Adrenocortical carcinoma overview: Difference between revisions
No edit summary |
Mchitsazan (talk | contribs) No edit summary |
||
| (13 intermediate revisions by 3 users not shown) | |||
| Line 4: | Line 4: | ||
==Overview== | ==Overview== | ||
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 [[Tumor|tumors]] successfully from 16 consecutive patients, most of whom had [[Cushing's syndrome|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. [[Genetics|Genetic basis]] of ACC depends on [[Genomics|genomic]] aberrations that contribute to neoplastic transformation of adrenocortical cells such as [[Clone (cell biology)|clonality,]] [[gene expression]] [[DNA microarray|arrays]], m[[MicroRNAs|icroRNAs]], [[Gene mutation|gene mutations,]] [[Chromosomal aberration|chromosomal aberrations]], [[Epigenetics|epigenetic]] changes. Intracellular signaling depends on suggested three pathways: I[[IGF|GF]] 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]] ([[Beckwith-Wiedemann syndrome|BWS]]), [[Carney complex]], [[Neurofibromatosis type I|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]], [[Pheochromocytoma|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 (gene)|TP53]] [[mutations]], which are the underlying [[Genetics|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|, Beckwith-Wiedemann syndrome,]] [[Carney complex|Carney complex,]] [[Neurofibromatosis type I|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 h[[Hyperglycemia|yperglycemia]], o[[Osteoporosis|steoporosis,]] delayed [[Wound healing|wound healing,]] h[[Hypertension|ypertension,]] [[Cerebrovascular disease]], and local or distant [[metastasis]]. [[Prognosis]] is generally poor, and the 5-year survival rate of patients with adrenocortical carcinoma [[Cancer staging|stage]] I-III is approximately 30%. Complications may include [[metastasis]], [[Conn's syndrome]] and [[Cushing's syndrome|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 [[Hirsuitism|hirsutism]], [[Irritability|acne]], and [[Irritability|deepening of the voice.]] Symptoms of [[Mineralcorticoid|mineralocorticoid]] excess include [[Headache|headache,]] [[Muscle weakness|muscle weakness,]] [[confusion]], [[Palpitations|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 [[Hirsuitism|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]], [[Calcification|calcifications]], CT density > 10 HU or [[necrosis]] increase the chances of ACC. [[Contrast enhanced CT|Contrast-enhanced CT]] scan is a reliable method of disease staging, identifying common [[metastatic]] sites such as regional and [[Paraaortic lymph node|para-aortic]] [[lymph nodes]], [[lungs]], [[Liver|liver,]] and [[bones]].[[Computed tomography|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 [[Metastasis|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 [[Metastasis|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 [[Metastasis|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 scan|PET/CT]] was 90% for the diagnosis of [[metastases]] as compared with 88% for diagnostic [[Computed tomography|CT]]. [[FDG]] [[PET scan|PET/CT]] is a useful modality for staging ACC and evaluating local recurrence. [[Needle aspiration biopsy|FNA cytology]] cannot distinguish a [[benign]] [[Adrenal mass causes|adrenal mass]] from adrenal carcinoma. Overexpression of ''[[TP53 (gene)|TP53]]''[[IGF2|, IGF-2]], and [[cyclin E]] are found in ACC but not a conclusive procedure. [[Chemotherapy]] and [[Hormone therapy|hormonal therap]]<nowiki/>y 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 therapy]]and [[radiofrequency ablation]] may be used for [[Palliative care|palliation]] in patients who are not surgical candidates. Recurrence is lower in the patient with [[Radiotherapy|adjuvant radiotherapy]] than in patients without [[Radiation therapy|radiotherapy]]. ACC with metastasis to bone experienced adequate pain relief after [[radiotherapy]]. | |||
== Historical perspective == | == Historical perspective == | ||
In 1893, Grawitz et al was the first one described ACC and falsely assumed it a hypernephroma. | 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 [[Tumor|tumors]] successfully from 16 consecutive patients, most of whom had [[Cushing's syndrome|Cushing’s syndrome.]] In 1960, [[mitotane]] was first used clinically to treat [[inoperable]] or recurrent ACC. | ||
==Classification== | ==Classification== | ||
Adrenocortical carcinoma | 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. | ||
==Pathophysiology== | ==Pathophysiology== | ||
