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| __NOTOC__ | | __NOTOC__ |
| {{Adrenocortical carcinoma}} | | {{Adrenocortical carcinoma}} |
| {{CMG}} {{AE}} {{RT}}{{AAM}} | | {{CMG}}; {{AE}} {{RT}} {{AAM}} {{MAD}} |
| ==Overview== | | ==Overview== |
| There are no established causes for adrenocortical carcinoma. | | 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 more than 50% to 80% of children. |
| ==Causes== | | ==Causes== |
| *There are no established causes for Adrenocortical carcinoma. | | *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. | | *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. |
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| == Genetics == | | == Genetics == |
| The [[Genetics|genetic]] dissection of ACC has revealed [[Genomics|genomic]] aberrations that contribute to [[Neoplastic disease|neoplastic]] transformation of [[Adrenal cortex|adrenocortical]] cells:
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| '''''1. [[Clone (cell biology)|Clonality]]'''''
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| * ACCs initiate from [[Monoclonal|monoclonal cell]] populations, suggesting that [[mutation]] events lead to [[Clonal selection|clonal expansion]] and ultimate progression to [[cancer]].<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid7915195-6|[6]]]</sup>
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| * [[Flow cytometry]] revealed [[aneuploidy]] in ACC. [[aneuploidy]] was observed in 75% of ACC.<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid7910530-7|[7]]]</sup>
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| * 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]]).<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid3617290-8|[8]]]</sup>
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| * No significant difference in overall survival was observed in patients with ACC exhibiting [[aneuploidy]] vs patients with ACC exhibiting [[Diploids|diploid]] [[Neoplasm|neoplasms]].<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid2403197-9|[9]]]</sup>
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| '''''2. [[Gene expression]] [[DNA microarray|arrays]]'''''
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| * An initial study identified elevated [[Gene expression|expression of genes]] involved in cell proliferation in ACC, such as ''[[IGF2]]'', compared with increased [[Gene expression|expression]] of steroidogenic [[genes]] in ACA.<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid15613424-10|[10]]]</sup>
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| * 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.<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid19147773-11|[11]]]</sup>
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| * Giordano et al (192) 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.
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| * Expression levels of ''BUB1B,'' ''[[PINK1]], and [[DLG7]]'' ''are'' identified in ACC.<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid19139432-12|[12]]]</sup>
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| ==== 3. '''''[[MicroRNAs]]''''' ====
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| * [[MicroRNAs]] are [[RNA|RNAs]] that are important in the regulation of [[gene expression]].
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| * Numerous [[MicroRNA|miRNAs]] have been identified in the regulation of various [[cellular]] processes such as [[proliferation]], [[Apoptosis|apoptosis,]] and [[differentiation]].<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid21116305-13|[13]]]</sup>
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| * Dysregulation of miRNAs, such as overexpression or deletion, plays an important role in diseases.
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| * Mistargeting of the miRNAs, resulting in inhibition or activation of various [[oncogenes]], [[Tumor suppressor|tumor suppressors]], and other factors important in [[tumor]] [[Angiogenesis|angiogenesis.]]<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid22337054-14|[14]]]</sup>
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| * The investigation identified 14 upregulated miRNAs and 9 downregulated miRNAs unique to ACC.<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid19996210-15|[15]]]</sup>
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| * Upregulated miRNAs in ACCs included miR-184, miR-210, and miR-503.
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| * Downregulated miRNAs included miR-214, miR-375, and miR-511.<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid19546168-16|[16]]]</sup>
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| * Levels of miR-184, miR-503, and miR-511 are able to distinguish benign from [[malignant]] [[Adrenal tumor|adrenal tumors]].<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid19546168-16|[16]]]</sup>
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| * MiR-483 was found to be significantly upregulated in pediatric ACCs.
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| * 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.<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid20484036-17|[17]]]</sup>
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| ==== 4. '''''[[Gene mutation|Gene mutations]]''''' ====
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| * 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]]''.<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid11454518-18|[18]]]</sup>
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| * ''[[TP53 (gene)|TP53]]'' located on 17p13 is the most commonly mutated [[gene]] in ACC, present in at least one-third of ACCs.<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid22504887-19|[19]]]</sup>
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| * 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.<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid10022445-20|[20]]]</sup>
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| * ''[[MEN1]]'' somatic mutations are unusual in sporadic ACC.<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid17854394-21|[21]]]</sup>
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| * 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.<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid18647815-22|[22]]]</sup>
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| ==== 5. '''''[[Chromosomal aberration|Chromosomal aberrations]]''''' ====
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| * [[Comparative genomic hybridization]]([[Comparative genomic hybridization|CGH]]) can identify structural [[chromosomal]] abnormalities within ACCs.<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid23093492-23|[23]]]</sup>
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| * ACCs showed complex chromosomal alterations. ACCs contained multiple chromosomal gains or losses with a mean of 10 events.
