Adrenocortical carcinoma (ACC) is an aggressive

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

originating in the

cortex Cortex or cortical may refer to: Biology * Cortex (anatomy), the outermost layer of an organ ** Cerebral cortex, the outer layer of the vertebrate cerebrum, part of which is the ''forebrain'' *** Motor cortex, the regions of the cerebral cortex i ...

(

steroid hormone A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into two classes: corticosteroids (typically made in the adrenal cortex, hence ''cortico-'') and sex steroids (typically made in the gonads or placenta). Wi ...

-producing tissue) of the

adrenal gland The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex which ...

. Adrenocortical carcinoma is remarkable for the many hormonal syndromes that can occur in patients with steroid hormone-producing ("functional") tumors, including

Cushing's syndrome Cushing's syndrome is a collection of signs and symptoms due to prolonged exposure to glucocorticoids such as cortisol. Signs and symptoms may include high blood pressure, abdominal obesity but with thin arms and legs, reddish stretch marks, a ...

, Conn syndrome,

virilization Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens. Virilization is most commonly used in three medical and biology ...

, and

feminization Feminization most commonly refers to: * Feminization (biology), the hormonally induced development of female sexual characteristics * Feminization (activity), a sexual or lifestyle practice where a person assumes a female role * Feminization (soci ...

. Adrenocortical carcinoma has often invaded nearby tissues or

metastasized Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

to distant organs at the time of diagnosis, and the overall 5-year survival rate is about 50%. Adrenocortical carcinoma is a rare tumor, with incidence of one to two per million population annually. It has a bimodal distribution by age, with cases clustering in children under 5 and in adults 30–40 years old. The widely used angiotensin-II-responsive

steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...

-producing

cell line An immortalised cell line is a population of cells from a multicellular organism which would normally not proliferate indefinitely but, due to mutation, have evaded normal cellular senescence and instead can keep undergoing division. The cell ...

H295R was originally isolated from a tumor diagnosed as adrenocortical carcinoma.

Signs and symptoms

Adrenocortical carcinoma may present differently in children and adults. Most tumors in children are functional, and

is by far the most common presenting symptom(s), followed by

and

precocious puberty In medicine, precocious puberty is puberty occurring at an unusually early age. In most cases, the process is normal in every aspect except the unusually early age and simply represents a variation of normal development. In a minority of childr ...

. Among adults presenting with hormonal syndromes, Cushing's syndrome alone is most common, followed by mixed Cushing's and virilization (

glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...

and

androgen An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This inc ...

overproduction).

Feminization Feminization most commonly refers to: * Feminization (biology), the hormonally induced development of female sexual characteristics * Feminization (activity), a sexual or lifestyle practice where a person assumes a female role * Feminization (soci ...

and Conn syndrome (

mineralocorticoid Mineralocorticoids are a class of corticosteroids, which in turn are a class of steroid hormones. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances (electrolyte balance and fluid balance). The primary mi ...

excess) occur in less than 10% of cases. Rarely,

pheochromocytoma Pheochromocytoma (PHEO or PCC) is a rare tumor of the adrenal medulla composed of chromaffin cells, also known as pheochromocytes. When a tumor composed of the same cells as a pheochromocytoma develops outside the adrenal gland, it is referred t ...

-like hypersecretion of

catecholamine A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Catechol can be either a free molecule or a subst ...

s has been reported in adrenocortical cancers. Nonfunctional tumors (about 40%, authorities vary) usually present with abdominal or flank pain, varicocele, and renal vein thrombosis or they may be asymptomatic and detected incidentally. All patients with suspected ACC should be carefully evaluated for signs and symptoms of hormonal syndromes. For Cushing's syndrome (glucocorticoid excess), these include

weight gain Weight gain is an increase in body weight. This can involve an increase in muscle mass, fat deposits, excess fluids such as water or other factors. Weight gain can be a symptom of a serious medical condition. Description Weight gain occurs wh ...

muscle wasting Muscle atrophy is the loss of skeletal muscle mass. It can be caused by immobility, aging, malnutrition, medications, or a wide range of injuries or diseases that impact the musculoskeletal or nervous system. Muscle atrophy leads to muscle weakness ...

