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# '''[[Bilateral adrenal hyperplasia]]''': It is associated with [[MEN1]], [[familial adenomatous polyposis]], and [[fumarate hydratase]] gene mutations. Several inactivating mutations of armadillo repeat containing 5 genes (ARMC5, chromosome 16p11.2) are also identified.
# '''[[Bilateral adrenal hyperplasia]]''': It is associated with [[MEN1]], [[familial adenomatous polyposis]], and [[fumarate hydratase]] gene mutations. Several inactivating mutations of armadillo repeat containing 5 genes (ARMC5, chromosome 16p11.2) are also identified.


==== <u>Mechanism of [[cortisol]] secretion</u> ====
==== <u>Mechanism of [[cortisol]] secretion</u><ref name="pmid254808002">{{cite journal| author=Raff H, Carroll T| title=Cushing's syndrome: from physiological principles to diagnosis and clinical care. | journal=J Physiol | year= 2015 | volume= 593 | issue= 3 | pages= 493-506 | pmid=25480800 | doi=10.1113/jphysiol.2014.282871 | pmc=4324701 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25480800  }}</ref> ====
* The secretion of cortisol is controlled by hypothalamic-pituitary axis by the following mechanism:
* The secretion of cortisol is controlled by hypothalamic-pituitary axis by the following mechanism:


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Pheochromocytoma arises from [[chromaffin cells]] of the [[adrenal medulla]] and [[Sympathetic ganglion|sympathetic ganglia]]. [[Malignant]] and [[benign]] pheochromocytomas share the same [[biochemical]] and [[histological]] features, the only difference is to have a distant spread or be locally invasive.
Pheochromocytoma arises from [[chromaffin cells]] of the [[adrenal medulla]] and [[Sympathetic ganglion|sympathetic ganglia]]. [[Malignant]] and [[benign]] pheochromocytomas share the same [[biochemical]] and [[histological]] features, the only difference is to have a distant spread or be locally invasive.


==== '''<u rel="mw:WikiLink" title="Catecholamines" href="catecholamines">Basic physiology of [[catecholamines]]</u>''' ====
==== '''<u rel="mw:WikiLink" title="Catecholamines" href="catecholamines">Basic physiology of [[catecholamines]]</u>'''<ref name="pmid3521311">{{cite journal| author=Arnall DA, Marker JC, Conlee RK, Winder WW| title=Effect of infusing epinephrine on liver and muscle glycogenolysis during exercise in rats. | journal=Am J Physiol | year= 1986 | volume= 250 | issue= 6 Pt 1 | pages= E641-9 | pmid=3521311 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3521311  }}</ref> ====
* [[Epinephrine]] acts on nearly all body tissues. Its actions vary by tissue type and tissue expression of [[adrenergic receptors]].
* [[Epinephrine]] acts on nearly all body tissues. Its actions vary by tissue type and tissue expression of [[adrenergic receptors]].
* [[Epinephrine]] is a nonselective agonist of all [[adrenergic receptors]], including the major subtypes [[Alpha-1 adrenergic receptor|α<sub>1</sub>]], [[Alpha-2 adrenergic receptor|α<sub>2</sub>]], [[Β1-adrenoreceptors|β<sub>1</sub>]], [[Beta-2 adrenergic receptor|β<sub>2</sub>]], and [[Beta-3 adrenergic receptor|β<sub>3:</sub>]]
* [[Epinephrine]] is a nonselective agonist of all [[adrenergic receptors]], including the major subtypes [[Alpha-1 adrenergic receptor|α<sub>1</sub>]], [[Alpha-2 adrenergic receptor|α<sub>2</sub>]], [[Β1-adrenoreceptors|β<sub>1</sub>]], [[Beta-2 adrenergic receptor|β<sub>2</sub>]], and [[Beta-3 adrenergic receptor|β<sub>3:</sub>]]
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* On gross pathology, A multinodular and multicentric pattern of growth of pheochromocytoma may be seen. 
* On gross pathology, A multinodular and multicentric pattern of growth of pheochromocytoma may be seen. 


