Adrenocortical carcinoma

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

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, often with an unfavorable prognosis. It originates from the adrenal cortex. In 1893, Grawitz et al was the first one who described ACC and falsely assumed it to be a hypernephroma. By 1938, the Mayo group had removed tumors successfully from 16 consecutive patients, most of whom had Cushing’s syndrome. In 1960, mitotane was first used clinically to treat inoperable or recurrent ACC. Adrenocortical carcinoma may be classified according to hormone production and histological appearance. ACCs are typically large tumors upon clinical presentation, often measuring more than 6 cm in diameter. They are bilateral in 2% to 10% of cases. Genetic basis of ACC depends on genomic aberrations that contribute to neoplastic transformation of adrenocortical cells such as clonality, gene expression arrays, microRNAs, gene mutations, chromosomal aberrations, epigenetic changes. Intracellular signaling depends on suggested three pathways: IGF pathway, WNT signaling pathway, Vascular endothelial growth factor pathway. On gross pathology, a large tan-yellow surface with areas of hemorrhage and necrosis is a characteristic finding of adrenocortical carcinoma. On microscopic histopathological analysis, sheets of atypical cells with some resemblance to the cells of the normal adrenal cortex are a characteristic finding of adrenocortical carcinoma. ACC may be associated with other neoplastic syndromes such as Lynch syndrome, Beckwith-Wiedemann syndrome (BWS), Carney complex, Neurofibromatosis type 1. There are no established causes for Adrenocortical carcinoma. Adrenocortical carcinoma must be differentiated from other diseases such as adrenocortical adenoma, adrenal metastasis, adrenal medullary tumors, and Cushing’s syndrome. The incidence of adrenocortical carcinoma is believed to be 0.72 per million cases per year leading to 0.2% of all cancer deaths in the United States and 0.2 to 0.3 per million children per year worldwide but valid data are lacking. A bimodal distribution was observed, the first one in pediatrics and the second one in the fifth to the sixth decade. There is a predilection for the female gender. The relatively increased incidence in childhood is mainly explained by germline TP53 mutations, which are the underlying genetic cause of ACC in >50% to 80% of children. The most potent risk factors in the development of adrenocortical cancer are Lynch syndrome, Beckwith-Wiedemann syndrome, Carney complex, Neurofibromatosis type 1, Multiple endocrine neoplasia type 1 (MEN1), and Caney Complex. Screening is not recommended for adrenocortical carcinoma. If left untreated, patients with adrenocortical carcinoma may progress to develop hyperglycemia, osteoporosis, delayed wound healing, hypertension, Cerebrovascular disease, and local or distant metastasis. Prognosis is generally poor, and the 5-year survival rate of patients with adrenocortical carcinoma stage I-III is approximately 30%. Complications may include metastasis, Conn’s syndrome and Cushing’a syndrome. According to the TNM staging system, there are four stages of adrenocortical cancer based on the tumor size, lymph nodes, and distant metastasis. Each stage is assigned a number and letter that designates the number of lymph nodes involved and presence/absence of distant metastasis. Symptoms of adrenocortical carcinoma include symptoms of androgen, glucocorticoid, mineralocorticoid, or estrogen excess. Symptoms of glucocorticoid excess include weight gain, acne, irritability. Symptoms of androgen excess symptoms include hirsutism, acne, and deepening of the voice. Symptoms of mineralocorticoid excess include headache, muscle weakness, confusion, palpitations. Common physical examination findings of Adrenocortical carcinoma include Cushing’s syndrome findings such as hypertension, weakness, gynecomastia, and acne. Hyperandrogenic cases may show findings such as clitoromegaly and hirsutism. Some patients with adrenocortical carcinoma may have elevated concentrations of serum cortisol, aldosterone, testosterone or estrogen and reduced concentration of plasma renin and potassium. There are no findings associated with adrenocortical carcinoma. Adrenal CT scan may be helpful in the diagnosis of Adrenocortical carcinoma (ACC) and differentiating it from other diseases, such as adrenocortical adenoma. Signs such as Internal hemorrhage, calcifications, CT density > 10 HU or necrosis increase the chances of ACC. Contrast-enhanced CT scan is a reliable method of disease staging, identifying common metastatic sites such as regional and para-aortic lymph nodes, lungs, liver, and bones.CT imaging of the chest, liver, and bone scan are used for staging workup to detect metastasis. MRI scans are helpful in differentiating between adrenal adenoma, carcinoma, and metastatic lesions. Due to the multiplanar capability of MRI, direct invasion of adjacent organs may be better shown. MRI scans are helpful in differentiating between adrenal adenoma, carcinoma, and metastatic lesions. Due to the multiplanar capability of MRI, direct invasion of adjacent organs may be better shown. Inferior vena cava invasion has been reported in 9% to 19% of cases at presentation. Intraoperative and intravascular ultrasound may be used for metastatic deposits recognition. Adrenal angiography, venography, positron emission tomography and MIBG may be used in the diagnosis of adrenocortical carcinoma. The sensitivity of FDG PET/CT was 90% for the diagnosis of metastases as compared with 88% for diagnostic CT. FDG PET/CT is a useful modality for staging ACC and evaluating local recurrence. FNA cytology cannot distinguish a benign adrenal mass from adrenal carcinoma. Overexpression of TP53, IGF-2, and cyclin E are found in ACC but not a conclusive procedure. Chemotherapy and hormonal therapy may be required in the treatment of adrenocortical carcinoma. Mitotane is the only approved drug in the U.S. until now. Mitotane causes a destruction of the inner zones of the adrenal cortex, the zona fasciculata, and zona reticularis. Other drugs such as ketoconazole, metyrapone, aminoglutethimide, etomidate, and mifepristone can be used also. Target therapy such as sunitinib is IGF-1R antagonists that also may be effective. Surgery is the mainstay of treatment for adrenocortical carcinoma. Appropriate preoperative evaluation and operative planning are the most important to assure the best outcome. Lymph nodes should be removed as part of the en bloc resection. Recurrence in the peritoneum outside the tumor bed having the worst survival. Surgery is indicated in those patients with disease confined to one site or organ. Radiation therapyand radiofrequency ablation may be used for palliation in patients who are not surgical candidates. Recurrence is lower in the patient with adjuvant radiotherapy than in patients without radiotherapy. ACC with metastasis to bone experienced adequate pain relief after radiotherapy.

