Leiomyosarcoma

Slide 1 · Leiomyosarcoma

Uterine smooth muscle malignancy

Morphology • Differential diagnosis • Clinical behavior

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes for uterine smooth muscle tumors

Explain why uterine leiomyosarcoma is biologically distinct from leiomyoma.

Recognize the gross and microscopic features used in malignancy assessment.

Explain STUMP and major benign diagnostic pitfalls.

Relate tumor morphology to recurrence, metastasis, and prognosis.

Slide 3 · The central diagnostic problem

Benign leiomyoma

Common uterine smooth muscle neoplasm.

Usually circumscribed; Low mitotic activity.

May be large or morphologically atypical.

Leiomyosarcoma

Uncommon malignant uterine smooth muscle neoplasm.

Often invasive; Potentially marked atypia and tumor necrosis.

Recurrence and distant spread are major concerns.

Slide 4 · Three possible classifications

Leiomyoma

Benign smooth muscle tumor. Some variants show unusual nuclei or distribution.

STUMP

Smooth muscle tumor of uncertain malignant potential when definitive classification is not possible.

Leiomyosarcoma

Malignant smooth muscle tumor distinguished using morphology and clinical behavior.

Slide 5 · Anatomic setting: Uterine myometrium

The myometrium is the uterine smooth muscle layer.

Leiomyomas usually develop within the corpus myometrium.

Submucosal, intramural, and subserosal positions have different local effects.

Schematic

Submucosal

Intramural

Subserosal

Slide 6 · Leiomyosarcoma is a malignant myometrial neoplasm

Uterine leiomyosarcoma is uncommon compared with benign leiomyoma.

Origin from myometrium or endometrial stromal precursor cells.

The tumor is clinically important because of aggressive behavior.

Slide 7 · Most leiomyosarcomas arise de novo

Myometrial / precursor cell

→

Distinct malignant process

→

Leiomyosarcoma

The usual model is not a stepwise transformation of an existing leiomyoma.

Slide 8 · Why a leiomyoma is not the usual precursor

Leiomyoma

Benign tumor of smooth muscle.

Malignant transformation is extremely rare.

Genetic changes often are limited.

Leiomyosarcoma

Typically develops independently.

Complex and variable karyotypes.

Recurrent abnormalities in tumor-suppressor and oncogenic genes.

Slide 9 · Genomic complexity is characteristic of leiomyosarcoma

Leiomyosarcoma frequently has a complex, highly variable karyotype.

Structural and numerical genomic changes are more extensive than in typical leiomyoma.

The illustrated genes are associated abnormalities, not a single necessary pathway.

TP53

RB

PTEN

Complex, heterogeneouschromosomal changes

Slide 10 · Genes highlighted by Robbins: TP53, RB, PTEN

TP53

A tumor suppressor gene included among alterations reported in leiomyosarcoma.

RB

A tumor suppressor pathway component listed among recurrent genomic abnormalities.

PTEN

Another tumor suppressor gene affected in subsets of these tumors.

Slide 11 · MED12 mutations do not separate benign and malignant

A subset of leiomyosarcomas harbors MED12 mutations.

MED12 mutations also occur in many leiomyomas.

Shared mutation status does not demonstrate that a leiomyosarcoma arose from a fibroid.

Leiomyoma

Leiomyosarcoma

MED12 subset

Slide 12 · Leiomyoma genetics provide the comparator

Approximately 40% show simple chromosomal abnormalities in the Robbins text.

Described cytogenetic groups include 12q14 and 6p rearrangements.

MED12 mutations occur in roughly 70% of leiomyomas, per the textbook.

MED12

12q14 / HMGIC

6p / HMGIY

Distinct genetic subgroups

Slide 13 · MED12 and transcription: What is known

MED12 mutation

→

Mediator complex affected

→

Leiomyoma development

The textbook supports a causal role in leiomyomas; The precise mechanism remains incompletely defined.

Slide 14 · FH mutations define an important leiomyoma context

Inherited setting

HLRCC syndrome is associated with germline FH variants.

Clinical significance extends beyond the uterine mass.

Sporadic setting

Somatic FH mutations can occur in uterine leiomyomas.

Bizarre nuclear morphology may be present in some FH-altered tumors.

Slide 15 · Leiomyoma: Typical gross appearance

Sharply circumscribed and discrete.

Round, firm, gray-white nodules.

A whorled appearance on the cut surface reflects organized smooth muscle bundles.

Schematic

Circumscribed nodule

Slide 16 · Leiomyoma morphology: Bland smooth muscle cells

Intersecting bundles of smooth muscle resemble surrounding myometrium.

Cells are relatively uniform with oval nuclei and elongated bipolar processes.

Mitotic figures are usually scarce.

