Definition/General
Introduction:
Endometrial Ewing sarcoma is an extremely rare malignant small round cell tumor occurring in the uterus
It belongs to the Ewing sarcoma family of tumors (ESFT)
It represents less than 1% of all uterine sarcomas
It is characterized by EWSR1 gene rearrangements.
Origin:
Arises from primitive neuroectodermal cells or pluripotent mesenchymal cells
May develop from endometrial stroma
Part of Ewing sarcoma family
Neural crest origin proposed
Occurs as primary uterine tumor.
Classification:
Classified as small round cell sarcoma by WHO classification
Part of Ewing sarcoma/PNET family
High-grade malignant neoplasm
Defined by EWSR1 rearrangements
May show neural differentiation.
Epidemiology:
Extremely rare in uterine location
Peak incidence in 2nd-3rd decades (adolescents and young adults)
Younger age group than other uterine sarcomas
No clear racial predilection
Associated with t(11;22)(q24;q12) translocation.
Clinical Features
Presentation:
Abnormal uterine bleeding (most common)
Rapidly enlarging pelvic mass
Pelvic pain
Menorrhagia in young women
Constitutional symptoms possible.
Symptoms:
Heavy menstrual bleeding
Pelvic pain and pressure
Abdominal distension
Weight loss
Fever (B symptoms)
Fatigue and malaise
Rapid symptom progression.
Risk Factors:
Young age (10-30 years)
No established environmental risk factors
Genetic predisposition unclear
Family history of sarcomas rare
Previous radiation exposure (rare).
Screening:
No specific screening recommendations
High suspicion in young patients with rapidly growing masses
Imaging studies for staging
Molecular testing essential for diagnosis.
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Gross Description
Appearance:
Soft, fleshy mass with gray-white cut surface
Hemorrhagic and necrotic areas
Friable consistency
May be well-circumscribed or infiltrative
Fish-flesh appearance.
Characteristics:
Size ranges from 4-15 cm
Lobulated external surface
Cut surface shows homogeneous appearance
Extensive necrosis common
Hemorrhagic foci.
Size Location:
Usually large at presentation
Mean size 8-12 cm
Involves uterine corpus
May extend to cervix
Extrauterine spread common.
Multifocality:
Usually unifocal presentation
Aggressive local growth
Lymph node metastases common
Hematogenous spread to lungs and bones
Multiple organ involvement possible.
Microscopic Description
Histological Features:
Sheets of small round cells
Uniform cellular morphology
High nuclear-to-cytoplasmic ratio
Round to oval nuclei
Fine chromatin
High mitotic activity
Extensive necrosis.
Cellular Characteristics:
Small, round, uniform cells
Scant cytoplasm
Round nuclei with fine chromatin
Inconspicuous nucleoli
Fragile cytoplasm (crush artifact common)
Mitotic figures abundant.
Architectural Patterns:
Diffuse sheets of cells
Lobular pattern
Perivascular arrangement
Rosette formation (Homer-Wright or perivascular)
Geographic necrosis.
Grading Criteria:
All cases considered high-grade by definition
High mitotic rate (>10/10 HPF)
Extensive necrosis
Ki-67 >50%
Aggressive behavior regardless of morphology.
Immunohistochemistry
Positive Markers:
CD99 (diffuse membranous staining, highly sensitive)
FLI-1 (nuclear, specific)
Vimentin
NSE (neuron-specific enolase)
Synaptophysin (variable)
CD117 (may be positive).
Negative Markers:
Cytokeratins (negative)
Desmin (negative)
S-100 (negative)
LCA (negative)
MyoD1 (negative)
Myogenin (negative)
WT1 (negative).
Diagnostic Utility:
CD99 positivity highly sensitive but not specific
FLI-1 nuclear staining more specific
Negative epithelial and lymphoid markers exclude other small round cell tumors
EWSR1 rearrangement confirmatory.
Molecular Subtypes:
EWSR1-FLI1 fusion (85% cases)
EWSR1-ERG fusion (10% cases)
EWSR1-ETV1 fusion (rare)
EWSR1-FEV fusion (rare)
FUS-ERG fusion (rare).
Molecular/Genetic
Genetic Mutations:
t(11;22)(q24;q12) - EWSR1-FLI1 fusion (most common)
t(21;22)(q22;q12) - EWSR1-ERG fusion
STAG2 mutations (20-25%)
TP53 mutations (10-15%)
CDKN2A deletions.
Molecular Markers:
EWSR1-FLI1 fusion protein
High Ki-67 index (>50%)
p53 overexpression (subset)
Loss of STAG2 expression
CD99 overexpression.
Prognostic Significance:
Fusion type may influence prognosis
EWSR1-FLI1 most common
STAG2 mutations associated with poor prognosis
Size >8 cm indicates poor outcome
Metastatic disease at presentation common.
Therapeutic Targets:
IGF-1R inhibitors
mTOR pathway inhibitors
PARP inhibitors
Immunotherapy (adoptive T-cell therapy)
Multi-agent chemotherapy (VIDE protocol)
Targeted EWS-FLI1 therapies.
Differential Diagnosis
Similar Entities:
Lymphoma (small lymphocytic)
Rhabdomyosarcoma (small cell variant)
Undifferentiated carcinoma
Wilms tumor (blastematous component)
Metastatic small round cell tumor.
Distinguishing Features:
Lymphoma: LCA positive
Rhabdomyosarcoma: MyoD1/Myogenin positive
Carcinoma: Cytokeratin positive
Ewing sarcoma: CD99 positive
Ewing sarcoma: EWSR1 rearrangement.
Diagnostic Challenges:
Distinguishing from other small round cell tumors
Confirming EWSR1 rearrangement
Recognizing crush artifacts
Excluding metastatic disease
Molecular testing essential for diagnosis.
Rare Variants:
Classic Ewing sarcoma
Atypical Ewing sarcoma
PNET with neural differentiation
Adamantinoma-like Ewing sarcoma
Sclerosing epithelioid fibrosarcoma-like.
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, soft/fleshy consistency
Diagnosis
Ewing sarcoma of the endometrium
Classification
WHO Classification: Small round cell sarcoma, Ewing sarcoma family
Histological Features
Small round cell tumor with uniform morphology, mitoses: [count]/10 HPF
Necrosis
Necrosis: [present/absent], [percentage if present]%
Immunohistochemistry
CD99: [+/-] (membranous), FLI-1: [+/-] (nuclear)
Negative: Cytokeratins, Desmin, S-100, LCA
Ki-67: [percentage]%
Molecular Studies
EWSR1 rearrangement: [EWSR1-FLI1/EWSR1-ERG/other/not detected/pending]
Staging
Local extent: [confined/extrauterine], metastases: [present/absent/unknown]
Final Diagnosis
Ewing sarcoma of endometrium with [fusion type] rearrangement