Definition/General

Introduction:
-Phyllodes tumor with Ewing sarcoma is an exceptionally rare malignant phyllodes tumor where the stromal component shows primitive neuroectodermal tumor (PNET)/Ewing sarcoma differentiation
-This represents one of the most aggressive forms of phyllodes tumor.
Origin:
-Develops from intralobular breast stroma with secondary primitive neuroectodermal differentiation
-May arise de novo or through malignant transformation of pre-existing phyllodes tumor with acquisition of EWSR1 gene rearrangements.
Classification:
-WHO Classification categorizes this as malignant phyllodes tumor with heterologous sarcomatous elements
-Represents an extremely rare subtype with PNET/Ewing sarcoma family tumor characteristics.
Epidemiology:
-Extremely rare with fewer than 20 cases reported worldwide
-Peak age 30-50 years
-More aggressive behavior than conventional malignant phyllodes tumor
-High metastatic potential.

Clinical Features

Presentation:
-Rapidly growing, painful breast mass
-Large size at presentation (typically >8 cm)
-May present with skin ulceration
-Systemic symptoms possible.
Symptoms:
-Rapidly enlarging breast mass over weeks to months
-Breast pain and tenderness
-Skin changes or ulceration
-Fever and constitutional symptoms rare.
Risk Factors:
-Previous phyllodes tumor history
-Genetic predisposition to sarcomas
-Young age
-Possible association with neurofibromatosis type 1.
Screening:
-No specific screening available
-Clinical examination for rapidly growing masses
-Imaging with ultrasound and MRI
-Tissue sampling essential for diagnosis.

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Gross Description

Appearance:
-Large, lobulated mass with firm to hard consistency
-Cut surface shows gray-white to tan areas with necrosis
-Focal hemorrhage and cystic degeneration.
Characteristics:
-Size typically >5 cm (range 3-20 cm)
-Well-circumscribed to infiltrative borders
-Leaf-like clefts may be focally preserved
-Extensive necrosis common.
Size Location:
-Usually involves significant portion of breast
-Can occur in any quadrant
-Unilateral presentation
-May extend to pectoralis fascia.
Multifocality:
-Typically unifocal large mass
-Satellite nodules rare
-Surface ulceration in large tumors
-Deep extension possible.

Microscopic Description

Histological Features:
-Biphasic tumor with epithelial and primitive mesenchymal components
-Small round blue cells in sheets
-High nuclear-to-cytoplasmic ratio
-Frequent mitoses and apoptosis.
Cellular Characteristics:
-Primitive small round cells with hyperchromatic nuclei
-Minimal cytoplasm
-Fine chromatin pattern
-High mitotic rate (>20 per 10 HPF)
-Geographic necrosis.
Architectural Patterns:
-Sheets of primitive cells
-Focal rosette formation possible
-Perivascular pseudorosettes
-Lobular architecture with peripheral palisading.
Grading Criteria:
-High-grade malignant phyllodes tumor
-Marked stromal overgrowth
-High-grade primitive sarcoma features
-Extensive necrosis (>50%).

Immunohistochemistry

Positive Markers:
-CD99 strong diffuse positive (>95%)
-FLI-1 positive (nuclear)
-NKX2.2 positive
-CD56 positive
-Epithelial component: CK7+, EMA+.
Negative Markers:
-Desmin negative
-S-100 negative
-SMA negative
-Myogenin negative
-WT1 negative
-TTF-1 negative.
Diagnostic Utility:
-CD99 membranous staining characteristic
-FLI-1 nuclear positivity supports diagnosis
-Combined with molecular studies confirms Ewing sarcoma.
Molecular Subtypes:
-EWSR1 gene rearrangements
-Most common EWSR1-FLI1 fusion
-Rare EWSR1-ERG fusions
-Immunohistochemistry-molecular correlation essential.

Molecular/Genetic

Genetic Mutations:
-EWSR1-FLI1 fusion (85% of cases)
-EWSR1-ERG fusion (10%)
-Rare EWSR1-ETV1, EWSR1-ETV4 fusions
-TP53 mutations common.
Molecular Markers:
-EWSR1 gene rearrangement (pathognomonic)
-FLI-1 overexpression
-High Ki-67 proliferation index (>50%)
-p53 overexpression.
Prognostic Significance:
-EWSR1-FLI1 fusion associated with aggressive behavior
-High grade predicts poor prognosis
-Large size (>10 cm) adverse factor.
Therapeutic Targets:
-IGF-1R pathway inhibitors
-mTOR inhibitors under investigation
-Trabectedin shows activity
-Immune checkpoint inhibitors in trials.

Differential Diagnosis

Similar Entities:
-Primary breast Ewing sarcoma
-Malignant phyllodes tumor with other sarcomas
-Metaplastic carcinoma with small cell features
-Lymphoma.
Distinguishing Features:
-Phyllodes with Ewing: Leaf-like areas, EWSR1 fusion
-Primary Ewing: No epithelial component
-Lymphoma: LCA positive, different genetics.
Diagnostic Challenges:
-Recognition of primitive features
-FISH confirmation essential
-Distinction from other round cell tumors
-Assessment of phyllodes components.
Rare Variants:
-Atypical/large cell variant
-Adamantinoma-like variant
-Combined with other sarcomatous elements
-Metastatic Ewing sarcoma to breast.

Sample Pathology Report

Template Format

Sample Pathology Report

Complete Report: This is an example of how the final pathology report should be structured for this condition.

Specimen Information

[specimen type], measuring [size] cm in greatest dimension

Diagnosis

[diagnosis name]

Classification

Classification: [classification system] [grade/type]

Histological Features

Shows [architectural pattern] with [nuclear features] and [mitotic activity]

Size and Extent

Size: [X] cm, extent: [local/regional/metastatic]

Margins

Margins are [involved/uninvolved] with closest margin [X] mm

Lymphovascular Invasion

Lymphovascular invasion: [present/absent]

Lymph Node Status

Lymph nodes: [X] positive out of [X] examined

Special Studies

IHC: [marker]: [result]

Molecular: [test]: [result]

[other study]: [result]

Prognostic Factors

Prognostic factors: [list factors]

Final Diagnosis

Final diagnosis: [complete diagnosis]