Conceptual cell schematic — not a photomicrograph

Slide 17 · Large leiomyomas may undergo degenerative changes

Large benign tumors can develop yellow-brown or red softening.

The gross finding must be interpreted with the rest of the lesion.

A single region of softening does not establish leiomyosarcoma.

Slide 18 · Leiomyoma manifestations follow mass and location

Bleeding

Submucosal distortion can accompany abnormal uterine bleeding.

Pressure

Compression of adjacent structures may cause urinary frequency.

Fertility and pain

Impaired fertility or sudden pain with infarction may occur.

Slide 19 · Pregnancy makes benign leiomyoma clinically important

Leiomyomas may contribute to spontaneous abortion and malpresentation.

Uterine inertia can impair effective contraction during labor.

Postpartum hemorrhage is another recognized complication.

Pregnancy also matters when interpreting a mitotically active smooth muscle tumor.

Slide 20 · Leiomyoma with bizarre nuclei is a benign mimic

Some leiomyomas contain marked nuclear atypia and giant cells.

The mitotic index remains low in the described benign variant.

Atypia in isolation must not determine malignant classification.

Conceptual cell schematic — not a photomicrograph

Slide 21 · Cellular leiomyoma: Cellularity is not malignancy

Cellular leiomyoma

Increased cellular density is a recognized benign morphologic variant.

Low mitotic index helps separate it from leiomyosarcoma.

Leiomyosarcoma

Classification also considers nuclear atypia, mitotic activity, and tumor necrosis.

No single descriptive adjective is sufficient.

Slide 22 · Intravenous leiomyomatosis: Extension without malignancy

Uterine leiomyoma

→

Venous extension

→

Vena cava / right atrium

An exceptionally rare benign variant, despite its dramatic vascular distribution.

Slide 23 · Disseminated peritoneal leiomyomatosis: Unusual benign spread

Smooth muscle nodules

→

Multiple peritoneal lesions

→

Benign classification

Distribution alone is not synonymous with leiomyosarcoma.

Slide 24 · Contrast: Unusual benign behavior versus true sarcoma

Finding

Interpretation in context

Intravenous leiomyomatosis

Benign tumor despite vascular extension

Disseminated peritoneal leiomyomatosis

Benign process despite numerous nodules

Leiomyosarcoma

Malignant tumor with recurrent and metastatic potential

Slide 25 · Gross leiomyosarcoma: Bulky, fleshy invasive mass

One major growth pattern is a bulky, fleshy tumor.

The lesion invades the uterine wall rather than remaining neatly circumscribed.

Gross inspection directs histologic assessment but does not replace it.

Schematic

Infiltrating wall

Slide 26 · Gross leiomyosarcoma: Polypoid cavity mass

The other described pattern protrudes into the uterine lumen.

A polypoid configuration does not imply benign behavior.

Assessment requires sampling and histologic evaluation.

Schematic

Projects into cavity

Slide 27 · Two growth patterns can represent the same malignancy

Infiltrative intramural growth

Bulky fleshy expansion.

Invasion of the uterine wall.

Macroscopic focus is within the myometrium.

Polypoid intracavitary growth

Tumor projects into the uterine cavity.

Macroscopic presentation differs.

Histologic malignant features remain decisive.

Slide 28 · Cytologic differentiation ranges from bland to anaplastic

Leiomyosarcoma shows a wide spectrum of atypia.

Some tumors are very well differentiated.

Others are highly anaplastic.

Diagnostic evaluation therefore weighs multiple features.

Conceptual cell schematic — not a photomicrograph

Slide 29 · The histologic diagnostic triad

Nuclear atypia

Morphologic variation and abnormal nuclei are weighed in context.

Mitotic activity

Increased mitoses support malignancy; Benign exceptions occur.

Tumor necrosis

Coagulative tumor necrosis contributes to the malignant pattern.

Slide 30 · Nuclear atypia must be evaluated on its own terms

Consider the severity and distribution of atypical nuclei.

Marked atypia is part of the malignant morphologic pattern.

Bizarre-nuclei leiomyoma illustrates why atypia alone can mislead.

Conceptual cell schematic — not a photomicrograph

Slide 31 · Mitotic activity is important but not autonomous

Mitotic figures reflect proliferative activity.

Counts per 10 high-power fields in its diagnostic discussion.

An increased count becomes more persuasive with cytologic atypia or coagulative necrosis.

Age and pregnancy-related benign exceptions require caution.

Slide 32 · Coagulative tumor necrosis strengthens malignancy assessment

Malignant-associated necrosis

Coagulative tumor necrosis is one of the diagnostic discriminators identified by Robbins.

Interpret with atypia and mitoses.