, purple lines on the abdomen, a fatty "

buffalo hump Buffalo Hump (Comanche language, Comanche ''Potsʉnakwahipʉ'' "Buffalo Bull's Back") (born c. 1800 — died post 1861 / ante 1867) was a War Chief of the Penateka band of the Comanche Indians. He came to prominence after the Council House Figh ...

" on the neck, a "moon-like" face, and thinning, fragile skin. Virilism (androgen excess) is most obvious in women, and may produce excess facial and body hair,

acne Acne, also known as ''acne vulgaris'', is a long-term Cutaneous condition, skin condition that occurs when Keratinocyte, dead skin cells and Sebum, oil from the skin clog hair follicles. Typical features of the condition include comedo, black ...

, enlargement of the

clitoris The clitoris ( or ) is a female sex organ present in mammals, ostriches and a limited number of other animals. In humans, the visible portion – the glans – is at the front junction of the labia minora (inner lips), above the ope ...

, deepening of the voice, coarsening of facial features, cessation of menstruation. Conn syndrome (mineralcorticoid excess) is marked by

high blood pressure Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

, which can result in

headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a result ...

and

hypokalemia Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an abno ...

(low serum potassium, which can in turn produce muscle weakness, confusion, and

palpitations Palpitations are perceived abnormalities of the heartbeat characterized by awareness of cardiac muscle contractions in the chest, which is further characterized by the hard, fast and/or irregular beatings of the heart. Symptoms include a rapi ...

), low plasma

renin Renin (etymology and pronunciation), also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body's renin–angiotensin–aldosterone system (RAAS)—also known as the r ...

activity, and high serum

aldosterone Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a c ...

. Feminization (

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...

excess) is most readily noted in men, and includes

breast enlargement Breast enlargement is the enlargement of the breasts. It may occur naturally as in mammoplasia or may occur artificially through active intervention. Many women regard their breasts, which are female secondary sex characteristics, as important to t ...

, decreased

libido Libido (; colloquial: sex drive) is a person's overall sexual drive or desire for sexual activity. Libido is influenced by biological, psychological, and social factors. Biologically, the sex hormones and associated neurotransmitters that act up ...

, and

impotence Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men.Cunningham GR, Rosen RC. Overview of male ...

Pathophysiology

The main etiologic factor of ACC is unknown, although families with

Li–Fraumeni syndrome Li–Fraumeni syndrome is a rare, autosomal dominant, hereditary disorder that predisposes carriers to cancer development. It was named after two American physicians, Frederick Pei Li and Joseph F. Fraumeni, Jr., who first recognized the syndrom ...

, caused by an inherited inactivation mutation in ''

TP53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often ...

'', have increased risk. Several genes have been shown to be recurrently mutated, including ''TP53'', ''

CTNNB1 Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcripti ...

'', ''

MEN1 Menin is a protein that in humans is encoded by the ''MEN1'' gene. Menin is a putative tumor suppressor associated with multiple endocrine neoplasia type 1 (MEN-1 syndrome). ''In vitro'' studies have shown that menin is localized to the nucleus, ...

'', ''

PRKAR1A cAMP-dependent protein kinase type I-alpha regulatory subunit is an enzyme that in humans is encoded by the ''PRKAR1A'' gene. Function cAMP is a signaling molecule important for a variety of cellular functions. cAMP exerts its effects by acti ...

'', '' RPL22'', and ''

DAXX Death-associated protein 6 also known as Daxx is a protein that in humans is encoded by the ''DAXX'' gene. Function Daxx, a Death domain-associated protein, was first discovered through its cytoplasmic interaction with the classical death r ...

''. The

telomerase Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. A telomere is a region of repetitive sequences at each end of the chromosomes of most euka ...

gene ''

TERT Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a catalytic subunit of the enzyme telomerase, which, together with the telomerase RNA component (TERC), comprises the most important unit of the telomerase complex. T ...

'' is often amplified while '' ZNRF3'' and ''

CDKN2A CDKN2A, also known as cyclin-dependent kinase inhibitor 2A, is a gene which in humans is located at chromosome 9, band p21.3. It is ubiquitously expressed in many tissues and cell types. The gene codes for two proteins, including the INK4 family ...

