3,881
edits
Changes
BRST5:Adenoid Cystic Carcinoma (view source)
Revision as of 13:17, 29 February 2024
, 13:17, 29 February 2024Jennelleh moved page Adenoid Cystic Carcinoma to BRST5:Adenoid Cystic Carcinoma without leaving a redirect: Move to namespace BRST5
|-
|-
|'''Laboratory Findings'''
|'''Laboratory Findings'''
|Not applicable
|N/A
|}
|}
==Morphologic Features==
==Morphologic Features==
Tubular, cribriform, and solid patterns are observed.
The classic subtype contains epithelial and myoepithelial cells with spaces called pseudolamina that contain stromal matrix with stromal cells (endothelial cells, fibroblasts) and basement membrane material (stains positive for collagen IV and laminin). Two cell populations are observed: an epithelial component that stains with low molecular weight cytokeratins (CK7, CK8), EMA, and sometimes CK5/6, and a myoepithelial component that stains with high molecular weight cytokeratins (CK14, CK5/6, p63) and typically also with myoepithelial markers (heavy-chain myosin, calponin, S100, CD10).
The solid basaloid subtype contains solid nests of basaloid cells with high grade nuclear features (marked nuclear atypia, high mitotic count, and necrosis).
Rare cases of adenoid cystic carcinoma can undergo high-grade transformation.
==Immunophenotype==
==Immunophenotype==
!Finding!!Marker
!Finding!!Marker
|-
|-
|Positive (universal)||Epithelial cells: low molecular weight cytokeratins CK7 and CK8; EMA
|Positive (universal)||Epithelial cells: low molecular weight cytokeratins CK7 and CK8; EMA; SOX10<ref name=":0">{{Cite journal|last=Yang|first=Chen|last2=Zhang|first2=Lingxin|last3=Sanati|first3=Souzan|date=2019|title=SOX10 Is a Sensitive Marker for Breast and Salivary Gland Adenoid Cystic Carcinoma: Immunohistochemical Characterization of Adenoid Cystic Carcinomas|url=https://pubmed.ncbi.nlm.nih.gov/31105427|journal=Breast Cancer: Basic and Clinical Research|volume=13|pages=1178223419842185|doi=10.1177/1178223419842185|issn=1178-2234|pmc=6501487|pmid=31105427}}</ref>
Myoepithelial cells: CK14, CK5/6, p63
Myoepithelial cells: MYB<ref>{{Cite journal|last=Poling|first=Justin S.|last2=Yonescu|first2=Raluca|last3=Subhawong|first3=Andrea P.|last4=Sharma|first4=Rajni|last5=Argani|first5=Pedram|last6=Ning|first6=Yi|last7=Cimino-Mathews|first7=Ashley|date=2017-07|title=MYB Labeling by Immunohistochemistry Is More Sensitive and Specific for Breast Adenoid Cystic Carcinoma than MYB Labeling by FISH|url=https://pubmed.ncbi.nlm.nih.gov/28498281|journal=The American Journal of Surgical Pathology|volume=41|issue=7|pages=973–979|doi=10.1097/PAS.0000000000000878|issn=1532-0979|pmid=28498281}}</ref>; CK14, CK5/6, SOX10<ref name=":0" />
|-
|-
|Positive (subset)||Epithelial cells: KIT (CD117)
|Positive (subset)||Epithelial cells: KIT (CD117)
Myoepithelial cells: heavy-chain myosin, calponin, S100, CD10
Myoepithelial cells: heavy-chain myosin, calponin, S100, CD10, p63
|-
|-
|Negative (universal)||ER, PR, HER2, neuroendocrine markers (chromogranin, synaptophysin)
|Negative (universal)||ER, PR, HER2, neuroendocrine markers (chromogranin, synaptophysin)
==Chromosomal Rearrangements (Gene Fusions)==
==Chromosomal Rearrangements (Gene Fusions)==
Recurrent rearrangements of ''MYB'' (or, more rarely, the paralogous gene ''MYBL1'') preserve the N-terminal DNA binding domain and transactivation domain in the chimeric gene product. The C-terminal regulatory domains of ''MYB'' or ''MYBL1'' is generally absent in the active fusion, but the intact gene sequence is preserved in reported cases of ''MYB'' amplification and in some ''MYBL1'' rearrangements.<ref name=":1">{{Cite journal|last=Persson|first=Marta|last2=Andrén|first2=Ywonne|last3=Mark|first3=Joachim|last4=Horlings|first4=Hugo M.