BRST5:Papillary ductal carcinoma in situ: Difference between revisions

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[[BRST5:Table_of_Contents|Breast Tumours (WHO Classification, 5th ed.)]]

==Primary Author(s)*==

Sresi Singh

Sresi Singh and Katherine Geiersbach, MD

==WHO Classification of Disease==

Line 56:

|}

==Individual Region Genomic Gain/Loss/LOH==

Copy-number alterations are common genomic events in ductal carcinoma in situ and other papillary breast neoplasms. Recurrent chromosomal changes include gains of chromosome arms 1q and 8q, loss of 16q~~, and amplification~~ of 17q12 containing the ERBB2 gene~~, which~~ contributes to HER2 overexpression in a subset of lesions.

Copy-number alterations are common genomic events in ductal carcinoma in situ and other papillary breast neoplasms. Recurrent chromosomal changes include gains of chromosome arms 1q and 8q, loss of 16q. Amplification of 17q12 containing the ''ERBB2'' gene contributes to HER2 overexpression in a subset of lesions and has been associated with malignancy rather than DCIS.<ref name=":0">{{Cite journal|last=Rakha|first=Emad A.|last2=Tan|first2=Puay Hoon|last3=Raymond|first3=Wendy A.|date=2026-03|title=The spectrum of breast in situ papillary carcinomas with invasion and invasive breast carcinomas with papillary features: an overview of histological subtypes and diagnostic challenges|url=https://pubmed.ncbi.nlm.nih.gov/41404713|journal=Histopathology|volume=88|issue=4|pages=747–768|doi=10.1111/his.70072|issn=1365-2559|pmc=12891923|pmid=41404713}}</ref>

{| class="wikitable sortable"

|-

Line 70:

|P

|No

|Gain of chromosome 1q is frequently observed in early breast neoplasia including DCIS and contributes to tumor progression.

|Gain of chromosome 1q is frequently observed in early breast neoplasia including DCIS and contributes to tumor progression. In papillary lesions, 1q gains including 1q21.3-1q23.1 (including PRCC and NTRK1) have been associated with intracystic papillary carcinoma but not concurrent DCIS.<ref name=":1">{{Cite journal|last=Khoury|first=Thaer|last2=Hu|first2=Qiang|last3=Liu|first3=Song|last4=Wang|first4=Jianmin|date=2014-02|title=Intracystic papillary carcinoma of breast: interrelationship with in situ and invasive carcinoma and a proposal of pathogenesis: array comparative genomic hybridization study of 14 cases|url=https://pubmed.ncbi.nlm.nih.gov/23907150|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=27|issue=2|pages=194–203|doi=10.1038/modpathol.2013.136|issn=1530-0285|pmc=4389629|pmid=23907150}}</ref>

|-

|8

|Gain

|8q24

|8q22-8q24

|MYC

|''SPAG1'', ''RHPN1'', MYC

|P

|No

|Gain of 8q results in MYC activation and increased cell proliferation in breast tumors.

|Gain of 8q results in ''MYC'' activation and increased cell proliferation in breast tumors. In papillary DCIS, gains on 8q including SPAG1 (8q22) RHPN1 (8q24) are associated with increased cell motility and cell adhesion programs.<ref name=":1" />

|-

|11

|Gain

|11q13

|CCND1

|''CCND1''

|P

|No

|Amplification of CCND1 leads to dysregulated cell cycle progression and has been reported in breast tumors.

|Amplification of ''CCND1'' leads to dysregulated cell cycle progression and has been reported in breast tumors.

|-

|13

|Loss

|13q14

|RB1

|''RB1''

|P

|No

|Loss of RB1 contributes to cell cycle dysregulation in breast cancer.

|Loss of ''RB1'' contributes to cell cycle dysregulation in breast cancer.

|-

|16

|Loss

|LOH

|16p13

|''TSC2'', ''PKD1''

|D

|No

|LOH on chromosome 16p13 was present in 10 of 16 (63%) informative cases of either papillary carcinoma or carcinoma arising in a papilloma as well as in 6 of 10 (60%) informative cases of intraductal papilloma with florid epithelial hyperplasia (IDH) in a 1998 study from the Armed Forces Institute of Pathology (AFIP), suggesting the presence of a tumor suppressor gene mutated early in papillary neoplasia. <ref>{{Cite journal|last=Lininger|first=R. A.|last2=Park|first2=W. S.|last3=Man|first3=Y. G.|last4=Pham|first4=T.|last5=MacGrogan|first5=G.|last6=Zhuang|first6=Z.|last7=Tavassoli|first7=F. A.|date=1998-10|title=LOH at 16p13 is a novel chromosomal alteration detected in benign and malignant microdissected papillary neoplasms of the breast|url=https://pubmed.ncbi.nlm.nih.gov/9781650|journal=Human Pathology|volume=29|issue=10|pages=1113–1118|doi=10.1016/s0046-8177(98)90422-1|issn=0046-8177|pmid=9781650}}</ref>

|-

|16

|Loss / LOH

|16q

|CDH1

|''CDH1''

|P

|No

|Loss of chromosome arm 16q is commonly associated with low-grade breast tumors and ductal carcinoma in situ.