'' are often homozygously deleted. The genes ''h19'', insulin-like growth factor II ( ''IGF-II''), and ''p57^kip2'' are important for fetal growth and development. They are located on chromosome 11p. Expression of the ''h19'' gene is markedly reduced in both nonfunctioning and functioning adrenal cortical carcinomas, especially in tumors producing

cortisol Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone. It is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal cortex in the adrenal gland ...

and

. Also, a loss occurs of activity of the ''p57kip2'' gene product in virilizing adenomas and adrenal cortical carcinomas. In contrast, ''IGF-II ''gene expression has been shown to be high in adrenal cortical carcinomas. Finally,'' c-myc ''gene expression is relatively high in neoplasms, and it is often linked to poor prognosis. Bilateral adrenocortical tumors are less common than unilateral. The majority of bilateral tumours can be distinguished according to size and aspect of the nodules: primary pigmented nodular adrenocortical disease, which can be sporadic or part of

Carney complex Carney complex and its subsets LAMB syndrome and NAME syndrome are autosomal dominant conditions comprising myxomas of the heart and skin, hyperpigmentation of the skin (lentiginosis), and endocrine overactivity. It is distinct from Carney's tr ...

, and primary bilateral macro nodular adrenal hyperplasia.

Metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

is most commonly to the

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

and

lung The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...

Diagnosis

Laboratory findings

Hormonal syndromes should be confirmed with laboratory testing. Laboratory findings in Cushing syndrome include increased serum glucose (blood sugar) and increased urine

. Adrenal virilism is confirmed by the finding of an excess of serum

androstenedione Androstenedione, or 4-androstenedione (abbreviated as A4 or Δ4-dione), also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroepia ...

and

dehydroepiandrosterone Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating steroids in humans. DHEA is produced in the adrenal glands, the gonads, and the brain. It functio ...

. Findings in Conn syndrome include low serum potassium, low plasma renin activity, and high serum aldosterone. Feminization is confirmed with the finding of excess serum estrogen.

Imaging

Radiological studies of the

abdomen The abdomen (colloquially called the belly, tummy, midriff, tucky or stomach) is the part of the body between the thorax (chest) and pelvis, in humans and in other vertebrates. The abdomen is the front part of the abdominal segment of the torso. ...

, such as CT scans and

magnetic resonance imaging Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio wave ...

are useful for identifying the site of the tumor, differentiating it from other diseases, such as

adrenocortical adenoma Adrenocortical adenoma is commonly described as a benign neoplasm emerging from the cells that comprise the adrenal cortex. Like most adenomas, the adrenocortical adenoma is considered a benign tumor since the majority of them are non-functioning ...

, and determining the extent of invasion of the tumor into surrounding organs and tissues. On CT, it shows heterogeneous appearance due to necrosis, calcifications, and haemorrhage. After contrast injection, it shows peripheral enhancement. Invasion of adjacent structures such as kidney, vena cava, liver, and retroperitoneal lymph nodes are also common. On MRI, it shows low intensity on T1-weighted images, and high T2 signal with strong heterogeneous contrast enhancement and slow washout. Haemorrhagic areas may show high T1-signal.

Pathology

Adrenal tumors are often not biopsied prior to surgery, so diagnosis is confirmed on examination of the surgical specimen by a

pathologist Pathology is the study of the causal, causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when us ...

. Grossly, ACCs are often large, with a tan-yellow cut surface, and areas of

hemorrhage Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vag ...

and

necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...

. On microscopic examination, the tumor usually displays sheets of atypical cells with some resemblance to the cells of the normal

adrenal cortex The adrenal cortex is the outer region and also the largest part of an adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. It is ...

. The presence of

invasion An invasion is a military offensive in which large numbers of combatants of one geopolitical entity aggressively enter territory owned by another such entity, generally with the objective of either: conquering; liberating or re-establishing con ...

and mitotic activity help differentiate small cancers from

s. Several relatively rare variants of ACC include: * Oncocytic adrenal cortical carcinoma * Myxoid adrenal cortical carcinoma * Carcinosarcoma * Adenosquamous adrenocortical carcinoma * Clear cell adrenal cortical carcinoma

Differential diagnosis

Incidences and prognoses of adrenal tumors

Differential diagnosis includes: *

Adrenocortical adenoma Adrenocortical adenoma is commonly described as a benign neoplasm emerging from the cells that comprise the adrenal cortex. Like most adenomas, the adrenocortical adenoma is considered a benign tumor since the majority of them are non-functioning ...

Renal cell carcinoma Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cancer in adults, resp ...

