Definition/General
Introduction:
Endometrial clear cell sarcoma is an extremely rare malignant soft tissue tumor occurring in the uterus
It is also known as melanoma of soft parts
It is characterized by clear cell morphology and melanocytic differentiation
It has a distinctive molecular signature.
Origin:
Arises from neural crest-derived cells
May develop from mesenchymal cells with melanocytic differentiation
Schwann cell origin proposed
Not related to cutaneous melanoma
Occurs as primary uterine tumor.
Classification:
Classified as soft tissue sarcoma with melanocytic features
High-grade malignancy
Defined by EWSR1-ATF1 or EWSR1-CREB1 fusions
Aggressive clinical behavior
Poor prognosis.
Epidemiology:
Extremely rare in uterine location
Peak incidence in 3rd-5th decades
Young to middle-aged women affected
No clear ethnic predilection
Associated with t(12;22)(q13;q12) translocation.
Clinical Features
Presentation:
Abnormal uterine bleeding (most common)
Pelvic mass
Pelvic pain
Rapidly growing tumor
Constitutional symptoms possible
Advanced disease at presentation.
Symptoms:
Heavy menstrual bleeding
Pelvic pressure
Abdominal pain
Weight loss
Fatigue
Systemic symptoms in advanced cases.
Risk Factors:
Young to middle age (20-50 years)
No established environmental risk factors
Genetic predisposition unclear
Sporadic occurrence
No association with UV exposure (unlike cutaneous melanoma).
Screening:
No specific screening recommendations
High index of suspicion for soft tissue masses in young women
Imaging studies for staging
Molecular testing essential for diagnosis.
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Gross Description
Appearance:
Well-circumscribed to infiltrative mass
Gray-white cut surface with areas of hemorrhage
Firm consistency
Multinodular appearance
Areas of necrosis variable.
Characteristics:
Size ranges from 3-10 cm
Lobulated external surface
Cut surface shows variegated appearance
Hemorrhagic areas
Solid consistency.
Size Location:
Variable size at presentation
Mean size 5-8 cm
Involves uterine corpus
May extend to parametrium
Infiltrative growth pattern.
Multifocality:
Usually unifocal presentation
Aggressive local growth
Early metastases common
Lymph node involvement frequent
Distant metastases to lung and liver.
Microscopic Description
Histological Features:
Sheets and fascicles of spindle to epithelioid cells
Clear to eosinophilic cytoplasm
Vesicular nuclei with prominent nucleoli
Melanin pigment variable
High mitotic activity
Necrosis common.
Cellular Characteristics:
Spindle to epithelioid cells
Clear cytoplasm (glycogen-rich)
Vesicular nuclei
Prominent nucleoli
Melanin granules (variable)
Multinucleated cells may be present.
Architectural Patterns:
Fascicular pattern
Nested arrangement
Alveolar pattern
Storiform pattern
Hemangiopericytoma-like vasculature
Areas of hemorrhage and necrosis.
Grading Criteria:
Considered high-grade by definition
High mitotic rate (>5/10 HPF)
Marked nuclear atypia
Necrosis present
Aggressive behavior.
Immunohistochemistry
Positive Markers:
S-100 (positive, strong and diffuse)
Melanoma markers (HMB-45, Melan-A variable)
Vimentin
NSE (neuron-specific enolase)
Microphthalmia transcription factor (MITF)
SOX10.
Negative Markers:
Cytokeratins (negative)
Desmin (negative)
Smooth muscle actin (negative)
CD34 (negative)
EMA (negative)
CD117 (negative).
Diagnostic Utility:
S-100 positivity highly sensitive
Melanoma markers may be variable
SOX10 supports neural crest origin
EWSR1 rearrangement confirmatory
Negative muscle and epithelial markers.
Molecular Subtypes:
EWSR1-ATF1 fusion (most common)
EWSR1-CREB1 fusion (less common)
Other EWSR1 fusions rare
ATF1/CREB1 overexpression.
Molecular/Genetic
Genetic Mutations:
t(12;22)(q13;q12) - EWSR1-ATF1 fusion (90% cases)
t(2;22)(q33;q12) - EWSR1-CREB1 fusion
TP53 mutations
CDKN2A deletions
Complex chromosomal alterations.
Molecular Markers:
EWSR1-ATF1 fusion protein
ATF1 overexpression
MITF upregulation
p53 overexpression
Loss of p16 expression.
Prognostic Significance:
EWSR1-ATF1 fusion indicates poor prognosis
Size >5 cm adverse prognostic factor
High mitotic rate correlates with aggressive behavior
Necrosis indicates poor outcome
Early metastases common.
Therapeutic Targets:
Multi-kinase inhibitors (sunitinib, pazopanib)
mTOR inhibitors
MEK inhibitors
Immunotherapy (limited efficacy)
Conventional chemotherapy (limited response)
Targeted EWSR1-ATF1 therapies (investigational).
Differential Diagnosis
Similar Entities:
Metastatic melanoma
Epithelioid sarcoma
Epithelioid smooth muscle tumor
Alveolar soft part sarcoma
Paraganglioma.
Distinguishing Features:
Melanoma: Primary site evident
Epithelioid sarcoma: Cytokeratin positive
Smooth muscle: Desmin positive
Clear cell sarcoma: EWSR1-ATF1 fusion
Clear cell sarcoma: S-100 positive
ASPS: TFE3 positive.
Diagnostic Challenges:
Distinguishing from metastatic melanoma
Recognizing clear cell morphology
Confirming EWSR1 rearrangement
Identifying melanocytic differentiation
Molecular confirmation essential.
Rare Variants:
Spindle cell variant
Epithelioid variant
Clear cell variant
Myxoid variant.
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, firm consistency
Diagnosis
Clear cell sarcoma of the endometrium
Classification
Soft tissue sarcoma with melanocytic differentiation
Histological Features
Spindle to epithelioid cells with clear cytoplasm, mitoses: [count]/10 HPF
Melanin Pigment
Melanin pigment: [present/absent/minimal]
Necrosis
Necrosis: [present/absent], [percentage if present]%
Immunohistochemistry
Melanocytic markers: S-100 [+/-], SOX10 [+/-], MITF [+/-]
HMB-45: [+/-], Melan-A: [+/-]
Negative: Cytokeratins, Desmin, SMA
Molecular Studies
EWSR1 rearrangement: [EWSR1-ATF1/EWSR1-CREB1/other/not detected/pending]
Final Diagnosis
Clear cell sarcoma with [fusion type] rearrangement