|Loss of chromosome arm 16q is commonly associated with low-grade breast tumors and ductal carcinoma in situ. In papillary lesions, 16q LOH is associated with malignancy.<ref>{{Cite journal|last=Di Cristofano|first=Claudio|last2=Mrad|first2=Karima|last3=Zavaglia|first3=Katia|last4=Bertacca|first4=Gloria|last5=Aretini|first5=Paolo|last6=Cipollini|first6=Giovanna|last7=Bevilacqua|first7=Generoso|last8=Ben Romdhane|first8=Kaled|last9=Cavazzana|first9=Andrea|date=2005-03|title=Papillary lesions of the breast: a molecular progression?|url=https://pubmed.ncbi.nlm.nih.gov/15770529|journal=Breast Cancer Research and Treatment|volume=90|issue=1|pages=71–76|doi=10.1007/s10549-004-3003-3|issn=0167-6806|pmid=15770529}}</ref><ref>{{Cite journal|last=Yoshida|first=Miwa|last2=Tsuda|first2=Hitoshi|last3=Yamamoto|first3=Sohei|last4=Kinoshita|first4=Takayuki|last5=Akashi-Tanaka|first5=Sadako|last6=Hojo|first6=Takashi|last7=Fukutomi|first7=Takashi|date=2012-05|title=Loss of heterozygosity on chromosome 16q suggests malignancy in core needle biopsy specimens of intraductal papillary breast lesions|url=https://pubmed.ncbi.nlm.nih.gov/22476400|journal=Virchows Archiv: An International Journal of Pathology|volume=460|issue=5|pages=497–504|doi=10.1007/s00428-012-1200-8|issn=1432-2307|pmid=22476400}}</ref>

|-

|17

|Amp

|17q12

|ERBB2

|''ERBB2''

|D, P, T

|Yes (NCCN)

|Amplification of ERBB2 results in HER2 overexpression and may guide targeted therapy decisions in breast cancer.

|Amplification of ''ERBB2'' results in HER2 overexpression and may guide targeted therapy decisions in breast cancer. In papillary lesions, ERBB2 amplification / overexpression (HER2 positive status) is primarily associated with solid papillary carcinoma and encapsulated papillary carcinoma with apocrine features.<ref name=":0" />

|-

|

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|}

==Gene Mutations (SNV/INDEL)==

Breast tumors including ductal carcinoma in situ frequently harbor recurrent somatic mutations affecting pathways involved in cell proliferation, transcriptional regulation, and genomic stability. Commonly mutated genes include PIK3CA, TP53, and GATA3, among others. The mutational profile of papillary DCIS largely overlaps with other luminal-type breast neoplasms.

Breast tumors including ductal carcinoma in situ frequently harbor recurrent somatic mutations affecting pathways involved in cell proliferation, transcriptional regulation, and genomic stability. Commonly mutated genes include PIK3CA, TP53, and GATA3, among others<ref>{{Cite journal|last=Kader|first=Tanjina|last2=Elder|first2=Kenneth|last3=Zethoven|first3=Magnus|last4=Semple|first4=Timothy|last5=Hill|first5=Prue|last6=Goode|first6=David L.|last7=Thio|first7=Niko|last8=Cheasley|first8=Dane|last9=Rowley|first9=Simone M.|date=2020|title=The genetic architecture of breast papillary lesions as a predictor of progression to carcinoma|url=https://pubmed.ncbi.nlm.nih.gov/32195332|journal=NPJ breast cancer|volume=6|pages=9|doi=10.1038/s41523-020-0150-6|issn=2374-4677|pmc=7067788|pmid=32195332}}</ref>. The mutational profile of papillary DCIS largely overlaps with other luminal-type breast neoplasms. Intraductal papilloma (IDP) is a non-obligate precursor of papillary DCIS with a high frequency of ''PIK3CA'' and ''AKT1'' mutations observed; the majority of synchronous DCIS in cases of IDP exhibit non-papillary morphology.<ref>{{Cite journal|last=Kader|first=Tanjina|last2=Elder|first2=Kenneth|last3=Zethoven|first3=Magnus|last4=Semple|first4=Timothy|last5=Hill|first5=Prue|last6=Goode|first6=David L.|last7=Thio|first7=Niko|last8=Cheasley|first8=Dane|last9=Rowley|first9=Simone M.|date=2020|title=The genetic architecture of breast papillary lesions as a predictor of progression to carcinoma|url=https://pubmed.ncbi.nlm.nih.gov/32195332|journal=NPJ breast cancer|volume=6|pages=9|doi=10.1038/s41523-020-0150-6|issn=2374-4677|pmc=7067788|pmid=32195332}}</ref><ref>{{Cite journal|last=Troxell|first=Megan L.|last2=Levine|first2=Judith|last3=Beadling|first3=Carol|last4=Warrick|first4=Andrea|last5=Dunlap|first5=Jennifer|last6=Presnell|first6=Ajia|last7=Patterson|first7=Janice|last8=Shukla|first8=Arielle|last9=Olson|first9=Neal R.|date=2010-01|title=High prevalence of PIK3CA/AKT pathway mutations in papillary neoplasms of the breast|url=https://pubmed.ncbi.nlm.nih.gov/19898424|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=23|issue=1|pages=27–37|doi=10.1038/modpathol.2009.142|issn=1530-0285|pmid=19898424}}</ref>