On gross pathology, a large tan-yellow surface with areas | 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. [[Genetics|Genetic basis]] of ACC depends on [[Genomics|genomic]] aberrations that contribute to neoplastic transformation of adrenocortical cells such as [[Clone (cell biology)|clonality,]] [[gene expression]] [[DNA microarray|arrays]], m[[MicroRNAs|icroRNAs]], [[Gene mutation|gene mutations,]] [[Chromosomal aberration|chromosomal aberrations]], [[Epigenetics|epigenetic]] changes. Intracellular signaling depends on suggested three pathways: I[[IGF|GF]] 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]] ([[Beckwith-Wiedemann syndrome|BWS]]), [[Carney complex]], [[Neurofibromatosis type I|Neurofibromatosis type 1]]. | ||
==Causes== | ==Causes== | ||
There are no established causes for Adrenocortical carcinoma. The relatively increased [[incidence]] in childhood is mainly explained by [[germline]] [[TP53 (gene)|TP53]] [[mutations]], which are the underlying [[Genetics|genetic]] cause of ACC in >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 (gene)|TP53]] [[mutations]], which are the underlying [[Genetics|genetic]] cause of ACC in >50% to 80% of children. | ||
| Line 19: | Line 19: | ||
Adrenocortical carcinoma must be differentiated from other diseases such as [[adrenocortical adenoma]], adrenal [[metastasis]], [[Pheochromocytoma|adrenal medullary tumors]], and [[Cushing's syndrome]]. | Adrenocortical carcinoma must be differentiated from other diseases such as [[adrenocortical adenoma]], adrenal [[metastasis]], [[Pheochromocytoma|adrenal medullary tumors]], and [[Cushing's syndrome]]. | ||
==Epidemiology and Demographics== | ==Epidemiology and Demographics== | ||
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 sixth decade. There is a predilection for the female gender. | 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. | ||
==Risk Factors== | ==Risk Factors== | ||
| Line 26: | Line 26: | ||
Screening is not recommended for adrenocortical carcinoma. | Screening is not recommended for adrenocortical carcinoma. | ||
==Natural History, | ==Natural History, Complications and Prognosis== | ||
If left untreated, patients with adrenocortical carcinoma may progress to develop h[[Hyperglycemia|yperglycemia]], o[[Osteoporosis|steoporosis,]] delayed [[Wound healing|wound healing,]] h[[Hypertension|ypertension,]] [[Cerebrovascular disease]], and local or distant [[metastasis]]. [[Prognosis]] is generally poor, and the 5-year survival rate of patients with adrenocortical carcinoma [[Cancer staging|stage]] I-III is approximately 30%. Complications may include [[metastasis]], [[Conn's syndrome]] and [[Cushing's syndrome|Cushing'a syndrome]]. | If left untreated, patients with adrenocortical carcinoma may progress to develop h[[Hyperglycemia|yperglycemia]], o[[Osteoporosis|steoporosis,]] delayed [[Wound healing|wound healing,]] h[[Hypertension|ypertension,]] [[Cerebrovascular disease]], and local or distant [[metastasis]]. [[Prognosis]] is generally poor, and the 5-year survival rate of patients with adrenocortical carcinoma [[Cancer staging|stage]] I-III is approximately 30%. Complications may include [[metastasis]], [[Conn's syndrome]] and [[Cushing's syndrome|Cushing'a syndrome]]. | ||
==Diagnosis== | ==Diagnosis== | ||
| Line 32: | Line 32: | ||
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. | 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. | ||
===History and Symptoms=== | ===History and Symptoms=== | ||
Symptoms | 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 [[hirsuitism|hirsutism]], [[Irritability|acne]], and [[Irritability|deepening of the voice.]] Symptoms of [[mineralcorticoid|mineralocorticoid]] excess include [[headache|headache,]] [[Muscle weakness|muscle weakness,]] [[confusion]], [[Palpitations|palpitations.]] | ||
===Physical Examination=== | ===Physical Examination=== | ||
Common physical examination findings of Adrenocortical carcinoma include [[hypertension]], [[weakness]], gynecomastia, and [[acne]]. | 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 [[hirsuitism|hirsutism]]. | ||
===Laboratory Findings=== | ===Laboratory Findings=== | ||
Some patients with adrenocortical carcinoma may have elevated | Some patients with adrenocortical carcinoma may have elevated concentrations of serum [[cortisol]], [[aldosterone]], [[testosterone]] or [[estrogen]] and reduced concentration of plasma [[renin]] and [[potassium]]. | ||
=== X-ray === | === X-ray === | ||
| Line 42: | Line 42: | ||
===MRI=== | ===MRI=== | ||
[[MRI]] scans are helpful in differentiating between [[adrenal adenoma]], carcinoma, and [[Metastasis|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 [[Metastasis|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 [[Metastasis|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. | ||
===CT=== | ===CT=== | ||
