Difference between revisions of "BRST5:Phyllodes tumour"

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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
  
−
Emilie Lalonde, PhD, London Health Sciences Center and Western University, London, Ontario, Canada
+
Katherine B. Geiersbach, MD, Mayo Clinic, MN, USA
−
 
 
−
Patricija Zot, MD, Mayo Clinic, MN, USA
 
  
 
__TOC__
 
__TOC__
Line 21: Line 21:
 
==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==
Line 36: Line 36:
 
{| class="wikitable"
 
{| class="wikitable"
 
|'''Signs and Symptoms'''
 
|'''Signs and Symptoms'''
−
|
+
|Unilateral, well-circumscribed mass
 
|-
 
|-
 
|'''Laboratory Findings'''
 
|'''Laboratory Findings'''
Line 74: Line 74:
 
|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)
Line 91: Line 91:
 
!Notes
 
!Notes
 
|-
 
|-
−
|NA|| || ||
+
|7p11.2||''EGFR''
 +
|N/A
 
|
 
|
 
|
 
|
 
|
 
|
 
|
 
|
 +
|Intragenic deletion resulting in loss of exons 2-7, also known as EGFRvIII.
 
|}
 
|}
 
 
Line 108: Line 110:
 
!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
 
|
 
|
Line 115: Line 126:
 
|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>.
−
|Mostly borderline or malignant tumors <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=":0" /><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
 
|
 
|
Line 133: Line 162:
 
|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
−
|Yes
 
 
|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==
Line 156: Line 185:
 
!Notes
 
!Notes
 
|-
 
|-
−
|EXAMPLE
+
|<span style="color:#0070C0">N/A</span>
−
 
+
|
−
Co-deletion of 1p and 18q
+
|
−
|Yes
+
|
−
|No
+
|
−
|No
 
−
|EXAMPLE:
 
−
 
 
−
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
 
 
|}
 
|}
 
==Gene Mutations (SNV / INDEL)==
 
==Gene Mutations (SNV / INDEL)==
  
−
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity.'') </span>
+
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"
Line 178: Line 203:
 
!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
 
−
|
 
−
|
 
−
|
 
−
|
 
−
|
 
−
|
 
−
|
 
−
|
 
−
|-
 
−
|RB1
 
−
|
 
−
|
 
−
|
 
−
|
 
−
|
 
−
|
 
−
|
 
−
|
 
−
|-
 
−
|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.
Line 326: Line 341:
 
==Genetic Diagnostic Testing Methods==
 
==Genetic Diagnostic Testing Methods==
  
−
Put your text here
+
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==
  
−
Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>
+
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==
  
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Put your text here
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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==
  
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Put your text placeholder here (or anywhere appropriate on the page) and use the "Link" icon at the top of the page <span style="color:#0070C0">(''Instructions: Once you have a text placeholder entered to which you want to add a link, highlight that text, select the "Link" icon at the top of the page, and search the name of the internal page to which you want to link this text, or enter an external internet address including the "<nowiki>http://www</nowiki>." portion.'')</span>
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https://www.pathologyoutlines.com/topic/breastphyllodesgeneral.html
  
 
==References==
 
==References==

Revision as of 15:22, 10 February 2024

(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples). Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support)

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

Katherine B. Geiersbach, MD, Mayo Clinic, MN, USA

Cancer Category / Type

Breast cancer / Fibroepithelial Tumors of the Breast

Cancer Sub-Classification / Subtype

Phyllodes Tumor

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, and 8-20% are malignant.

Synonyms / Terminology

Cystosarcoma phyllodes (Historical)

Epidemiology / Prevalence

Rare, less than 1% of all breast tumors and 2.5% of all fibroepithelial neoplasms. The incidence is higher, ~7% of breast tumors, among Asian women. Phyllodes tumor is more common in older women (in their 50s), in contrast to fibroadenomas which are more common in younger women (in their 20s).

Clinical Features

PT usually present clinically as unilateral, well circumscribed mass. Lymph node metastases are infrequent.

Signs and Symptoms Unilateral, well-circumscribed mass
Laboratory Findings

Sites of Involvement

There is no specific predilection for location in the breast.

