Definition/General

Introduction:
-Endometrial Leiomyosarcoma is a malignant smooth muscle tumor of the uterus
-It represents 1-2% of all uterine malignancies
-It is the most common uterine sarcoma (40-50%)
-It has aggressive behavior with tendency for local recurrence and distant metastasis.
Origin:
-Arises de novo from myometrial smooth muscle cells
-Rarely develops from pre-existing leiomyoma (<0.1%)
-Results from malignant transformation of smooth muscle
-Genetic alterations drive tumorigenesis
-Complex karyotypes common.
Classification:
-WHO classification: Leiomyosarcoma
-Conventional type (most common)
-Epithelioid variant
-Myxoid variant
-FIGO staging applies
-Grade based on mitotic count, atypia, and necrosis.
Epidemiology:
-Peak incidence in 5th-6th decades
-Rare tumor: 0.4 per 100,000 women
-Accounts for 40-50% of uterine sarcomas
-Higher incidence in African American women
-Associated with previous pelvic radiation
-Tamoxifen therapy possible risk factor.

Clinical Features

Presentation:
-Abnormal uterine bleeding (most common)
-Rapidly enlarging uterine mass
-Pelvic pain
-Abdominal distension
-Pressure symptoms
-Postmenopausal bleeding
-Weight loss
-Palpable abdominal mass.
Symptoms:
-Heavy menstrual bleeding (80-90%)
-Pelvic pain and pressure
-Rapid uterine enlargement
-Abdominal bloating
-Urinary frequency
-Constipation
-Fatigue and weight loss
-Dyspnea (pulmonary metastases).
Risk Factors:
-Age (perimenopausal/postmenopausal)
-Previous pelvic radiation
-Tamoxifen therapy
-African American ethnicity
-Hereditary cancer syndromes
-Nulliparity
-Obesity
-No clear association with pre-existing leiomyomas.
Screening:
-Pelvic examination
-Transvaginal ultrasound
-MRI (preferred imaging)
-CT scan (metastatic workup)
-LDH (may be elevated)
-Endometrial biopsy (limited utility)
-Tissue diagnosis challenging preoperatively.

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Gross Description

Appearance:
-Large, fleshy masses
-Soft, tan-gray cut surface
-Areas of necrosis and hemorrhage
-Ill-defined borders
-Infiltrative growth
-May show cystic degeneration
-Fish-flesh appearance
-Bulky tumors (>5cm usually).
Characteristics:
-Soft consistency (versus firm leiomyomas)
-Necrotic areas common
-Hemorrhagic foci
-Yellow-tan coloration
-Infiltrative margins
-Myometrial invasion
-May extend to serosal surface
-Vascular invasion possible.
Size Location:
-Usually large tumors (>5cm at diagnosis)
-Can arise anywhere in uterus
-May involve fundus or body
-Intramural or submucosal location
-May extend extrauterinely
-Metastases to lungs, liver, bone.
Multifocality:
-Usually unifocal
-Large, dominant mass
-May have satellite nodules
-Vascular invasion common
-Lymph node metastases (15-20%)
-Hematogenous spread to lungs (most common site).

Microscopic Description

Histological Features:
-Malignant smooth muscle cells
-Significant nuclear atypia
-High mitotic activity (>10 mitoses/10 HPF)
-Tumor necrosis
-Infiltrative growth
-Vascular invasion
-Loss of fascicular architecture
-Pleomorphic cells.
Cellular Characteristics:
-Pleomorphic spindle cells
-Nuclear atypia and hyperchromasia
-Prominent nucleoli
-Abundant mitoses including atypical forms
-Eosinophilic cytoplasm
-Giant cells possible
-Loss of smooth muscle differentiation.
Architectural Patterns:
-Fascicular arrangement (if differentiated)
-Storiform pattern
-Sheet-like growth
-Infiltrative borders
-Vascular invasion
-Perineural invasion possible
-Extensive necrosis
-Myxoid areas possible.
Grading Criteria:
-Based on mitotic count, nuclear atypia, and necrosis
-FNCLCC system: Grade 1-3
-High-grade most common
-Mitotic count: >10/10 HPF
-Moderate to marked atypia
-Tumor necrosis present.

