Adrenocortical carcinoma pathophysiology: Difference between revisions

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__NOTOC__
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{{Adrenocortical carcinoma}}
{{Adrenocortical carcinoma}}
{{CMG}} {{AE}} {{RT}}{{SM}}{{AAM}}
{{CMG}}; {{AE}} {{RT}} {{SM}} {{AAM}} {{MAD}}


==Overview==
==Overview==
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.
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 [[Genomics|genomic]] aberrations that contribute to [[neoplastic]] transformation of [[adrenocortical]] [[Cells (biology)|cells]] such as [[Gene mutation|gene mutations,]] [[Chromosomal aberration|chromosomal aberrations]], and [[Epigenetics|epigenetic]] changes. [[Intracellular signaling]] can occur via three pathways: [[IGF|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]] ([[Beckwith-Wiedemann syndrome|BWS]]), [[Carney complex]], and [[Neurofibromatosis type I|Neurofibromatosis type1]].


==Pathophysiology==
==Pathophysiology==
This tumor can produce the hormones [[cortisol]], [[aldosterone]], [[estrogen]], or [[testosterone]], as well as other hormones.  In women the [[tumor]] often releases these hormones, which can lead to male characteristics.
* ACCs are typically large [[tumors]] upon clinical presentation, often measuring more than 6 cm in diameter.<ref name="pmid19755599">{{cite journal| author=Johnson PT, Horton KM, Fishman EK| title=Adrenal mass imaging with multidetector CT: pathologic conditions, pearls, and pitfalls. | journal=Radiographics | year= 2009 | volume= 29 | issue= 5 | pages= 1333-51 | pmid=19755599 | doi=10.1148/rg.295095027 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19755599  }} </ref>
[Mutations]] of the tumor suppressor genes TP53 and TP57 might also be possible contributing factors for the development of [[Adrenocortical carcinoma]].
* They are [[bilateral]] in 2% to 10% of cases.
===Genetics===
* [[Metastases]] to the [[Liver|liver,]] [[lungs]], or [[Lymph node|lymph nodes]] can be seen, and [[invasion]] of adjacent [[organs]] or venous extension into the [[renal vein]] and [[inferior vena cava]] may be present.<ref name="pmid7142516">{{cite journal| author=Dunnick NR, Heaston D, Halvorsen R, Moore AV, Korobkin M| title=CT appearance of adrenal cortical carcinoma. | journal=J Comput Assist Tomogr | year= 1982 | volume= 6 | issue= 5 | pages= 978-82 | pmid=7142516 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7142516  }}</ref>
The [[p53]], [[retinoblastoma gene]] (RB) [[tumor suppressor gene]]s located on chromosomes 17p, 13q respectively,  may be changed. The genes h19, insulin-like growth factor II (IGF-II), p57<sup>kip2</sup> are important for fetal growth and development. They are located on chromosome 11p. Expression of the h19 gene is markedly reduced in both nonfunctioning and functioning adrenal cortical carcinomas, especially in tumors producing [[cortisol]] and [[aldosterone]]. There is also a loss of activity of the p57<small>kip2</small> gene product in [[virilizing]] adenomas and adrenal cortical carcinomas. In contrast, IGF-II gene expression has been shown to be high in adrenal cortical carcinomas. Finally, c-myc gene expression is relatively high in neoplasms, and it is often linked to poor prognosis.<ref>{{cite book |author=Kufe D |editor=Benedict RC, Holland JF |title=Cancer medicine |publisher=B.C. Decker |location=Hamilton, Ont |year=2000 |edition=5th |isbn=1-55009-113-1 |oclc=156944448 }}</ref>
* [[Inferior vena cava]] [[invasion]] has been reported in 9% to 19% of cases at presentation.<ref name="pmid21606258">{{cite journal| author=Bharwani N, Rockall AG, Sahdev A, Gueorguiev M, Drake W, Grossman AB et al.| title=Adrenocortical carcinoma: the range of appearances on CT and MRI. | journal=AJR Am J Roentgenol | year= 2011 | volume= 196 | issue= 6 | pages= W706-14 | pmid=21606258 | doi=10.2214/AJR.10.5540 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21606258 }}</ref>
===Gross Pathology===
* Due to the presence of internal [[hemorrhage]], [[Necrosis|necrosis,]] and [[Calcification|calcifications]], these [[tumors]] tend to vary in appearance with frequent [[heterogeneous]] enhancement.
On gross pathology, adrenocortical carcinomas are often large, with a tan-yellow cut surface, and areas of [[hemorrhage]] and [[necrosis]].
[[Metastasis|Spread]] can take several forms: <ref name="pmid19326954">{{cite journal| author=Dehner LP, Hill DA| title=Adrenal cortical neoplasms in children: why so many carcinomas and yet so many survivors? | journal=Pediatr Dev Pathol | year= 2009 | volume= 12 | issue= 4 | pages= 284-91 | pmid=19326954 | doi=10.2350/08-06-0489.1 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19326954  }}</ref>
* Direct [[invasion]] of the [[tumor]] [[Capsule|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.<ref name="pmid3697922">{{cite journal| author=Cagle PT, Hough AJ, Pysher TJ, Page DL, Johnson EH, Kirkland RT et al.| title=Comparison of adrenal cortical tumors in children and adults. | journal=Cancer | year= 1986 | volume= 57 | issue= 11 | pages= 2235-7 | pmid=3697922 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3697922  }}</ref>