In 1893, Grawitz et al was the first one who described ACC and falsely assumed it to be a hypernephroma. By 1938, the Mayo group had removed tumors successfully from 16 consecutive patients, most of whom had Cushing’s syndrome. In 1960, mitotane was first used clinically to treat inoperable or recurrent ACC.

Adrenocortical carcinoma may be classified according to hormone production and histological appearance. ACC may secrete cortisol, aldosterone, testosterone or estrogen. Other variants include oncocytic adrenal cortical carcinoma, myxoid adrenal cortical carcinoma, and carcinosarcoma.

ACCs are typically large tumors upon clinical presentation, often measuring more than 6 cm in diameter. They are bilateral in 2% to 10% of cases. Genetic basis of ACC depends on genomic aberrations that contribute to neoplastic transformation of adrenocortical cells such as clonality, gene expression arrays, microRNAs, gene mutations, chromosomal aberrations, epigenetic changes. Intracellular signaling depends on suggested three pathways: IGF pathway, WNT signaling pathway, Vascular endothelial growth factor pathway. On gross pathology, a large tan-yellow surface with areas of hemorrhage and necrosis is a characteristic finding of adrenocortical carcinoma. On microscopic histopathological analysis, sheets of atypical cells with some resemblance to the cells of the normal adrenal cortex are a characteristic finding of adrenocortical carcinoma. ACC may be associated with other neoplastic syndromes such as Lynch syndrome, Beckwith-Wiedemann syndrome (BWS), Carney complex, Neurofibromatosis type 1.

There are no established causes for Adrenocortical carcinoma. The relatively increased incidence in childhood is mainly explained by germline TP53 mutations, which are the underlying genetic cause of ACC in >50% to 80% of children.

Adrenocortical carcinoma must be differentiated from other diseases such as adrenocortical adenoma, adrenal metastasis, adrenal medullary tumors, and Cushing’s syndrome.

The incidence of adrenocortical carcinoma is believed to be 0.72 per million cases per year leading to 0.2% of all cancer deaths in the United States and 0.2 to 0.3 per million children per year worldwide but valid data are lacking. A bimodal distribution was observed, the first one in pediatrics and the second one in the fifth to the sixth decade. There is a predilection for the female gender.

The most potent risk factors in the development of adrenocortical cancer are Lynch syndrome, Beckwith-Wiedemann syndrome, Carney complex, Neurofibromatosis type 1, Multiple endocrine neoplasia type 1 (MEN1), and Carney complex.

Screening is not recommended for adrenocortical carcinoma.

If left untreated, patients with adrenocortical carcinoma may progress to develop hyperglycemia, osteoporosis, delayed wound healing, hypertension, Cerebrovascular disease, and local or distant metastasis. Prognosis is generally poor, and the 5-year survival rate of patients with adrenocortical carcinoma stage I-III is approximately 30%. Complications may include metastasis, Conn’s syndrome and Cushing’a syndrome.

According to the TNM staging system, there are four stages of adrenocortical cancer based on the tumor size, lymph nodes, and distant metastasis. Each stage is assigned a number and letter that designates the number of lymph nodes involved and presence/absence of distant metastasis.

Symptoms of adrenocortical carcinoma include symptoms of androgen, glucocorticoid, mineralocorticoid, or estrogen excess. Symptoms of glucocorticoid excess include weight gain, acne, irritability. Symptoms of androgen excess symptoms include hirsutism, acne, and deepening of the voice. Symptoms of mineralocorticoid excess include headache, muscle weakness, confusion, palpitations. 

Common physical examination findings of Adrenocortical carcinoma include Cushing’s syndrome findings such as hypertension, weakness, gynecomastia, and acne. Hyperandrogenic cases may show findings such as clitoromegaly and hirsutism.

Some patients with adrenocortical carcinoma may have elevated concentrations of serum cortisol, aldosterone, testosterone or estrogen and reduced concentration of plasma renin and potassium.

There are no findings associated with adrenocortical carcinoma.

MRI scans are helpful in differentiating between adrenal adenoma, carcinoma, and metastatic lesions. Due to the multiplanar capability of MRI, direct invasion of adjacent organs may be better shown. MRI scans are helpful in differentiating between adrenal adenoma, carcinoma, and metastatic lesions. Due to the multiplanar capability of MRI, direct invasion of adjacent organs may be better shown. Inferior vena cava invasion has been reported in 9% to 19% of cases at presentation.