|last5=Persson|first5=Fredrik|last6=Stenman|first6=Göran|date=2009-11-03|title=Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck|url=https://pubmed.ncbi.nlm.nih.gov/19841262|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=106|issue=44|pages=18740–18744|doi=10.1073/pnas.0909114106|issn=1091-6490|pmc=2773970|pmid=19841262}}</ref><ref name=":2">{{Cite journal|last=Kim|first=Jisun|last2=Geyer|first2=Felipe C.|last3=Martelotto|first3=Luciano G.|last4=Ng|first4=Charlotte Ky|last5=Lim|first5=Raymond S.|last6=Selenica|first6=Pier|last7=Li|first7=Anqi|last8=Pareja|first8=Fresia|last9=Fusco|first9=Nicola|date=2018-02|title=MYBL1 rearrangements and MYB amplification in breast adenoid cystic carcinomas lacking the MYB-NFIB fusion gene|url=https://pubmed.ncbi.nlm.nih.gov/29149504|journal=The Journal of Pathology|volume=244|issue=2|pages=143–150|doi=10.1002/path.5006|issn=1096-9896|pmc=5839480|pmid=29149504}}</ref> Single cases of other fusions have been reported, including a ''KMT2C''::''WEE2'' fusion reported by Schwartz and others<ref name=":8">{{Cite journal|last=Schwartz|first=Christopher J.|last2=Brogi|first2=Edi|last3=Marra|first3=Antonio|last4=Da Cruz Paula|first4=Arnaud F.|last5=Nanjangud|first5=Gouri J.|last6=da Silva|first6=Edaise M.|last7=Patil|first7=Sujata|last8=Shah|first8=Shreena|last9=Ventura|first9=Katia|date=2022-02|title=The clinical behavior and genomic features of the so-called adenoid cystic carcinomas of the solid variant with basaloid features|url=https://pubmed.ncbi.nlm.nih.gov/34599282|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=35|issue=2|pages=193–201|doi=10.1038/s41379-021-00931-6|issn=1530-0285|pmc=9197148|pmid=34599282}}</ref>,
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
|No
|No
|Yes
|Yes
|Most common fusion breakpoints involve exon 14 of MYB fused to exon 9 or exon 8c of NFIB
|Most common fusion breakpoints involve exon 14 of ''MYB'' fused to exon 9 or exon 8c of ''NFIB''.<ref name=":1" /><ref>{{Cite journal|last=D'Alfonso|first=Timothy M.|last2=Mosquera|first2=Juan Miguel|last3=MacDonald|first3=Theresa Y.|last4=Padilla|first4=Jessica|last5=Liu|first5=Yi-Fang|last6=Rubin|first6=Mark A.|last7=Shin|first7=Sandra J.|date=2014-11|title=MYB-NFIB gene fusion in adenoid cystic carcinoma of the breast with special focus paid to the solid variant with basaloid features|url=https://pubmed.ncbi.nlm.nih.gov/25217885|journal=Human Pathology|volume=45|issue=11|pages=2270–2280|doi=10.1016/j.humpath.2014.07.013|issn=1532-8392|pmid=25217885}}</ref><ref name=":3">{{Cite journal|last=Martelotto|first=Luciano G.|last2=De Filippo|first2=Maria R.|last3=Ng|first3=Charlotte K. Y.|last4=Natrajan|first4=Rachael|last5=Fuhrmann|first5=Laetitia|last6=Cyrta|first6=Joanna|last7=Piscuoglio|first7=Salvatore|last8=Wen|first8=Huei-Chi|last9=Lim|first9=Raymond S.|date=2015-10|title=Genomic landscape of adenoid cystic carcinoma of the breast|url=https://pubmed.ncbi.nlm.nih.gov/26095796|journal=The Journal of Pathology|volume=237|issue=2|pages=179–189|doi=10.1002/path.4573|issn=1096-9896|pmc=4676955|pmid=26095796}}</ref>
|-
|t(8;9)(q13.1;p23)
|''MYBL1''::''NFIB''
|
|
|
|
|
|Reported breakpoints involve exon 14 of ''MYBL1'' fused to exon 9 of ''NFIB''<ref name=":2" />
|-
|t(6;v)(q23.3;v)
|''MYB''
|
|
|
|
|
|Fusions involving ''MYB'' with other gene partners or complex structural abnormalities associated with ''MYB'' gene fusion generate more complex karyotypes. Loss of 3' portion of ''MYB'' reported in one case<ref name=":2" />. Other reported ''MYB'' fusion partners include ''EWSR1'' (with ''EWSR1'' as the 5' partner, exon 10, fused to exon 2 of ''MYB'')<ref>{{Cite journal|last=Lei|first=Ting|last2=Shi|first2=Yongqiang|last3=Da|first3=Wenyue|last4=Xia|first4=Cunyan|last5=Wang|first5=Hui|date=2023-01-31|title=A novel EWSR1-MYB fusion in an aggressive advanced breast adenoid cystic carcinoma with mixed classical and solid-basaloid components|url=https://pubmed.ncbi.nlm.nih.gov/36719454|journal=Virchows Archiv: An International Journal of Pathology|doi=10.1007/s00428-023-03500-1|issn=1432-2307|pmid=36719454}}</ref>.