[[Image:Adrenal_cortical_carcinoma.JPG‎|400px]]
==Genetics==
The genetic dissection of ACC has revealed [[Genomics|genomic]] aberrations that contribute to [[neoplastic]] transformation of the [[adrenocortical]] cells:


<sup>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 tumor. Patient had evidence of virilization.</sup>
'''''1. [[Clone (cell biology)|Clonality]]'''''
===Microscopic Pathology===
* ACCs originate from [[Monoclonal|monoclonal cell]] populations, suggesting that [[mutation]] events lead to [[Clonal selection|clonal expansion]] and ultimate progression to [[cancer]].<ref name="pmid7915195">{{cite journal| author=Beuschlein F, Reincke M, Karl M, Travis WD, Jaursch-Hancke C, Abdelhamid S et al.| title=Clonal composition of human adrenocortical neoplasms. | journal=Cancer Res | year= 1994 | volume= 54 | issue= 18 | pages= 4927-32 | pmid=7915195 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7915195  }}</ref>
On [[histopathology|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 [[mitosis|mitotic activity]] help differentiate small cancers from [[adrenocortical adenoma]]s.<ref name="Weidner's">{{cite book |author=Richard Cote, Saul Suster, Lawrence Weiss, Noel Weidner (Editor) |title=Modern Surgical Pathology (2 Volume Set) |publisher=W B Saunders |location=London |year= |pages= |isbn=0-7216-7253-1 |oclc= |doi=}}</ref>
* [[Flow cytometry|Flowcytometry]] revealed [[aneuploidy]] in ACC. [[aneuploidy]] was observed in 75% of the ACCs.<ref name="pmid7910530">{{cite journal| author=Gicquel C, Leblond-Francillard M, Bertagna X, Louvel A, Chapuis Y, Luton JP et al.| title=Clonal analysis of human adrenocortical carcinomas and secreting adenomas. | journal=Clin Endocrinol (Oxf) | year= 1994 | volume= 40 | issue= 4 | pages= 465-77 | pmid=7910530 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7910530  }}</ref>
* Assessment of [[aneuploidy]] with [[histopathological]] criteria in 7 of 9 [[Adrenal tumor|adrenal tumors]] revealed a high correlation with Weiss score >3 (indicative of [[malignancy]]).<ref name="pmid3617290">{{cite journal| author=Amberson JB, Vaughan ED, Gray GF, Naus GJ| title=Flow cytometric determination of nuclear DNA content in benign adrenal pheochromocytomas. | journal=Urology | year= 1987 | volume= 30 | issue= 2 | pages= 102-4 | pmid=3617290 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3617290  }}</ref>  
* No significant difference in overall survival was observed in patients with ACC exhibiting [[aneuploidy]] vs patients with ACC exhibiting [[Diploids|diploid]] [[Neoplasm|neoplasms]].<ref name="pmid2403197">{{cite journal| author=Cibas ES, Medeiros LJ, Weinberg DS, Gelb AB, Weiss LM| title=Cellular DNA profiles of benign and malignant adrenocortical tumors. | journal=Am J Surg Pathol | year= 1990 | volume= 14 | issue= 10 | pages= 948-55 | pmid=2403197 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2403197  }}</ref>
'''''2. [[Gene expression]] [[DNA microarray|arrays]]'''''
* An initial study identified elevated [[Gene expression|expression of genes]] involved in cell [[proliferation]] in [[Adrenocortical carcinoma|ACC]], such as ''[[IGF2]]'', compared with increased [[Gene expression|expression]] of [[steroidogenic]] [[genes]] in [[Adrenocortical adenoma|ACA]].<ref name="pmid15613424">{{cite journal| author=de Fraipont F, El Atifi M, Cherradi N, Le Moigne G, Defaye G, Houlgatte R et al.| title=Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic Acid microarrays identifies several candidate genes as markers of malignancy. | journal=J Clin Endocrinol Metab | year= 2005 | volume= 90 | issue= 3 | pages= 1819-29 | pmid=15613424 | doi=10.1210/jc.2004-1075 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15613424  }}</ref>  


