Uterine Sarcoma Classification
Entity-based diagnostic criteria for adenosarcoma, leiomyosarcoma, endometrial stromal sarcoma, and undifferentiated sarcoma.
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Educational and decision-support tool only. Does not replace the current CAP protocol, WHO classification, or professional pathologist judgment. Molecular confirmation is required or strongly recommended for several of these diagnoses.
Reference
No single numeric grading system
Unlike carcinomas graded on one scale (e.g., FIGO), uterine sarcomas are classified into distinct entities, each with its own diagnostic and risk criteria — some quantitative (mitotic rate thresholds, feature counts), some primarily morphologic and molecular. This tool is organized by entity, matching how the source protocol itself is structured.
Adenosarcoma
Benign epithelial component + malignant stromal component, classically with phyllodes architecture and cleft-like or dilated glands lined by benign endometrial or ciliated epithelium, surrounded by hypercellular proliferative stroma. Stromal atypia and mitotic activity are present but may be minimal or even absent. The epithelial component may show cytologic atypia and metaplastic change. Homologous sarcomatous differentiation is most common; rhabdomyosarcomatous or (rarely) sex cord differentiation is possible.
Sarcomatous overgrowth is defined as pure sarcoma — usually high-grade, without an epithelial component — occupying at least 25% of the tumor. A recognized route to transformation to high-grade sarcoma.
IHC context: conventional adenosarcoma stroma is typically positive for CD10, ER, and PR (often negative in sarcomatous overgrowth); p53 "wild-type" with a low MIB1 proliferation index — an immunophenotype resembling low-grade endometrial stromal sarcoma. SMA and desmin may also be positive. In high-grade sarcoma / sarcomatous overgrowth areas, MIB1 is higher and p53 may be positive/aberrant.
Endometrial stromal sarcoma — two-tier classification
A morphologic and molecular pattern-match, not a numeric score.
Mimicry pitfall: the ZC3H7B-BCOR variant of HG-ESS often mimics myxoid leiomyosarcoma, but usually has more uniform nuclei and more collagen bands; BCOR molecular analysis will typically identify this variant.
| Category | Features |
|---|---|
| Low-grade ESS (LG-ESS) | Proliferative-phase endometrial stromal-type tumor cells infiltrating the myometrium, with or without lymphovascular invasion |
| Low-grade ESS (LG-ESS) | ~60% show a genetic fusion — JAZF1-SUZ12 most common, followed by JAZF1-PHF1, EPC1-PHF1, MEAF6-PHF1 |
| Low-grade ESS (LG-ESS) | IHC: diffuse strong CD10, IFITM1, ER, PR; focal cyclin D1 |
| High-grade ESS (HG-ESS) | Malignant, uniform high-grade round and/or spindle morphology (a low-grade component may also be present) |
| High-grade ESS (HG-ESS) | Usually shows lymphovascular invasion, brisk mitotic activity, necrosis; invasion may be expansile, permeative, or infiltrative |
| High-grade ESS (HG-ESS) | Molecular: YWHAE-NUTM2A/B fusion, ZC3H7B-BCOR fusion, or BCOR ITD |
| High-grade ESS (HG-ESS) | Diagnosis requires: monomorphic high-grade round/spindle cells, brisk mitoses, and cyclin D1 + BCOR positivity if associated with YWHAE-NUTM2A/B, ZC3H7B-BCOR, BCOR ITD, or a low-grade ESS component (if HG-ESS, NOS) |
Leiomyosarcoma — subtype criteria
Most common uterine sarcoma (~40–50%). Patients are generally >50 years of age. Each subtype has its own diagnostic threshold.
Mitotic rate source calibration: field diameter 0.55 mm, area 0.24 mm² (10 HPF ≈ 2.4 mm²). HPF area = π(d/2)²; rate = mitoses ÷ (HPF area × HPFs examined).
IHC context: h-caldesmon (most specific), desmin, and SMA are typically expressed — may be weak/patchy in poorly differentiated or myxoid tumors. CD10, EMA, and cytokeratin positivity are common (EMA/cytokeratin more frequent in epithelioid tumors). Spindle LMS often expresses ER/PR; p16 and/or p53 overexpression is also common.
| Subtype | Morphology | Diagnostic criteria |
|---|---|---|
| Conventional (spindle) | Cellular tumor with fascicles of spindle-shaped cells showing smooth muscle differentiation, with moderate to severe pleomorphism. | 2 of 3: tumor cell necrosis; marked cytologic atypia; mitotic rate ≥4/mm² (≥10/10 HPF at source calibration) |
| Epithelioid | >50% round or polygonal cells with eosinophilic-to-clear cytoplasm; nested, plexiform, corded, nodular, or diffuse growth. Focal rhabdoid or signet-ring-like cells and pseudo-glandular spaces may occur; may be extensively hyalinized. | Any one: moderate to severe cytologic atypia; tumor cell necrosis; mitotic rate ≥1.6/mm² (≥4/10 HPF at source calibration) |
| Myxoid | Abundant myxoid stroma, often paucicellular with fewer mitoses; vague fascicular or nodular growth. Extensive sampling may be required. | Any one: any degree of cytologic atypia; tumor cell necrosis; mitotic rate >0.4/mm² (>1/10 HPF at source calibration) |
Undifferentiated uterine/endometrial sarcoma
A high-grade sarcoma lacking specific differentiation — a shrinking category as molecular analysis improves. Marked cellular pleomorphism, abundant mitotic activity with atypical forms; lacks the infiltrative growth and vascularity of LG-ESS and displaces (rather than infiltrates) the myometrium. Often resembles the sarcomatous component of a carcinosarcoma. Most are aneuploid, ER/PgR-negative.
