2023, Volume 39, Number 1, Page(s) 075-082
High Tumor Infiltrating Lymphocytes Are Associated with Overall Survival and Good Prognostic Parameters in Endometrial Endometrioid Carcinoma Patients
Cigdem OZTURK1, Gokce ASKAN1, Seda DUMAN OZTURK1, Oguzhan OKCU2, Bayram SEN3, Recep BEDIR2
1Recep Tayyip Erdogan University Training and Research Hospital, Department of Pathology, RIZE, TURKIYE
2Recep Tayyip Erdogan University, Faculty of Medicine, Department of Pathology, RIZE, TURKIYE
3Recep Tayyip Erdogan University Training and Research Hospital, Department of Biochemistry, RIZE, TURKIYE
Keywords: Tumor-infiltrating lymphocytes, Endometrial carcinomas, Prognosis, Practical parameter
The mortality incidence of endometrial carcinomas (ECs) has increased in recent years. Therefore, recent studies have focused on
the cellular and microenvironmental properties of ECs. Tumor-infiltrating lymphocytes (TILs), a component of the microenvironment, have
been found to be associated with the prognosis in many tumors. Although TILs were mostly evaluated by immunohistochemical studies in ECs,
in our study, the evaluation was done with a light microscope as a practical approach, and we aimed to determine the prognostic importance of
TILs in endometrioid ECs.
Material and Method: 104 patients were included in the study. TILs in the stromal area (sTILs) were evaluated on hematoxylin and eosin (HE)
stained-sections at X200 objective. The presence of TILs was evaluated as follows; 0-10% as low, 20-40% as moderate, and 50-90% as intense.
Then TILs were grouped as low and high.
Results: Tumors with high TILs were more prone to have FIGO (International Federation of Gynecology and Obstetrics) grade 1 tumors, low
nuclear grade, early pathological stage, smaller size, no lymphovascular invasion, myometrial invasion below 50%, and no cervical involvement.
In the presence of high TILs, the overall survival showed significant increase but no significant correlation was found with disease-free survival.
Conclusion: Interest in the molecular properties of ECs has increased in recent years. TIL, which can be easily evaluated in HE sections, is an
important parameter in patient selection for molecular tests and determining the prognosis of patients.
Endometrial carcinomas (ECs) are the most common
gynecological malignancies in developed countries 1,2
Due to rise in the mortality incidence of EC, recent studies
have focused on determining the risk by evaluating the
histopathological features 1-3
Endometrioid type endometrial carcinoma (ECC) was
divided into 4 different molecular subtypes in 2013 4.
These subtypes are POLE ultramutated, microsatellite
instable (hypermutated), copy number low, and copy
number high 4. In the following years, many validations
and recommendation studies have been carried out on
these classifications 5.
Cellular properties of the tumor as well as the tumor
microenvironment play a role in tumor progression and metastasis 6. Various studies have been conducted to
determine the immune response components of the microenvironment
in ECCs by immunohistochemical methods.
The majority of these studies are based on the association
between immune response and molecular subtypes. This is
because molecular testing is technically difficult, not always
readily available, and has a financial burden. Therefore, it
seems that determining the component of the microenvironment
by immunohistochemistry is more cost-effective
7-9. However, it is not always possible to conduct immunohistochemistry
in daily pathology practice, and not practical
to evaluate several immunohistochemical markers
In 2017, the International Tumor-Infiltrating Lymphocytes
Working Group (ITILWG) standardized the evaluation of
TILs in various solid tumors, based on the methodology in breast cancers 10,11. Accordingly, TIL is evaluated only
under a light microscope, which is easy to apply and much
more practical. In our study, with the recommendation of
ITILWG, we aimed to determine the prognostic importance
of TILs in ECCs, regardless of molecular subtypes.
|Patients and Tissue Samples
Patients who underwent hysterectomy for ECC at our
hospital between January 2010 and December 2020 were
included in our study. Hematoxylin and eosin (HE) stainedsections
were retrieved from the pathology archive. Patients
whose paraffin-embedded blocks and/or HE stainedslides
were not obtained, who had insufficient clinical
information, who underwent neoadjuvant radiotherapy or
distant organ metastasis at the time of diagnosis, as well as
those with a second primary or who died within the first
month after surgery were excluded from the study. As a
result, a total of 104 patients with ECC were included.