Adrenal CT scan may be helpful in the diagnosis of Adrenocortical carcinoma (ACC) and differentiating it from other diseases, such as adrenocortical adenoma. Signs such as Internal hemorrhage, calcifications, CT density > 10 HU or necrosis increase the chances of ACC. Contrast-enhanced CT scan is a reliable method of disease staging, identifying common metastatic sites such as regional and para-aortic lymph nodes, lungs, liver, and bones.CT imaging of the chest, liver, and bone scan are used for staging workup to detect metastasis.

Intraoperative and intravascular ultrasound may be used for metastatic deposits recognition.

Adrenal angiography, venography, positron emission tomography and MIBG may be used in the diagnosis of adrenocortical carcinoma. The sensitivity of FDG PET/CT was 90% for the diagnosis of metastases as compared with 88% for diagnostic CT. FDG PET/CT is a useful modality for staging ACC and evaluating local recurrence.

FNA cytology cannot distinguish a benign adrenal mass from adrenal carcinoma. Overexpression of TP53, IGF-2, and cyclin E are found in ACC but not a conclusive procedure.

Chemotherapy and hormonal therapy may be required in the treatment of adrenocortical carcinoma. Mitotane is the only approved drug in the U.S. until now. Mitotane causes a destruction of the inner zones of the adrenal cortex, the zona fasciculata, and zona reticularis. Other drugs such as ketoconazole, metyrapone, aminoglutethimide, etomidate, and mifepristone can be used also. Target therapy such as sunitinib is IGF-1R antagonists that also may be effective.

Surgery is the mainstay of treatment for adrenocortical carcinoma. Appropriate preoperative evaluation and operative planning are the most important to assure the best outcome. Lymph nodes should be removed as part of the en bloc resection. Recurrence in the peritoneum outside the tumor bed having the worst survival. Surgery is indicated in those patients with disease confined to one site or organ.

Radiation therapyand radiofrequency ablation may be used for palliation in patients who are not surgical candidates. Recurrence is lower in the patient with adjuvant radiotherapy than in patients without radiotherapy. ACC with metastasis to bone experienced adequate pain relief after radiotherapy.

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

In 1893, Grawitz et al was the first one who described adrenocortical carcinoma (ACC), and falsely assumed that it was hypernephroma. By 1938, the Mayo group had removed tumors successfully from 16 consecutive patients, most of whom had Cushing’s syndrome. In 1960, mitotane was first used clinically to treat inoperable or recurrent ACC.

• In 1811, an association of virilization and an adrenal tumor was first observed during an autopsy.
• In 1890, virilization was first documented following resection of an adrenal tumor.
• In 1893, Grawitz et al was the first one who described ACC and falsely assumed it was a hypernephroma.^[1]
• In 1934, Walters et al described Cushing’s syndrome in patients with adrenal tumors and emphasized that the characteristic findings were not exclusively related to the pituitary disease.^[2]
• In 1899, Knowsly Thornton of London was the first surgeon to successfully remove the adrenal cancer.
• From 1905 to 1929, a number of patients were described with what was termed the adrenogenital syndrome and others with adrenal tumors with virilism.
• By 1933, there was a clear evidence that the pituitary secretes an adrenocortical factor which was later recognized as ACTH.^[3]
• By 1938, the Mayo group had removed tumors successfully from 16 consecutive patients, most of whom had Cushing’s syndrome.
• In 1949, cortisol was discovered for the first time as a preparation.^[4]
• Between 1930 and 1949, nearly 300 patients with ACC were published.
• In 1949, the first patient with Cushing’s disease was treated with pre-operative cortisol.
• By 1955, Tait and Simpson in London and Reichstein in Basel had isolated and prepared aldosterone for clinical use as fludrocortisone.
• By 1957, an intravenous preparation of cortisol, hydrocortisone, was used for the first time intraoperatively and in urgent situations of adrenal insufficiency.^[5]
• In 1960, mitotane was first used clinically to treat inoperable or recurrent ACC.

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

Adrenocortical carcinoma can be classified according to hormone production, and histological appearance. ACC may secrete cortisol, aldosterone, testosterone or estrogen. Other variants include oncocytic adrenal cortical carcinoma, myxoid adrenal cortical carcinoma, and carcinosarcoma. According to the TNM staging system, there are four stages of adrenocortical cancer based on the tumor size, lymph nodes, and distant metastasis. Each stage is assigned a number and letter that designates the number of lymph nodes involved and presence/absence of distant metastasis.

Adrenocortical carcinomas are classified based on:^[1]

A Functional adrenocortical carcinoma may produce one or more of the following hormones:^[2]

• Cortisol
• Aldosterone
• Testosterone
• Estrogen

A nonfunctional adrenocortical carcinoma does not procuce any of the above hormones.

