Teaching Hospital of the

Medical University Graz

Pathology

Mesenchymal Tumors of the Uterus

Sigurd Lax

Department of Pathology,
General Hospital Graz West, Graz, Austria
sigurd.lax@lkh-grazwest.at or sigurd.lax@medunigraz.at
 Mesenchymal Tumors of the Uterus
(WHO 2003)

• Smooth muscle tumors

• Stromal tumors
• Others

• More than 90% of uterine mesenchymal tumors are of

smooth muscle differentiation
• Tumors of endometrial stromal differentiation are rare
• Basically all tumors may occur
 Uterine smooth muscle tumors

• Most frequent uterine neoplasms

• Leiomyoma (fibroids): 20-25% of women
• Typical uterine corpus, less frequent cervix
• Leiomyosarcomas sind most frequent uterine sarcomas
• Leiomyosarcomas of uterine cervix rare
Uterine smooth muscle tumors (WHO 2003)

• Leiomyosarcoma
Variants (epitheloid, myxoid)
• Smooth muscle tumors of uncertain malignant potential
• Leiomyoma
Variants
Abeler et al., Histopathology 2009
 Uterine smooth muscle tumors:
A diagnostic challenge

• 12431 malignant uterine neoplasms in the Norwegian Cancer

Registry
• 4.7% sarcomas (587 cases) >>3.4% (419 cases)
• 29% of diagnosis (168 cases) revised (WHO 2003 criteria)
Abeler et al., Histopathology 2009
 What are the diagnostic problems of
uterine smooth muscle tumors?
• Most tumors are not problematic: Leiomyomas
• Most sarcomas are not problematic but the diagnostic
criteria have changed
• Groups of uncertain biological behavior and limited
experience, respectively (“Borderline”)
• Even in large studies number of cases within the
problematic categories small
 Change of criteria for malignancy for
uterine smooth muscle tumors
• Number of mitosis: >5/10 HPF

• Cellular atypia: “No atypia, no

sarcoma” (Henry J. Norris, 1993)

• Complex criteria “Stanford” (Bell et

al. 1994)
 Problematic uterine smooth muscle neoplasms
Bell et al., AJSP 1994

• 213 cases with > 2 years of follow up

• 5 groups according to mitosis, necrosis, atypia
• Emphasis the importance of tumor cell necrosis
• Reduces the value of mitotic index
• Study is a mile stone but the number of cases in some
groups small
Problematic uterine smooth muscle neoplasms
Bell et al., AJSP 1994

Atypia TC-Necrosis Mitosis “Failure”

0 0 >5 0,5%
+ 0 <10 2%
+ 0 >10% 40%
+ + any 75%
0 + >10 50%
Focal 0 any 0
 TCN Atypia MI Diagnosis
Present Diffuse moderate any Leiomyosarcoma
to severe
No to mild > 10 Leiomyosarcoma

< 10 Leiomyosarcoma (Differential diagnosis:

acute infarction of leiomyoma, e.g after
torsion or submucosal
Absent Diffuse moderate > 10 Leiomyosarcoma
to severe
< 10 Atypical leiomyoma (low risk of recurrence)

No to mild < 10 Leiomyoma

> 10 Mitotically active leiomyoma

Focal moderate < 15 Leiomyoma with limited experience
to severe regarding the clinical course
> 15 STUMP

Blaustein, 2002
 Algorithm for the diagnosis of
conventional smooth muscle tumors
(Robboy 2008)
 Criteria for the evaluation of uterine
smooth muscle tumors (WHO 2003)
• Cell type
• Cellular atypia
• Type of necrosis
• Number of mitosis
• Behavior with respect to the surrounding tissue
• Vascular invasion
 Cell Type

• Usual (conventional) smooth muscle differentiation

• Epitheloid smooth muscle cells
• Clear smooth muscle cells
• Myxoid differentiation
 Moderate / Severe Cellular Atypia

• Pleomorphic Type:
Nuclear polymorphism recognizable at low power
• Uniform Type:
No nuclear polymorphism but remarkable chromatin changes
Smooth muscle tumors: Type of necrosis (WHO)
Coagulative tumor cell Infarction type necrosis
necrosis (“hyaline necrosis”)
Abrupt transition from vital Zone of fibrous tissue
to necrotic tumor between vital and non-vital
tumor
Shadows of necrotic cells No cell shadows visible

Bleeding and inflammation Bleeding usual

unusual
 Smooth muscle tumors: Type of necrosis
(Robboy 2008)

Coagulative Hyaline

Borders Abrupt Zonal

Blood vessels Spared Involved

Nuclei Most atypical, Pale

hyperchromatic
Outline Complex, “geographic” Simple
 Mitotic Index: Rules (WHO 2003)

• Evaluation per 10 HPF= high power fields= fields with

400x magnification (10x Okular, 40x Objektiv)
• Count areas with highest number of mitosis
• Count only unequivocal mitosis (Cave: inflammatory
cells, karyorrhexis)
• 4 sets of 10 HPF evaluated
• Cave: no standardized field (like for grading of breast
carcinoma)!
Conventional smooth muscle tumors: Criteria
of malignancy

• Any tumor cell necrosis.