==== Myelolipoma ====
==== Myelolipoma<ref name="pmid26266130">{{cite journal| author=Sajjanar AB, Athanikar VS, Dinesh US, Nanjappa B, Patil PB| title=Non Functional Unilateral Adrenal Myelolipoma, A Case Report. | journal=J Clin Diagn Res | year= 2015 | volume= 9 | issue= 6 | pages= ED03-4 | pmid=26266130 | doi=10.7860/JCDR/2015/13209.6070 | pmc=4525519 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26266130  }}</ref> ====
* On gross pathology, myelolipoma are usually found to occur alone in one adrenal gland, but not both.  
* On gross pathology, myelolipoma are usually found to occur alone in one adrenal gland, but not both.  
* They can vary widely in size, from as small as a few millimetres to as large as 34 centimeters in diameter. The cut surface has colours varying from yellow to red to mahogany brown, depending on the distribution of fat, blood, and blood-forming cells.  
* They can vary widely in size, from as small as a few millimetres to as large as 34 centimeters in diameter. The cut surface has colours varying from yellow to red to mahogany brown, depending on the distribution of fat, blood, and blood-forming cells.  
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==Microscopic Pathology==
==Microscopic Pathology==


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 help differentiate small cancers from adrenocortical adenomas.<sup>[5]</sup>
=== Adrenal adenoma and carcinoma ===
* 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 help differentiate small cancers from adrenocortical adenomas.<sup>[5]</sup><ref name="pmid24125979">{{cite journal| author=Mondal SK, Dasgupta S, Jain P, Mandal PK, Sinha SK| title=Histopathological study of adrenocortical carcinoma with special reference to the Weiss system and TNM staging and the role of immunohistochemistry to differentiate it from renal cell carcinoma. | journal=J Cancer Res Ther | year= 2013 | volume= 9 | issue= 3 | pages= 436-41 | pmid=24125979 | doi=10.4103/0973-1482.119329 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24125979  }}</ref>


On microscopic pathology, Pheochromocytoma typically demonstrates a nesting (Zellballen) pattern on microscopy. This pattern is composed of well-defined clusters of tumor cells containing eosinophilic cytoplasm separated by fibrovascular stroma. 
* In comparison to surrounding adrenal gland, Adrenal cortical adenoma cells are larger, different cytoplasm, increased variation in nuclear size
* Distinct cell borders, cells have abundant foamy cytoplasm reminiscent of zona fasciculata
* Balloon cells: clusters of cells with enlarged lipid-rich cytoplasm
 
=== Pheochromocytoma ===
On microscopic pathology, Pheochromocytoma typically demonstrates a nesting (Zellballen) pattern on microscopy. This pattern is composed of well-defined clusters of tumor cells containing eosinophilic cytoplasm separated by fibrovascular stroma.<ref name="pmid16821216">{{cite journal| author=Sporny S, Musiał J| title=[Markers of malignancy in pheochromocytomas]. | journal=Endokrynol Pol | year= 2005 | volume= 56 | issue= 6 | pages= 946-51 | pmid=16821216 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16821216  }}</ref> 
 
=== Myelolipoma ===
* Islands of hematopoietic cells and mature fat
* Usually show normal trilineage hematopoiesis, but often with markedly increased megakaryocytes
* Larger tumors may have hemorrhage, necrosis, calcification and cysts
* Rarely may have areas of fibromyxoid degeneration resembling low grade fibromyxoid sarcoma 


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

Overview

The pathophysiology of [disease/malignancy] depends on the histological subtype.

Pathophysiology

  • Incidentalomas are adrenal tumors that often discovered as an incidental finding.
  • Most incidentalomas are nonfunctional, 9% are found to secrete low levels of cortisol, 4% are pheochromocytomas, and 1.5% are aldosteronomas.[1]
  • Malignancy is an uncommon cause of adrenal incidentaloma in patients without a known diagnosis of cancer.
  • Frequency of primary adrenal carcinoma is approximately 2 to 5 percent; and 0.7 to 2.5% have nonadrenal metastases to the adrenal gland.[2]
  • Adrenal mass size is important because the smaller the adrenocortical carcinoma is at the time of diagnosis, the better the overall prognosis. A 4 cm cutoff had a 93 percent sensitivity of detecting adrenocortical carcinoma with 90% being more than 4 cm in diameter when discovered.
  • Most adrenocortical carcinomas are sporadic, but some occur as a component of hereditary cancer syndromes.[3]

Subclinical Cushing's syndrome pathogenesis

The pathophysiology of Cushing's syndrome is linked to hypercortisolism which can develop by excess ACTH secretion or excess cortisol secretion by adrenal glands. The underlying mechanisms are usually genetic mutations or overexpression of proteins.[4]

  1. Benign Adrenocortical adenoma: Common defects leading to adrenocortical adenoma are mutations or activation of the cAMP-dependent or β-catenin signaling pathways and aberrant expression and function of various G-protein-coupled receptors (GPCR).[5]
  2. Adrenal cortical carcinoma It is associated with germline TP53 mutations and MEN syndrome.[6]
  3. Bilateral adrenal hyperplasia: It is associated with MEN1, familial adenomatous polyposis, and fumarate hydratase gene mutations. Several inactivating mutations of armadillo repeat containing 5 genes (ARMC5, chromosome 16p11.2) are also identified.