Adrenocortical carcinoma can be classified according to the differentiation of the tissue under the microscope into:

• Well-differentiated
• Intermediate differentiated
• Poorly differentiated
• Anaplastic

• Oncocytic adrenal cortical carcinoma
• Myxoid adrenal cortical carcinoma
• Carcinosarcoma
• Adenosquamous adrenocortical carcinoma
• Clear cell adrenal cortical carcinoma

The AJCC has designated staging by TNM to define adrenocortical carcinoma: ^[3]

Adrenal cancer TNM staging

Stage	Description
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
T1	Tumor ≤5 cm in greatest dimension limited to the adrenals
T2	Tumor >5 cm in greatest dimension, limited to the adrenals
T3	Tumor of any size with local invasion, but not invading adjacent organs
T4	Tumor of any size with invasion of adjacent organs

Regional Lymph Nodes (N)

Stage	Description
NX	Regional lymph node cannot be assessed
N0	No regional lymph node metastasis
N1	Regional lymph node metastasis

Distant Metastasis (M)

Stage	Description
M0	No distant metastasis
M1	Distant metastasis

Anatomic Stage/Prognostic Groups

Stage	T	N	M
I	T1	N0	M0
II	T2	N0	M0
III	T1	N1	M0
	T2	N1	M0
	T3	N0	M0
IV	T3	N1	M0
	T4	N0	M0
	T4	N1	M0
	Any T	Any N	M1

A new study showed staging system that incorporates the patient’s age better and predicts 5-year survival among patients with stages I/II ACC. Consideration should be given to include age in staging for ACC, because it may better inform providers about treatment and prognosis.^[4]

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

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

• ACCs are typically large tumors upon clinical presentation, often measuring more than 6 cm in diameter.^[1]
• They are bilateral in 2% to 10% of cases.
• Metastases to the liver, lungs, or lymph nodes can be seen, and invasion of adjacent organs or venous extension into the renal vein and inferior vena cava may be present.^[2]
• Inferior vena cava invasion has been reported in 9% to 19% of cases at presentation.^[3]
• Due to the presence of internal hemorrhage, necrosis, and calcifications, these tumors tend to vary in appearance with frequent heterogeneous enhancement.

Spread can take several forms: ^[4]

• Direct invasion of the tumor capsule, invasion through the tumor capsule into extra-adrenal soft tissue.
• Direct invasion of lymphatic vessels in and around the capsule and nearby blood vessels. Metastatic deposits are largely similar to the primary tumor.

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

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

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

1. Clonality

• ACCs originate from monoclonal cell populations, suggesting that mutation events lead to clonal expansion and ultimate progression to cancer.^[6]
• Flowcytometry revealed aneuploidy in ACC. aneuploidy was observed in 75% of the ACCs.^[7]
• Assessment of aneuploidy with histopathological criteria in 7 of 9 adrenal tumors revealed a high correlation with Weiss score >3 (indicative of malignancy).^[8]
• No significant difference in overall survival was observed in patients with ACC exhibiting aneuploidy vs patients with ACC exhibiting diploid neoplasms.^[9]

2. Gene expression arrays

• An initial study identified elevated expression of genes involved in cell proliferation in ACC, such as IGF2, compared with increased expression of steroidogenic genes in ACA.^[10]

• Giordano et al identified unique transcriptionally activated (12q and 5q) and repressed (11q, 1p, and 17p) chromosomal regions in 33 ACCs vs 22 ACAs in a microarray study.^[11]

• Giordano et al determined that ACC with high histological grade exhibited overexpression of cell cycle and functional aneuploidy genes and leading to the decreased survival of patients.

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

• MicroRNAs are RNAs that are important in the regulation of gene expression.
• Numerous microRNAs have been identified in the regulation of various cellular processes such as proliferation, apoptosis, and differentiation.^[13]
• Dysregulation of miRNAs, such as overexpression or deletion, plays an important role in diseases.
• Mistargeting of the miRNAs, resulting in inhibition or activation of various oncogenes, tumor suppressors, and other factors important in tumor angiogenesis.^[14]
• The investigation identified 14 upregulated miRNAs and 9 downregulated miRNAs unique to ACC.^[15]
• Upregulated miRNAs in ACCs included miR-184, miR-210, and miR-503.
• Downregulated miRNAs included miR-214, miR-375, and miR-511.^[16]
• Levels of miR-184, miR-503, and miR-511 are able to distinguish benign from malignant adrenal tumors.^[16]
• MiR-483 was found to be significantly upregulated in pediatric ACCs.
• MiR-99a and miR-100 are bioinformatically predicted to target the 3- untranslated regions of IGF1R, RPTOR, and FRAP1 and were experimentally confirmed to target several components of the IGF-1 signaling pathway.^[17]

• Targeted genetic analyses have identified somatic genetic changes in TP53, MEN1, IGF2, IGF2R, and p16.^[18]

• TP53 located on 17p13 is the most commonly mutated gene in ACC, present in at least one-third of ACCs.^[19]
• LOH in the gene encoding p16ink/ p14arf, CDKN2A is observed in a subset of ACCs. The tumor suppressor function of this gene has been established in multiple cancers. LOH of 11q13 has been identified in 83% of samples.^[20]
• MEN1 somatic mutations are unusual in sporadic ACC.^[21]
• The canonical Wnt pathway, the catenin gene, and CTNNB1 have been identified as activating point mutations in over 25% of both ACAs and ACCs in children and adults.^[22]

• Comparative genomic hybridization(CGH) can identify structural chromosomal abnormalities within ACCs.^[23]

• ACCs showed complex chromosomal alterations.
• ACCs contained multiple chromosomal gains or losses with a mean of 10 events.

• The newest study confirmed increased alterations in ACC (44%) compared with ACAs (10%).

• In ACCs, the frequently observed chromosomal gains at 5, 7, 12, 16, 19, and 20 and losses at 13 and 22 were confirmed.

• In these regions, the following genes with potential carcinogenic potential were found:
  • Fibroblast growth factor 4 (FGF4),
  • cyclin-dependent kinase 4 (CDK4),
  • cyclin E1 (CCNE1).