[[Image: 800px-Adrenal_cortical_carcinoma_-_low_mag.jpg‎|400px]]
* Giordano et al identified unique [[Transcription (genetics)|transcriptionally]] activated (12q and 5q) and repressed (11q, 1p, and 17p) [[chromosomal]] regions in 33 ACCs vs 22 ACAs in a [[DNA microarray|microarray]] study.<ref name="pmid19147773">{{cite journal| author=Giordano TJ, Kuick R, Else T, Gauger PG, Vinco M, Bauersfeld J et al.| title=Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling. | journal=Clin Cancer Res | year= 2009 | volume= 15 | issue= 2 | pages= 668-76 | pmid=19147773 | doi=10.1158/1078-0432.CCR-08-1067 | pmc=2629378 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19147773  }}</ref>
 
* Giordano et al determined that ACC with high [[histological]] [[Grading (tumors)|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.<ref name="pmid19139432">{{cite journal| author=de Reyniès A, Assié G, Rickman DS, Tissier F, Groussin L, René-Corail F et al.| title=Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival. | journal=J Clin Oncol | year= 2009 | volume= 27 | issue= 7 | pages= 1108-15 | pmid=19139432 | doi=10.1200/JCO.2008.18.5678 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19139432  }}</ref>
 
==== 3. '''''[[MicroRNAs]]'''''  ====
* [[MicroRNAs]] are [[RNA|RNAs]] that are important in the regulation of [[gene expression]].
* Numerous [[MicroRNA|microRNAs]] have been identified in the regulation of various [[cellular]] processes such as [[proliferation]], [[Apoptosis|apoptosis,]] and [[differentiation]].<ref name="pmid21116305">{{cite journal| author=Czech B, Hannon GJ| title=Small RNA sorting: matchmaking for Argonautes. | journal=Nat Rev Genet | year= 2011 | volume= 12 | issue= 1 | pages= 19-31 | pmid=21116305 | doi=10.1038/nrg2916 | pmc=3703915 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21116305  }}</ref>
* Dysregulation of [[MicroRNA|miRNAs]], such as [[overexpression]] or [[deletion]], plays an important role in [[diseases]].
* Mistargeting of the [[MicroRNA|miRNAs]], resulting in inhibition or activation of various [[oncogenes]], [[Tumor suppressor|tumor suppressors]], and other factors important in [[tumor]] [[Angiogenesis|angiogenesis.]]<ref name="pmid22337054">{{cite journal| author=Lujambio A, Lowe SW| title=The microcosmos of cancer. | journal=Nature | year= 2012 | volume= 482 | issue= 7385 | pages= 347-55 | pmid=22337054 | doi=10.1038/nature10888 | pmc=3509753 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22337054  }}</ref>
* The investigation identified 14 upregulated [[MicroRNA|miRNAs]] and 9 downregulated [[MicroRNA|miRNAs]] unique to ACC.<ref name="pmid19996210">{{cite journal| author=Soon PS, Tacon LJ, Gill AJ, Bambach CP, Sywak MS, Campbell PR et al.| title=miR-195 and miR-483-5p Identified as Predictors of Poor Prognosis in Adrenocortical Cancer. | journal=Clin Cancer Res | year= 2009 | volume= 15 | issue= 24 | pages= 7684-7692 | pmid=19996210 | doi=10.1158/1078-0432.CCR-09-1587 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19996210  }}</ref>
* Upregulated [[MicroRNA|miRNAs]] in ACCs included miR-184, miR-210, and miR-503.
* Downregulated [[MicroRNA|miRNAs]] included miR-214, miR-375, and miR-511.<ref name="pmid19546168">{{cite journal| author=Tömböl Z, Szabó PM, Molnár V, Wiener Z, Tölgyesi G, Horányi J et al.| title=Integrative molecular bioinformatics study of human adrenocortical tumors: microRNA, tissue-specific target prediction, and pathway analysis. | journal=Endocr Relat Cancer | year= 2009 | volume= 16 | issue= 3 | pages= 895-906 | pmid=19546168 | doi=10.1677/ERC-09-0096 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19546168  }}</ref>
* Levels of miR-184, miR-503, and miR-511 are able to distinguish benign from [[malignant]] [[Adrenal tumor|adrenal tumors]].<ref name="pmid19546168" />
* 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]].<ref name="pmid20484036">{{cite journal| author=Doghman M, El Wakil A, Cardinaud B, Thomas E, Wang J, Zhao W et al.| title=Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors. | journal=Cancer Res | year= 2010 | volume= 70 | issue= 11 | pages= 4666-75 | pmid=20484036 | doi=10.1158/0008-5472.CAN-09-3970 | pmc=2880211 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20484036  }}</ref>
[[File:MiRNA.png|300px|center|thumb|microRNA function, source: By Kelvinsong - Own work, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=23311105]]
==== 4. '''''[[Gene mutation|Gene mutations]]'''''  ====
* Targeted [[Genetics|genetic]] analyses have identified [[somatic]] [[Genetics|genetic]] changes in ''[[TP53 (gene)|TP53]]'', ''[[MEN1]]'', [[Insulin-like growth factor 2|''IGF2'',]] ''[[IGF2R]]'', and ''[[P16 (gene)|p16]]''.<ref name="pmid11454518">{{cite journal| author=Barzon L, Chilosi M, Fallo F, Martignoni G, Montagna L, Palù G et al.| title=Molecular analysis of CDKN1C and TP53 in sporadic adrenal tumors. | journal=Eur J Endocrinol | year= 2001 | volume= 145 | issue= 2 | pages= 207-12 | pmid=11454518 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11454518  }}</ref>
 
