Definition/General

Introduction:
-Phyllodes tumor with neuroendocrine tumor is an exceptionally rare malignant phyllodes tumor where the stromal component contains neuroendocrine neoplasm
-This represents a unique form of heterologous phyllodes tumor with neuroendocrine differentiation.
Origin:
-Develops from intralobular breast stroma with neuroendocrine differentiation
-May arise through transdifferentiation of stromal cells or ectopic development of neuroendocrine cells within phyllodes tumor stroma.
Classification:
-WHO Classification categorizes this as malignant phyllodes tumor with heterologous elements
-Neuroendocrine component shows characteristic neuroendocrine markers and organized growth pattern.
Epidemiology:
-Exceptionally rare with fewer than 10 cases reported in medical literature
-Peak age 40-70 years
-Female predominance
-Clinical behavior depends on grade of neuroendocrine component.

Clinical Features

Presentation:
-Large, slowly to rapidly growing breast mass
-May be associated with hormonal symptoms if functional
-Usually asymptomatic initially but becomes symptomatic with growth.
Symptoms:
-Progressive breast enlargement over months
-Possible hormonal symptoms (flushing, diarrhea, carcinoid syndrome) if hormonally active
-Breast pain variable
-Constitutional symptoms possible.
Risk Factors:
-Previous phyllodes tumor history
-Multiple endocrine neoplasia (MEN) syndrome possible
-Family history of neuroendocrine tumors
-Advanced age.
Screening:
-No specific screening available
-Clinical examination for masses
-Assessment for hormonal symptoms
-Biochemical markers (chromogranin A, serotonin) if symptomatic.

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Gross Description

Appearance:
-Large, well-circumscribed to partially circumscribed mass
-Cut surface shows gray-white to tan areas with possible yellow or hemorrhagic foci
-Firm to soft consistency.
Characteristics:
-Size typically >4 cm (range 3-15 cm)
-Variable consistency
-May have lobulated appearance
-Focal hemorrhage or necrosis possible in high-grade tumors.
Size Location:
-Can occur in any breast region
-Usually involves significant breast tissue
-Unilateral presentation typical
-Rarely extends beyond breast parenchyma.
Multifocality:
-Typically unifocal mass
-Multifocal neuroendocrine areas within tumor possible
-Satellite lesions rare
-Local extension uncommon.

Microscopic Description

Histological Features:
-Biphasic tumor with epithelial and mesenchymal components
-Neuroendocrine areas show typical architecture with uniform cells in nests, ribbons, or trabecular pattern
-Rosette formation possible.
Cellular Characteristics:
-Uniform small to medium-sized cells with round to oval nuclei
-Finely granular chromatin (salt-and-pepper)
-Moderate eosinophilic cytoplasm
-Low to moderate mitotic activity in well-differentiated tumors.
Architectural Patterns:
-Nested, trabecular, or ribbon-like growth pattern
-Insular arrangement typical
-Organoid pattern possible
-Rich capillary network
-Pseudorosette formation.
Grading Criteria:
-WHO grading system: Grade 1 (<2 mitoses/10 HPF, <3% Ki-67)
-Grade 2 (2-20 mitoses/10 HPF, 3-20% Ki-67)
-Grade 3 (>20 mitoses/10 HPF, >20% Ki-67).

Immunohistochemistry

Positive Markers:
-Chromogranin A positive
-Synaptophysin positive
-CD56/NCAM positive
-Neuron-specific enolase positive
-INSM1 positive
-Epithelial component: CK7+, EMA+.
Negative Markers:
-TTF-1 negative (distinguishes from lung primary)
-CDX2 variable
-CK20 negative
-Thyroglobulin negative
-Calcitonin negative unless C-cell differentiation.
Diagnostic Utility:
-Chromogranin A and synaptophysin confirm neuroendocrine differentiation
-INSM1 highly specific for neuroendocrine tumors
-CD56 supportive marker.
Molecular Subtypes:
-Well-differentiated neuroendocrine tumor (Grade 1)
-Moderately differentiated (Grade 2)
-Poorly differentiated neuroendocrine carcinoma (Grade 3).

Molecular/Genetic

Genetic Mutations:
-MEN1 gene mutations (if associated with MEN1 syndrome)
-ATRX mutations possible
-DAXX mutations
-Chromosome 11q loss
-RB1 pathway alterations in high-grade tumors.
Molecular Markers:
-Low Ki-67 proliferation index in well-differentiated tumors
-Neuroendocrine gene expression profile
-Loss of RB expression in high-grade tumors.
Prognostic Significance:
-Grade most important prognostic factor
-Ki-67 index correlates with outcome
-Size >2 cm may predict worse outcome
-Functioning status affects quality of life.
Therapeutic Targets:
-Somatostatin receptor imaging and therapy (if receptor positive)
-mTOR inhibitors (everolimus)
-VEGF inhibitors
-Peptide receptor radionuclide therapy (PRRT).

Differential Diagnosis

Similar Entities:
-Primary breast neuroendocrine tumor
-Metastatic neuroendocrine tumor to breast
-Solid papillary carcinoma with neuroendocrine features
-Invasive carcinoma with neuroendocrine differentiation.
Distinguishing Features:
-Phyllodes with NET: Leaf-like areas, neuroendocrine markers
-Primary NET: No phyllodes component
-Metastatic: Clinical history, other sites.
Diagnostic Challenges:
-Recognition of neuroendocrine features
-Distinction from metastatic neuroendocrine tumor
-Assessment of phyllodes components
-Grading of neuroendocrine component.
Rare Variants:
-Large cell neuroendocrine carcinoma
-Small cell carcinoma
-Mixed neuroendocrine-non-neuroendocrine neoplasm
-Composite patterns.

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]