• The study confirmed the diagnostic utility of 6 loci (5q, 7p, 11p, 13q, 16q, and 22q) in the differentiation of ACA and ACC.

• Genomic aberration at chromosomes 5, 12, and 17 are predicted to illustrate genes that initiate or maintain neoplastic transformation. Chromosome 17, specifically at 17p13, contains the well-known tumor suppressor gene TP53.

• DNA methylation involves the addition of a methyl group to the cytosine pyrimidine ring or adenine purine ring.^[24]
• Dysregulation in this process is observed in tumor cells.
• A recent study revealed hypermethylation of promoters in ACC with correlation to poor survival and identified H19, PLAGL1, G0S2, and NDRG2 as silenced genes and thus provided evidence about the role of methylation in ACC tumorigenesis, particularly in the 11p15 locus containing IGF2 and H19.

• In the adult adrenal cortex, both IGF-1 and IGF-2 stimulate basal and ACTH-induced steroidogenesis.^[25]
• Overall, the main role of IGF-2 lies in fetal development and growth, whereas IGF-1 acts mainly postnatally.^[26]
• Prominent overexpression of IGF2 and alterations of the IGF2/H19 locus have been identified in sporadic ACC.^[27]
• The IGF2 gene is located on 11p15, which also includes a noncoding H19 gene and a cyclin-dependent kinase inhibitor, CDKN1C (p57KIP2) (216, 217), and 80% to 90% of all ACCs show very high IGF2 expression. Pediatric ACCs reveal a 20-fold overexpression of IGF2.^[28][29]
• Patients with high IGF2 expression levels and 11p15 LOH are associated with a 5-fold increased risk for recurrence and a shorter disease-free survival.^[30]
• Loss of maternally expressed CDKN1C and H19 may contribute to adrenal tumorigenesis.^[31]
• The combination treatment of IGF-1R antagonists and mitotane resulted in a synergistic antiproliferative effect.^[32]

2. WNT signaling pathway

• The WNT/ catenin signaling pathway is a major developmental pathway in multiple organ systems, including the adrenal gland.^[33]

• The pathway is divided into 3 diverging signaling cascades dependent on signal conduction through:
  • Catenin (canonical pathway)
  • Ras homolog gene family small GTPase (planar cell polarity pathway)
  • Phospholipase C (Wnt/ calcium pathway)

• Initial alterations of the WNT/ catenin system/pathway were identified in FAP.^[34]

• Recent examinations of adrenocortical tumors suggest that the WNT/ catenin signaling pathway plays an important role in sporadic adrenocortical tumorigenesis.

• Immunohistochemical analysis of 39 adrenal tumors revealed the accumulation of catenin in ACCs.^[35]

• Mutational analysis of the catenin gene CTNNB1 identified activating point mutations in ACCs.

• Inactivating mutations of AXIN2 (a component of the catenin destruction complex) have also been described in some adrenocortical tumors.^[36]

• Both nuclear catenin accumulation and activating CTNNB1 mutations are present in ACCs suggesting WNT activation to be a part of ACA tumorigenesis.

• The vascular endothelial growth factor (VEGF) is a chief regulator of cancer angiogenesis. Its effects are mediated through its receptors (VEGFRs).^[37]
• Elevated VEGF levels were identified in blood samples from ACC patients.^[38]
• Overexpression of VEGFR type 2 in ACC samples was observed by immunohistochemistry.^[39]
• The increased expression of VEGF correlates with the expression of IGF2.^[40]
• The pharmacological inhibition of VEGFRs is considered an attractive option for cancer treatment.^[41]

• Cortisol is synthesized from cholesterol. Synthesis takes place in the zona fasciculata of the adrenal cortex.
• Aldosterone is produced in the zona glomerulosa
• Sex hormones are synthesized in in the zona reticularis
• The secretion of cortisol is controlled by hypothalamic-pituitary axis by the following mechanism:^[1][2]
  • Paraventricular nuclei in the hypothalamus release corticotropin-releasing hormone (CRH).
  • CRH is transferred to anterior pituitary via the portal veins.
  • CRH stimulates the activity of corticotrophs; cells that produce proopiomelanocortin (POMC) in the anterior pituitary.
  • Corticotrophs produce adrenocorticotropic hormone (ACTH) by the post-translational modification of POMC.
  • ACTH is drained into systemic circulation via the pituitary capillaries and stimulates the adrenal cortex (zona fasciculata) to produce cortisol.
  • Cortisol acts on the hypothalamus and pituitary through a feedback mechanism to regulate the secretion of CRH and ACTH.

Associated diseases with adrenocortical carcinoma are:

• Lynch syndrome
• Beckwith-Wiedemann syndrome (BWS)
• Carney complex
• Neurofibromatosis type 1
• Multiple endocrine neoplasia type1 (MEN1)

• On gross pathology, adrenocortical carcinomas are often large (>5 cm in largest diameter), with a tan-yellow cut surface and areas of hemorrhage and necrosis.
• Their cut surface ranges from brown to orange to yellow depending on the lipid content of their cells. Necrosis is almost always present.
• Typical ACC with a hypercellular population of cells with the earliest form of tumor necrosis.
• Atypical ACC with a solid growth pattern and abundant eosinophilic cytoplasm with focal clear areas, consistent with lipid.