|-
|t(8;v)(q13.1;v)
|''MYBL1''
|
|
|
|
|
|Fusions involving ''MYBL1'' with other gene partners or more complex structural abnormalities associated with ''MYBL1'' gene fusion generate more complex karyotypes. Other reported ''MYBL1'' gene partners include ''ACTN1''<ref name=":2" />.
|}
|}
==Individual Region Genomic Gain/Loss/LOH==
==Individual Region Genomic Gain/Loss/LOH==
Amplification or copy state transitions (gain or loss) on 6q23.3 associated with ''MYB'' rearrangement are the most commonly reported alterations in adenoid cystic carcinoma. Other individually reported alterations include gains of 1p36.12–p35.3, 11p15.5, 12p13.31, 16p13.3, and 19p13, and losses of 6q25.3-q26 and 9p11.1–q21.11 in an array CGH study of 14 adenoid cystic carcinomas by Wetterskog and others<ref name=":4">{{Cite journal|last=Wetterskog|first=Daniel|last2=Lopez-Garcia|first2=Maria Angeles|last3=Lambros|first3=Maryou B.|last4=A'Hern|first4=Roger|last5=Geyer|first5=Felipe C.|last6=Milanezi|first6=Fernanda|last7=Cabral|first7=Maria C.|last8=Natrajan|first8=Rachael|last9=Gauthier|first9=Arnaud|date=2012-01|title=Adenoid cystic carcinomas constitute a genomically distinct subgroup of triple-negative and basal-like breast cancers|url=https://pubmed.ncbi.nlm.nih.gov/22015727|journal=The Journal of Pathology|volume=226|issue=1|pages=84–96|doi=10.1002/path.2974|issn=1096-9896|pmid=22015727}}</ref>, gains of 17q21-q25.1 and losses of 12q12-q14.1 detected by whole exome sequencing on 12 adenoid cystic carcinoma in a study by Martelotto and others<ref name=":3" />, and a terminal 6q loss in one case (6q23.3-6q27) and whole chromosome losses (-4, -7, -14, -X) in a second case by targeted next generation sequencing in a study by Fusco and others<ref name=":6">{{Cite journal|last=Fusco|first=Nicola|last2=Geyer|first2=Felipe C.|last3=De Filippo|first3=Maria R.|last4=Martelotto|first4=Luciano G.|last5=Ng|first5=Charlotte K. Y.|last6=Piscuoglio|first6=Salvatore|last7=Guerini-Rocco|first7=Elena|last8=Schultheis|first8=Anne M.|last9=Fuhrmann|first9=Laetitia|date=2016-11|title=Genetic events in the progression of adenoid cystic carcinoma of the breast to high-grade triple-negative breast cancer|url=https://pubmed.ncbi.nlm.nih.gov/27491809|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=29|issue=11|pages=1292–1305|doi=10.1038/modpathol.2016.134|issn=1530-0285|pmc=5083185|pmid=27491809}}</ref>. A terminal loss on 6q (6q23.3-6q27) detected by array CGH was separately reported in a case with ''MYB'' rearrangement by Kovacs and others<ref name=":7">{{Cite journal|last=Kovács|first=Anikó|last2=Persson|first2=Fredrik|last3=Persson|first3=Marta|last4=Andersson|first4=Mattias K.|last5=Stenman|first5=Göran|date=2017-09|title=Genomic imbalances and MYB fusion in synchronous bilateral adenoid cystic carcinoma and invasive lobular carcinoma of the breast|url=https://pubmed.ncbi.nlm.nih.gov/28894575|journal=Molecular and Clinical Oncology|volume=7|issue=3|pages=322–326|doi=10.3892/mco.2017.1330|issn=2049-9450|pmc=5582535|pmid=28894575}}</ref>. Recurrent copy number alterations reported in a study by Masse and others included losses on 12q, losses or gains on 17p, and amplification of ''CCND1'' on 11q13.3 detected by array CGH<ref name=":5" />. The common recurrent alterations are shown in the table below.