{| class="wikitable sortable"

|-

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!Clinical Relevance Details/Other Notes

|-

|PIK3CA

|''PIK3CA''

|Activating mutations

|Oncogene

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|T

|Yes (NCCN)

|Activates PI3K–AKT signaling pathway leading to increased cell growth and survival. Targeted therapy for invasive disease.

|Activates PI3K–AKT signaling pathway leading to increased cell growth and survival. Targeted therapy is reserved for invasive disease.

|-

|TP53

|''AKT1''

|Activating mutations

|Oncogene

|Recurrent

|T

|Yes (NCCN)

|Activates PI3K–AKT signaling pathway leading to increased cell growth and survival. Targeted therapy is reserved for invasive disease.

|-

|''TP53''

|Inactivating mutations

|TSG

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|P

|Yes

|Associated with genomic instability and aggressive tumor behavior

|Associated with genomic instability and aggressive tumor behavior. In papillary lesions, ''TP53'' mutation is associated with malignancy.<ref>{{Cite journal|last=Di Cristofano|first=Claudio|last2=Mrad|first2=Karima|last3=Zavaglia|first3=Katia|last4=Bertacca|first4=Gloria|last5=Aretini|first5=Paolo|last6=Cipollini|first6=Giovanna|last7=Bevilacqua|first7=Generoso|last8=Ben Romdhane|first8=Kaled|last9=Cavazzana|first9=Andrea|date=2005-03|title=Papillary lesions of the breast: a molecular progression?|url=https://pubmed.ncbi.nlm.nih.gov/15770529|journal=Breast Cancer Research and Treatment|volume=90|issue=1|pages=71–76|doi=10.1007/s10549-004-3003-3|issn=0167-6806|pmid=15770529}}</ref>

|-

|GATA3

|''GATA3''

|Inactivating mutations

|Other

Line 193:

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|P

|No

|Transcription factor regulating luminal cell differentiation in breast epithelium<ref>{{Cite journal|last=Medford|first=Arielle J.|last2=Velimirovic|first2=Marko|last3=Gefen|first3=Yifat|last4=Niemierko|first4=Andrzej|last5=Gerratana|first5=Lorenzo|last6=Davis|first6=Andrew A.|last7=Clifton|first7=Katherine|last8=Keenan|first8=Jennifer|last9=Podany|first9=Emily|date=2025-08|title=Genomic and proteomic profiling of GATA3 mutant metastatic hormone receptor-positive breast cancer and impact on clinical outcomes|url=https://pubmed.ncbi.nlm.nih.gov/40439821|journal=Breast Cancer Research and Treatment|volume=212|issue=3|pages=437–447|doi=10.1007/s10549-025-07710-w|issn=1573-7217|pmc=12209021|pmid=40439821}}</ref>

|Transcription factor regulating luminal cell differentiation in breast epithelium.<ref>{{Cite journal|last=Medford|first=Arielle J.|last2=Velimirovic|first2=Marko|last3=Gefen|first3=Yifat|last4=Niemierko|first4=Andrzej|last5=Gerratana|first5=Lorenzo|last6=Davis|first6=Andrew A.|last7=Clifton|first7=Katherine|last8=Keenan|first8=Jennifer|last9=Podany|first9=Emily|date=2025-08|title=Genomic and proteomic profiling of GATA3 mutant metastatic hormone receptor-positive breast cancer and impact on clinical outcomes|url=https://pubmed.ncbi.nlm.nih.gov/40439821|journal=Breast Cancer Research and Treatment|volume=212|issue=3|pages=437–447|doi=10.1007/s10549-025-07710-w|issn=1573-7217|pmc=12209021|pmid=40439821}}</ref>

|-

|ERBB2

|''ERBB2''

|Activating mutations, amplification

|Oncogene

Line 201:

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|D, P, T

|Yes (NCCN)

|Drives HER2 signaling and may guide targeted therapy decisions.