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

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

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

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

• Nuclear grade III or IV
• More than 5 mitotic figures/50 HPF, counting 10 random fields in area of greatest number of mitotic figures on 5 slides with the greatest number of mitosis
• Presence of atypical mitotic figures (abnormal distribution of chromosomes or excessive number of mitotic spindles)
• Clear or vacuolated cells comprising 25% or less of tumor
• Diffuse architecture (more than 1/3 of the tumor forms patternless sheets of cells)
• Microscopic necrosis
• Venous invasion (veins must have smooth muscles in wall; tumor cell clusters or sheets forming polypoid projections into vessel lumen or polypoid tumor thrombi covered by endothelial layer)
• Sinusoidal 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

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

Shown below is a video explaining the histology of adrenocortical carcinoma

{{#ev:youtube|7jMFENhPaOM}}

Template:WH Template:WS

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

There are no established causes for adrenocortical carcinoma. The relatively increased incidence in childhood is mainly explained by germline TP53 mutations, which are the underlying genetic cause of ACC in more than 50% to 80% of children.

• There are no established causes for adrenocortical carcinoma.
• The relatively increased incidence in childhood is mainly explained by germline TP53 mutations, which are the underlying genetic cause of ACC in >50% to 80% of children.

• Lynch syndrome

• Beckwith-Wiedemann syndrome
• Carney complex
• Neurofibromatosis type 1
• MEN1

Associated conditions	Gene mutations	Clinical picture
Lynch syndrome[1]	MSH2, MSH6, MLH1, PMS2	Colorectal cancer Endometrial cancer Sebaceous neoplasms Ovarian cancer Pancreatic cancer Brain cancer
Neurofibromatosis type 1	NF1	Malignant peripheral nerve sheet tumor Pheochromocytoma Café au lait spots Neurofibroma Optic glioma Lisch nodule Skeletal abnormalities
MEN1[2]	MENIN	Foregut neuroendocrine tumors Pituitary tumors Parathyroid hyperplasia Collagenoma Angiofibroma Adrenal adenoma/hyperplasia
Carney complex	PRKAR1A	Adrenal disease Sertoli cell tumors Thyroid adenoma Myxoma Somatotroph pituitary adenoma
BWS[3]	IGF2, CDKN1C, H19	Wilm’s tumor Hepatoblastoma Macrosomia Adrenocortical cytomegaly Adrenal adenoma Adrenal cyst Hemihypertrophy Macroglossia Omphalocele

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

Adrenocortical carcinoma must be differentiated from other adrenal tumors such as adrenocortical adenoma, adrenal metastasis, adrenal medullary tumors, and Cushing’s syndrome.

Adrenocortical carcinoma must be differentiated from other adrenal tumors such as adrenocortical adenoma, adrenal metastasis, adrenal medullary tumors, and Cushing’s syndrome.

Differential Diagnosis	Clinical picture	Imagings	Laboratory tests
Adrenocortical carcinoma	Mass effect symptoms Symptoms related to excess glucocorticoid Symptoms related to excess mineralocorticoid Symptoms related to excess androgen or estrogen secretion	Irregular shape Non-homogeneous density because of central areas of low attenuation due to tumor necrosis Tumor calcification Diameter usually >4 cm Unilateral location High unenhanced CT attenuation values (>20 HU) Non-homogeneous enhancement on CT with intravenous contrast Delay in contrast medium washout (10 minutes after administration of contrast, an absolute contrast medium washout of less than 50 percent) Hypointensity compared with liver on T1 weighted MRI and high to intermediate signal intensity on T2 weighted MRI High standardized uptake value (SUV) on FDG–PET-CT study Evidence of local invasion or metastases	Adrenal androgens (DHEAS) Androstenedione Bioavailable testosterone should be measured in every patient. 17-hydroxyprogesterone Serum estradiol in men and postmenopausal women Cortisol level Fasting serum cortisol at 8 AM following a 1 mg dose of dexamethasone at bedtime
Adrenal adenoma	Symptoms related to excess glucocorticoid Symptoms related to excess mineralocorticoid	Round, homogeneous with sharp margination Unilateral with diameter less than 4 cm Low unenhanced CT attenuation values (<10 HU) Rapid contrast medium washout after administration of contrast An absolute contrast medium washout of more than 50 percent Chemical shift: evidence of lipid on MRI Isointensity with liver on both T1 and T2 weighted MRI sequences	Cortisol level Fasting serum cortisol at 8 AM following a 1 mg dose of dexamethasone at bedtime Renin (PRA) or plasma renin concentration (PRC): very low in patients with primary aldosteronism, usually less than 1 ng/mL per hour for PRA and usually undetectable for PRC[1]
Cushing’s syndrome	Rapid weight gain, particularly of the trunk and face with limbs sparing (central obesity) Proximal muscle weakness A round face often referred to as a “moon face“ Excess sweating Headache	Imaging may show mass if presents	24-hour urine cortisol Midnight salivary cortisol Low-dose dexamethasone suppression test; high cortisol level after the dexamethasone test is suggestive of hypercortisolism.
Pheochromocytoma	Palpitations especially in epinephrine-producing tumors. Anxiety often resembling that of a panic attack Sweating Headaches occur in 90 % of patients. Paroxysmal attacks of hypertension but some patients have normal blood pressure. It may be asymptomatic and discovered incidentally after screening for MEN patients.	Increased attenuation on non-enhanced CT (>20 HU) Increased mass vascularity Delay in contrast medium washout (10 minutes after administration of contrast, an absolute contrast medium washout of less than 50 percent) High signal intensity on T2 weighted MRI Cystic and hemorrhagic changes Variable size and may be bilateral	Plasma fractionated metanephrines  24-hour urinary fractionated metanephrines
Adrenal metastasis	Symptoms and signs of primary malignancy especially lung cancer General constitutional symptoms: Fever Fatigue Weight loss	Irregular shape and non-homogeneous nature Tendency to be bilateral High un-enhanced CT attenuation values (>20 HU) and enhancement with intravenous contrast on CT Delay in contrast medium washout (10 minutes after administration of contrast, an absolute contrast medium washout of less than 50 percent) Isointensity or slightly less intense than the liver on T1 weighted MRI and high to intermediate signal intensity on T2 weighted MRI (representing an increased water content) Elevated standardized uptake value on FDG–PET scan