Required exclusions before this diagnosis: poorly differentiated carcinoma; carcinosarcoma; high-grade ESS; sarcomatous overgrowth in adenosarcoma; IHC/molecular testing for ZC3H7B-BCOR, YWHAE-NUTM2 (FAM22), and BCOR ITD high-grade ESS; NTRK sarcoma; molecular testing considered to exclude fusion genes of other sarcoma types.
This checklist documents the required work-up — it does not itself render or confirm the diagnosis. Undifferentiated uterine/endometrial sarcoma remains a diagnosis of exclusion requiring adequate sampling and pathologist judgment.
PEComa — malignant potential
It has been proposed that the benign PEComa category be eliminated: ≥3 of the following 5 features → malignant PEComa. Fewer than 3 → uncertain malignant potential (PEComa-UMP).
IHC: HMB45 most sensitive (positive in nearly all); melan-A more specific (positive, sometimes focally, in ≥half); cathepsin K positive in essentially all. TFE3-translocation PEComas are diffusely TFE3-positive.
| Feature |
|---|
| Size ≥5 cm |
| High nuclear grade |
| Mitotic count >1 mitosis/50 HPF (>1/12 mm²) |
| Necrosis |
| Vascular invasion |
Rhabdomyosarcoma
Rare, but the most common uterine heterologous sarcoma. Pleomorphic and embryonal subtypes are most frequent; alveolar and spindled variants are extremely rare. IHC: positive for desmin, muscle-specific actin, myogenin, MyoD1, myoglobin; negative for SMA. Pleomorphic and alveolar subtypes carry a worse prognosis than embryonal. No formal grading criteria were given in the supplied excerpt.
Inflammatory myofibroblastic tumor (IMT)
Rare; majority benign, but a minority follow an aggressive course. Factors associated with aggressive behavior: necrosis, size >7 cm, moderate-to-severe atypia, high mitotic activity, and lymphovascular invasion. ~95% are ALK-positive by IHC (commonly IGFBP5, THBS1, TIMP3 fusion partners).
No formal cutoff (e.g., "≥N of 5 factors") was given in the source for these risk factors — they are listed as associated with aggressive course, not as a validated scoring rule.
SMARCA4-deficient uterine sarcoma (SDUS)
May mimic adenosarcoma (leaf-like architecture, entrapped benign glands). Younger patients (median 42 years), advanced stage at presentation, aggressive and uniformly fatal. Monotonous, loosely cohesive cells with frequent rhabdoid morphology. Negative for pankeratin, CAM5.2, PAX8, S100, EMA (rare positive cells), CD10, ER, PR, claudin-4, SOX10, SMA, desmin. Positive for cyclin D1 (often patchy); intact MMR; microsatellite stable; loss of SMARCA4. SWI/SNF gene inactivation (SMARCA4 or SMARCB1); rare germline SMARCA4 loss-of-function mutations reported.
NTRK-rearranged spindle cell neoplasm
Low-grade spindle cell sarcoma with NTRK gene rearrangement, predominantly in the cervix or lower uterine segment. Positive for S100, CD34, TRK, cyclin D1; negative for CD10, SMA, desmin, BCOR, ER, PR. NTRK rearrangement is diagnostic. Some are associated with metastasis and aggressive course.
Also considered in this differential: uterine tumor resembling ovarian sex cord tumor (staged as uterine sarcoma), angiosarcoma, liposarcoma, and alveolar soft part sarcoma.
Sources
Clement PB, Scully RE. Mullerian adenosarcoma of the uterus: a clinicopathologic analysis of 100 cases. Hum Pathol. 1990;21:363-381.
Lee CH, Nucci MR. Endometrial stromal sarcoma — the new genetic paradigm. Histopathology. 2015;67:1-19.
Bell SW, Kempson RL, Hendrickson MR. Problematic uterine smooth muscle neoplasms. Am J Surg Pathol. 1994;18:535-558.
Kolin DL, Quick CM, Dong F, et al. SMARCA4-deficient uterine sarcoma and undifferentiated endometrial carcinoma are distinct clinicopathologic entities. Am J Surg Pathol. 2020;44(2):263-270.
Folpe AL, Mentzel T, Lehr HA, et al. Perivascular epithelioid cell neoplasms of soft tissue and gynecologic origin. Am J Surg Pathol. 2005;29:1558-1575.
College of American Pathologists. Protocol for the Examination of Specimens From Patients With Sarcoma of the Uterus (document Uterus.Sarc_4.4.0.0.REL_CAPCP).
The source excerpt cites 26 references total, including several WHO Classification of Tumours online chapter entries for individual entities. Only the most load-bearing references for the quantitative criteria reproduced here are listed — consult the complete published protocol for exact citations.