|Drives HER2 signaling and may guide targeted therapy decisions. In papillary lesions, ''ERBB2'' amplification is primarily associated with solid papillary carcinoma and encapsulated papillary carcinoma with apocrine features and is a marker of high risk and chemotherapy benefit.<ref name=":0" />

|-

|MAP3K1

|''MAP3K1''

|Inactivating mutations

|TSG

Line 211:

Line 227:

|Implicated in MAPK signaling and luminal breast cancer development.

|-

|CDH1

|''CDH1''

|Inactivating mutations

|TSG

Line 239:

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==Genes and Main Pathways Involved==

~~Put your text here~~ and ~~fill~~ in the ~~table ~~(''Instructions~~: ~~Please include references throughout the table~~. ~~Do not delete the table~~.~~)''~~</~~span>

Overexpression of MET may be a key factor in papillary differentiation.<ref>{{Cite journal|last=Ruco|first=L. P.|last2=Stoppacciaro|first2=A.|last3=Ballarini|first3=F.|last4=Prat|first4=M.|last5=Scarpino|first5=S.|date=2001-05|title=Met protein and hepatocyte growth factor (HGF) in papillary carcinoma of the thyroid: evidence for a pathogenetic role in tumourigenesis|url=https://pubmed.ncbi.nlm.nih.gov/11329134|journal=The Journal of Pathology|volume=194|issue=1|pages=4–8|doi=10.1002/path.847|issn=0022-3417|pmid=11329134}}</ref><ref>{{Cite journal|last=Nusrat|first=A.|last2=Parkos|first2=C. A.|last3=Bacarra|first3=A. E.|last4=Godowski|first4=P. J.|last5=Delp-Archer|first5=C.|last6=Rosen|first6=E. M.|last7=Madara|first7=J. L.|date=1994-05|title=Hepatocyte growth factor/scatter factor effects on epithelia. Regulation of intercellular junctions in transformed and nontransformed cell lines, basolateral polarization of c-met receptor in transformed and natural intestinal epithelia, and induction of rapid wound repair in a transformed model epithelium|url=https://pubmed.ncbi.nlm.nih.gov/8182137|journal=The Journal of Clinical Investigation|volume=93|issue=5|pages=2056–2065|doi=10.1172/JCI117200|issn=0021-9738|pmc=294323|pmid=8182137}}</ref>

{| class="wikitable sortable"

|-

!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome

|-

|PIK3CA, AKT1; activating mutations

|''PIK3CA'', ''AKT1''; activating mutations / PTEN inactivating mutations

|PI3K-AKT-mTOR signaling

|Increased cell proliferation and survival

|-

|~~PTEN~~; ~~inactivating mutations~~

|''MET''; c-Met overexpression

|~~PI3K-AKT~~-~~mTOR signaling~~

|HGF/c-Met

|~~Increased cell proliferation and survival~~

|Cell motility, epithelial-to-mesenchymal transition

|-

|TP53; inactivating mutations

|''TP53''; inactivating mutations

|DNA damage response

|Genomic instability and tumor progression

|-

|ERBB2; amplification or activating mutations

|''ERBB2''; amplification or activating mutations

|MAPK/PI3K signaling pathways

|Enhanced growth signaling and tumorigenesis

|-

|GATA3; inactivating mutations

|''GATA3''; inactivating mutations

|Estrogen signaling pathways

|Altered luminal epithelial cell differentiation

|-

|''FOXA1''; activating mutations

|Estrogen signaling pathways

|Maintains papillary phenotype

|-

|''VEGFA''; VEGF overexpression

|VEGF signaling pathway

|Angiogenesis, promotes cancer cell survival, proliferation, and migration

|}

==Genetic Diagnostic Testing Methods==

Genetic alterations in breast cancers can be identified through various molecular diagnostic methods. Next-generation sequencing (NGS) panel tests may be used to identify somatic mutations ~~in PIK3CA, TP53, and GATA3 genes~~. Immunohistochemistry and in situ hybridization (ISH) are used to identify overexpression and amplification of the ERBB2 (HER2) gene, respectively. In addition, various PCR tests and comparative genomic hybridization (CGH) may be used to identify particular mutations and copy number variations.

Genetic alterations in breast cancers can be identified through various molecular diagnostic methods. Next-generation sequencing (NGS) panel tests may be used to identify somatic mutations. Immunohistochemistry and in situ hybridization (ISH) are used to identify overexpression and amplification of the ERBB2 (HER2) gene, respectively. In addition, various PCR tests and comparative genomic hybridization (CGH) may be used to identify particular mutations and copy number variations.

==Familial Forms==

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==References==

(use the "Cite" icon at the top of the page) (''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''''.'')