* ''[[TP53 (gene)|TP53]]'' located on 17p13 is the most commonly mutated [[gene]] in ACC, present in at least one-third of ACCs.<ref name="pmid22504887">{{cite journal| author=Jain M, Rechache N, Kebebew E| title=Molecular markers of adrenocortical tumors. | journal=J Surg Oncol | year= 2012 | volume= 106 | issue= 5 | pages= 549-56 | pmid=22504887 | doi=10.1002/jso.23119 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22504887  }}</ref>
* LOH in the gene encoding [[P16INK4a|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.<ref name="pmid10022445">{{cite journal| author=Kjellman M, Roshani L, Teh BT, Kallioniemi OP, Höög A, Gray S et al.| title=Genotyping of adrenocortical tumors: very frequent deletions of the MEN1 locus in 11q13 and of a 1-centimorgan region in 2p16. | journal=J Clin Endocrinol Metab | year= 1999 | volume= 84 | issue= 2 | pages= 730-5 | pmid=10022445 | doi=10.1210/jcem.84.2.5506 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10022445  }}</ref>
* ''[[MEN1]]'' [[somatic]] [[mutations]] are unusual in sporadic ACC.<ref name="pmid17854394">{{cite journal| author=Tadjine M, Lampron A, Ouadi L, Bourdeau I| title=Frequent mutations of beta-catenin gene in sporadic secreting adrenocortical adenomas. | journal=Clin Endocrinol (Oxf) | year= 2008 | volume= 68 | issue= 2 | pages= 264-70 | pmid=17854394 | doi=10.1111/j.1365-2265.2007.03033.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17854394  }}</ref>
* The canonical [[Wnt signaling pathway|Wnt pathway]], the [[Catenin|catenin gene]], and ''CTNNB1'' have been identified as activating [[point mutations]] in over 25% of both ACAs and ACCs in children and adults.<ref name="pmid18647815">{{cite journal| author=Gaujoux S, Tissier F, Groussin L, Libé R, Ragazzon B, Launay P et al.| title=Wnt/beta-catenin and 3',5'-cyclic adenosine 5'-monophosphate/protein kinase A signaling pathways alterations and somatic beta-catenin gene mutations in the progression of adrenocortical tumors. | journal=J Clin Endocrinol Metab | year= 2008 | volume= 93 | issue= 10 | pages= 4135-40 | pmid=18647815 | doi=10.1210/jc.2008-0631 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18647815  }}</ref>
[[File:Wnt signaling in biological signal transduction.png|300px|center|thumb|WNT pathwayssource: By Fred the OysteriThe source code of this SVG is valid.This vector graphics image was created with Adobe Illustrator., GFDL, https://commons.wikimedia.org/w/index.php?curid=36340188]]
==== 5. '''''[[Chromosomal aberration|Chromosomal aberrations]]''''' ====
* [[Comparative genomic hybridization]]([[Comparative genomic hybridization|CGH]]) can identify structural [[chromosomal]] abnormalities within ACCs.<ref name="pmid23093492">{{cite journal| author=Barreau O, Assié G, Wilmot-Roussel H, Ragazzon B, Baudry C, Perlemoine K et al.| title=Identification of a CpG island methylator phenotype in adrenocortical carcinomas. | journal=J Clin Endocrinol Metab | year= 2013 | volume= 98 | issue= 1 | pages= E174-84 | pmid=23093492 | doi=10.1210/jc.2012-2993 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23093492  }}</ref>
 
* 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 [[Adrenocortical adenoma|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|Fibroblast growth factor 4]] (''[[FGF4]]''),
** [[cyclin-dependent kinase 4]] (''[[CDK4]]''),
** [[cyclin E1]] ([[CCNE1|''CCNE1'')]]. 
 
* The study confirmed the diagnostic utility of 6 [[loci]] (5q, 7p, 11p, 13q, 16q, and 22q) in the [[differentiation]] of [[Adrenocortical adenoma|ACA]] and ACC.
 
* [[Genomic]] aberration at [[chromosomes]] 5, 12, and 17 are predicted to illustrate [[genes]] that initiate or maintain [[Neoplasm|neoplastic]] transformation. [[Chromosome]] 17, specifically at 17p13, contains the well-known [[tumor suppressor gene]] ''[[TP53 (gene)|TP53]]''.
 
