Description: Detailed review of uterine leiomyosarcoma histopathology, WHO 2022 diagnostic criteria, subtypes, differential diagnosis and exam‑oriented MCQs for pathology residents.
Author: PathologyMCQ Editorial Team
Category: Gynecologic Pathology – Uterine Mesenchymal Tumors
Last Updated: February 2026
Estimated Read Time: 20–25 minutes
This is a medical, educational, exam-oriented pathology review focused on diagnosis and histopathology.
At a Glance
- Focus: Histopathologic diagnosis of uterine leiomyosarcoma with WHO 2022 criteria and Stanford rules.
- Key Triad: Diffuse moderate–severe cytologic atypia, tumor cell necrosis, and high mitotic index.
- Subtypes: Conventional (spindle), epithelioid and myxoid uterine leiomyosarcoma with subtype-specific mitotic thresholds.
Difficulty Level: Moderate–Difficult (postgraduate pathology level)
Table of Contents
Uterine Leiomyosarcoma Histopathology – WHO 2022 Diagnostic Criteria
Uterine leiomyosarcoma histopathology is the microscopic evaluation of malignant smooth muscle tumors of the uterus using standardized criteria for atypia, mitotic activity and tumor cell necrosis.
What is uterine leiomyosarcoma histopathology?
Uterine leiomyosarcoma histopathology refers to the systematic microscopic assessment of uterine smooth muscle tumors to determine whether they fulfill malignant criteria for leiomyosarcoma rather than leiomyoma or STUMP.
Uterine leiomyosarcoma (uLMS) is the most common pure mesenchymal sarcoma of the uterine corpus but remains rare, accounting for about 1–2% of uterine malignancies and 30–40% of uterine sarcomas.
Histologically it arises from myometrial smooth muscle and shows destructive growth, marked cytologic atypia, elevated mitotic counts and characteristic tumor cell necrosis that separate it from benign leiomyomas.
How is uterine leiomyosarcoma classified in WHO 2022?
The WHO 2020/2022 classification groups uterine leiomyosarcoma under uterine smooth muscle tumors and recognizes spindle (conventional), epithelioid and myxoid subtypes based on predominant microscopic pattern.
What are the WHO-recognized subtypes?
WHO defines three main histologic subtypes of uterine leiomyosarcoma: conventional spindle cell, epithelioid and myxoid leiomyosarcoma.
- Conventional (spindle cell) LMS: Composed of intersecting fascicles of malignant spindle cells resembling smooth muscle but with diffuse atypia, brisk mitoses and necrosis.
- Epithelioid LMS: Shows predominantly round to polygonal cells with eosinophilic or clear cytoplasm arranged in nests or sheets, often requiring lower mitotic thresholds for diagnosis.
- Myxoid LMS: Characterized by hypocellular malignant cells embedded in abundant myxoid stroma and infiltrative margins; necrosis may be subtle and mitotic counts low, so diagnosis integrates growth pattern.
What are the core histopathologic diagnostic criteria?
The core histopathologic diagnostic criteria for uterine leiomyosarcoma are the presence of at least two of the following three features: diffuse moderate–severe cytologic atypia, tumor cell (coagulative) necrosis, and high mitotic index (≥10 mitoses per 10 HPF or ≥10 per 2 mm²).
What is cytologic atypia in uterine leiomyosarcoma?
Cytologic atypia in uterine leiomyosarcoma is defined as diffuse moderate to severe nuclear atypia characterized by enlarged pleomorphic nuclei, coarse chromatin and prominent nucleoli.
- Nuclei often show size variation exceeding a 2–3:1 ratio when compared with normal myocytes.
- Multinucleation, irregular nuclear membranes and atypical mitotic figures are frequent and support malignancy when combined with necrosis or high mitotic counts.
What is tumor cell (coagulative) necrosis?
Tumor cell necrosis in uterine leiomyosarcoma is a sharply demarcated area where an abrupt transition occurs from viable hypercellular tumor to necrotic eosinophilic cells, often with ghost outlines and karyorrhectic debris.
- The necrotic region lacks the inflammatory infiltrate and hyalinized background typical of infarct-type necrosis seen in benign leiomyoma.
- Identification of genuine tumor cell necrosis is critical because its presence, even with borderline mitotic counts, shifts a lesion toward leiomyosarcoma or STUMP rather than leiomyoma variants.
How do the histologic subtypes differ morphologically?
The histologic subtypes of uterine leiomyosarcoma differ in architecture, cytology, mitotic thresholds and the relative importance of infiltrative growth for diagnosis.
Conventional (spindle cell) uterine leiomyosarcoma histopathology
Conventional uterine leiomyosarcoma histopathology shows densely cellular fascicles of spindle cells with cigar-shaped nuclei, coarse chromatin and eosinophilic cytoplasm, resembling but more atypical than smooth muscle of leiomyoma.
- Atypia is typically diffuse and marked, and mitotic activity usually exceeds 10 mitoses per 10 HPF, often with atypical forms.
- Tumor cell necrosis is usually present; tumors lacking necrosis but meeting atypia and mitotic thresholds may still be classified as leiomyosarcoma under Stanford criteria.
Epithelioid uterine leiomyosarcoma histopathology
Epithelioid uterine leiomyosarcoma histopathology shows round to polygonal cells with abundant eosinophilic or clear cytoplasm arranged in nests, cords or sheets, often mimicking carcinoma or PEComa.
- Cytologic atypia is usually moderate to severe, but mitotic activity may be lower; WHO and ICCR recommend thresholds of ≥4 mitoses per 10 HPF or ≥1.6 per mm² when necrosis and atypia are present.