@@ Line 2: / Line 2: @@
 [[BRST5:Table_of_Contents|Breast Tumours (WHO Classification, 5th ed.)]]
 ==Primary Author(s)*==
-Sresi Singh
+Sresi Singh and Katherine Geiersbach, MD
 ==WHO Classification of Disease==
@@ Line 56: / Line 56: @@
 |}
 ==Individual Region Genomic Gain/Loss/LOH==
-Copy-number alterations are common genomic events in ductal carcinoma in situ and other papillary breast neoplasms. Recurrent chromosomal changes include gains of chromosome arms 1q and 8q, loss of 16q, and amplification of 17q12 containing the ERBB2 gene, which contributes to HER2 overexpression in a subset of lesions.
+Copy-number alterations are common genomic events in ductal carcinoma in situ and other papillary breast neoplasms. Recurrent chromosomal changes include gains of chromosome arms 1q and 8q, loss of 16q. Amplification of 17q12 containing the ''ERBB2'' gene contributes to HER2 overexpression in a subset of lesions and has been associated with malignancy rather than DCIS.<ref name=":0">{{Cite journal|last=Rakha|first=Emad A.|last2=Tan|first2=Puay Hoon|last3=Raymond|first3=Wendy A.|date=2026-03|title=The spectrum of breast in situ papillary carcinomas with invasion and invasive breast carcinomas with papillary features: an overview of histological subtypes and diagnostic challenges|url=https://pubmed.ncbi.nlm.nih.gov/41404713|journal=Histopathology|volume=88|issue=4|pages=747–768|doi=10.1111/his.70072|issn=1365-2559|pmc=12891923|pmid=41404713}}</ref>
 {| class="wikitable sortable"
 |-
@@ Line 70: / Line 70: @@
 |P
 |No
-|Gain of chromosome 1q is frequently observed in early breast neoplasia including DCIS and contributes to tumor progression.
+|Gain of chromosome 1q is frequently observed in early breast neoplasia including DCIS and contributes to tumor progression. In papillary lesions, 1q gains including 1q21.3-1q23.1 (including PRCC and NTRK1) have been associated with intracystic papillary carcinoma but not concurrent DCIS.<ref name=":1">{{Cite journal|last=Khoury|first=Thaer|last2=Hu|first2=Qiang|last3=Liu|first3=Song|last4=Wang|first4=Jianmin|date=2014-02|title=Intracystic papillary carcinoma of breast: interrelationship with in situ and invasive carcinoma and a proposal of pathogenesis: array comparative genomic hybridization study of 14 cases|url=https://pubmed.ncbi.nlm.nih.gov/23907150|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=27|issue=2|pages=194–203|doi=10.1038/modpathol.2013.136|issn=1530-0285|pmc=4389629|pmid=23907150}}</ref>
 |-
 |8
 |Gain
-|8q24
+|8q22-8q24
-|MYC
+|''SPAG1'', ''RHPN1'', MYC
 |P
 |No
-|Gain of 8q results in MYC activation and increased cell proliferation in breast tumors.
+|Gain of 8q results in ''MYC'' activation and increased cell proliferation in breast tumors. In papillary DCIS, gains on 8q including SPAG1 (8q22) RHPN1 (8q24) are associated with increased cell motility and cell adhesion programs.<ref name=":1" />
 |-
 |11
 |Gain
 |11q13
-|CCND1
+|''CCND1''
 |P
 |No
-|Amplification of CCND1 leads to dysregulated cell cycle progression and has been reported in breast tumors.
+|Amplification of ''CCND1'' leads to dysregulated cell cycle progression and has been reported in breast tumors.
 |-
 |13
 |Loss
 |13q14
-|RB1
+|''RB1''
 |P
 |No
-|Loss of RB1 contributes to cell cycle dysregulation in breast cancer.
+|Loss of ''RB1'' contributes to cell cycle dysregulation in breast cancer.
 |-
 |16
-|Loss
+|LOH
+|16p13
+|''TSC2'', ''PKD1''
+|D
+|No
+|LOH on chromosome 16p13 was present in 10 of 16 (63%) informative cases of either papillary carcinoma or carcinoma arising in a papilloma as well as in 6 of 10 (60%) informative cases of intraductal papilloma with florid epithelial hyperplasia (IDH) in a 1998 study from the Armed Forces Institute of Pathology (AFIP), suggesting the presence of a tumor suppressor gene mutated early in papillary neoplasia. <ref>{{Cite journal|last=Lininger|first=R. A.|last2=Park|first2=W. S.|last3=Man|first3=Y. G.|last4=Pham|first4=T.|last5=MacGrogan|first5=G.|last6=Zhuang|first6=Z.|last7=Tavassoli|first7=F. A.|date=1998-10|title=LOH at 16p13 is a novel chromosomal alteration detected in benign and malignant microdissected papillary neoplasms of the breast|url=https://pubmed.ncbi.nlm.nih.gov/9781650|journal=Human Pathology|volume=29|issue=10|pages=1113–1118|doi=10.1016/s0046-8177(98)90422-1|issn=0046-8177|pmid=9781650}}</ref>