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| * The newest study confirmed increased alterations in ACC (44%) compared with ACAs (10%).
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| * In ACCs, the frequently observed [[chromosomal]] gains at 5, 7, 12, 16, 19, and 20 and losses at 13 and 22 were confirmed.
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| * The group identified genes within these regions with potential tumorigenic potential including [[Fibroblast growth factor|fibroblast growth factor 4]] (''[[FGF4]]''), [[cyclin-dependent kinase 4]] (''[[CDK4]]''), and [[cyclin E1]]([[CCNE1|''CCNE1'')]]. The study confirmed the diagnostic utility of 6 [[loci]] (5q, 7p, 11p, 13q, 16q, and 22q) in the differentiation of ACA and ACC.
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| * [[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]]''.
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| === 6. '''''[[Epigenetics|Epigenetic]]''''' ===
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| * [[DNA methylation]] involves the addition of a [[methyl group]] to the [[cytosine]] [[pyrimidine]] ring or [[adenine]] [[purine]] ring.<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid25111790-24|[24]]]</sup>
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| * Dysregulation in this process is observed in [[Tumor cell|tumor cells.]]
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| * 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 also provided evidence about the role of [[methylation]] in ACC [[tumorigenesis]], particularly in the 11p15 [[locus]] containing ''[[IGF2]]'' and ''[[H19 (gene)|H19]]''.
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| === Hereditary syndromes associated with adrenocortical carcinoma are: === | | === Hereditary syndromes associated with adrenocortical carcinoma are: === |
| * [[Lynch syndrome]] | | * [[Lynch syndrome]] |
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| ! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Differential Diagnosis}} | | ! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Associated conditions}} |
| ! style="background: #4479BA; width: 300px;" | {{fontcolor|#FFF|Gene mutations}}
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| ! style="background: #4479BA; width: 300px;" | {{fontcolor|#FFF|Clinical picture}}
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| | style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |Lynch syndrome
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| * MSH2, MSH6, MLH1, PMS2
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| * Colorectal cancer
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| * Endometrial cancer
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| * Sebaceous neoplasms
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| * Ovarian cancer
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| * Pancreatic cancer
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| * Brain cancer
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| | style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |Neurofibromatosis
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| type 1
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| * NF1
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| * Malignant peripheral nerve sheet tumor
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| * Pheochromocytoma
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| * Café au lait spots
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| * Neurofibroma
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| * Optic glioma
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| * Lisch nodule
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| * Skeletal abnormalities
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| | '''MEN1'''
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| * MENIN
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| * Foregut neuroendocrine tumors
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| * Pituitary tumors
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| * Parathyroid hyperplasia
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| * Collagenoma
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| * Angiofibroma
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| * Adrenal adenoma/hyperplasia
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| | style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |Carney complex
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| * PRKAR1A
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| * Primary pigmented nodular
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| * Adrenal disease
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| * Large-cell calcifying Sertoli cell tumors
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| * Thyroid adenoma
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| * Myxoma
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| * Somatotroph pituitary adenoma
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| | style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |BWS 41
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| * IGF2, CDKN1C, H19
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| * Wilms’ tumor
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| * Hepatoblastoma
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| * Macrosomia
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| * Adrenocortical cytomegaly
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| * Adrenal adenoma
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| * Adrenal cyst
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| * Hemihypertrophy
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| * Macroglossia
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| * Omphalocele
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| |}
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| {| style="border: 0px; font-size: 90%; margin: 3px; width: 1000px" align="center"
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| ! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Differential Diagnosis}}
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| ! style="background: #4479BA; width: 300px;" | {{fontcolor|#FFF|Gene mutations}} | | ! style="background: #4479BA; width: 300px;" | {{fontcolor|#FFF|Gene mutations}} |
| ! style="background: #4479BA; width: 300px;" | {{fontcolor|#FFF|Clinical picture}} | | ! style="background: #4479BA; width: 300px;" | {{fontcolor|#FFF|Clinical picture}} |
| |- | | |- |
| | style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |[[Lynch syndrome]] | | | style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |[[Lynch syndrome]]<ref name="pmid26309352">{{cite journal| author=Carethers JM, Stoffel EM| title=Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer. | journal=World J Gastroenterol | year= 2015 | volume= 21 | issue= 31 | pages= 9253-61 | pmid=26309352 | doi=10.3748/wjg.v21.i31.9253 | pmc=4541378 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26309352 }}</ref> |
| | style="padding: 5px 5px; background: #F5F5F5;" | | | | style="padding: 5px 5px; background: #F5F5F5;" | |
| * [[MSH2]], [[MSH6]], [[MLH1]], [[PMS2]] | | * [[MSH2]], [[MSH6]], [[MLH1]], [[PMS2]] |
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| * [[Omphalocele]] | | * [[Omphalocele]] |
| |} | | |} |
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| ==References== | | ==References== |