Morphologic Features

Malignant phyllodes tumor is diagnosed when all of the following morphologic features are present [1]:

·       Marked stromal nuclear pleomorphism

·       Stromal overgrowth (absence of epithelial elements in one low-power microscopic field)

·       Increased mitoses (>=10 mitoses/10 high power fields (hpf))

·       Increased stromal cellularity

·       Permeative tumor border

Or, when malignant heterologous elements are present (with the exception of well-differentiated liposarcoma).

Borderline phyllodes tumor is diagnosed when one or more of the above adverse histologic features are present but histologic criteria fall short of malignant PT.

Benign phyllodes tumor has well defined borders, shows mild stromal cellularity, does not show atypia, and has a mitotic count <5/10 hpf

Immunophenotype

Finding Marker
Positive (universal) CD34 (in benign PT)
Positive (subset) EGFR (97%) of Malignant PT [2], 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 (subset) EXAMPLE CD4

Chromosomal Rearrangements (Gene Fusions)

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
7p11.2 EGFR N/A Intragenic deletion resulting in loss of exons 2-7, also known as EGFRvIII.

Individual Region Genomic Gain / Loss / LOH

Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
1 Gain 1q (whole arm) No Unknown No Clinically relevant genes unknown. The frequency in benign tumors varies from 0-33% across studies.[3][4][5]
7 Amplification 7p11.2 No No No 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 [2][6]
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 [5].
8 Gain 8q No Unknown No Clinically relevant gene(s) unknown. Associated with higher grade tumors [3][5]. Significantly more common in malignant versus borderline tumors [3].
9 Deletion 9p21.3 No Yes No Relevant genes: CDKN2A/ CDKN2B. Borderline and malignant tumors; associated with recurrent disease [7].
10 Deletion 10q23.31 No Yes No Relevant gene: PTEN may be enriched in borderline and malignant tumors [7][4][5][8][3].
13 Deletion 13q14.2 No No No Relevant gene: RB1. Mostly borderline or malignant tumors [4][5][3]. Focal deletions support the minimal cytoband 13q14.2 including RB1 [5][3]

Characteristic Chromosomal Patterns

Put your text here (EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis)

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
N/A

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.

Gene; Genetic Alteration Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) Prevalence (COSMIC / TCGA / Other) Concomitant Mutations Mutually Exclusive Mutations Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EGFR Oncogene 6-8% No No No No Yes (off-label/ clinical trials) More common in malignant tumors [7]
FLNA Oncogene 19-35% [6][7] No No No No No No significant difference between benign, borderline, and malignant tumors.
KMT2D (previously MLL2) Tumor suppressor gene 13-15% [6][7][9] 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% [6][7][10] RARA, TERT promoter, SETD2, EGFR N/A Yes No Unknown No significant difference between benign, borderline, and malignant tumors. G44 residue is a hotspot.


NF1 Tumor suppressor gene 8-10% [7][9] No No No No No
PIK3CA Oncogene 9-11% [7][9] No No No No No More common in malignant tumors [7].
RARA Oncogene 23-37% [7][9] MED12 No No Yes No
RB1 Tumor suppressor gene 10-15% [7][9] No No No No No
SETD2 Other 15-22% [7][9] No No No No No Histone methyltransferase gene; inactivation results in aberrant transcription regulation.
TERT promoter Oncogene ~60% [7][9] No No No No No No significant difference between benign, borderline, and malignant tumors [7]
TP53 Tumor suppressor gene 15% No No No No No More common in malignant tumors [7]. Germline TP53 pathogenic mutations have been associated with PT [11].

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.

Epigenomic Alterations

Put your text here

Genes and Main Pathways Involved

Put your text here and fill in the table (Instructions: Can include references in the table.)

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations EXAMPLE: MAPK signaling EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations EXAMPLE: Cell cycle regulation EXAMPLE: Unregulated cell division
EXAMPLE:  KMT2C and ARID1A; Inactivating mutations EXAMPLE:  Histone modification, chromatin remodeling EXAMPLE:  Abnormal gene expression program

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

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

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

https://www.pathologyoutlines.com/topic/breastphyllodesgeneral.html

References

(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted. 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.)