+|-
+|16
+|Loss / LOH
 |16q
-|CDH1
+|''CDH1''
 |P
 |No
-|Loss of chromosome arm 16q is commonly associated with low-grade breast tumors and ductal carcinoma in situ.
+|Loss of chromosome arm 16q is commonly associated with low-grade breast tumors and ductal carcinoma in situ. In papillary lesions, 16q LOH is associated with malignancy.<ref>{{Cite journal|last=Di Cristofano|first=Claudio|last2=Mrad|first2=Karima|last3=Zavaglia|first3=Katia|last4=Bertacca|first4=Gloria|last5=Aretini|first5=Paolo|last6=Cipollini|first6=Giovanna|last7=Bevilacqua|first7=Generoso|last8=Ben Romdhane|first8=Kaled|last9=Cavazzana|first9=Andrea|date=2005-03|title=Papillary lesions of the breast: a molecular progression?|url=https://pubmed.ncbi.nlm.nih.gov/15770529|journal=Breast Cancer Research and Treatment|volume=90|issue=1|pages=71–76|doi=10.1007/s10549-004-3003-3|issn=0167-6806|pmid=15770529}}</ref><ref>{{Cite journal|last=Yoshida|first=Miwa|last2=Tsuda|first2=Hitoshi|last3=Yamamoto|first3=Sohei|last4=Kinoshita|first4=Takayuki|last5=Akashi-Tanaka|first5=Sadako|last6=Hojo|first6=Takashi|last7=Fukutomi|first7=Takashi|date=2012-05|title=Loss of heterozygosity on chromosome 16q suggests malignancy in core needle biopsy specimens of intraductal papillary breast lesions|url=https://pubmed.ncbi.nlm.nih.gov/22476400|journal=Virchows Archiv: An International Journal of Pathology|volume=460|issue=5|pages=497–504|doi=10.1007/s00428-012-1200-8|issn=1432-2307|pmid=22476400}}</ref>
 |-
 |17
 |Amp
 |17q12
-|ERBB2
+|''ERBB2''
 |D, P, T
 |Yes (NCCN)
-|Amplification of ERBB2 results in HER2 overexpression and may guide targeted therapy decisions in breast cancer.
+|Amplification of ''ERBB2'' results in HER2 overexpression and may guide targeted therapy decisions in breast cancer. In papillary lesions, ERBB2 amplification / overexpression (HER2 positive status) is primarily associated with solid papillary carcinoma and encapsulated papillary carcinoma with apocrine features.<ref name=":0" />
 |-
 |
@@ Line 162: / Line 170: @@
 |}
 ==Gene Mutations (SNV/INDEL)==
-Breast tumors including ductal carcinoma in situ frequently harbor recurrent somatic mutations affecting pathways involved in cell proliferation, transcriptional regulation, and genomic stability. Commonly mutated genes include PIK3CA, TP53, and GATA3, among others. The mutational profile of papillary DCIS largely overlaps with other luminal-type breast neoplasms.
+Breast tumors including ductal carcinoma in situ frequently harbor recurrent somatic mutations affecting pathways involved in cell proliferation, transcriptional regulation, and genomic stability. Commonly mutated genes include PIK3CA, TP53, and GATA3, among others<ref>{{Cite journal|last=Kader|first=Tanjina|last2=Elder|first2=Kenneth|last3=Zethoven|first3=Magnus|last4=Semple|first4=Timothy|last5=Hill|first5=Prue|last6=Goode|first6=David L.|last7=Thio|first7=Niko|last8=Cheasley|first8=Dane|last9=Rowley|first9=Simone M.|date=2020|title=The genetic architecture of breast papillary lesions as a predictor of progression to carcinoma|url=https://pubmed.ncbi.nlm.nih.gov/32195332|journal=NPJ breast cancer|volume=6|pages=9|doi=10.1038/s41523-020-0150-6|issn=2374-4677|pmc=7067788|pmid=32195332}}</ref>. The mutational profile of papillary DCIS largely overlaps with other luminal-type breast neoplasms. Intraductal papilloma (IDP) is a non-obligate precursor of papillary DCIS with a high frequency of ''PIK3CA'' and ''AKT1'' mutations observed; the majority of synchronous DCIS in cases of IDP exhibit non-papillary morphology.<ref>{{Cite journal|last=Kader|first=Tanjina|last2=Elder|first2=Kenneth|last3=Zethoven|first3=Magnus|last4=Semple|first4=Timothy|last5=Hill|first5=Prue|last6=Goode|first6=David L.|last7=Thio|first7=Niko|last8=Cheasley|first8=Dane|last9=Rowley|first9=Simone M.