• In the absence of tumo cell necrosis diffuse moderate to
severe nuclear atypia and a mitotic index of ≥ 10 per 10
HPF erforderlich.
• If the mitotic index is < 10 per 10 HPF low risk of
recurrence (< 2-3%) and late recurrence (atypical
leiomyoma).
 Conventional smooth muscle tumors

• Without tumor cell necrosis and significant

atypia benign even if mitotic index is high
(possibility of malignant course <<1% acc. to
Bell et al., 1994).
 Epithelioid and myxoid smooth muscle
tumors
• Criteria for malignancy
Any tumor cell necrosis
In the absence of tumor cell necrosis diffuse
moderate to severe nuclear atypia and mitotic index
of < 5 per 10 HPF.
 Uterine Leiomyosarcoma: Grading

• According to WHO no grading performed

• (Alternative: French Grading System for soft

tissue sarcomas)
 Atypical Leiomyoma

• Diffuse Atypia without tumor cell necrosis

• Mitotic index ≤10/10 HPF
• Benign course (1 malignant case in the
literature)
• Low risk for recurrence after enucleation
• Focal atypia: controversially discussed but
generally considered as benign
 Leiomyoma: Cases with limited
experience
• According to WHO 2003 limited experience with:
 focal moderate to severe atypia
 > 15 mitosis per 10 HPF
 STUMP

• Smooth muscle tumors of uncertain malignant potential

• Criteria:
 Possibility of a malignant tumor, e.g. due to poor clinical information wenig
klinische Info (some myxoid and epitheloid tumors)
 Uncertainty of cell type
 Uncertainty of mitotic index
 Uncertainty of type of necrosis
• But: Even world experts don‘t know what STUMPS are
• Thus: You should not use it too often, if ever
 Leiomyosarcoma with Metastases
Jones&Norris, IJGP 1995

• 28 cases, Follow up 1 month -13 years

• Size 3-14 cm (median 8.5 cm)
• Age 20-84 years (median 52 years)
• Mitosis <3 - 41/10 HPF (median 22)
• Atypia ++ or +++ in 27/28 patients
• Coagulative tumor cell necrosis in 22/28 patients
• Cell type: 10 epithelioid, 2 myxoid, 16 conventional
 Leiomyosarcoma with Metastases
Jones&Norris, IJGP 1995

• Important criteria
Age >50 (in 79%)
Size >5 cm (in 79%)
Atypia (++/+++)
Tumor cell necrosis
Epithelioid cell type (even with low mitotic index and
without tumor cell necrosis)
 Leiomyosarcoma with Metastases
Jones&Norris, IJGP 1995

• 6 metastasizing tumors <5 cm

5 tumors with tumor cell necrosis, 3 of which with increased
mitotic index and ++/+++ atypia
1 tumor with + atypia and without tumor cell necrosis, but
with invasive growth and angioinvasion
 Leiomyosarcoma with Metastases
Jones&Norris, IJGP 1995

• 6 metastasizing tumors <50 years of age

4 tumors >5cm
4 tumors with ++/+++ atypia and tumor cell necrosis
1 tumors with ++/+++ atypia and 10 MF/10 HPF
1 tumors with + atypia and without tumor cell necrosis, but
with invasive growth and angioinvasion
Prognostic Factors of Uterine Sarcomas
Abeler et al., Histopathology 2009

Sarcoma Type Prognostic Factors

Leiomyosarcoma Tumor size + Mitoseindex

ESS Mitotic index + Tumor cell

necrosis
Adenosarcoma Tumor cell necrosis

Undifferentiated Sarcoma Angioinvasion

Leiomyosarcoma of the Uterus: Risik groups from Tumor Size and Mitotic Count

Low: ≤10 cm and ≤10MF

Medium: >10 cm or >10 MF
High: >10 cm and >10 MF

Abeler et al., Histopathology 2009

LMS: Importance of Optimal Surgical
Tumor Reduction

Dinh et al. 2004

 Uterine smooth muscle tumors and p53
Mutations

• P53 Mutations frequent in leiomyosarcomas

• P53 immunoreactivity predictive for survival
• No presence in leiomyoma
• but: no data for cases of uncertain malignant
potential
 Immunohistochemistry for the diagnosis of
uterine mesenchymal tumors

• General rule:
Panel of CD 10, desmin, caldesmon recommended
CD10 always positive in stromal tumors
Caldesmon, desmin always positive in smooth
muscle tumors
SMA not useful, also expressed in stromal tumors
 Immunohistochemistry for the diagnosis of
uterine mesenchymal tumors