==== 6. '''''[[Epigenetics|Epigenetic]] changes''''' ====
* [[DNA methylation]] involves the addition of a [[methyl group]] to the [[cytosine]] [[pyrimidine]] ring or [[adenine]] [[purine]] ring.<ref name="pmid25111790">{{cite journal| author=Hofland J, Steenbergen J, Voorsluijs JM, Verbiest MM, de Krijger RR, Hofland LJ et al.| title=Inhibin alpha-subunit (INHA) expression in adrenocortical cancer is linked to genetic and epigenetic INHA promoter variation. | journal=PLoS One | year= 2014 | volume= 9 | issue= 8 | pages= e104944 | pmid=25111790 | doi=10.1371/journal.pone.0104944 | pmc=4128726 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25111790  }}</ref>
* Dysregulation in this process is observed in [[Tumor cell|tumor cells.]]
* A recent study revealed [[Methylation|hypermethylation]] of [[promoters]] in ACC with correlation to poor survival and identified ''[[H19 (gene)|H19]]'', ''[[PLAGL1]]'', ''[[G0 phase|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 (gene)|H19]]''.
 
== Cellular signaling pathway ==
 
==== '''''1. [[IGF]] pathway '''''<nowiki/> ====
* In the adult [[adrenal cortex]], both [[IGF-1]] and [[Insulin-like growth factor 2|IGF-2]] stimulate [[Basal (medicine)|basal]] and [[Adrenocorticotropic hormone|ACTH]]-induced [[steroidogenesis]].<ref name="pmid3031644">{{cite journal| author=Voutilainen R, Miller WL| title=Coordinate tropic hormone regulation of mRNAs for insulin-like growth factor II and the cholesterol side-chain-cleavage enzyme, P450scc [corrected], in human steroidogenic tissues. | journal=Proc Natl Acad Sci U S A | year= 1987 | volume= 84 | issue= 6 | pages= 1590-4 | pmid=3031644 | doi= | pmc=304481 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3031644  }}</ref>
* Overall, the main role of [[Insulin-like growth factor 2|IGF-2]] lies in fetal development and growth, whereas [[IGF-1]] acts mainly postnatally.<ref name="pmid1446644">{{cite journal| author=Han VK, Lu F, Bassett N, Yang KP, Delhanty PJ, Challis JR| title=Insulin-like growth factor-II (IGF-II) messenger ribonucleic acid is expressed in steroidogenic cells of the developing ovine adrenal gland: evidence of an autocrine/paracrine role for IGF-II. | journal=Endocrinology | year= 1992 | volume= 131 | issue= 6 | pages= 3100-9 | pmid=1446644 | doi=10.1210/endo.131.6.1446644 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1446644  }}</ref>
* Prominent [[overexpression]] of ''[[Insulin-like growth factor 2|IGF2]]'' and alterations of the ''[[Insulin-like growth factor 2|IGF2]]''/''[[H19 (gene)|H19]]'' locus have been identified in sporadic ACC.<ref name="pmid12547710">{{cite journal| author=Giordano TJ, Thomas DG, Kuick R, Lizyness M, Misek DE, Smith AL et al.| title=Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. | journal=Am J Pathol | year= 2003 | volume= 162 | issue= 2 | pages= 521-31 | pmid=12547710 | doi=10.1016/S0002-9440(10)63846-1 | pmc=1851158 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12547710  }}</ref>
* The ''[[Insulin-like growth factor 2|IGF2]]'' [[gene]] is located on 11p15, which also includes a noncoding ''[[H19 (gene)|H19]]'' [[gene]] and a [[cyclin-dependent kinase]] inhibitor, ''[[CDKN1C]]'' (''p57KIP2'') (216, 217), and 80% to 90% of all ACCs show very high ''[[Insulin-like growth factor 2|IGF2]]'' expression. [[Pediatric]] ACCs reveal a 20-fold [[overexpression]] of ''[[IGF2]]''.<ref name="pmid11436121">{{cite journal| author=Gaston V, Le Bouc Y, Soupre V, Burglen L, Donadieu J, Oro H et al.| title=Analysis of the methylation status of the KCNQ1OT and H19 genes in leukocyte DNA for the diagnosis and prognosis of Beckwith-Wiedemann syndrome. | journal=Eur J Hum Genet | year= 2001 | volume= 9 | issue= 6 | pages= 409-18 | pmid=11436121 | doi=10.1038/sj.ejhg.5200649 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11436121  }}</ref><ref name="pmid8370710">{{cite journal| author=Ilvesmäki V, Kahri AI, Miettinen PJ, Voutilainen R| title=Insulin-like growth factors (IGFs) and their receptors in adrenal tumors: high IGF-II expression in functional adrenocortical carcinomas. | journal=J Clin Endocrinol Metab | year= 1993 | volume= 77 | issue= 3 | pages= 852-8 | pmid=8370710 | doi=10.1210/jcem.77.3.8370710 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8370710  }}</ref>
* 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.<ref name="pmid18854392">{{cite journal| author=Barlaskar FM, Spalding AC, Heaton JH, Kuick R, Kim AC, Thomas DG et al.| title=Preclinical targeting of the type I insulin-like growth factor receptor in adrenocortical carcinoma. | journal=J Clin Endocrinol Metab | year= 2009 | volume= 94 | issue= 1 | pages= 204-12 | pmid=18854392 | doi=10.1210/jc.2008-1456 | pmc=2630877 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18854392  }}</ref>
* Loss of maternally expressed ''[[CDKN1C]]'' and ''[[H19 (gene)|H19]]'' may contribute to [[Adrenal gland|adrenal]] [[tumorigenesis]].<ref name="pmid11559548">{{cite journal| author=Gicquel C, Bertagna X, Gaston V, Coste J, Louvel A, Baudin E et al.| title=Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors. | journal=Cancer Res | year= 2001 | volume= 61 | issue= 18 | pages= 6762-7 | pmid=11559548 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11559548  }}</ref>
* The combination treatment of IGF-1R [[antagonists]] and [[mitotane]] resulted in a [[synergistic]] antiproliferative effect.<ref name="pmid18611974">{{cite journal| author=Almeida MQ, Fragoso MC, Lotfi CF, Santos MG, Nishi MY, Costa MH et al.| title=Expression of insulin-like growth factor-II and its receptor in pediatric and adult adrenocortical tumors. | journal=J Clin Endocrinol Metab | year= 2008 | volume= 93 | issue= 9 | pages= 3524-31 | pmid=18611974 | doi=10.1210/jc.2008-0065 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18611974  }}</ref>
'''''2. WNT signaling pathway'''''
* The WNT/ [[catenin]] signaling pathway is a major developmental pathway in multiple [[organ systems]], including [[Adrenal gland|the adrenal gland]].<ref name="pmid18599507">{{cite journal| author=Kim AC, Reuter AL, Zubair M, Else T, Serecky K, Bingham NC et al.| title=Targeted disruption of beta-catenin in Sf1-expressing cells impairs development and maintenance of the adrenal cortex. | journal=Development | year= 2008 | volume= 135 | issue= 15 | pages= 2593-602 | pmid=18599507 | doi=10.1242/dev.021493 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18599507  }}</ref>
 