Immunohistochemistry

Positive Markers:
-Smooth muscle actin (usually positive)
-Desmin (positive but may be focal)
-Caldesmon (h-caldesmon positive)
-Calponin (variable)
-ER positive (50-60%)
-PR positive (40-50%)
-p53 overexpression (common).
Negative Markers:
-Cytokeratin negative (usually)
-CD117 negative
-DOG1 negative
-S-100 negative
-Inhibin negative
-CD10 negative
-EMA negative.
Diagnostic Utility:
-Smooth muscle markers confirm origin
-h-Caldesmon most specific
-p53 overexpression supports malignancy
-High Ki-67 (>10%)
-ER/PR variable expression
-CD117 negative excludes GIST
-Desmin may be lost in high-grade tumors.
Molecular Subtypes:
-Conventional leiomyosarcoma
-Epithelioid variant
-Myxoid variant
-Pleomorphic type
-High-grade (most common)
-Low-grade (rare).

Molecular/Genetic

Genetic Mutations:
-TP53 mutations (common)
-RB1 alterations
-PTEN mutations
-ATRX mutations
-Complex karyotypes
-Chromosomal instability
-MYC amplification
-CDKN2A deletions.
Molecular Markers:
-p53 overexpression
-High Ki-67 proliferation index
-p16 overexpression
-MDM2 amplification
-Loss of RB1
-Aneuploidy
-High mutational burden.
Prognostic Significance:
-Poor prognosis overall
-5-year survival 40-60%
-Stage most important prognostic factor
-Size, grade, and mitotic count significant
-Age affects outcome
-Recurrence common (50-70%)
-Metastatic potential high.
Therapeutic Targets:
-Complete surgical resection
-Adjuvant chemotherapy (doxorubicin-based)
-Radiation therapy (selected cases)
-Targeted therapy: pazopanib, trabectedin
-Immunotherapy (investigational)
-Hormone therapy (limited role).

Differential Diagnosis

Similar Entities:
-Leiomyoma with degenerative changes
-Smooth muscle tumor of uncertain malignant potential (STUMP)
-Endometrial stromal sarcoma
-Carcinosarcoma
-Undifferentiated sarcoma
-GIST
-Metastatic sarcoma.
Distinguishing Features:
-Leiomyosarcoma: >10 mitoses/10 HPF, atypia, necrosis
-Leiomyoma: <5 mitoses/10 HPF, no atypia
-STUMP: Intermediate features
-ESS: CD10 positive, spiral arteries
-Carcinosarcoma: Epithelial component
-GIST: CD117 positive.
Diagnostic Challenges:
-Distinguishing from atypical leiomyoma
-STUMP diagnosis challenges
-Degenerative leiomyoma with atypia
-Sampling adequacy
-Heterogeneous tumors
-Mitotic count accuracy
-Necrosis interpretation.
Rare Variants:
-Epithelioid leiomyosarcoma
-Myxoid leiomyosarcoma
-Inflammatory leiomyosarcoma
-Dedifferentiated leiomyosarcoma
-Leiomyosarcoma with rhabdoid features
-Low-grade leiomyosarcoma.

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.

Patient Information

Name: [Patient Name]\nAge: [X] years\nMRN: [Medical Record Number]\nDate of Procedure: [Date]

Clinical History

Clinical indication: [Rapidly enlarging uterine mass/Abnormal uterine bleeding/Pelvic pain/Weight loss]\nSymptoms: [Heavy menstrual bleeding/Pelvic pressure/Rapid uterine growth/Constitutional symptoms]\nImaging: [Ultrasound/CT/MRI findings]\nPreoperative suspicion: [Leiomyosarcoma/Atypical leiomyoma/Other]\nProcedure: Total hysterectomy +/- staging procedures

