Difference between revisions of "BRST5:Phyllodes tumour"
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Latest revision as of 16:32, 12 July 2024
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
| 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
- ↑ 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) - ↑ 2.0 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.
- ↑ 3.0 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) - ↑ 4.0 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) - ↑ 5.0 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) - ↑ 6.0 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) - ↑ 7.00 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) - ↑ 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) - ↑ 9.0 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) - ↑ 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) - ↑ 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)
Notes
*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.