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==Primary Author(s)*==
==Primary Author(s)*==
Emilie Lalonde, PhD, London Health Sciences Center and Western University, London, Ontario, Canada
H. Evin Gulbahce, MD, MSCI, University of Utah, UT, USA
H. Evin Gulbahce, MD, MSCI, University of Utah, UT, USA
Katherine B. Geiersbach, MD, Mayo Clinic, MN, USA
__TOC__
__TOC__
==Definition / Description of Disease==
==Definition / Description of Disease==
Phyllodes Tumor (PT) is a rare fibroepithelial neoplasm. Phyllodes tumors are subclassified as benign, borderline, or malignant based on a combination of several histologic features including stromal cellularity, atypia, mitotic activity, tumor border, and stromal overgrowth. The majority (60-75%) are benign, 15-25% are borderline, 8-20% are malignant.
Phyllodes Tumor (PT) is a rare fibroepithelial neoplasm. Phyllodes tumors are subclassified as benign, borderline, or malignant based on a combination of several histologic features including stromal cellularity, atypia, mitotic activity, tumor border, and stromal overgrowth. The majority (60-75%) are benign, 15-25% are borderline, and 8-20% are malignant.
==Synonyms / Terminology==
==Synonyms / Terminology==
{| class="wikitable"
{| class="wikitable"
|'''Signs and Symptoms'''
|'''Signs and Symptoms'''
|
|Unilateral, well-circumscribed mass
|-
|-
|'''Laboratory Findings'''
|'''Laboratory Findings'''
|Positive (universal)||CD34 (in benign PT)
|Positive (universal)||CD34 (in benign PT)
|-
|-
|Positive (subset)||EGFR (97%) of Malignant PT <ref>{{Cite journal|last=Gatalica|first=Zoran|last2=Vranic|first2=Semir|last3=Ghazalpour|first3=Anatole|last4=Xiu|first4=Joanne|last5=Ocal|first5=Idris Tolgay|last6=McGill|first6=John|last7=Bender|first7=Ryan P.|last8=Discianno|first8=Erin|last9=Schlum|first9=Aaron|date=2016-01-12|title=Multiplatform molecular profiling identifies potentially targetable biomarkers in malignant phyllodes tumors of the breast|url=https://pubmed.ncbi.nlm.nih.gov/26625196|journal=Oncotarget|volume=7|issue=2|pages=1707–1716|doi=10.18632/oncotarget.6421|issn=1949-2553|pmc=4811491|pmid=26625196}}</ref>, CD34 (majority of borderline PT, subset of malignant PT), beta-catenin (94%) of benign lesions
|Positive (subset)||EGFR (97%) of Malignant PT <ref name=":3">{{Cite journal|last=Gatalica|first=Zoran|last2=Vranic|first2=Semir|last3=Ghazalpour|first3=Anatole|last4=Xiu|first4=Joanne|last5=Ocal|first5=Idris Tolgay|last6=McGill|first6=John|last7=Bender|first7=Ryan P.|last8=Discianno|first8=Erin|last9=Schlum|first9=Aaron|date=2016-01-12|title=Multiplatform molecular profiling identifies potentially targetable biomarkers in malignant phyllodes tumors of the breast|url=https://pubmed.ncbi.nlm.nih.gov/26625196|journal=Oncotarget|volume=7|issue=2|pages=1707–1716|doi=10.18632/oncotarget.6421|issn=1949-2553|pmc=4811491|pmid=26625196}}</ref>, CD34 (majority of borderline PT, subset of malignant PT), beta-catenin (94%) of benign lesions
|-
|-
|Negative (universal)||p63 and p40 (in benign and borderline PT)
|Negative (universal)||p63 and p40 (in benign and borderline PT)
!Notes
!Notes
|-
|-
|NA|| || ||
|7p11.2||''EGFR''
|N/A
|
|
|
|
|
|
|
|
|Intragenic deletion resulting in loss of exons 2-7, also known as EGFRvIII.