• Exceptions:
CD 10 also positive in smooth muscle tumors, in particular in
leiomyosarcomas
• Desmin rarely positive in stromal tumors
• Literature: Oliva et al. AJSP 2002; McCluggage
Histopathology 2001
 ImHC and Biological Behavior
Lee C-H et al., Mod Pathol 2009

• Ki-67>10%, p53/p16 ≥50%:

evidence for malignancy
• Positivity of 1 marker in 92% of
sarcomas and 2% of myomas
 Pathology Report: Important informations

• Size
• Tumor cell necrosis
• Degree of atypia
• Extension of the tumor (invasion of extrauterine tissue)
• Vascular invasion
• Mitotic index
• TNM classification
 FIGO/UICC 2009: Leiomyosarcoma & ESS
Stage pTNM Definition
I Tumor limited to the uterus
IA pT1a < 5 cm diameter
IB pT1b > 5 cm diameter
II Tumor extends to pelvic tissue
IIA pT2a Extension to adnexae
IIB pT2b Extension to extrauterine pelvic tissue
III Invasion abdominal tissue (not protrusion into the abdomen)
IIIA pT3a 1 site
IIIB pT3b >1 sites
IIIC pN1 Metastases in pelvic and/or para-aortic lymph nodes
IV Invasion of urinary bladder and/or rectum; distant metastases
IVA pT4 Invasion of urinary bladder and/or rectum
IVB pM1 Distant metastases
 Differential Diagnosis of Uterine
Smooth Muscle Tumors
• Stromal tumors
• Mixed smooth muscle and stromal tumors
• UTROSCT
• PEComa
 Endometrial Stromal Tumors
(WHO 2003)
• Stromal nodule
• Endometrial stromal sarcoma (low grade) (ESS)
• Undifferentiated sarcoma
 High grade / low grade

Undifferentiated sarcoma ESS / Stromal nodule

 ESS / undifferentiated Sarcoma
ESS Undifferentiated
Sarcoma
Cytology monomorphous highly atypical, often
polymorphic
Growth pattern Infiltrative Expansile
Vascular Intravascular Vascular invasion
growth growth
Age 50-55 70-80
Course and Good, late Poor, early recurrence,
prognosis recurrence frequent metastases
Estrogen Estrogen-related Not estrogen-related (ER
(ER positive) negative)
 ESS: Growth pattern

• Diffuse enlargement of the myometrium

• Nodular tumor mass
• Infiltration of myometrium by mutlitple small nodules
 Diagnostic Problem

• Differential diagnosis from leiomyomatosis or

leiomyoma in frozen section, in particular in the setting
of extrauterine growth
Metaplastic Changes in Stromal Tumors

• Myogenic, chondroid,
osteogenic and
lipomatous
differentiation
 Sex cord Differentiation

• In ESS and ESN

• Inhibin, CD 99,
calretinin positive
• CD 10 may be negative
• DD: sex cord like tumor
of the uterus
(UTROSCT)
 Undifferentiated Sarcoma of the
Endometrium (WHO)
• Definition:
A high grade endometrial sarcoma that lacks specific
differentiation and bears no histological resemblance to
endometrial stroma
Resemblance to sarcomatous component in carcinosarcoma
(ruled out by sampling)
• No comment on immunohistochemistry
 Low/High grade/undifferentiated
Endometrial Sarcoma Dilemma
• Some investigators distinguish between low und high
grade endometrial stromal sarcoma, others do not
• WHO: “all inclusive endometrial stromal”
• Thus, no reliable data, in particular for undifferentiated
sarcoma
• Undifferentiated sarcoma with / without
immunohistochemistry?!
Molecular Pathology of Uterine Stromal
Tumors
Kurihara et al. AJSP 2008

ESS UES

JAZF1-JJAZ1 Fusion Frequent Rare

P53 Mutations No Frequent

Estrogen receptors Almost always Rare

 FIGO/UICC 2009: Adenosarcoma
Stage pTNM Definition
I Tumor limited to the uterus
IA pT1a Limited to endometrium or endocervix, no myometrial invasion
IB pT1b Invasion into inner half of the myometrium
IC pT1c Invasion into outer half of the myometrium
II Extension beyond the uterus within the pelvis
IIA pT2a Extension to adnexae
IIB pT2b Involvement of other pelvic tissue
III Invasion of abdominal tissues (not protrusion into the abdomen)
IIIA pT3a 1 Localisation
IIIB pT3b >1 Localisation
IIIC pN1 Metastases in pelvic and/or para-aortic lymph nodes
IV Tumor invasion of bladder and/or rectum; distant metastases
IVA pT4 Tumor invasion of bladder and/or rectum
IVB pM1 Distant metastases
 Immunohistochemistry: Antibody Panel

• CD 10
• Desmin
• Caldesmon
• Ki-67
• CK
• Calretinin
• CD99
• Inhibin
• Melan A, HMB 45
• Estrogen- and Progesterone receptors