* The pathway is divided into 3 diverging signaling cascades dependent on signal conduction through:
** [[Catenin]] (canonical pathway)
** [[Ras oncogene|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]].<ref name="pmid1651562">{{cite journal| author=Kinzler KW, Nilbert MC, Su LK, Vogelstein B, Bryan TM, Levy DB et al.| title=Identification of FAP locus genes from chromosome 5q21. | journal=Science | year= 1991 | volume= 253 | issue= 5020 | pages= 661-5 | pmid=1651562 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1651562  }}</ref>
 
* Recent examinations of [[Adrenal mass causes|adrenocortical tumors]] suggest that the WNT/ catenin signaling pathway plays an important role in sporadic adrenocortical [[tumorigenesis]].
 
* [[Immunohistochemistry|Immunohistochemical]] analysis of 39 [[Adrenal tumor|adrenal tumors]] revealed the accumulation of [[catenin]] in ACCs.<ref name="pmid1651174">{{cite journal| author=Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H et al.| title=Identification and characterization of the familial adenomatous polyposis coli gene. | journal=Cell | year= 1991 | volume= 66 | issue= 3 | pages= 589-600 | pmid=1651174 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1651174  }}</ref>
 
* [[Mutation|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 [[Adrenal tumor|adrenocortical tumors]].<ref name="pmid21733995">{{cite journal| author=Chapman A, Durand J, Ouadi L, Bourdeau I| title=Identification of genetic alterations of AXIN2 gene in adrenocortical tumors. | journal=J Clin Endocrinol Metab | year= 2011 | volume= 96 | issue= 9 | pages= E1477-81 | pmid=21733995 | doi=10.1210/jc.2010-2987 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21733995  }}</ref>
 
* Both [[nuclear]] [[catenin]] accumulation and activating ''CTNNB1'' mutations are present in ACCs suggesting  WNT activation to be a part of ACA [[tumorigenesis]].
 