|}
|}
!Notes
!Notes
|-
|-
|''EGFR''
|1
|Gain
|
|1q (whole arm)
|No
|Unknown
|No
|Clinically relevant genes unknown. The frequency in benign tumors varies from 0-33% across studies.<ref name=":4">{{Cite journal|last=Laé|first=Marick|last2=La Rosa|first2=Philippe|last3=Mandel|first3=Jonas|last4=Reyal|first4=Fabien|last5=Hupé|first5=Philippe|last6=Terrier|first6=Philippe|last7=Couturier|first7=Jérôme|date=2016-12|title=Whole-genome profiling helps to classify phyllodes tumours of the breast|url=https://pubmed.ncbi.nlm.nih.gov/27207013|journal=Journal of Clinical Pathology|volume=69|issue=12|pages=1081–1087|doi=10.1136/jclinpath-2016-203684|issn=1472-4146|pmid=27207013}}</ref><ref name=":5">{{Cite journal|last=Lv|first=Shuhua|last2=Niu|first2=Yun|last3=Wei|first3=Li|last4=Liu|first4=Qingjie|last5=Wang|first5=Xiaowei|last6=Chen|first6=Yan|date=2008-12|title=Chromosomal aberrations and genetic relations in benign, borderline and malignant phyllodes tumors of the breast: a comparative genomic hybridization study|url=https://pubmed.ncbi.nlm.nih.gov/18189161|journal=Breast Cancer Research and Treatment|volume=112|issue=3|pages=411–418|doi=10.1007/s10549-007-9876-1|issn=1573-7217|pmid=18189161}}</ref><ref name=":6">{{Cite journal|last=Jones|first=A. M.|last2=Mitter|first2=R.|last3=Springall|first3=R.|last4=Graham|first4=T.|last5=Winter|first5=E.|last6=Gillett|first6=C.|last7=Hanby|first7=A. M.|last8=Tomlinson|first8=I. P. M.|last9=Sawyer|first9=E. J.|date=2008-04|title=A comprehensive genetic profile of phyllodes tumours of the breast detects important mutations, intra-tumoral genetic heterogeneity and new genetic changes on recurrence|url=https://pubmed.ncbi.nlm.nih.gov/18288784|journal=The Journal of Pathology|volume=214|issue=5|pages=533–544|doi=10.1002/path.2320|issn=0022-3417|pmid=18288784}}</ref>
|-
|7
|Amplification
|Amplification
|
|
|No
|No
|No
|No
|Borderline and malignant tumors <ref name=":0">{{Cite journal|last=Tan|first=Jing|last2=Ong|first2=Choon Kiat|last3=Lim|first3=Weng Khong|last4=Ng|first4=Cedric Chuan Young|last5=Thike|first5=Aye Aye|last6=Ng|first6=Ley Moy|last7=Rajasegaran|first7=Vikneswari|last8=Myint|first8=Swe Swe|last9=Nagarajan|first9=Sanjanaa|date=2015-11|title=Genomic landscapes of breast fibroepithelial tumors|url=https://pubmed.ncbi.nlm.nih.gov/26437033|journal=Nature Genetics|volume=47|issue=11|pages=1341–1345|doi=10.1038/ng.3409|issn=1546-1718|pmid=26437033}}</ref> <ref>{{Cite journal|last=Gatalica|first=Zoran|last2=Vranic|first2=Semir|last3=Ghazalpour|first3=Anatole|last4=Xiu|first4=Joanne|last5=Ocal|first5=Idris Tolgay|last6=McGill|first6=John|last7=Bender|first7=Ryan P.|last8=Discianno|first8=Erin|last9=Schlum|first9=Aaron|date=2016-01-12|title=Multiplatform molecular profiling identifies potentially targetable biomarkers in malignant phyllodes tumors of the breast|url=https://pubmed.ncbi.nlm.nih.gov/26625196|journal=Oncotarget|volume=7|issue=2|pages=1707–1716|doi=10.18632/oncotarget.6421|issn=1949-2553|pmc=4811491|pmid=26625196}}</ref>