The age, adjuvant treatment history, status of metastasis,
and survival data were obtained from the hospital database.
Tumor size information was obtained from the pathology
reports, while FIGO (International Federation of Gynecology
and Obstetrics) grade, nuclear grade, pathological
stage, myometrium invasion rate, lymphovascular invasion,
lymph node metastasis, and necrosis were re-evaluated.
All were classified as endometrioid type endometrial
adenocarcinoma according to the World Health Organization
(WHO) criteria and were graded according to FIGO
Evaluation of Tumor-Infiltrating Lymphocytes (TILs)
In our study, TILs in the tumor stroma were evaluated,
based on the recommendation of the ITILWG, since
it is easier, more reliable, and reproducible than the
intratumoral area 10,11. The assessment was done
within the invasive component of the tumor, while areas
of endometrial hyperplasia or necrosis around the tumor
were not evaluated. It has been recommended to evaluate
TIL in all solid tumors by HE stained-sections under a light
microscope with a x200 or x400 objective.
In our study, TILs were evaluated by three pathologists
(CO, GA, OO) under the x200 objective (Olympus, BX-51,
ocular 22 mm, field size 0.950 mm2) blinded to the clinical
and other pathological features of the patients. The patients
with different scores were re-evaluated under a five-headed
microscope and consensus was achieved. The presence of TIL was evaluated as follows: 0-10% low, 20-40% moderate,
and 50-90% intense (Figure 1). The low and moderate
groups were taken as a single group, since the number
of cases forming the groups was low. As a result, the TIL
groups were divided into two as low and high.
Click Here to Zoom
|Figure 1: Hematoxylin and eosin stained 4 μm sections of
endometrioid type endometrial carcinoma. A) Example of low
Tumor infiltrating Lymphocytes (H&E x400), B) moderate
Tumor infiltrating Lymphocytes (H&E x200), C) Intense Tumor
infiltrating Lymphocytes patients (H&E x200).
Ethics committee confirmation for our study was obtained
from the non-interventional clinical research ethics
committee of Recep Tayyip Erdogan University Faculty
of Medicine (E-40465587-050.01.04-439). The study was
conducted under the Declaration of Helsinki and the
ethical standards of the institutional research committee
and the Reporting recommendations for tumor marker
prognostic studies (REMARK) guidelines 14.
Statistical analyses were performed using IBM SPSS
Statistics, Version 22.0 (SPSS Inc., Chicago, USA). Fleiss
Kappa analysis was used to compare the agreement of
TIL assessment among three pathologists. The Chisquare
test (Pearson Chi-square) or Fishers Exact test,
where appropriate, was used to compare the correlation
of categorical variables. The possible factors identified
with univariate analyses were further entered into the
Cox regression analysis with backward selection to specify
independent predictors of overall and disease-free survival
and a hazard ratio (HR) with 95% CI is presented. The
Kaplan-Meier method was used for survival analysis and
evaluation was performed with the log-rank test to identify
the effect of tumor infiltrating lymphocytes on survival.
For statistical significance, a 5% type-1 error level was used.
The mean age of the 104 patients included in the study was
59 years (ranging from 41 to 87). The majority of the patients
(76%) were in the early stage at the time of diagnosis. 61.5%
of the patients were FIGO grade 1, 33% were FIGO grade
2, and 5.8% were FIGO grade 3. Lymph node dissection
was performed in 83 (80%) patients, and lymph node
metastasis was observed in 6 (6%). The clinicopathological
characteristics of the patients are summarized in Table I.
Relationship Between TIL and Clinicopathological
The Fleiss kappa coefficient revealed an almost perfect
agreement in TILs assesment (kappa value: 0.938 (p<
0.001)) among the three observers (CO, GA and OO).
The majority of patients with high TILs were FIGO grade 1 (p=0.016). Patients with high TILs were more prone to
have low nuclear grade (p=0.001). A high TILs value was
also associated with early pathological stage, smaller tumor
size, myometrial invasion below 50%, no lymphovascular
invasion, and no cervical involvement. The relationship
between TILs and the clinicopathological parameters is
shown in Table II.