Specimen Received

Specimen type: [Total hysterectomy/Radical hysterectomy] +/- [bilateral salpingo-oophorectomy/pelvic lymph nodes]\nUterine weight: [X] grams (normal: 40-100g)\nTumor size: [X] cm in greatest dimension\nFixative: 10% neutral buffered formalin

Gross Examination

The uterus weighs [X] grams and measures [X] x [X] x [X] cm. A large, fleshy tumor measuring [X] cm occupies [specify location within uterus]. The tumor has [ill-defined/infiltrative] borders and shows [soft/firm] consistency. Cut surface reveals [tan-gray/yellow] tissue with areas of [necrosis/hemorrhage/cystic degeneration]. The tumor [extends to the serosal surface/is confined within the myometrium/invades the cervix]. The endometrium measures [X] mm in thickness. [Lymph nodes/adnexa] are [involved/uninvolved/not submitted]. Representative sections submitted: [X] sections of tumor, [X] sections of normal myometrium, [X] sections of endometrium.

Microscopic Examination

Sections show a malignant smooth muscle tumor composed of pleomorphic spindle cells arranged in [fascicular/storiform/sheet-like] patterns. The cells demonstrate significant nuclear atypia with enlarged, hyperchromatic nuclei, prominent nucleoli, and marked pleomorphism. Mitotic activity is high with [X] mitoses per 10 high power fields, including atypical mitotic figures. Tumor necrosis comprises approximately [X]% of the tumor area. [Lymphovascular invasion is present/absent]. The tumor shows [infiltrative growth/pushing borders] and [extends to the serosal surface/is confined to the myometrium]. [Normal smooth muscle differentiation is lost/partially retained].

Immunohistochemistry

Smooth Muscle Actin: [Positive/Focal positive/Negative]\nDesmin: [Positive/Focal positive/Negative]\nh-Caldesmon: [Positive/Negative]\np53: [Overexpressed/Wild-type pattern]\nKi-67 proliferation index: [X]% (high)\nEstrogen Receptor: [Positive/Negative]\nProgesterone Receptor: [Positive/Negative]\nCD117: [Negative] (excludes GIST)

Histological Grade (FNCLCC)

Differentiation: [1/2/3] points ([well/moderately/poorly] differentiated)\nMitotic count: [1/2/3] points ([<9/10-19/>20] mitoses per 10 HPF)\nNecrosis: [0/1/2] points ([absent/<50%/>50%])\nTotal score: [X]/8 points\nFNCLCC Grade: [I/II/III] ([Low/Intermediate/High] grade)

Staging Assessment

Tumor size: [X] cm\nMyometrial invasion: [<50%/>50%]\nCervical involvement: [Present/Absent]\nExtrauterine extension: [Present/Absent]\nLymphovascular invasion: [Present/Absent]\nLymph node status: [Positive/Negative/Not assessed]\nFIGO Stage: [IA/IB/II/III/IV] (pending clinical correlation)

Final Diagnosis

LEIOMYOSARCOMA OF UTERUS\n\nHistological type: [Conventional/Epithelioid/Myxoid] leiomyosarcoma\nFNCLCC Grade: [I/II/III] ([Low/Intermediate/High] grade)\nSize: [X] cm\nFIGO Stage: [IA/IB/II/III/IV]\nMitotic count: [X] per 10 HPF\nNecrosis: [X]%\nLymphovascular invasion: [Present/Absent]\nMargins: [Negative/Positive]

Comments and Prognosis

• Leiomyosarcoma is a rare, aggressive malignant smooth muscle tumor.\n• Overall 5-year survival: 40-60%, strongly dependent on stage and grade.\n• High risk of local recurrence and distant metastasis (lungs most common).\n• Complete surgical resection is the primary treatment.\n• Consider adjuvant chemotherapy (doxorubicin-based regimens).\n• Multidisciplinary tumor board discussion recommended.\n• Regular imaging surveillance for recurrence/metastasis indicated.\n• Prognosis depends on stage, grade, age, and completeness of resection.

Reported By

Dr. [Pathologist Name], MD\nConsultant Pathologist\nDate: [Report Date]\n\nReviewed by: Dr. [Senior Pathologist], MD (if applicable)