beta-hydroxysteroid dehydrogenase deficiency) - General (Hypogonadism, Delayed puberty, Precocious puberty)

Other|

Androgen insensitivity syndrome \- Autoimmune polyendocrine syndrome \- Carcinoid syndrome \- Gigantism \- Short stature (Laron syndrome, Psychogenic dwarfism) - Multiple endocrine neoplasia (1, 2) - Progeria \- Woodhouse-Sakati syndrome

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