Definition/General
Introduction:
Endometrial malignant peripheral nerve sheath tumor (MPNST) is an extremely rare malignant neoplasm with nerve sheath differentiation occurring in the uterus
It represents less than 0.1% of all uterine sarcomas
It shows schwannian or perineurial differentiation
It has an aggressive clinical behavior.
Origin:
Arises from peripheral nerve elements in endometrium
May develop from Schwann cells or perineurial cells
Can occur in the setting of neurofibromatosis type 1
May arise de novo or from pre-existing neurofibroma
Neural crest origin.
Classification:
Classified as malignant nerve sheath tumor by WHO
High-grade sarcoma
Sporadic vs NF1-associated
May show heterologous differentiation
Aggressive malignant neoplasm.
Epidemiology:
Extremely rare in uterine location
Peak incidence in 3rd-5th decades
Young to middle-aged women affected
Strong association with neurofibromatosis type 1
NF1 patients have 8-10% lifetime risk of MPNST.
Clinical Features
Presentation:
Abnormal uterine bleeding (most common)
Pelvic mass
Pelvic pain
Neurological symptoms (rare)
Constitutional symptoms
History of neurofibromatosis.
Symptoms:
Heavy menstrual bleeding
Pelvic pressure
Abdominal pain
Weight loss
Fatigue
Neurological deficits (if nerve involvement)
B symptoms in advanced cases.
Risk Factors:
Neurofibromatosis type 1 (strongest risk factor)
Previous radiation therapy
Family history of NF1
Pre-existing neurofibromas
Age 20-50 years.
Screening:
NF1 screening important
Genetic counseling for familial cases
Regular surveillance in NF1 patients
Imaging studies for staging
Neurological examination.
Master Malignant Peripheral Nerve Sheath Tumor Pathology with RxDx
Access 100+ pathology videos and expert guidance with the RxDx app
Gross Description
Appearance:
Large, multinodular mass with infiltrative margins
Gray-white cut surface with areas of necrosis
Firm consistency
Whorled appearance may be present
Hemorrhagic areas.
Characteristics:
Size ranges from 4-15 cm
Irregular margins
Cut surface shows variegated appearance
Solid consistency
Extensive necrosis common.
Size Location:
Usually large at presentation
Mean size 8-12 cm
Involves uterine corpus
May extend to parametrium
Infiltrative growth pattern.
Multifocality:
Usually unifocal presentation
Aggressive local growth
Lymph node metastases possible
Distant metastases to lung
Local recurrence common.
Microscopic Description
Histological Features:
Fascicles of spindle cells with wavy nuclei
Alternating cellular and hypocellular areas
Nuclear palisading may be present
Herringbone pattern
High mitotic activity
Geographic necrosis.
Cellular Characteristics:
Spindle cells with elongated, wavy nuclei
Eosinophilic cytoplasm
Nuclear pleomorphism
Prominent nucleoli
Bizarre cells in high-grade areas
Mitotic figures abundant.
Architectural Patterns:
Fascicular pattern
Storiform pattern
Marbled appearance
Perivascular accentuation
Alternating cellularity
Areas of heterologous differentiation (rhabdomyoblastic, chondroid).
Grading Criteria:
High-grade by definition
High mitotic rate (>10/10 HPF)
Marked nuclear atypia
Necrosis present
Hypercellularity
Loss of schwannian features.
Immunohistochemistry
Positive Markers:
S-100 (variable, often focal or lost)
Vimentin
SOX10 (may be positive)
GFAP (may be focal)
p75 (nerve growth factor receptor)
Claudin-1 (perineurial differentiation).
Negative Markers:
Cytokeratins (negative)
Desmin (negative unless heterologous elements)
Smooth muscle actin (negative)
CD34 (negative)
EMA (negative unless perineurial).
Diagnostic Utility:
S-100 positivity variable (often focal or lost)
SOX10 supports neural differentiation
Loss of S-100 in high-grade areas typical
p75 positivity supports nerve sheath origin
Heterologous markers if present.
Molecular Subtypes:
NF1 gene inactivation
CDKN2A/B deletions
TP53 mutations
SUZ12 loss
H3K27me3 loss.
Molecular/Genetic
Genetic Mutations:
NF1 mutations (biallelic inactivation)
CDKN2A deletions (80-90%)
TP53 mutations (40-50%)
SUZ12 mutations
EED mutations
Complex chromosomal alterations.
Molecular Markers:
Loss of NF1 expression
Loss of p16 expression (CDKN2A deletion)
p53 overexpression
Loss of H3K27me3 (PRC2 complex inactivation)
High Ki-67 index.
Prognostic Significance:
NF1-associated MPNST has worse prognosis
Size >5 cm adverse prognostic factor
High-grade morphology indicates poor outcome
Complete resection improves survival
Heterologous differentiation may worsen prognosis.
Therapeutic Targets:
MEK inhibitors (selumetinib)
mTOR inhibitors
PARP inhibitors (investigational)
Immunotherapy (limited efficacy)
Conventional chemotherapy (doxorubicin-based)
Radiation therapy (adjuvant).
Differential Diagnosis
Similar Entities:
Leiomyosarcoma
Fibrosarcoma
Synovial sarcoma
Dedifferentiated liposarcoma
Schwannoma with atypia.
Distinguishing Features:
Leiomyosarcoma: Desmin/SMA positive
Fibrosarcoma: S-100 negative
Synovial sarcoma: TLE1 positive
MPNST: S-100 variable
MPNST: Neural markers positive
Schwannoma: Low mitotic rate.
Diagnostic Challenges:
Distinguishing from other spindle cell sarcomas
Recognizing neural differentiation
Confirming NF1 association
Identifying heterologous elements
S-100 may be focal or lost.
Rare Variants:
Epithelioid MPNST
MPNST with heterologous differentiation
Superficial MPNST
Glandular MPNST.
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
Malignant peripheral nerve sheath tumor of the endometrium
Classification
High-grade malignant nerve sheath tumor
Histological Features
Fascicles of spindle cells with neural features, mitoses: [count]/10 HPF
Heterologous Elements
Heterologous differentiation: [present/absent], type: [specify if present]
Immunohistochemistry
Neural markers: S-100 [+/-/focal], SOX10 [+/-], p75 [+/-]
GFAP: [+/-], Claudin-1: [+/-]
Negative: Cytokeratins, Desmin, SMA
NF1 Association
Clinical history of NF1: [yes/no/unknown]
Molecular Studies
H3K27me3: [lost/retained/not performed], p16: [lost/retained]
Final Diagnosis
Malignant peripheral nerve sheath tumor, high-grade [NF1-associated/sporadic]