|Relevant gene: ''EGFR.'' Amplified (and/or with structural rearrangement, most commonly loss of exons 2-7, also known as EGFRvIII) in 33% of borderline and malignant tumors <ref name=":3" /><ref name=":0">{{Cite journal|last=Tan|first=Jing|last2=Ong|first2=Choon Kiat|last3=Lim|first3=Weng Khong|last4=Ng|first4=Cedric Chuan Young|last5=Thike|first5=Aye Aye|last6=Ng|first6=Ley Moy|last7=Rajasegaran|first7=Vikneswari|last8=Myint|first8=Swe Swe|last9=Nagarajan|first9=Sanjanaa|date=2015-11|title=Genomic landscapes of breast fibroepithelial tumors|url=https://pubmed.ncbi.nlm.nih.gov/26437033|journal=Nature Genetics|volume=47|issue=11|pages=1341–1345|doi=10.1038/ng.3409|issn=1546-1718|pmid=26437033}}</ref>
|-
|7
|Gain
|
|7q
|No
|Unknown
|No
|Clinically relevant gene(s) unknown. Observed in 39-57% of malignant tumors, 7-13% of borderline tumors; not seen in benign tumors <ref name=":6" />.
|-
|8
|Gain
|
|8q
|No
|Unknown
|No
|Clinically relevant gene(s) unknown. Associated with higher grade tumors <ref name=":4" /><ref name=":6" />. Significantly more common in malignant versus borderline tumors <ref name=":4" />.
|-
|-
|''RB1''
|9
|Deletion
|Deletion
|
|
|13q14.2
|9p21.3
|No
|No
|Yes
|No
|No
|No
|Relevant genes: ''CDKN2A''/ ''CDKN2B.'' Borderline and malignant tumors; associated with recurrent disease <ref name=":2">{{Cite journal|last=Tsang|first=Julia Y.|last2=Shao|first2=Yan|last3=Poon|first3=Ivan K.|last4=Ni|first4=Yun-Bi|last5=Kwan|first5=Johnny S.|last6=Chow|first6=Chit|last7=Shea|first7=Ka-Ho|last8=Tse|first8=Gary M.|date=2022-10|title=Analysis of recurrent molecular alterations in phyllodes tumour of breast: insights into prognosis and pathogenesis|url=https://pubmed.ncbi.nlm.nih.gov/35691725|journal=Pathology|volume=54|issue=6|pages=678–685|doi=10.1016/j.pathol.2022.03.008|issn=1465-3931|pmid=35691725}}</ref>.
|-
|-
|''PTEN''
|10
|Deletion
|Deletion
|
|
|Yes
|Yes
|No
|No
|Malignant tumors; less common <ref name=":1" /><ref name=":2" />
|Relevant gene: ''PTEN'' may be enriched in borderline and malignant tumors <ref name=":2" /><ref name=":5" /><ref name=":6" /><ref name=":1">{{Cite journal|last=Kim|first=Ji-Yeon|last2=Yu|first2=Jong Han|last3=Nam|first3=Seok Jin|last4=Kim|first4=Seok Won|last5=Lee|first5=Se Kyung|last6=Park|first6=Woong-Yang|last7=Noh|first7=Dong-Young|last8=Nam|first8=Do-Hyun|last9=Park|first9=Yeon Hee|date=2018-02|title=Genetic and Clinical Characteristics of Phyllodes Tumors of the Breast|url=https://pubmed.ncbi.nlm.nih.gov/29145046|journal=Translational Oncology|volume=11|issue=1|pages=18–23|doi=10.1016/j.tranon.2017.10.002|issn=1936-5233|pmc=5684533|pmid=29145046}}</ref><ref name=":4" />.
