Definition/General

Introduction:
-Phyllodes tumor with small cell carcinoma is an extraordinarily rare malignant phyllodes tumor where the stromal component contains small cell carcinoma (neuroendocrine carcinoma)
-This represents one of the most aggressive forms of heterologous phyllodes tumor.
Origin:
-Develops from intralobular breast stroma with neuroendocrine differentiation toward small cell carcinoma
-May arise through dedifferentiation of stromal cells with loss of RB1 expression.
Classification:
-WHO Classification categorizes this as malignant phyllodes tumor with heterologous elements
-Small cell carcinoma component shows high-grade neuroendocrine carcinoma features.
Epidemiology:
-Exceptionally rare with fewer than 5 cases reported worldwide
-Peak age 50-70 years
-Female predominance
-Associated with extremely aggressive behavior and poor prognosis.

Clinical Features

Presentation:
-Large, rapidly growing breast mass
-Often presents with advanced local disease
-May be associated with paraneoplastic syndromes
-Systemic symptoms common.
Symptoms:
-Rapid breast enlargement over weeks to months
-Constitutional symptoms (weight loss, fatigue)
-Possible paraneoplastic syndromes
-Breast pain and tenderness.
Risk Factors:
-Previous phyllodes tumor history
-Smoking history
-Radiation exposure
-Genetic predisposition to neuroendocrine tumors
-Advanced age.
Screening:
-No specific screening available
-Clinical examination for rapidly growing masses
-Assessment for paraneoplastic syndromes
-Staging workup essential if diagnosed.

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Gross Description

Appearance:
-Large, lobulated mass with firm to hard consistency
-Cut surface shows gray-white areas with extensive necrosis
-Hemorrhage and friable areas common.
Characteristics:
-Size typically >6 cm (range 4-20 cm)
-Irregular borders
-Firm consistency
-Extensive central necrosis typical
-Areas of hemorrhage and necrosis.
Size Location:
-Can occur in any breast region
-Usually involves significant breast volume
-Unilateral presentation
-May extend to chest wall and skin.
Multifocality:
-Typically unifocal large lesion
-Multiple necrotic areas within tumor
-Local invasion common
-Extensive involvement possible.

Microscopic Description

Histological Features:
-Biphasic tumor with epithelial and mesenchymal components
-Small cell carcinoma areas show sheets of small cells with high nuclear-cytoplasmic ratio
-Extensive necrosis and mitotic activity.
Cellular Characteristics:
-Small cells with scant cytoplasm
-Hyperchromatic nuclei with fine chromatin
-Nucleoli inconspicuous
-Extremely high mitotic rate (>20 per 10 HPF)
-Extensive apoptosis.
Architectural Patterns:
-Sheets of small cells with little stroma
-Trabecular pattern rare
-Crush artifact common
-Extensive geographic necrosis
-Vascular invasion frequent.
Grading Criteria:
-High-grade neuroendocrine carcinoma by definition
-Grade 3 neuroendocrine tumor (>20 mitoses/10 HPF, >20% Ki-67)
-Extensive necrosis present.

Immunohistochemistry

Positive Markers:
-Chromogranin A focally positive
-Synaptophysin focally positive
-CD56 positive
-INSM1 positive
-TTF-1 negative (breast primary)
-Epithelial component: CK7+, EMA+.
Negative Markers:
-CK20 negative
-CDX2 negative
-Thyroglobulin negative
-Calcitonin negative
-RB1 protein loss (characteristic).
Diagnostic Utility:
-INSM1 most reliable neuroendocrine marker
-Loss of RB1 expression characteristic of small cell carcinoma
-High Ki-67 (>50%) typical.
Molecular Subtypes:
-Pure small cell carcinoma
-Combined small cell and large cell neuroendocrine carcinoma
-Mixed with other carcinoma types.

Molecular/Genetic

Genetic Mutations:
-RB1 gene inactivation (characteristic)
-TP53 mutations (>90%)
-CREBBP mutations
-EP300 mutations
-Complex chromosomal alterations.
Molecular Markers:
-Loss of RB1 protein expression by immunohistochemistry
-p53 overexpression common
-Extremely high Ki-67 index (>50%)
-High tumor mutational burden.
Prognostic Significance:
-RB1 loss confirms diagnosis
-TP53 mutation associated with poor prognosis
-High Ki-67 indicates aggressive behavior
-Complex karyotype adverse factor.
Therapeutic Targets:
-Platinum-based chemotherapy
-Immune checkpoint inhibitors (pembrolizumab, nivolumab)
-PARP inhibitors in select cases
-Clinical trials recommended.

Differential Diagnosis

Similar Entities:
-Primary breast small cell carcinoma
-Metastatic small cell carcinoma to breast
-High-grade neuroendocrine carcinoma
-Lymphoma
-Poorly differentiated carcinoma.
Distinguishing Features:
-Phyllodes with small cell: Leaf-like areas, RB1 loss
-Primary small cell: No phyllodes component
-Metastatic: Clinical history, lung primary.
Diagnostic Challenges:
-Recognition of small cell features
-Distinction from metastatic small cell carcinoma
-Assessment of phyllodes components
-Crush artifact interpretation.
Rare Variants:
-Combined small cell and large cell carcinoma
-Mixed neuroendocrine-non-neuroendocrine carcinoma
-Small cell with squamous differentiation.

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]