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]

Overview

Adrenocortical carcinoma, also adrenal cortical carcinoma (ACC) and adrenal cortex cancer, is an aggressive cancer originating in the cortex (steroid hormone-producing tissue) of the adrenal gland. Adenocortical 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.

Historical perspective

• In 2017, WHO presented an update on recent classification of adrenal tumors (in fourth edition of the World Health Organization classification of endocrine tumors)

Classification

• Adrenal cancer is subclassified according to its activity into:
  • 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:

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

Normal anatomy and physiology of adrenal glands

• 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}}

Epigenetics

• Adrenal tumors are usually not biopsied prior to surgery, hence, the diagnosis is confirmed on examination of the surgical specimen by a pathologist.
• Following genes are involved in the development of adrenal tumors:
  • IGF2 gene (increased expression at 11p15 locus-adrenocortical carcinoma)
  • 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

Gross pathology

Adrenocortical carcinoma

• 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

• 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

• 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

• Different pathological criterias for adrenocortical carcinoma are given in the table below:

Pathologic criteria	Details	Age applicability
Weiss criteria	Adrenocortical carcinoma can be diagnosed by the presence of at least 3 of the 9 Weiss criteria: High nuclear grade (III or IV) 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) Atypical mitoses (abnormal distribution of chromosomes or excessive number of mitotic spindles) Cleared or vacuolated cytoplasm in >/= 25% of the tumor cells Sheeting (diffuse architecture of patternless sheets of cells)) in >= 1/3 of tumor cells Necrosis in nests (microscopic necrosis) 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) Adrenal sinusoid invasion (sinusoid is endothelial lined vessel in adrenal gland with little supportive tissue; consider only sinusoids within tumor) 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): 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: Abundant mitoses >5/50 high-power fields - definition suffers from HPFitis Necrosis 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

• Adrenal carcinoma is a relatively rare tumor.
• It accounts for only 0.02-0.2% of all the cancer-related deaths.
• It has bimodal age distribution i.e. occurs in children or in adults round the age of 40-50 years.
• Prevalence of adrenocortical carcinoma is estimated to be between 4 and 12 per million in adults.
• 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.
• 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

• Risk factors for adrenal carcinoma include:
  • Genetic mutations
  • Family history of adrenal carcinoma
  • Having some genetic diseases increases the chance of getting adrenal carcinoma upto 15% and include:
    • 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

• 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%.
• Metastatic adrenocortical carcinoma has an overall survival of less than one year.
• Local adrenal tumors of McFarlane stages 1 and 2 have a better outcome and prognosis.
• 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.
• 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

History and Symptoms

• Adrenocortical carcinoma may present differently in children and adults

Symptoms in children

• 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

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Symptoms in adults

• 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:
    • High blood pressure causing:
      • Headache
    • Hypokalemia causing:
      • Muscle weakness
      • Confusion
      • Palpitations
• Pheochromocytoma-like hypersecretion of catecholamines (rarely)

Presentation of non-functional adrenal carcinoma

• 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

• 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

• Hormonal syndromes should be confirmed with laboratory testing

Laboratory findings of different hormonal syndromes in adrenal carcinoma

Hormonal syndrome	Laboratory findings
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

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

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

Adrenalectomy

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

Treatment

Medical Therapy

• Different treatment options for the medical therapy of adrenal carcinoma are given in the table below:

Different types of medical therapies for treatment of adrenal carcinoma

Type of medical therapy	Details
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 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.
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)	Chemotherapy regimens typically include the drug mitotane, an inhibitor of steroid synthesis which is toxic to cells of the 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 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 in order to identify and attack specific cancer cells without providing any harm to the normal cells.

Surgery

• The only curative treatment is complete surgical excision of the tumor, which can be performed even in the case of invasion into large blood vessells, such as the renal vein or inferior vena cava
• The 5-year survival rate after successful surgery is 50-60%, but unfortunately, a large percentage of patients are not surgical candidates
• surgical (McFarlane) criteria
  

Differentiating Adrenal carcinoma from other Diseases

Bilateral

• 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

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

References

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