|-
|-
|''CDKN2A''/ ''CDKN2B''
|13
|Deletion
|Deletion
|
|
|9p21.3
|13q14.2
|No
|No
|No
|No
|No
|Borderline and malignant tumors; associated with recurrent disease <ref name=":2" />
|Relevant gene: ''RB1.'' Mostly borderline or malignant tumors <ref name=":5" /><ref name=":6" /><ref name=":4" />. Focal deletions support the minimal cytoband 13q14.2 including RB1 <ref name=":6" /><ref name=":4" />
|}
|}
==Characteristic Chromosomal Patterns==
==Characteristic Chromosomal Patterns==
!Notes
!Notes
|-
|-
|EXAMPLE
|<span style="color:#0070C0">N/A</span>
|
|
|Yes
|
|No
|
|No
|EXAMPLE:
|}
|}
==Gene Mutations (SNV / INDEL)==
==Gene Mutations (SNV / INDEL)==
Prevalence estimates are drawn from the COSMIC database (url: https://cancer.sanger.ac.uk/cosmic) and from literature cited in the table.
{| class="wikitable sortable"
{| class="wikitable sortable"
!Notes
!Notes
|-
|-
|MED12
|''EGFR''
|Gain of function; G44 residue is a hotspot
|Oncogene
|73%, 67% (PMID:25593300, 26437033)
|6-8%
|Often co-occurring RARA, TERT promoter, SETD2, EGFR mutations
|No
|
|No
|No
|No
|Yes (off-label/ clinical trials)
|More common in malignant tumors <ref name=":2" />
|-
|''FLNA''
|Oncogene
|19-35% <ref name=":0" /><ref name=":2" />
|No
|No
|No
|No
|No
|No significant difference between benign, borderline, and malignant tumors.
|-
|''KMT2D'' (previously MLL2)
|Tumor suppressor gene
|13-15% <ref name=":0" /><ref name=":2" /><ref name=":7">{{Cite journal|last=Yeong|first=Joe|last2=Thike|first2=Aye Aye|last3=Young Ng|first3=Cedric Chuan|last4=Md Nasir|first4=Nur Diyana|last5=Loh|first5=Kiley|last6=Teh|first6=Bin Tean|last7=Tan|first7=Puay Hoon|date=2017-12|title=A genetic mutation panel for differentiating malignant phyllodes tumour from metaplastic breast carcinoma|url=https://pubmed.ncbi.nlm.nih.gov/29066183|journal=Pathology|volume=49|issue=7|pages=786–789|doi=10.1016/j.pathol.2017.07.011|issn=1465-3931|pmid=29066183}}</ref>
|No
|No
|No
|No
|No
|Histone methyltransferase gene; inactivation results in aberrant transcription regulation. No significant difference between benign, borderline, and malignant tumors.
|-
|''MED12''
|Oncogene
|53-73% <ref name=":0" /><ref name=":2" /><ref>{{Cite journal|last=Cani|first=Andi K.|last2=Hovelson|first2=Daniel H.|last3=McDaniel|first3=Andrew S.|last4=Sadis|first4=Seth|last5=Haller|first5=Michaela J.|last6=Yadati|first6=Venkata|last7=Amin|first7=Anmol M.|last8=Bratley|first8=Jarred|last9=Bandla|first9=Santhoshi|date=2015-04|title=Next-Gen Sequencing Exposes Frequent MED12 Mutations and Actionable Therapeutic Targets in Phyllodes Tumors|url=https://pubmed.ncbi.nlm.nih.gov/25593300|journal=Molecular cancer research: MCR|volume=13|issue=4|pages=613–619|doi=10.1158/1541-7786.MCR-14-0578|issn=1557-3125|pmc=4936398|pmid=25593300}}</ref>
|''RARA'', ''TERT'' promoter, ''SETD2'', ''EGFR''
|N/A
|Yes
|Yes
|No
|No
|Unknown
|Unknown
|All (Benign, borderline, and malignant) grades
|No significant difference between benign, borderline, and malignant tumors. G44 residue is a hotspot.
