Adrenal carcinoma

For patient information, click here

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

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

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

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

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

• 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:

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

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

• 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.

• 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.

• 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.

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

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

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

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

• Adrenocortical carcinoma may present differently in children and adults^{[40][41][42][43]}

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

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

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

• 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

• 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

• Hormonal syndromes should be confirmed with laboratory testing

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

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

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

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

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

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

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

• 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

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

Template:WikiDoc Sources

Template:WH Template:WS