|date=2020|title=The genetic architecture of breast papillary lesions as a predictor of progression to carcinoma|url=https://pubmed.ncbi.nlm.nih.gov/32195332|journal=NPJ breast cancer|volume=6|pages=9|doi=10.1038/s41523-020-0150-6|issn=2374-4677|pmc=7067788|pmid=32195332}}</ref><ref>{{Cite journal|last=Troxell|first=Megan L.|last2=Levine|first2=Judith|last3=Beadling|first3=Carol|last4=Warrick|first4=Andrea|last5=Dunlap|first5=Jennifer|last6=Presnell|first6=Ajia|last7=Patterson|first7=Janice|last8=Shukla|first8=Arielle|last9=Olson|first9=Neal R.|date=2010-01|title=High prevalence of PIK3CA/AKT pathway mutations in papillary neoplasms of the breast|url=https://pubmed.ncbi.nlm.nih.gov/19898424|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=23|issue=1|pages=27–37|doi=10.1038/modpathol.2009.142|issn=1530-0285|pmid=19898424}}</ref>
 {| class="wikitable sortable"
 |-
@@ Line 171: / Line 179: @@
 !Clinical Relevance Details/Other Notes
 |-
-|PIK3CA
+|''PIK3CA''
 |Activating mutations
 |Oncogene
@@ Line 177: / Line 185: @@
 |T
 |Yes (NCCN)
-|Activates PI3K–AKT signaling pathway leading to increased cell growth and survival. Targeted therapy for invasive disease.
+|Activates PI3K–AKT signaling pathway leading to increased cell growth and survival. Targeted therapy is reserved for invasive disease.
 |-
-|TP53
+|''AKT1''
+|Activating mutations
+|Oncogene
+|Recurrent
+|T
+|Yes (NCCN)
+|Activates PI3K–AKT signaling pathway leading to increased cell growth and survival. Targeted therapy is reserved for invasive disease.
+|-
+|''TP53''
 |Inactivating mutations
 |TSG
@@ Line 185: / Line 201: @@
 |P
 |Yes
-|Associated with genomic instability and aggressive tumor behavior
+|Associated with genomic instability and aggressive tumor behavior. In papillary lesions, ''TP53'' mutation is associated with malignancy.<ref>{{Cite journal|last=Di Cristofano|first=Claudio|last2=Mrad|first2=Karima|last3=Zavaglia|first3=Katia|last4=Bertacca|first4=Gloria|last5=Aretini|first5=Paolo|last6=Cipollini|first6=Giovanna|last7=Bevilacqua|first7=Generoso|last8=Ben Romdhane|first8=Kaled|last9=Cavazzana|first9=Andrea|date=2005-03|title=Papillary lesions of the breast: a molecular progression?|url=https://pubmed.ncbi.nlm.nih.gov/15770529|journal=Breast Cancer Research and Treatment|volume=90|issue=1|pages=71–76|doi=10.1007/s10549-004-3003-3|issn=0167-6806|pmid=15770529}}</ref>
 |-
-|GATA3
+|''GATA3''
 |Inactivating mutations
 |Other
@@ Line 193: / Line 209: @@
 |P
 |No
-|Transcription factor regulating luminal cell differentiation in breast epithelium<ref>{{Cite journal|last=Medford|first=Arielle J.|last2=Velimirovic|first2=Marko|last3=Gefen|first3=Yifat|last4=Niemierko|first4=Andrzej|last5=Gerratana|first5=Lorenzo|last6=Davis|first6=Andrew A.|last7=Clifton|first7=Katherine|last8=Keenan|first8=Jennifer|last9=Podany|first9=Emily|date=2025-08|title=Genomic and proteomic profiling of GATA3 mutant metastatic hormone receptor-positive breast cancer and impact on clinical outcomes|url=https://pubmed.ncbi.nlm.nih.gov/40439821|journal=Breast Cancer Research and Treatment|volume=212|issue=3|pages=437–447|doi=10.1007/s10549-025-07710-w|issn=1573-7217|pmc=12209021|pmid=40439821}}</ref>
+|Transcription factor regulating luminal cell differentiation in breast epithelium.<ref>{{Cite journal|last=Medford|first=Arielle J.|last2=Velimirovic|first2=Marko|last3=Gefen|first3=Yifat|last4=Niemierko|first4=Andrzej|last5=Gerratana|first5=Lorenzo|last6=Davis|first6=Andrew A.|last7=Clifton|first7=Katherine|last8=Keenan|first8=Jennifer|last9=Podany|first9=Emily|date=2025-08|title=Genomic and proteomic profiling of GATA3 mutant metastatic hormone receptor-positive breast cancer and impact on clinical outcomes|url=https://pubmed.ncbi.nlm.nih.gov/40439821|journal=Breast Cancer Research and Treatment|volume=212|issue=3|pages=437–447|doi=10.1007/s10549-025-07710-w|issn=1573-7217|pmc=12209021|pmid=40439821}}</ref>
 |-
-|ERBB2
+|''ERBB2''
 |Activating mutations, amplification
 |Oncogene
@@ Line 201: / Line 217: @@
 |D, P, T
 |Yes (NCCN)
-|Drives HER2 signaling and may guide targeted therapy decisions.
+|Drives HER2 signaling and may guide targeted therapy decisions. In papillary lesions, ''ERBB2'' amplification is primarily associated with solid papillary carcinoma and encapsulated papillary carcinoma with apocrine features and is a marker of high risk and chemotherapy benefit.<ref name=":0" />
