Incidentaloma pathophysiology: Difference between revisions

Jump to navigation Jump to search
← Older editNewer edit →
VisualWikitext
Medhat (talk | contribs)
nocaptcha
2,763 edits
No edit summary
Medhat (talk | contribs)
nocaptcha
2,763 edits
No edit summary
Line 72: Line 72:
* In additional reports, the same mutation was found in over 50 percent of patients with Cushing's syndrome due to adrenal adenomas.<ref name="pmid27389594">{{cite journal| author=Ronchi CL, Di Dalmazi G, Faillot S, Sbiera S, Assié G, Weigand I et al.| title=Genetic Landscape of Sporadic Unilateral Adrenocortical Adenomas Without PRKACA p.Leu206Arg Mutation. | journal=J Clin Endocrinol Metab | year= 2016 | volume= 101 | issue= 9 | pages= 3526-38 | pmid=27389594 | doi=10.1210/jc.2016-1586 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27389594  }}</ref>  
* In additional reports, the same mutation was found in over 50 percent of patients with Cushing's syndrome due to adrenal adenomas.<ref name="pmid27389594">{{cite journal| author=Ronchi CL, Di Dalmazi G, Faillot S, Sbiera S, Assié G, Weigand I et al.| title=Genetic Landscape of Sporadic Unilateral Adrenocortical Adenomas Without PRKACA p.Leu206Arg Mutation. | journal=J Clin Endocrinol Metab | year= 2016 | volume= 101 | issue= 9 | pages= 3526-38 | pmid=27389594 | doi=10.1210/jc.2016-1586 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27389594  }}</ref>  
* 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.
* 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 
Mutations in aldosterone-producing adenomas<ref name="pmid25958045">{{cite journal| author=Monticone S, Castellano I, Versace K, Lucatello B, Veglio F, Gomez-Sanchez CE et al.| title=Immunohistochemical, genetic and clinical characterization of sporadic aldosterone-producing adenomas. | journal=Mol Cell Endocrinol | year= 2015 | volume= 411 | issue=  | pages= 146-54 | pmid=25958045 | doi=10.1016/j.mce.2015.04.022 | pmc=4474471 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25958045  }}</ref> 
* The most frequent causes of primary aldosteronism include bilateral idiopathic hyperplasia and unilateral aldosterone-producing adenoma.
* 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.
* Somatic mutations in ''KCNJ5'' have been identified in patients with primary aldosteronism due to APAs.
Line 79: Line 79:


==Gross Pathology==
==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 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.


Myelolipoma
==== Adrenocortical carcinoma ====
* Grossly, adrenocortical carcinomas are often large, with a tan-yellow cut surface, and areas of hemorrhage and necrosis. 


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


Grossly, adrenocortical carcinomas are often large, with a tan-yellow cut surface, and areas of hemorrhage and necrosis. 
==== Myelolipoma ====
 
* On gross pathology, myelolipoma are usually found to occur alone in one adrenal gland, but not both.
On gross pathology, A multinodular and multicentric pattern of growth of pheochromocytoma may be seen. 
* 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.
<gallery>
<gallery>
File:Adrenal gland Conn syndrome4.jpg|center|300px|thumb|Adrenocortical adenoma gross pathology, source: By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=5938524
File:Adrenal gland Conn syndrome4.jpg|center|300px|thumb|Adrenocortical adenoma gross pathology, source: By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=5938524

Revision as of 18:18, 31 August 2017

Incidentaloma Microchapters

Home

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Incidentaloma from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Criteria

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

X-ray

Echocardiography and Ultrasound

CT scan

MRI

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Incidentaloma pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Incidentaloma pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Incidentaloma pathophysiology

CDC on Incidentaloma pathophysiology

Incidentaloma pathophysiology in the news

Blogs on Incidentaloma pathophysiology

Directions to Hospitals Treating Psoriasis

Risk calculators and risk factors for Incidentaloma pathophysiology

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

  • 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

Associated Conditions

  • Most adrenocortical carcinomas are sporadic, but some occur as a component of hereditary cancer syndromes.[7]
  • 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.[8]

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.[9]

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.[10]

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.[11] However, other growth-related tumor suppressor genes at this locus may also be involved.[12]

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[13].
  • 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.[14]
  • 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.[15]

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.[16]

  • In additional reports, the same mutation was found in over 50 percent of patients with Cushing's syndrome due to adrenal adenomas.[17]
  • 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[18] 

  • 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

  • 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

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]

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. 

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. ↑ 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.
  8. ↑ Lynch HT, Radford B, Lynch JF (1990). "SBLA syndrome revisited". Oncology. 47 (1): 75–9. PMID 2300390.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ Kikuchi A (2003). "Tumor formation by genetic mutations in the components of the Wnt signaling pathway". Cancer Sci. 94 (3): 225–9. PMID 12824913.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.

Template:WH Template:WS

Retrieved from "https://www.wikidoc.org/index.php?title=Incidentaloma_pathophysiology&oldid=1348324"