==== 3. '''''[[Vascular endothelial growth factor]]''''' ====
* The [[vascular endothelial growth factor]] (''[[Vascular endothelial growth factor|VEGF]]'') is a chief regulator of [[cancer]] [[angiogenesis]]. Its effects are mediated through its [[receptors]] ([[VEGFRs|VEGFRs)]].<ref name="pmid15523889">{{cite journal| author=Affara NI, Robertson FM| title=Vascular endothelial growth factor as a survival factor in tumor-associated angiogenesis. | journal=In Vivo | year= 2004 | volume= 18 | issue= 5 | pages= 525-42 | pmid=15523889 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15523889  }}</ref>
* Elevated [[Vascular endothelial growth factor|VEGF]] levels were identified in blood samples from ACC patients.<ref name="pmid11134136">{{cite journal| author=de Fraipont F, El Atifi M, Gicquel C, Bertagna X, Chambaz EM, Feige JJ| title=Expression of the angiogenesis markers vascular endothelial growth factor-A, thrombospondin-1, and platelet-derived endothelial cell growth factor in human sporadic adrenocortical tumors: correlation with genotypic alterations. | journal=J Clin Endocrinol Metab | year= 2000 | volume= 85 | issue= 12 | pages= 4734-41 | pmid=11134136 | doi=10.1210/jcem.85.12.7012 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11134136  }}</ref>
* Overexpression of [[VEGFR-1|VEGFR]] type 2 in ACC samples was observed by [[immunohistochemistry]].<ref name="pmid19903796">{{cite journal| author=Wortmann S, Quinkler M, Ritter C, Kroiss M, Johanssen S, Hahner S et al.| title=Bevacizumab plus capecitabine as a salvage therapy in advanced adrenocortical carcinoma. | journal=Eur J Endocrinol | year= 2010 | volume= 162 | issue= 2 | pages= 349-56 | pmid=19903796 | doi=10.1530/EJE-09-0804 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19903796  }}</ref>
* The increased expression of ''[[VEGF]]'' correlates with the expression of ''[[IGF2]].''<ref name="pmid191477732">{{cite journal| author=Giordano TJ, Kuick R, Else T, Gauger PG, Vinco M, Bauersfeld J et al.| title=Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling. | journal=Clin Cancer Res | year= 2009 | volume= 15 | issue= 2 | pages= 668-76 | pmid=19147773 | doi=10.1158/1078-0432.CCR-08-1067 | pmc=2629378 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19147773  }}</ref>
* The [[pharmacological]] [[inhibition]] of [[VEGFRs]] is considered an attractive option for cancer treatment.<ref name="pmid20189876">{{cite journal| author=Bagri A, Kouros-Mehr H, Leong KG, Plowman GD| title=Use of anti-VEGF adjuvant therapy in cancer: challenges and rationale. | journal=Trends Mol Med | year= 2010 | volume= 16 | issue= 3 | pages= 122-32 | pmid=20189876 | doi=10.1016/j.molmed.2010.01.004 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20189876  }}</ref>
[[File:VEGF receptors.png|300px|center|thumb|VEGF signaling, source: By Mikael Häggström.When using this image in external works, it may be cited as:Häggström, Mikael (2014). "Medical gallery of Mikael Häggström 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 2002-4436. Public Domain.orBy Mikael Häggström, used with permission. - [1]Interactions of VEGF ligands and VEGF receptors ResearchVEGF.com, retrieved on November, 13, 2009, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3475250]]
 
== Hormones biosynthesis in adrenal cortex ==
* [[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 adrenal axis|hypothalamic-pituitary axis]] by the following mechanism:<sup>[[Cushing's syndrome pathophysiology#cite note-pmid26004339-1|[1]]][[Cushing's syndrome pathophysiology#cite note-pmid25480800-2|[2]]]</sup>
** [[Paraventricular nucleus|Paraventricular nuclei]] in the [[hypothalamus]] release [[Corticotropin-releasing hormone|corticotropin-releasing hormone]] ([[Corticotropin-releasing hormone|CRH]]).
**[[Corticotropin-releasing hormone|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]] ([[Adrenocorticotropic hormone|ACTH]]) by the [[post-translational modification]] of [[Proopiomelanocortin|POMC]].
**[[Adrenocorticotropic hormone|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]].
[[File:Steroidogenesis.png|500px|center|thumb|source: By David Richfield (User:Slashme) and Mikael Häggström. Derived from previous version by Hoffmeier and Settersr.In external use, this diagram may be cited as:Häggström M, Richfield D (2014). "Diagram of the pathways of human steroidogenesis". Wikiversity Journal of Medicine 1 (1). DOI:10.15347/wjm/2014.005. ISSN 20018762. - Self-made using bkchem and inkscape, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=6355511]]
 
== Associated Conditions ==
Associated diseases with [[adrenocortical carcinoma]] are:
* [[Lynch syndrome]]
* [[Beckwith-Wiedemann syndrome]] ([[Beckwith-Wiedemann syndrome|BWS]])
* [[Carney complex]]
* [[Neurofibromatosis type I|Neurofibromatosis type 1]]
* [[Multiple endocrine neoplasia type 1|Multiple endocrine neoplasia type1]] ([[MEN1]])
 
==Gross Pathology==
* On [[gross]] [[pathology]], [[Adrenocortical carcinoma|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 (biology)|cells]]. [[Necrosis]] is almost always present.
* Typical ACC with a hypercellular population of [[Cells (biology)|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]].
[[Image:Adrenal_cortical_carcinoma.JPG‎|400px|center|thumb|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. - By AFIP Atlas of Tumor Pathology - [1], Domena publiczna, https://commons.wikimedia.org/w/index.php?curid=6719487]]
 