Benign degenerative change

Large leiomyomas may show red or yellow-brown softening.

The pathological meaning of altered tissue depends on context.

Slide 33 · The three findings must be interpreted together

Atypia

Is nuclear atypia present, and how prominent is it?

Mitoses

How many mitotic figures are seen in the specified evaluated fields?

Necrosis

Is the pattern compatible with coagulative tumor necrosis?

Slide 34 · Robbins threshold: At least 10 mitoses / 10 HPF

≥10 / 10 HPF

High-power fields (400× as printed)

This threshold with malignancy in most situations.

Accompanying nuclear atypia or coagulative necrosis strengthens the diagnosis.

Exceptions exist; This is a textbook-level teaching rule, not a universal stand-alone algorithm.

Slide 35 · Robbins threshold in atypical or epithelioid lesions

≥4 / 10 HPF

Textbook-described exception for selected atypical or epithelioid tumors

A lower threshold when nuclear atypia or large epithelioid cells are present.

Histologic subtype and morphology matter when interpreting counts.

Do not extend this simplification to every contemporary diagnostic variant.

Slide 36 · Mitotically active leiomyoma is a diagnostic exception

Clinical setting

Some leiomyomas in younger or pregnant females can show increased mitoses.

The finding should trigger cautious assessment.

Diagnostic consequence

An elevated count without the complete malignant context may be misleading.

Do not reduce classification to one number.

Slide 37 · Counting errors change diagnostic interpretation

The denominator is 10 high-power fields.

Field magnification, field area, and counting conventions are not specified in the extracted text.

Avoid implying a laboratory-independent absolute cutoff without confirming the microscopy methodology.

Slide 38 · STUMP: The category for unresolved classification

Leiomyoma

Available morphologic evidence supports benign classification.

STUMP

The evidence does not support confident benign versus malignant assignment.

Leiomyosarcoma

The combination of findings supports malignancy.

Slide 39 · Why STUMP is not a histologic synonym for malignancy

STUMP means smooth muscle tumor of uncertain malignant potential.

It explicitly states that classification remains indeterminate.

Neither a benign outcome nor definite sarcomatous behavior should be asserted on that label alone.

Slide 40 · Benign, uncertain, and malignant tumors: Comparison

Domain

Leiomyoma

STUMP

Leiomyosarcoma

Nature

Benign

Uncertain

Malignant

Morphology

Usually bland

Indeterminate

Atypia/mitoses/necrosis considered

Clinical behavior

Usually local morbidity

Not predictable from label

Recurrent/metastatic potential

Genetics

Often simple changes

Not specified

Complex variable karyotype

Slide 41 · A single abnormal finding can be a trap

Unexpected morphology

→

Check all three discriminators

→

Classify only when defensible

Bizarre nuclei, cellularity, or mitoses alone may coexist with benign smooth muscle tumors.

Slide 42 · Build a defensible morphologic description

State the gross configuration: Circumscribed, infiltrative, or intracavitary.

Describe nuclear atypia and overall cytologic differentiation.

Document mitotic activity with the source-specific counting context.

Record whether coagulative tumor necrosis is present.

Explicitly preserve uncertainty when definitive classification is not possible.

Slide 43 · The other uterine mesenchymal lineage is endometrial stroma

Smooth muscle lineage

Leiomyoma and leiomyosarcoma.

Myometrium is the principal anatomical setting.

Endometrial stromal lineage

Stromal nodule and low-/high-grade stromal sarcoma.

Infiltration and molecular fusions enter their own classification.

Slide 44 · Endometrial stromal nodule: Benign comparator

Stromal nodules are described as well-circumscribed, benign tumors.

They arise in the separate family of endometrial stromal neoplasms.

Their classification cannot be inferred from leiomyosarcoma mitotic criteria.

Slide 45 · Low-grade stromal sarcoma: Infiltration matters

Low-grade endometrial stromal sarcoma resembles stromal nodule but infiltrates myometrium.

A JAZF1 fusion involving SUZ12 or other polycomb factors is associated with many lesions.

This context belongs to a distinct mesenchymal differential.

Schematic

Conceptual wall infiltration

Slide 46 · High-grade stromal sarcoma has distinct molecular associations

High-grade endometrial stromal sarcoma is associated with marked atypia.

YWHAE–NUTM2A/B and ZC3H7B–BCOR fusions.

BCOR internal tandem duplication is also described.

These alterations should not be recast as usual drivers of leiomyosarcoma.