Mechanism of cortisol secretion[7]

  • The secretion of cortisol is controlled by hypothalamic-pituitary axis by the following mechanism:

Pathogenesis of pheochromocytoma

Pheochromocytoma arises from chromaffin cells of the adrenal medulla and sympathetic ganglia. Malignant and benign pheochromocytomas share the same biochemical and histological features, the only difference is to have a distant spread or be locally invasive.

Basic physiology of catecholamines[8]

Associated Conditions

  • Most adrenocortical carcinomas are sporadic, but some occur as a component of hereditary cancer syndromes.[9]
  • Hereditary cancer syndromes 
  • Li-Fraumeni syndrome (breast cancer, soft tissue and bone sarcoma, brain tumors), associated with inactivating mutations of the TP53 tumor suppressor gene on chromosome 17p.
  • Beckwith-Wiedemann syndrome (Wilms' tumor, neuroblastoma, hepatoblastoma), associated with abnormalities in 11p15.
  • Multiple endocrine neoplasia type 1 (MEN1) (parathyroid, pituitary, and pancreatic neuroendocrine tumors and adrenal adenomas, as well as carcinomas), associated with inactivating mutations of the MEN1 gene on chromosome 11q.[10]

Genetics

TP53 gene, located on chromosome 17p13, is the most frequently mutated gene in human cancers. A role for the TP53 tumor suppressor gene in sporadic ACCs is suggested by the frequent finding of loss of heterozygosity (LOH) at the 17p13 locus in sporadic ACCs.[11]

Although loss of heterozygosity at 17p13 is common, only approximately one-third of these tumors have a mutation of TP53. This suggests that another as yet unidentified suppressor gene is present in this locus.[12]

Another chromosomal locus that is strongly implicated in the pathogenesis of ACC is 11p, the area of abnormality in Beckwith-Wiedemann syndrome and the site of the insulin-like growth factor-2 (IGF-2) gene. LOH at the 11p15 locus and overexpression of IGF-2 have been associated with the malignant phenotype in sporadic ACCs.[13] However, other growth-related tumor suppressor genes at this locus may also be involved.[14]

Most adrenocortical tumors are monoclonal, suggesting that they result from accumulated genetic abnormalities, such as activation of proto-oncogenes and inactivation of tumor suppressor genes.

Beta-catenin mutations (CTNNB1) 

  • Constitutive activation of beta-catenin in the Wnt signaling pathway has been identified as a frequent alteration in benign and malignant adrenocortical tumors[15].
  • The increased occurrence of adrenal tumors in patients with mutations of adenomatous polyposis coli (APC) suggested that the Wnt/beta-catenin pathway could be involved in adrenal tumorigenesis.[16]
  • This pathway is essential for embryonic development of the adrenal, and its ectopic constitutive activation is associated with cancer development in a number of tissues.[17]

Aberrant receptors 

  • Cortisol hypersecretion is the most frequent hormonal abnormality detected in patients with functioning unilateral adrenal adenomas. It had been assumed that the mechanism for this was non-ACTH-dependent autonomous cortisol secretion from the adenoma.

Somatic mutations of protein kinase A (PKA) catalytic subunit (PRKACA) were identified in patients with overt Cushing's syndrome but not in adenomas secreting less cortisol.[18]

  • In additional reports, the same mutation was found in over 50 percent of patients with Cushing's syndrome due to adrenal adenomas.[19]
  • The most frequent hotspot p.Leu206Arg mutation is located in the active cleft of the catalytic subunit, inactivating the site where the regulatory subunit RII-beta usually binds, thus causing a constitutive PKA activation.

Mutations in aldosterone-producing adenomas[20] 

  • The most frequent causes of primary aldosteronism include bilateral idiopathic hyperplasia and unilateral aldosterone-producing adenoma.
  • Somatic mutations in KCNJ5 have been identified in patients with primary aldosteronism due to APAs.
  • These mutations are more common in women than men; APAs with KCNJ5mutations are larger than those without mutations.
  • Somatic mutations in other important genes implicated in regulation of aldosterone synthesis (ATP1A1, ATP2B3, CACNA1D, CTNNB1, ARMC5) have also been identified.