<sup>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.</sup>
 
==Microscopic Pathology==
On [[histopathology|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 [[mitosis|mitotic activity]] helps [[differentiate|differentiating]] [[benign tumors]] from [[adrenocortical adenoma]]s.<ref name="Weidner's">{{cite book |author=Richard Cote, Saul Suster, Lawrence Weiss, Noel Weidner (Editor) |title=Modern Surgical Pathology (2 Volume Set) |publisher=W B Saunders |location=London |year= |pages= |isbn=0-7216-7253-1 |oclc= |doi=}}</ref>
 
'''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 spindle|mitotic figures]]/50 HPF, counting 10 random fields in area of greatest number of [[Mitotic spindle|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 spindle|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 muscle|smooth muscles]] in wall; [[tumor]] cell clusters or sheets forming polypoid projections into vessel lumen or polypoid [[tumor]] [[thrombi]] covered by [[Endothelium|endothelial]] layer)
* [[Sinusoidal]] [[invasion]] ([[sinusoid]] is [[endothelial]] lined [[vessel]] in [[adrenal gland]] with little supportive [[Tissue (anatomy)|tissue]]; consider only [[sinusoids]] within [[tumor]])
* [[Capsule|Capsular]] [[invasion]] (nests or cords of [[tumor]] extending into or through [[capsule]] with a [[stromal]] reaction); either incomplete or complete
 
==== '''Modified Weiss criteria (score of 3 or more suggests malignancy):''' ====
* [[Mitotic spindle|Mitotic rate]] >5 per 50 high-power fields
* [[Cytoplasm]] (clear cells comprising 25% or less of the [[tumor]])
* Abnormal [[mitoses]]
* [[Necrosis]]
* [[Capsule|Capsular]] [[invasion]]
 
[[Image:800px-Adrenal_cortical_carcinoma_-_low_mag.jpg‎|centre|thumb|800x800px|Micrograph of an adrenocortical carcinoma (left of image - dark blue) and the adrenal cortex it arose from (right-top of image - pink/light blue). Benign adrenal medulla is present (right-middle of image - gray/blue). H&E stain. - Source: https://librepathology.org]]
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<sup>Micrograph of an adrenocortical carcinoma (left of image - dark blue) and the adrenal cortex it arose from (right-top of image - pink/light blue). Benign adrenal medulla is present (right-middle of image - gray/blue). H&E stain.</sup>
====Video====
====Video====
Shown below is a video explaining the histology of adrenocortical carcinoma
Shown below is a video explaining the histology of adrenocortical carcinoma


{{#ev:youtube|7jMFENhPaOM}}
{{#ev:youtube|7jMFENhPaOM}}
==References==
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Latest revision as of 18:46, 30 October 2017

Adrenocortical carcinoma Microchapters

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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]

Overview

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.

Pathophysiology

Spread can take several forms: [4]

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]

Genetics

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

1. Clonality

2. Gene expression arrays

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

3. MicroRNAs

microRNA function, source: By Kelvinsong - Own work, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=23311105

4. Gene mutations

  • 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]
WNT pathwayssource: By Fred the OysteriThe source code of this SVG is valid.This vector graphics image was created with Adobe Illustrator., GFDL, https://commons.wikimedia.org/w/index.php?curid=36340188

5. Chromosomal aberrations

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

6. Epigenetic changes

Cellular signaling pathway

1. IGF pathway

2. WNT signaling pathway

  • Initial alterations of the WNT/ catenin system/pathway were identified in FAP.[34]
  • Both nuclear catenin accumulation and activating CTNNB1 mutations are present in ACCs suggesting WNT activation to be a part of ACA tumorigenesis.

3. Vascular endothelial growth factor

VEGF signaling, source: By Mikael Häggström.When using this image in external works, it may be cited as:Häggström, Mikael (2014). "Medical gallery of Mikael Häggström 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 2002-4436. Public Domain.orBy Mikael Häggström, used with permission. - [1]Interactions of VEGF ligands and VEGF receptors ResearchVEGF.com, retrieved on November, 13, 2009, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3475250

Hormones biosynthesis in adrenal cortex

source: By David Richfield (User:Slashme) and Mikael Häggström. Derived from previous version by Hoffmeier and Settersr.In external use, this diagram may be cited as:Häggström M, Richfield D (2014). "Diagram of the pathways of human steroidogenesis". Wikiversity Journal of Medicine 1 (1). DOI:10.15347/wjm/2014.005. ISSN 20018762. - Self-made using bkchem and inkscape, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=6355511

Associated Conditions

Associated diseases with adrenocortical carcinoma are:

Gross Pathology

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. - By AFIP Atlas of Tumor Pathology - [1], Domena publiczna, https://commons.wikimedia.org/w/index.php?curid=6719487

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.

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 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:

Modified Weiss criteria (score of 3 or more suggests malignancy):

Micrograph of an adrenocortical carcinoma (left of image - dark blue) and the adrenal cortex it arose from (right-top of image - pink/light blue). Benign adrenal medulla is present (right-middle of image - gray/blue). H&E stain. - Source: https://librepathology.org







Video

Shown below is a video explaining the histology of adrenocortical carcinoma

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