Slide 47 · Molecular contrast: Smooth muscle vs stromal sarcoma

Leiomyosarcoma context

Endometrial stromal sarcoma context

Highly variable karyotypes; TP53, RB, PTEN changes

Recurrent fusion-gene patterns provide clues to lineage

MED12 mutations in a subset

Low grade: JAZF1 / polycomb partners, often SUZ12

No single obligatory alteration listed

High grade: YWHAE–NUTM2A/B; BCOR-associated changes

Slide 48 · Epidemiology: Peak between 40 and 60 years

40–60 years

Peak incidence

Uterine leiomyosarcoma can occur before menopause.

It also occurs after menopause.

Age alone does not distinguish benign from malignant smooth muscle tumors.

Slide 49 · Postoperative recurrence is a major clinical concern

Leiomyosarcoma frequently recurs following surgery.

Local treatment does not erase the risk of subsequent aggressive disease.

Follow-up risk must be considered alongside primary morphologic diagnosis.

Slide 50 · Hematogenous dissemination is a defining risk

More than one-half of patients eventually develop distant hematogenous metastases,.

Metastasis is not dependent on direct extension alone.

The observed dissemination pattern reflects systemic malignant behavior.

Uterineprimary tumor

→

Hematogenousspread

→

Distant organmetastases

Schematic route of spread

Slide 51 · Metastatic targets include lung, bone, and brain

Lungs

A typical distant organ listed in the source.

Bone

Another recognized destination for hematogenous metastasis.

Brain

Can be involved as part of distant metastatic disease.

Slide 52 · Abdominal dissemination is another pattern

Disease may disseminate throughout the abdominal cavity.

This route adds to the burden beyond the primary uterine mass.

Do not confuse sarcomatous dissemination with benign peritoneal leiomyomatosis.

Uterineprimary tumor

→

Abdominal cavity

→

Peritonealspread

Schematic route of spread

Slide 53 · Overall survival illustrates the aggressive course

≈40%

Overall 5-year survival reported

This estimate is taken from the 2026 textbook description.

It is a cohort-level summary, not an individualized risk calculator.

Do not infer a stage-specific survival rate from this number.

Slide 54 · Anaplastic lesions have poorer reported outcomes

10–15%

Textbook-reported 5-year survival for anaplastic lesions

Highly anaplastic morphology with a poor prognosis.

The figure is a historical textbook summary, not a personalized prediction.

The text does not provide the contributing cohort or treatment-era details.

Slide 55 · Why gross, microscopic, and clinical facts must align

Gross pattern

→

Atypia + mitoses + necrosis

→

Clinical behavior

Pathology classification and subsequent dissemination describe related, not interchangeable, disease attributes.

Slide 56 · Application case: Circumscribed uterine nodule

A uterine mass is discrete, firm, gray-white, and whorled. Microscopy shows intersecting, relatively uniform smooth muscle cells with scarce mitotic figures.

Which primary category is most consistent with this pattern?

Slide 57 · Application answer: Features favor leiomyoma

Circumscription and the whorled, firm cut surface are typical benign gross features.

Cellular uniformity and scarce mitoses favor leiomyoma.

The vignette does not describe features that require calling this tumor leiomyosarcoma.

Slide 58 · Application case: Invasive fleshy mass

A fleshy uterine tumor invades the wall. Histology shows marked nuclear atypia, prominent mitotic activity, and coagulative tumor necrosis.

Which constellation is most concerning for leiomyosarcoma?

Slide 59 · Application answer: Malignant features converge

Invasive fleshy growth conforms to the reported gross pattern.

Nuclear atypia, mitoses, and coagulative necrosis reinforce one another.

The combined pattern is substantially more informative than any isolated finding.

Slide 60 · Application case: Atypia without a secure answer

A uterine smooth muscle tumor shows some worrisome features, but complete assessment does not permit a confident benign or malignant classification.

Which diagnostic label preserves that uncertainty?

Slide 61 · Application answer: Preserve diagnostic uncertainty

STUMP denotes a smooth muscle tumor of uncertain malignant potential.

The label communicates unresolved classification rather than assured benignity.

Avoid inventing a prognosis from the label when the source supplies none.

Slide 62 · Five contrasts to retain

Domain

Leiomyoma

Leiomyosarcoma

Frequency

Very common

Uncommon

Origin

Benign smooth muscle

Usually de novo malignant tumor

Gross pattern

Well circumscribed; Whorled

Fleshy invasive or polypoid

Histology

Uniform cells; Scarce mitoses

Atypia, mitoses, necrosis evaluated

Clinical impact

Local morbidity

Recurrence and distant metastasis

Slide 63 · Primary reference and interpretive limits

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th ed. (2026), Chapter 22, “The Female Genital Tract,” pp. 920–922.

The diagnostic count thresholds shown are the statements in this source edition; contemporary variant-specific criteria were not independently verified.

All uterine and cellular drawings are native PowerPoint schematics, not gross or histologic specimens.

The original textbook figure plates were not provided or reproduced.