<br />
<br />
|-
|-
|TERT promoter
|''NF1''
|
|Tumor suppressor gene
|
|8-10% <ref name=":2" /><ref name=":7" />
|
|No
|
|No
|
|No
|
|No
|
|No
|
|
|-
|-
|RARA
|''PIK3CA''
|
|Oncogene
|
|9-11% <ref name=":2" /><ref name=":7" />
|
|No
|
|No
|
|No
|
|No
|
|No
|
|More common in malignant tumors <ref name=":2" />.
|-
|-
|EGFR
|''RARA''
|
|Oncogene
|
|23-37% <ref name=":2" /><ref name=":7" />
|
|''MED12''
|
|No
|
|No
|
|Yes
|
|No
|
|
|-
|-
|TP53
|''RB1''
|
|Tumor suppressor gene
|
|10-15% <ref name=":2" /><ref name=":7" />
|
|No
|
|No
|
|No
|
|No
|
|No
|
|
|-
|-
|PIK3CA
|''SETD2''
|
|Other
|
|15-22% <ref name=":2" /><ref name=":7" />
|
|No
|
|No
|
|No
|
|No
|
|No
|
|Histone methyltransferase gene; inactivation results in aberrant transcription regulation.
|-
|-
|KMT2D (synonym MLL2)
|''TERT'' promoter
|
|Oncogene
|
|~60% <ref name=":2" /><ref name=":7" />
|
|No
|
|No
|
|No
|
|No
|
|No
|
|No significant difference between benign, borderline, and malignant tumors <ref name=":2" />
|-
|-
|ZNF703
|''TP53''
|
|Tumor suppressor gene
|
|15%
|
|No
|
|No
|
|No
|
|No
|
|No
|
|More common in malignant tumors <ref name=":2" />. Germline TP53 pathogenic mutations have been associated with PT <ref>{{Cite journal|last=Rosenberger|first=Laura H.|last2=Thomas|first2=Samantha M.|last3=Nimbkar|first3=Suniti N.|last4=Hieken|first4=Tina J.|last5=Ludwig|first5=Kandice K.|last6=Jacobs|first6=Lisa K.|last7=Miller|first7=Megan E.|last8=Gallagher|first8=Kristalyn K.|last9=Wong|first9=Jasmine|date=2020-10|title=Germline Genetic Mutations in a Multi-center Contemporary Cohort of 550 Phyllodes Tumors: An Opportunity for Expanded Multi-gene Panel Testing|url=https://pubmed.ncbi.nlm.nih.gov/32504368|journal=Annals of Surgical Oncology|volume=27|issue=10|pages=3633–3640|doi=10.1245/s10434-020-08480-z|issn=1534-4681|pmc=9945652|pmid=32504368}}</ref>.
|-
|SETD2
|
|
|
|
|
|
|
|
|-
|FLNA
|
|
|
|
|
|
|
|-
|
|
|
|
|
|
|-
|NF1
|
|}
|}
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. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==
Next-generation sequencing (NGS) panel including genes listed in Gene Mutations table at a minimum. Standard somatic breast cancer panels are not appropriate for phyllodes tumors due to differences in mutational profiles.
Chromosomal microarray for CNV detection can be considered if NGS panel does not call CNVs. Detection of CNVs can help differentiate between fibroadenomas and phyllodes tumors. FISH for EGFR amplification can also be considered in the absence of chromosome microarray or appropriate NGS assay.
==Familial Forms==
==Familial Forms==
Patients with Li-Fraumeni syndrome (germline ''TP53'' pathogenic variant) are at increased risk for phyllodes tumor (NCCN breast cancer guidelines). However, phyllodes tumor is not listed as a syndrome-associated tumor in the Genetic/Familial High-Risk Assessment guidelines.
==Additional Information==
==Additional Information==
Due to the rare incidence of phyllodes tumors, most genomic studies are limited in number, and studies including patient follow-up information are very rare. Thus, the true mutation rate for rare events may vary compared to the numbers presented. In addition, very few studies have evaluated the prognostic outcome of genomic abnormalities. Additional studies are needed to better characterize the landscape and clinical significance of genomic abnormalities in phyllodes tumors.
==Links==
==Links==
https://www.pathologyoutlines.com/topic/breastphyllodesgeneral.html
==References==
==References==