Disease	Gene	Chromosome	Differentiating Features	Components of MEN			Diagnosis
				Parathyroid	Pitutary	Pancreas
von Hippel-Lindau syndrome	Von Hippel–Lindau tumor suppressor	3p25.3	Angiomatosis,  Hemangioblastomas, Pheochromocytoma,  Renal cell carcinoma, Pancreatic cysts (pancreatic serous cystadenoma) Endolymphatic sac tumor, Bilateral papillary cystadenomas of the epididymis (men) or broad ligament of the uterus (women)	–	–	+	Clinical diagnosis In hereditary VHL, disease techniques such as Southern blotting and gene sequencing can be used to analyse DNA and identify mutations.
Carney complex	PRKAR1A	17q23-q24	Myxomas of the heart Hyperpigmentation of the skin (lentiginosis) Endocrine (ACTH-independent Cushing’s syndrome due to primary pigmented nodular adrenocortical disease)	–	–	–	Clinical diagnosis
Neurofibromatosis type 1	RAS	17	Scoliosis Learning disabilities Vision disorders Cutaneous lesions Epilepsy.	–	–	–	Prenatal Chorionic villus sampling or amniocentesis can be used to detect NF-1 in the fetus. Postnatal Cardinal Clinical Features” are required for positive diagnosis. Six or more café-au-lait spots over 5 mm in greatest diameter in pre-pubertal individuals and over 15 mm in greatest diameter in post-pubertal individuals. Two or more neurofibromas of any type or 1 plexiform neurofibroma Freckling in the axillary (Crowe sign) or inguinal regions Optic glioma Two or more Lisch nodules (pigmented iris hamartomas) A distinctive osseous lesion such as sphenoid dysplasia, or thinning of the long bone cortex with or without pseudarthrosis.
Li-Fraumeni syndrome	TP53	17	Early onset of diverse amount of cancers such as Sarcoma Cancers of Breast Brain Adrenal glands	–	–	–	Criteria Sarcoma at a young age (below 45) A first-degree relative diagnosed with any cancer at a young age (below 45) A first or second degree relative with any cancer diagnosed before age 60.
Gardner’s syndrome	APC	5q21	Multiple polyps in the colon  Osteomas of the skull Thyroid cancer, Epidermoid cysts, Fibromas Desmoid tumors	–	–	–	Clinical diagnosis Colonoscopy
Multiple endocrine neoplasia type 2	RET	–	Medullary thyroid carcinoma (MTC) Pheochromocytoma Primary hyperparathyroidism	+	–	–	Hypercalcemia Hypophosphatemia, Elevated parathyroid hormone, Elevated norepinephrine Criteria Two or more specific endocrine tumors Medullary thyroid carcinoma Pheochromocytoma Parathyroid hyperplasia
Cowden syndrome	PTEN	–	Hamartomas	–	–	–	PTEN mutation probability risk calculator
Acromegaly/gigantism	–	–	Enlargement of the hands, feet, nose, lips and ears, and a general thickening of the skin Hypertrichosis Hyperpigmentation Hyperhidrosis Carpal tunnel syndrome.	–	+	–	An elevated concentration of serum growth hormone (GH) and insulin-like growth factor 1(IGF-1) levels is diagnostic of acromegaly.
Pituitary adenoma	–	–	Visual field defects classically bitemporal hemianopsia Increased intracranial pressure Migraine Lateral rectus palsy	–	+	–	Elevated serum level of prolactin Elevated or decreased serum level of adrenocorticotropic hormone (ACTH) Elevated or decreased serum level of growth hormone (GH) Elevated or decreased serum level of thyroid-stimulating hormone (TSH) Elevated or decreased serum level of follicle-stimulating hormone (FSH) Elevated or decreased serum level of luteinizing hormone (LH)
Hyperparathyroidism	–	–	– Kidney stones Hypercalcemia, Constipation Peptic ulcers Depression	+	–	–	An elevated concentration of serum calcium with elevated parathyroid hormone level is diagnostic of primary hyperparathyroidism. Most consistent laboratory findings associated with the diagnosis of secondary hyperparathyroidism include elevated serum parathyroid hormone level and low to normal serum calcium. An elevated concentration of serum calcium with elevated parathyroid hormone level in post renal transplant patients is diagnostic of tertiary hyperparathyoidism.
Pheochromocytoma/paraganglioma	VHL RET NF1   SDHB  SDHD	–	Characterized by Episodic hypertension Palpitations Anxiety Diaphoresis Weight loss	–	–	–	Increased catecholamines and metanephrines in plasma (blood) or through a 24-hour urine collection.
Adrenocortical carcinoma	p53 Retinoblastoma h19 Insulin-like growth factor II (IGF-II) p57kip2	17p, 13q	Cushing syndrome (cortisol hypersecretion) Conn syndrome (aldosterone hypersecretion) virilization (testosterone hypersecretion)	–	–	–	Increased serum glucose Increased urine cortisol Serum androstenedione and dehydroepiandrosterone Low serum potassium Low plasma renin activity High serum aldosterone. Excess serum estrogen.
Adapted from Toledo SP, Lourenço DM, Toledo RA. A differential diagnosis of inherited endocrine tumors and their tumor counterparts, journal=Clinics (Sao Paulo), volume= 68, issue= 7, 07/24/2013[2]