Gross Pathology

Adrenocortical adenoma

  • On gross pathology, adrenocortical adenoma is a well circumscribed, yellow tumour in the adrenal cortex, which is usually 2–5 cm in diameter. The color oftumorr, as with adrenal cortex as a whole, is due to the stored lipid (mainly cholesterol), from which the cortical hormones are synthesized.

Adrenocortical carcinoma

  • Grossly, adrenocortical carcinomas are often large, with a tan-yellow cut surface, and areas of hemorrhage and necrosis. 

Pheochromocytoma

  • On gross pathology, A multinodular and multicentric pattern of growth of pheochromocytoma may be seen. 

Myelolipoma[21]

  • On gross pathology, myelolipoma are usually found to occur alone in one adrenal gland, but not both.
  • They can vary widely in size, from as small as a few millimetres to as large as 34 centimeters in diameter. The cut surface has colours varying from yellow to red to mahogany brown, depending on the distribution of fat, blood, and blood-forming cells.
  • The cut surface of larger myelolipomas may contain haemorrhage or infarction.

Microscopic Pathology

Adrenal adenoma and carcinoma

  • 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 help differentiate small cancers from adrenocortical adenomas.[5][22]
  • In comparison to surrounding adrenal gland, Adrenal cortical adenoma cells are larger, different cytoplasm, increased variation in nuclear size
  • Distinct cell borders, cells have abundant foamy cytoplasm reminiscent of zona fasciculata
  • Balloon cells: clusters of cells with enlarged lipid-rich cytoplasm

Pheochromocytoma

On microscopic pathology, Pheochromocytoma typically demonstrates a nesting (Zellballen) pattern on microscopy. This pattern is composed of well-defined clusters of tumor cells containing eosinophilic cytoplasm separated by fibrovascular stroma.[23] 

Myelolipoma

  • Islands of hematopoietic cells and mature fat
  • Usually show normal trilineage hematopoiesis, but often with markedly increased megakaryocytes
  • Larger tumors may have hemorrhage, necrosis, calcification and cysts
  • Rarely may have areas of fibromyxoid degeneration resembling low grade fibromyxoid sarcoma 

