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Association of tumor morphology with mismatch-repair
protein status in endometrial cancers:
a single Unit Experience
Surgical Pathology Residency
“A.M. Mancini”, Bologna
University Surgical Pathology “M. Malpighi”
S. Orsola-Malpighi University Hospital, Bologna
ESP, Bilbao, 8-12 September 2018
Doriana D. Di Nanni, Antonio De Leo, Claudio Ceccarelli,
Anna Myriam Perrone, Pierandrea De Iaco and Donatella Santini
Endometrial Cancer is the most common form of a malignancy found in women with Lynch syndrome.
EC – SENTINEL EVENTthe risk of a second cancer is of 25% in 10 years.
This syndrome accounts 2-3% of new cases of EC.
Peritumoral lymphsTumor-infiltrating lymphsTumor heterogeneity/ambiguous featuresUndifferentiated/dedifferentiated morphologiesLow Uterine Segment (LUS)
MLH1PMS2MSH2MSH6
MSI analysis, MLH1 hypermethylation
OBJECTIVE: to analyze the clinicopathological and molecular characteristics of EC correlated to MMR alterations.
MORPHOLOGICAL EVALUATION: - Histotype- Tumor grade- Isthmus involvement- Pattern of invasion- TILs- LVI- Myometrial invasion- Lymph node metastases- Endometriosis- Tubaric lesions
+IHC EVALUATION: - MLH1- PMS2- MSH2- MSH6
MSI ANALYSIS +
Review of cases of EC collected between 2015 and 2017 in the secondary referral centre at S.Orsola-Malpighi University Hospital,
in Bologna.
UNIVERSAL IHC SCREENING
Hysterectomy with endometrial cancer
Universal screening
IHC testing MMR protein
MMR intactMLH1/PMS2 of expression
MSH2 and/ or MSH6, PMS2
loss of expression
Clinicalsuspicion high
No clinicalsuspicion
SPORADIC EC
MLH1 hypermethylation
Hypermethylated Non-methylated
MMR GERMLINE TESTINGFORMAL GENETIC COUNSELING
MSI TEST
106 cases of EC
23 cases (21%) with IHC MMR proteins deficient
7 cases (33%) with loss of MLH1/PMS2
with MLH1 promoter hypermethylation
16 cases (66.7%) with loss of MSH2 and/or MSH6
PARAMETERS MSS (90 cases) MSI-H (16 cases)
MEDIAN AGE 58 years 57.2 years
FAMILIAR HISTORY 47.7% for neoplasia (37% included in Bethesda criteria)
81% cases for neoplasia(30% included in Bethesda criteria)
ISTHMUS INVOLVEMENT 27.7% 30.4%
DEPTH OF MYOMETRIAL INVASION
M0-M1: 57.8%M2: 42.2%
M0-M1: 56.25%M2: 43.75%
PARAMETERS MSS (90 cases) MSI-H (16 cases)
HISTOLOGY
EndometrioidAmbiguous featuresClear cellSerousDedifferentiatedCarcinosarcoma
77%2.2%3.3% 5.5% 2.2% 1%
68%25%\6.2%\\
Ambiguous features
PARAMETERS MSS MSI-H
TILs (>40/10HPF) 10.8% 21.7%
MELF pattern of invasion 28.3% 39.1%
TILSMELF pattern of invasion
PARAMETERS MSS MSI-H
LVI FOCAL: 16.8%DIFFUSE: 25.3%
FOCAL: 21.7%DIFFUSE: 34.7%
LN METASTASES 10.8% 21.7%
TUBALLESIONS
1 case of STIC13 cases of SCOUT4 cases of STIL
1 case of STIC1 case of SCOUT9 cases of STIL
LVI
LN metastases
Statistically significant association between loss of MMR-IHC and EC with ambiguous features, TILs and/or MELF pattern of invasion
• 100% concordance between IHC results and molecular analysis
• Among 23 cases with MSI-H, 26% was confirmed to have Lynch syndrome by genetic study
• The percentage of women with Lynch syndrome was about 5.6% of new cases of EC in all our cases
• The half of women with Lynch syndrome was not included in the Bethesda criteria
• 4 women with Lynch syndrome were over 50 years old• Good results of universal screening in spite of the relative number of
our cases
Morphological characteristics, in particular ambiguous features, MELF pattern of invasion and TILs together with IHC –MMR proteins enhance the detection of EC patients at risk of Lynch Syndrome.
Importance of universal IHC screening that is faster and cheaper thanmolecular pathology. It does not lose patients over 50 years old.
The pathologist plays a fundamental role in the whole medical equipe to identify this category of women.
Importance of multidisciplinary approach (gynecologist, genetist, oncologist….)