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

The incidence of adrenocortical carcinoma is believed to be 0.72 per million cases per year leading to 0.2% of all cancer deaths in the United States and 0.2 to 0.3 per million children per year worldwide but valid data is lacking. A bimodal distribution is observed, the first one in pediatrics and the second one in the fifth to the sixth decade with a predilection for the female gender.

• The incidence of adrenocortical carcinoma is 7.2 cases per 100,000 individuals per year leading to 0.2% of all cancer deaths in the United States and 3 cases per 100,000 children per year worldwide but valid data is lacking.^[1]

• A bimodal distribution was observed, the first one in pediatrics and the second one in the fifth to the sixth decade.^[2]

• There is a predilection for the female gender.^[3]
• Girls are also more commonly affected than boys with a ratio of 1.6:1.^[4]

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

The most important risk factors for developing adrenocortical cancer are Lynch syndrome, Beckwith-Wiedemann syndrome, Carney complex, Neurofibromatosis type 1, Multiple endocrine neoplasia type 1 (MEN1), and Carney complex.

Risk factors associated with adrenocortical carcinoma are:

• Lynch syndrome^[1]
• Beckwith-Wiedemann syndrome (BWS)^[2]
• Carney complex^[3]
• Neurofibromatosis type 1 ^[4]
• Multiple endocrine neoplasia type 1(MEN1)^[5]

Differential Diagnosis	Gene mutations	Clinical picture
Lynch syndrome[1]	MSH2, MSH6, MLH1, PMS2	Colorectal cancer Endometrial cancer Sebaceous neoplasms Ovarian cancer Pancreatic cancer Brain cancer
Neurofibromatosis type 1 [4]	NF1	Malignant peripheral nerve sheet tumor Pheochromocytoma Café au lait spots Neurofibroma Optic glioma Lisch nodule Skeletal abnormalities
MEN1[5]	MENIN	Foregut neuroendocrine tumors Pituitary tumors Parathyroid hyperplasia Collagenoma Angiofibroma Adrenal adenoma/hyperplasia
Carney complex[3]	PRKAR1A	Adrenal disease Sertoli cell tumors Thyroid adenoma Myxoma Somatotroph pituitary adenoma
BWS[2]	IGF2, CDKN1C, H19	Wilm’s tumor Hepatoblastoma Macrosomia Adrenocortical cytomegaly Adrenal adenoma Adrenal cyst Hemihypertrophy Macroglossia Omphalocele

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

Screening is not recommended for adrenocortical carcinoma.

Screening is not recommended for adrenocortical carcinoma.

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

If left untreated, patients with adrenocortical carcinoma may develop diabetes mellitus, osteoporosis, delayed wound healing, hypertension, Cerebrovascular disease, and local or distant metastasis. Prognosis is generally poor, and the 5-year survival rate of patients with adrenocortical carcinoma stage I-III is approximately 30%. Complications may include metastasis, Conn’s syndrome and Cushing’a syndrome.

The symptoms of adrenocortical carcinoma usually develop in the fifth to sixth decade of life and start with symptoms of Cushing’s syndrome such as weight gain, acne, irritability, insomnia, symptoms of androgen excess such as virilization, deepening of the voice, and coarsening of the facial features.

Without treatment, the patient may develop complications such as diabetes mellitus, osteoporosis, hypertension, hypercoagulable states, metastasis to other organs, cardiovascular and cerebrovascular diseases.

The following are the complications of Adrenocortical carcinoma:

• Cushing’s syndrome-related complications
  • Hyperglycemia 
  • Diabetes mellitus
  • Osteoporosis
  • Delayed wound healing
  • Hypertension
  • Myocardial infarction
  • Cerebrovascular disease
  • Hypercoagulable state
• Conn’s syndrome
• Local and distant metastasis
  • Invasion of adjacent organs or venous extension into the renal vein and inferior vena cava may be present.^[2]
  • Inferior vena cava invasion has been reported in 9% to 19% of cases at presentation.^[3]
• Paraneoplastic syndrome
• Tumor thrombus formation.

• Adrenocortical carcinoma, generally, carries a poor prognosis.^[1]
• The five-year disease-free survival rate for a complete resection of a stage I-III is approximately 30%.^[1]
• Survival ranges from a few months to several years.^[2]

The most important prognostic factors are:

• Age of the patient ^[3]
• Stage of the tumor ^[4]
• Mitotic activity ^[5]
• Venous invasion
• Weight more than 50 Kg
• Size/Diameter more than 6.5 cm
• Cortisol production is an adverse prognostic factor
• Ki-67/MIB1 labeling index (antigen identified by monoclonal antibody Ki-67).

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