Adrenal CT scan may be helpful in the diagnosis of Adrenocortical carcinoma (ACC) and differentiating it from other diseases, such | 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]], [[Calcification|calcifications]], CT density > 10 HU or [[necrosis]] increase the chances of ACC. [[Contrast enhanced CT|Contrast-enhanced CT]] scan is a reliable method of disease staging, identifying common [[metastatic]] sites such as regional and [[Paraaortic lymph node|para-aortic]] [[lymph nodes]], [[lungs]], [[Liver|liver,]] and [[bones]].[[Computed tomography|CT imaging]] of the [[chest]], [[liver]], and [[bone scan]] are used for staging workup to detect [[metastasis]]. | ||
=== UltraSound === | |||
Intraoperative and [[intravascular ultrasound]] may be used for [[Metastasis|metastatic]] deposits recognition. | |||
===Other Imaging Studies=== | ===Other Imaging Studies=== | ||
Adrenal [[angiography]], [[venography]], positron emission tomography and MIBG may be used in the diagnosis of adrenocortical carcinoma. The sensitivity of [[FDG]] [[PET scan|PET/CT]] was 90% for the diagnosis of [[metastases]] as compared with 88% for diagnostic [[Computed tomography|CT]]. [[FDG]] [[PET scan|PET/CT]] is a useful modality for staging ACC and evaluating local recurrence. | |||
===Biopsy=== | ===Biopsy=== | ||
[[Needle aspiration biopsy|FNA cytology]] cannot distinguish a [[benign]] [[Adrenal mass causes|adrenal mass]] from adrenal carcinoma. Overexpression of ''[[TP53 (gene)|TP53]]''[[IGF2|, IGF-2]], and [[cyclin E]] are found in ACC but not a conclusive procedure. | [[Needle aspiration biopsy|FNA cytology]] cannot distinguish a [[benign]] [[Adrenal mass causes|adrenal mass]] from adrenal carcinoma. Overexpression of ''[[TP53 (gene)|TP53]]''[[IGF2|, IGF-2]], and [[cyclin E]] are found in ACC but not a conclusive procedure. | ||
| Line 52: | Line 56: | ||
==Treatment== | ==Treatment== | ||
===Medical Therapy=== | ===Medical Therapy=== | ||
[[Chemotherapy]] and [[Hormone therapy|hormonal | [[Chemotherapy]] and [[Hormone therapy|hormonal therap]]<nowiki/>y 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=== | ===Surgery=== | ||
Surgery is the mainstay of treatment for adrenocortical carcinoma. | 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 === | |||
[[Radiation therapy]]and [[radiofrequency ablation]] may be used for [[Palliative care|palliation]] in patients who are not surgical candidates. Recurrence is lower in the patient with [[Radiotherapy|adjuvant radiotherapy]] than in patients without [[Radiation therapy|radiotherapy]]. ACC with metastasis to bone experienced adequate pain relief after [[radiotherapy]]. | |||
==References== | ==References== | ||
{{reflist| | {{reflist|}} | ||
[[Category:Endocrinology]] | [[Category:Endocrinology]] | ||
Latest revision as of 17:36, 24 October 2019
|
Adrenocortical carcinoma Microchapters |
|
Differentiating Adrenocortical carcinoma from other Diseases |
|---|
|
Diagnosis |
|
Treatment |
|
Case Study |
|
Adrenocortical carcinoma overview On the Web |
|
American Roentgen Ray Society Images of Adrenocortical carcinoma overview |
|
Risk calculators and risk factors for Adrenocortical carcinoma overview |
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]
Overview
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.
Historical perspective
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.
Classification
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.
Pathophysiology
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.
Causes
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.
Differentiating Adrenal Carcinoma from other Diseases
Adrenocortical carcinoma must be differentiated from other diseases such as adrenocortical adenoma, adrenal metastasis, adrenal medullary tumors, and Cushing's syndrome.
Epidemiology and Demographics
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.
Risk Factors
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
Screening is not recommended for adrenocortical carcinoma.
Natural History, Complications and Prognosis
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.
Diagnosis
Staging
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.
History and Symptoms
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.
Physical Examination
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.
Laboratory Findings
Some patients with adrenocortical carcinoma may have elevated concentrations of serum cortisol, aldosterone, testosterone or estrogen and reduced concentration of plasma renin and potassium.
X-ray
There are no findings associated with adrenocortical carcinoma.
MRI
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.
CT
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.
UltraSound
Intraoperative and intravascular ultrasound may be used for metastatic deposits recognition.
Other Imaging Studies
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.
Biopsy
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.
Treatment
Medical Therapy
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
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
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.