  1. ↑ Zhang, Yanhong; et al. (2016-07). "Phyllodes Tumor of the Breast: Histopathologic Features, Differential Diagnosis, and Molecular/Genetic Updates". Archives of Pathology & Laboratory Medicine. 140 (7): 665–671. doi:10.5858/arpa.2016-0042-RA. ISSN 1543-2165. PMID 27362571. Check date values in: |date= (help)
  2. ↑ 2.0 2.1 Gatalica, Zoran; et al. (2016-01-12). "Multiplatform molecular profiling identifies potentially targetable biomarkers in malignant phyllodes tumors of the breast". Oncotarget. 7 (2): 1707–1716. doi:10.18632/oncotarget.6421. ISSN 1949-2553. PMC 4811491. PMID 26625196.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Laé, Marick; et al. (2016-12). "Whole-genome profiling helps to classify phyllodes tumours of the breast". Journal of Clinical Pathology. 69 (12): 1081–1087. doi:10.1136/jclinpath-2016-203684. ISSN 1472-4146. PMID 27207013. Check date values in: |date= (help)
  4. ↑ 4.0 4.1 4.2 Lv, Shuhua; et al. (2008-12). "Chromosomal aberrations and genetic relations in benign, borderline and malignant phyllodes tumors of the breast: a comparative genomic hybridization study". Breast Cancer Research and Treatment. 112 (3): 411–418. doi:10.1007/s10549-007-9876-1. ISSN 1573-7217. PMID 18189161. Check date values in: |date= (help)
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Jones, A. M.; et al. (2008-04). "A comprehensive genetic profile of phyllodes tumours of the breast detects important mutations, intra-tumoral genetic heterogeneity and new genetic changes on recurrence". The Journal of Pathology. 214 (5): 533–544. doi:10.1002/path.2320. ISSN 0022-3417. PMID 18288784. Check date values in: |date= (help)
  6. ↑ 6.0 6.1 6.2 6.3 Tan, Jing; et al. (2015-11). "Genomic landscapes of breast fibroepithelial tumors". Nature Genetics. 47 (11): 1341–1345. doi:10.1038/ng.3409. ISSN 1546-1718. PMID 26437033. Check date values in: |date= (help)
  7. ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 7.13 7.14 Tsang, Julia Y.; et al. (2022-10). "Analysis of recurrent molecular alterations in phyllodes tumour of breast: insights into prognosis and pathogenesis". Pathology. 54 (6): 678–685. doi:10.1016/j.pathol.2022.03.008. ISSN 1465-3931. PMID 35691725 Check |pmid= value (help). Check date values in: |date= (help)
  8. ↑ Kim, Ji-Yeon; et al. (2018-02). "Genetic and Clinical Characteristics of Phyllodes Tumors of the Breast". Translational Oncology. 11 (1): 18–23. doi:10.1016/j.tranon.2017.10.002. ISSN 1936-5233. PMC 5684533. PMID 29145046. Check date values in: |date= (help)
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 Yeong, Joe; et al. (2017-12). "A genetic mutation panel for differentiating malignant phyllodes tumour from metaplastic breast carcinoma". Pathology. 49 (7): 786–789. doi:10.1016/j.pathol.2017.07.011. ISSN 1465-3931. PMID 29066183. Check date values in: |date= (help)
  10. ↑ Cani, Andi K.; et al. (2015-04). "Next-Gen Sequencing Exposes Frequent MED12 Mutations and Actionable Therapeutic Targets in Phyllodes Tumors". Molecular cancer research: MCR. 13 (4): 613–619. doi:10.1158/1541-7786.MCR-14-0578. ISSN 1557-3125. PMC 4936398. PMID 25593300. Check date values in: |date= (help)
  11. ↑ Rosenberger, Laura H.; et al. (2020-10). "Germline Genetic Mutations in a Multi-center Contemporary Cohort of 550 Phyllodes Tumors: An Opportunity for Expanded Multi-gene Panel Testing". Annals of Surgical Oncology. 27 (10): 3633–3640. doi:10.1245/s10434-020-08480-z. ISSN 1534-4681. PMC 9945652 Check |pmc= value (help). PMID 32504368 Check |pmid= value (help). Check date values in: |date= (help)

EXAMPLE Book

  1. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.

Notes

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