References

  1. ↑ Grumbach MM, Biller BM, Braunstein GD, Campbell KK, Carney JA, Godley PA; et al. (2003). "Management of the clinically inapparent adrenal mass ("incidentaloma")". Ann Intern Med. 138 (5): 424–9. PMID 12614096.
  2. ↑ Young WF (2000). "Management approaches to adrenal incidentalomas. A view from Rochester, Minnesota". Endocrinol Metab Clin North Am. 29 (1): 159–85, x. PMID 10732270.
  3. ↑ Sidhu S, Sywak M, Robinson B, Delbridge L (2004). "Adrenocortical cancer: recent clinical and molecular advances". Curr Opin Oncol. 16 (1): 13–8. PMID 14685087.
  4. ↑ Lacroix A, Feelders RA, Stratakis CA, Nieman LK (2015). "Cushing's syndrome". Lancet. 386 (9996): 913–27. doi:10.1016/S0140-6736(14)61375-1. PMID 26004339.
  5. ↑ Raff H, Carroll T (2015). "Cushing's syndrome: from physiological principles to diagnosis and clinical care". J Physiol. 593 (3): 493–506. doi:10.1113/jphysiol.2014.282871. PMC 4324701. PMID 25480800.
  6. ↑ Else T, Kim AC, Sabolch A, Raymond VM, Kandathil A, Caoili EM; et al. (2014). "Adrenocortical carcinoma". Endocr Rev. 35 (2): 282–326. doi:10.1210/er.2013-1029. PMC 3963263. PMID 24423978.
  7. ↑ Raff H, Carroll T (2015). "Cushing's syndrome: from physiological principles to diagnosis and clinical care". J Physiol. 593 (3): 493–506. doi:10.1113/jphysiol.2014.282871. PMC 4324701. PMID 25480800.
  8. ↑ Arnall DA, Marker JC, Conlee RK, Winder WW (1986). "Effect of infusing epinephrine on liver and muscle glycogenolysis during exercise in rats". Am J Physiol. 250 (6 Pt 1): E641–9. PMID 3521311.
  9. ↑ Koch CA, Pacak K, Chrousos GP (2002). "The molecular pathogenesis of hereditary and sporadic adrenocortical and adrenomedullary tumors". J Clin Endocrinol Metab. 87 (12): 5367–84. doi:10.1210/jc.2002-021069. PMID 12466322.
  10. ↑ Lynch HT, Radford B, Lynch JF (1990). "SBLA syndrome revisited". Oncology. 47 (1): 75–9. PMID 2300390.
  11. ↑ Gicquel C, Bertagna X, Gaston V, Coste J, Louvel A, Baudin E; et al. (2001). "Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors". Cancer Res. 61 (18): 6762–7. PMID 11559548.
  12. ↑ Libè R, Groussin L, Tissier F, Elie C, René-Corail F, Fratticci A; et al. (2007). "Somatic TP53 mutations are relatively rare among adrenocortical cancers with the frequent 17p13 loss of heterozygosity". Clin Cancer Res. 13 (3): 844–50. doi:10.1158/1078-0432.CCR-06-2085. PMID 17289876.
  13. ↑ Gicquel C, Raffin-Sanson ML, Gaston V, Bertagna X, Plouin PF, Schlumberger M; et al. (1997). "Structural and functional abnormalities at 11p15 are associated with the malignant phenotype in sporadic adrenocortical tumors: study on a series of 82 tumors". J Clin Endocrinol Metab. 82 (8): 2559–65. doi:10.1210/jcem.82.8.4170. PMID 9253334.
  14. ↑ Bourcigaux N, Gaston V, Logié A, Bertagna X, Le Bouc Y, Gicquel C (2000). "High expression of cyclin E and G1 CDK and loss of function of p57KIP2 are involved in proliferation of malignant sporadic adrenocortical tumors". J Clin Endocrinol Metab. 85 (1): 322–30. doi:10.1210/jcem.85.1.6303. PMID 10634406.
  15. ↑ Mazzuco TL, Durand J, Chapman A, Crespigio J, Bourdeau I (2012). "Genetic aspects of adrenocortical tumours and hyperplasias". Clin Endocrinol (Oxf). 77 (1): 1–10. doi:10.1111/j.1365-2265.2012.04403.x. PMID 22471738.
  16. ↑ Smith TG, Clark SK, Katz DE, Reznek RH, Phillips RK (2000). "Adrenal masses are associated with familial adenomatous polyposis". Dis Colon Rectum. 43 (12): 1739–42. PMID 11156460.
  17. ↑ Kikuchi A (2003). "Tumor formation by genetic mutations in the components of the Wnt signaling pathway". Cancer Sci. 94 (3): 225–9. PMID 12824913.
  18. ↑ Beuschlein F, Fassnacht M, Assié G, Calebiro D, Stratakis CA, Osswald A; et al. (2014). "Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome". N Engl J Med. 370 (11): 1019–28. doi:10.1056/NEJMoa1310359. PMC 4727447. PMID 24571724.
  19. ↑ Ronchi CL, Di Dalmazi G, Faillot S, Sbiera S, Assié G, Weigand I; et al. (2016). "Genetic Landscape of Sporadic Unilateral Adrenocortical Adenomas Without PRKACA p.Leu206Arg Mutation". J Clin Endocrinol Metab. 101 (9): 3526–38. doi:10.1210/jc.2016-1586. PMID 27389594.
  20. ↑ Monticone S, Castellano I, Versace K, Lucatello B, Veglio F, Gomez-Sanchez CE; et al. (2015). "Immunohistochemical, genetic and clinical characterization of sporadic aldosterone-producing adenomas". Mol Cell Endocrinol. 411: 146–54. doi:10.1016/j.mce.2015.04.022. PMC 4474471. PMID 25958045.
  21. ↑ Sajjanar AB, Athanikar VS, Dinesh US, Nanjappa B, Patil PB (2015). "Non Functional Unilateral Adrenal Myelolipoma, A Case Report". J Clin Diagn Res. 9 (6): ED03–4. doi:10.7860/JCDR/2015/13209.6070. PMC 4525519. PMID 26266130.
  22. ↑ Mondal SK, Dasgupta S, Jain P, Mandal PK, Sinha SK (2013). "Histopathological study of adrenocortical carcinoma with special reference to the Weiss system and TNM staging and the role of immunohistochemistry to differentiate it from renal cell carcinoma". J Cancer Res Ther. 9 (3): 436–41. doi:10.4103/0973-1482.119329. PMID 24125979.
  23. ↑ Sporny S, Musiał J (2005). "[Markers of malignancy in pheochromocytomas]". Endokrynol Pol. 56 (6): 946–51. PMID 16821216.

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