Pheochromocytoma Pheochromocytoma (PHEO or PCC) is a rare tumor of the adrenal medulla composed of chromaffin cells, also known as pheochromocytes. When a tumor composed of the same cells as a pheochromocytoma develops outside the adrenal gland, it is referred t ...

Hepatocellular carcinoma Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide. It occurs in t ...

Adrenocortical carcinomas are most commonly distinguished from

s (their benign counterparts) by the Weiss system, as follows: Total score indicates: * 0-2: Adrenocortical adenoma * 3: Undetermined * 4-9: Adrenocortical carcinoma

Treatment

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 The renal veins are large-calibre veins that drain blood filtered by the kidneys into the inferior vena cava. There is one renal vein draining each kidney. Because the inferior vena cava is on the right half of the body, the left renal vein is lo ...

inferior vena cava The inferior vena cava is a large vein that carries the deoxygenated blood from the lower and middle body into the right atrium of the heart. It is formed by the joining of the right and the left common iliac veins, usually at the level of the ...

. The 5-year survival rate after successful surgery is 50–60%, but unfortunately, many patients are not surgical candidates.

Radiation therapy Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Radia ...

and

radiofrequency ablation Radiofrequency ablation (RFA), also called fulguration, is a medical procedure in which part of the electrical conduction system of the heart, tumor or other dysfunctional tissue is ablated using the heat generated from medium frequency alternat ...

may be used for

palliation Palliative care (derived from the Latin root , or 'to cloak') is an interdisciplinary medical caregiving approach aimed at optimizing quality of life and mitigating suffering among people with serious, complex, and often terminal illnesses. Wit ...

in patients who are not surgical candidates. Minimally invasive surgical techniques remain controversial due to the absence of long-term data, with a particular concern for rates of recurrence and peritoneal carcinomatosis.

Chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...

regimens typically include the drug

mitotane Mitotane, sold under the brand name Lysodren, is a steroidogenesis inhibitor and cytostatic antineoplastic medication which is used in the treatment of adrenocortical carcinoma and Cushing's syndrome. It is a derivative of the early insecticid ...

, an inhibitor of steroid synthesis, which is toxic to cells of the

, as well as standard cytotoxic drugs. A retrospective analysis showed a survival benefit for mitotane in addition to surgery when compared to surgery alone. The two most common regimens are

cisplatin Cisplatin is a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, br ...

doxorubicin Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used togeth ...

etoposide Etoposide, sold under the brand name Vepesid among others, is a chemotherapy medication used for the treatments of a number of types of cancer including testicular cancer, lung cancer, lymphoma, leukemia, neuroblastoma, and ovarian cancer. It is ...

(EDP) + mitotane, and

streptozotocin Streptozotocin or streptozocin (INN, USP) (STZ) is a naturally occurring alkylating antineoplastic agent that is particularly toxic to the insulin-producing beta cells of the pancreas in mammals. It is used in medicine for treating certain canc ...

+ mitotane. The FIRM-ACT trial demonstrated higher rates of response and longer progression-free survival with EDP + mitotane than with streptozotocin + mitotane.

Prognosis

ACC, generally, carries a poor prognosis,Free Full Text
with an overall 5-year survival rate of about 50%. Five-year disease-free survival for a complete resection of a

stage Stage or stages may refer to: Acting * Stage (theatre), a space for the performance of theatrical productions * Theatre, a branch of the performing arts, often referred to as "the stage" * ''The Stage'', a weekly British theatre newspaper * Sta ...

I–III ACC is about 30%. The most important prognostic factors are age of the patient and stage of the tumor. Poor prognostic factors include mitotic activity, venous invasion, weight of 50 g or more, diameter of 6.5 cm or more, Ki-67/MIB1 labeling index of 4% or more, and p53 positive. In its malignancy, adrenocortical carcinoma is unlike most tumours of the adrenal cortex, which are

benign Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malign ...

(

adenoma An adenoma is a benign tumor of epithelial tissue with glandular origin, glandular characteristics, or both. Adenomas can grow from many glandular organs, including the adrenal glands, pituitary gland, thyroid, prostate, and others. Some adenom ...

s) and only occasionally cause

References

External links

{{Endocrine gland neoplasia Rare cancers Endocrine neoplasia Endocrine-related cutaneous conditions Adrenal gland disorders