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
|6
|6
|Gain
|Amp
|chr6:135,502,453-135,540,311 [GRCh37/hg19]
|chr6:135,502,453-135,540,311 [GRCh37/hg19]
|6q23.3
|6q23.3
|No
|No
|No
|No
|MYB amplification
|''MYB'' amplification in one case reported as a range of 3-10 copies by FISH associated with ''MYB'' overexpression<ref name=":2" />; two others reported in a study by Yao and others without copy number specified<ref>{{Cite journal|last=Yao|first=Qian|last2=Hou|first2=Wei|last3=Chen|first3=Junbing|last4=Bai|first4=Yanhua|last5=Long|first5=Mengping|last6=Huang|first6=Xiaozheng|last7=Zhao|first7=Chen|last8=Zhou|first8=Lixin|last9=Niu|first9=Dongfeng|date=2022|title=Comparative proteomic and clinicopathological analysis of breast adenoid cystic carcinoma and basal-like triple-negative breast cancer|url=https://pubmed.ncbi.nlm.nih.gov/35966872|journal=Frontiers in Medicine|volume=9|pages=943887|doi=10.3389/fmed.2022.943887|issn=2296-858X|pmc=9366086|pmid=35966872}}</ref>
|-
|-
|
|6
|
|Gain or Loss
|
|chr6:135,502,453-135,540,311 [GRCh37/hg19]
|
|6q23.3
|
|Yes
|
|No
|
|No
|
|Copy state transitions within ''MYB'' gene region typically associated with ''MYB'' fusion<ref name=":6" /><ref name=":7" />
|}
|}
==Characteristic Chromosomal Patterns==
==Characteristic Chromosomal Patterns==
{| class="wikitable sortable"
{| class="wikitable sortable"
!Notes
!Notes
|-
|-
|
|N/A
|
|N/A
|
|N/A
|
|N/A
|
|N/A
|}
|}
==Gene Mutations (SNV/INDEL)==
==Gene Mutations (SNV/INDEL)==
Common recurrent mutations are shown in the table below. Others include ''ARID1A''<ref name=":5" />, ''PIK3R1''<ref name=":5" />, and ''TLN2''<ref name=":3" />.
{| class="wikitable sortable"
{| class="wikitable sortable"
!Notes
!Notes
|-
|-
|NOTCH1; inactivating sequence variants (missense, nonsense, truncating)
|''NOTCH1'', ''NOTCH2'', and ''NOTCH3''; sequence variants <ref name=":5">{{Cite journal|last=Massé|first=Julie|last2=Truntzer|first2=Caroline|last3=Boidot|first3=Romain|last4=Khalifa|first4=Emmanuel|last5=Pérot|first5=Gaëlle|last6=Velasco|first6=Valérie|last7=Mayeur|first7=Laétitia|last8=Billerey-Larmonier|first8=Claire|last9=Blanchard|first9=Larry|date=2020-06|title=Solid-type adenoid cystic carcinoma of the breast, a distinct molecular entity enriched in NOTCH and CREBBP mutations|url=https://pubmed.ncbi.nlm.nih.gov/31857685|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=33|issue=6|pages=1041–1055|doi=10.1038/s41379-019-0425-3|issn=1530-0285|pmid=31857685}}</ref>
|Gain of function
|22-28% solid basaloid subtype <ref name=":8" /> <ref name=":5" />
|
|
|
|
|
|Mostly solid basaloid subtype, with poorer prognosis <ref name=":8" /> NOTCH mutations cause resistance to BET bromodomain inhibitors<br />
|-
|''CREBBP''; inactivating sequence variants <ref name=":5" />
|Loss of function
|Loss of function
|26%
|17-33% solid basaloid subtype <ref name=":8" /><ref name=":5" />
|
|
|
|
|
|
|
|
|Mostly solid basaloid subtype<br />
|Mostly solid basaloid subtype, with poorer prognosis
|-
|-
|CREBBP; inactivating sequence variants (missense, nonsense, truncating)
|''KMT2C''; inactivating sequence variants, deletion <ref name=":5" />
|Loss of function
|Loss of function
|21%
|22% solid basaloid subtype in one study <ref name=":8" />
|
|
|
|
|
|
|
|
|Mostly solid basaloid subtype
|Mostly solid basaloid subtype, with poorer prognosis
|-
|''KDM6A''; inactivating sequence variants
|Loss of function
|22% solid basaloid subtype in one study <ref name=":8" />
|
|
|
|
|
|Mostly solid basaloid subtype, with poorer prognosis
|-
|''CDK12''; missense<ref name=":5" />
|Loss of function
|38% solid basaloid subtype in one study <ref name=":5" />
|
|
|
|
|
|Mostly solid basaloid subtype, with poorer prognosis
|}
|}
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases.