 |-
-|MAP3K1
+|''MAP3K1''
 |Inactivating mutations
 |TSG
@@ Line 211: / Line 227: @@
 |Implicated in MAPK signaling and luminal breast cancer development.
 |-
-|CDH1
+|''CDH1''
 |Inactivating mutations
 |TSG
@@ Line 239: / Line 255: @@
 ==Genes and Main Pathways Involved==
-Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Please include references throughout the table. Do not delete the table.)''</span>
+Overexpression of MET may be a key factor in papillary differentiation.<ref>{{Cite journal|last=Ruco|first=L. P.|last2=Stoppacciaro|first2=A.|last3=Ballarini|first3=F.|last4=Prat|first4=M.|last5=Scarpino|first5=S.|date=2001-05|title=Met protein and hepatocyte growth factor (HGF) in papillary carcinoma of the thyroid: evidence for a pathogenetic role in tumourigenesis|url=https://pubmed.ncbi.nlm.nih.gov/11329134|journal=The Journal of Pathology|volume=194|issue=1|pages=4–8|doi=10.1002/path.847|issn=0022-3417|pmid=11329134}}</ref><ref>{{Cite journal|last=Nusrat|first=A.|last2=Parkos|first2=C. A.|last3=Bacarra|first3=A. E.|last4=Godowski|first4=P. J.|last5=Delp-Archer|first5=C.|last6=Rosen|first6=E. M.|last7=Madara|first7=J. L.|date=1994-05|title=Hepatocyte growth factor/scatter factor effects on epithelia. Regulation of intercellular junctions in transformed and nontransformed cell lines, basolateral polarization of c-met receptor in transformed and natural intestinal epithelia, and induction of rapid wound repair in a transformed model epithelium|url=https://pubmed.ncbi.nlm.nih.gov/8182137|journal=The Journal of Clinical Investigation|volume=93|issue=5|pages=2056–2065|doi=10.1172/JCI117200|issn=0021-9738|pmc=294323|pmid=8182137}}</ref>
 {| class="wikitable sortable"
 |-
 !Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 |-
-|PIK3CA, AKT1; activating mutations
+|''PIK3CA'', ''AKT1''; activating mutations / PTEN inactivating mutations
 |PI3K-AKT-mTOR signaling
 |Increased cell proliferation and survival
 |-
-|PTEN; inactivating mutations
+|''MET''; c-Met overexpression
-|PI3K-AKT-mTOR signaling
+|HGF/c-Met
-|Increased cell proliferation and survival
+|Cell motility, epithelial-to-mesenchymal transition
 |-
-|TP53; inactivating mutations
+|''TP53''; inactivating mutations
 |DNA damage response
 |Genomic instability and tumor progression
 |-
-|ERBB2; amplification or activating mutations
+|''ERBB2''; amplification or activating mutations
 |MAPK/PI3K signaling pathways
 |Enhanced growth signaling and tumorigenesis
 |-
-|GATA3; inactivating mutations
+|''GATA3''; inactivating mutations
 |Estrogen signaling pathways
 |Altered luminal epithelial cell differentiation
+|-
+|''FOXA1''; activating mutations
+|Estrogen signaling pathways
+|Maintains papillary phenotype
+|-
+|''VEGFA''; VEGF overexpression
+|VEGF signaling pathway
+|Angiogenesis, promotes cancer cell survival, proliferation, and migration
 |}
 ==Genetic Diagnostic Testing Methods==
-Genetic alterations in breast cancers can be identified through various molecular diagnostic methods. Next-generation sequencing (NGS) panel tests may be used to identify somatic mutations in PIK3CA, TP53, and GATA3 genes. Immunohistochemistry and in situ hybridization (ISH) are used to identify overexpression and amplification of the ERBB2 (HER2) gene, respectively. In addition, various PCR tests and comparative genomic hybridization (CGH) may be used to identify particular mutations and copy number variations.
+Genetic alterations in breast cancers can be identified through various molecular diagnostic methods. Next-generation sequencing (NGS) panel tests may be used to identify somatic mutations. Immunohistochemistry and in situ hybridization (ISH) are used to identify overexpression and amplification of the ERBB2 (HER2) gene, respectively. In addition, various PCR tests and comparative genomic hybridization (CGH) may be used to identify particular mutations and copy number variations.
 ==Familial Forms==
@@ Line 283: / Line 307: @@
 ==References==
-(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span>
 <references />