- Diagnosis requires correlation with immunohistochemistry for smooth muscle markers and exclusion of other epithelioid neoplasms.
Myxoid uterine leiomyosarcoma histopathology
Myxoid uterine leiomyosarcoma histopathology is characterized by malignant spindle or stellate cells dispersed in abundant myxoid matrix, often with low cellularity and deceptively bland cytology.
- Because mitotic counts may be low (≥1 mitosis per 10 HPF or >1/mm²) and atypia can be only moderate, infiltrative growth into myometrium and surrounding tissues becomes a key diagnostic criterion.
- Tumor cell necrosis, when present, supports malignancy; however necrosis may be focal or absent, further complicating distinction from myxoid leiomyoma and STUMP.
How is mitotic activity assessed in uterine leiomyosarcoma?
Mitotic activity in uterine leiomyosarcoma is assessed by counting mitoses in the most active areas across 10 consecutive high-power fields (HPF) with standardized field diameter or by expressing counts per mm², following WHO 2022 technical recommendations.
WHO and ICCR specify an HPF diameter of 0.55 mm, corresponding to an area of 0.24 mm², and recommend reporting mitoses per mm² to allow comparison between microscopes.
For conventional uLMS, a count of ≥10 mitoses per 10 HPF (≥4 per mm²) usually fulfills the high mitotic index component of the diagnostic triad, while epithelioid and myxoid subtypes use lower cutoffs as noted earlier.
Table 1. Mitotic thresholds in uterine leiomyosarcoma histopathology
*Mitotic thresholds apply in conjunction with cytologic atypia and tumor cell necrosis as per WHO/ICCR guidance.
How is uterine leiomyosarcoma differentiated from leiomyoma and STUMP?
Uterine leiomyosarcoma is differentiated from benign leiomyoma and STUMP by integrating atypia, mitotic index, necrosis and growth pattern using Stanford criteria and WHO 2022 guidance.
What are key differences from typical leiomyoma?
Typical uterine leiomyoma shows bland spindle cells in fascicles, absent or mild atypia, low mitotic activity (<5 mitoses/10 HPF) and no tumor cell necrosis.
- Infarct-type necrosis may be present in leiomyoma but displays gradual transition from viable cells through hyalinization and necrosis with associated inflammation.
- Cellular, mitotically active and atypical leiomyoma variants may show increased cellularity or mitoses but lack the combination of diffuse atypia and tumor cell necrosis required for leiomyosarcoma.
How is STUMP defined relative to leiomyosarcoma?
STUMP (smooth muscle tumor of uncertain malignant potential) encompasses tumors that show worrisome features exceeding those of leiomyoma but insufficient for leiomyosarcoma, such as focal atypia with low–intermediate mitoses or equivocal necrosis.
- WHO and Stanford-derived schemes designate categories such as “atypical leiomyoma with limited experience”, “smooth muscle tumor of low malignant potential” and others based on combinations of borderline atypia, mitotic activity and necrosis.
- Tumors showing any two components of the triad (e.g., severe atypia and necrosis but low mitoses) are classified as leiomyosarcoma rather than STUMP because outcome data show significant risk of aggressive behavior.
Table 2. Simplified histologic distinction
| Entity | Atypia | Mitotic count | Tumor cell necrosis | Growth pattern |
|---|---|---|---|---|
| Typical leiomyoma | None–mild | <5/10 HPF | Absent; infarct-type only | Well-circumscribed |
| STUMP | Focal or moderate | Borderline (e.g., 5–9/10 HPF) or equivocal | May be absent or ambiguous | Often circumscribed, limited infiltration |
| Uterine leiomyosarcoma | Diffuse moderate–severe | Usually ≥10/10 HPF (lower in epithelioid/myxoid) | Definite tumor cell necrosis | Infiltrative, destructive |
What is the role of immunohistochemistry and molecular markers?
Immunohistochemistry in uterine leiomyosarcoma histopathology confirms smooth muscle differentiation and assists in excluding mimics, while emerging molecular markers help subclassify tumors and may have prognostic implications.
- Smooth muscle markers: Most LMS express smooth muscle actin (SMA), desmin and h-caldesmon, confirming smooth muscle lineage and helping to distinguish from endometrial stromal sarcoma and undifferentiated uterine sarcoma.
- Proliferation and p53: High Ki‑67 index and abnormal p53 overexpression or null pattern are frequent and support high-grade sarcoma; p16 is commonly positive.
- Molecular alterations: uLMS often display complex karyotypes with numerous copy number alterations and mutations in TP53, RB1, ATRX and MED12 pathways, differing from the limited mutations in leiomyoma.
These ancillary studies are adjunctive and cannot substitute for core morphologic criteria in diagnosing leiomyosarcoma.
What are the key prognostic and staging features?
Prognosis in uterine leiomyosarcoma is mainly determined by FIGO stage, tumor size, mitotic activity, necrosis, margin status and presence of extrauterine spread.
Early-stage, completely resected tumors without extrauterine disease have better survival, but even stage I uLMS carries a substantial risk of recurrence with 5‑year survival rates around 50–70%.
Recent work shows that uLMS with low mitotic counts but fulfilling other criteria may have somewhat more favorable outcomes, yet they still require classification as leiomyosarcoma and close follow-up because of documented metastatic potential.
High – yield MCQS
Exam Pearl
Diffuse moderate–severe atypia plus definite tumor cell necrosis is sufficient for uterine leiomyosarcoma diagnosis even when mitotic count is below 10 per 10 HPF.
Key Takeaway
Uterine leiomyosarcoma histopathology relies on a triad of atypia, mitotic index and tumor cell necrosis, modified by subtype-specific thresholds and infiltrative growth patterns in epithelioid and myxoid variants.
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