==Epigenomic Alterations==
==Epigenomic Alterations==
<br />
==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|-
|MYB; gene fusion or amplification
|''MYB''; gene fusion or amplification
|Cell cycle, DNA replication, DNA repair
|Cell cycle (MYC and NOTCH signaling), DNA replication, DNA repair
|Promotes cellular proliferation
|Promotes cellular proliferation
|-
|-
|
|''MYBL1''; gene fusion
|
|Cell cycle (MYC and NOTCH signaling), DNA replication, DNA repair
|
|Promotes cellular proliferation
|-
|-
|
|''NOTCH1'', ''NOTCH2'', ''NOTCH3''
|
|NOTCH signaling
|
|Promotes cellular proliferation
|}
|}
A study of adenoid cystic carcinoma of salivary glands by Drier and others delineates the mechanism of ''MYB'' gene pathway upregulation via rearrangements that increase MYB expression. ''MYB'' rearrangements typically juxtapose ''MYB'' with strong enhancers in regions downstream of ''NFIB, TGFBR3'' and ''RAD51B.'' Gene fusions most often occur on the 3' side of ''MYB'', a subset of gene fusions occur on the 5' side, and all serve to bring the ''MYB'' gene locus close to strong enhancer elements, thus upregulating MYB expression. The authors note that TP63 signaling is active in the myoepithelial component of low grade adenoid cystic carcinomas, while Notch signaling is active in luminal epithelial components. Furthermore, the authors suggest that Notch pathway mutations may underlie the switch to solid histology and the more aggressive clinical course of these tumors.<ref>{{Cite journal|last=Drier|first=Yotam|last2=Cotton|first2=Matthew J.|last3=Williamson|first3=Kaylyn E.|last4=Gillespie|first4=Shawn M.|last5=Ryan|first5=Russell J. H.|last6=Kluk|first6=Michael J.|last7=Carey|first7=Christopher D.|last8=Rodig|first8=Scott J.|last9=Sholl|first9=Lynette M.|date=2016-03|title=An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma|url=https://pubmed.ncbi.nlm.nih.gov/26829750|journal=Nature Genetics|volume=48|issue=3|pages=265–272|doi=10.1038/ng.3502|issn=1546-1718|pmc=4767593|pmid=26829750}}</ref>
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==
FISH for MYB rearrangement; RT-PCR for MYB-NFIB fusion transcript; RNA-based sequencing (whole transcriptome or targeted)
FISH for MYB rearrangement; RT-PCR for MYB-NFIB fusion transcript; RNA-based sequencing (whole transcriptome or targeted)
[[File:MYB FISH break-apart probe.png|none|thumb|FISH with a break-apart probe targeting the 5' (red) and 3' (green) ''MYB'' gene region. Juxtaposed red and green signals indicate alleles with an intact ''MYB'' gene locus, and split / separated red and green signals indicate alleles with ''MYB'' rearrangement. The separation in this case is small, suggesting an inversion (i.e., intrachromosomal rearrangement).]]
[[File:Negative MYB FISH.tif|none|thumb|FISH with a break-apart probe targeting the 5' (red) and 3' (green) ''MYB'' gene region. This sample was negative for ''MYB'' rearrangement, and the majority of cells showed 1-3 fused red/green signals (juxtaposed red and green probe signals), consistent with an intact (unrearranged) ''MYB'' gene region.]]
<br />
==Familial Forms==
==Familial Forms==
<br />
==Additional Information==
==Additional Information==
<br />
==Links==
==Links==
<br />
==References==
==Reference==
<references />
<references />
==Notes==
==Notes==
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.