TILs and Prognostic Association with Outcome
The median follow up of patients was 62 months, ranging
from 20 to 122 months. Ten (10%) died during the follow-up and distant organ metastases developed in 10 (10%)
patients. In the presence of high TILs, the overall survival
increased statistically (p=0.035). No significant correlation
was found with disease-free survival (p=0.952). Kaplan
Meier curves of the patients are shown in Figure 2A,B. In
Cox regression analysis, TILs (Hazard ratio (HR) 0.218;
95% CI 0.146-1.032; p: 0.055), age, FIGO grade, and
lymphovascular invasion were found to be risk factors
for OS, in univariate analysis. However, in multivariate
analysis, TILs were not an independent prognostic variable
for OS (Table III). For DFS, TILs were not an independent
prognostic variable in univariate and multivariate analyzes.
Click Here to Zoom
|Table III: Univariate and multivariate analysis results for overall survival.
Click Here to Zoom
|Figure 2: A) Kaplan Meier overall survival curve Tumor infiltrating Lymphocytes (p=0.035), B) Kaplan Meier disease free survival curves
for Tumor infiltrating Lymphocytes (p=0.952).
Various immune cells such as dendritic cells, natural
killer cells, mast cells, macrophages, and lymphocytes
contribute to the tumor microenvironment 15
. Some of
these components show antitumoral activity, while some
facilitate neoangiogenesis and growth of the tumor 15,16
For example, CD8 T lymphocytes, dendritic cells, tumor
antigen-specific T lymphocytes, CD45 RO+ T lymphocytes,
and tumor-associated memory T lymphocytes show
antitumor activity. By contrast, macrophages or Fox P3
+ regulatory T lymphocytes increase tumor invasion,
progression, metastasis, and neoangiogenesis 16
Most studies in ECCs have focused on the association
between TILs and molecular status rather than the
prognostic significance of the TILs 12. ECCs with
mutations in DNA mismatch repair genes (MMR), one of
the molecular subtypes, occur in approximately 10-20%
of all ECCs 17. Recent studies have shown that TILs
play a role in predicting MMR defects (18-20). Another
molecular subtype, the POLE mutant type, is observed
in 7% 21. TILs count was reported to be higher in this
subtype compared to POLE wild type 21,22. There are
also studies reporting that immune checkpoint inhibitors
can be used in the treatment of tumors with mutations
23-25. Therefore, it is important to report TILs both in
patient selection for molecular tests and in the treatment
management of patients.
There are also studies mainly focused on the relationship
between MMR and POLE status rather than the prognostic
value of TILs in ECCs 26-32. de Jong et al. have found
high CD8+T lymphocyte value, high CD8+/FoxP3+ ratio,
and the presence of CD45 RO+ T lymphocytes to be
good prognostic parameters. Moreover, they have been
associated with long DFS and OS 26. On the other hand,
Giatromalaki et al. have argued that an increase in FOXP3
released from CD4+ CD25+ regulator T cells (Tregs)
is associated with increased neoangiogenesis and poor
prognosis by suppressing effector T cells 27. Similar to
this study, Yamagami et al. have associated high Tregs with
poor DFS 28. Jiang et al. have investigated the presence of
tumor-associated macrophages (TAMs), which are thought
to have a role in tumor progression in patients with ECC and endometrial hyperplasia. According to this study, TAMs
play a role in the progression of precancerous endometrial
lesions to ECCs 29. In addition, several studies in the
literature claim that intraepithelial CD8+ T lymphocytes
are an independent prognostic factor and that stromal
CD3+ T lymphocytes have a prognostic value 26,30-32.
The results of studies advocating the relationship of all
these immune components with the prognosis have shown
that TIL is a prognostic parameter. In our study, TILs were
evaluated with the method suggested by the ITILWG.
According to our results, high TILs were associated with
low FIGO grade, early pathological stage, low nuclear
grade, low tumor diameter, myometrial invasion below
50%, no cervical involvement, and no lymphovascular
invasion. When the survival of the patients was evaluated,
OS was found to be longer in the presence of high TIL. The
results of our study and studies advocating the relationship
of all these immune components with the prognosis have
shown that TIL is a prognostic parameter.
Almost all of these studies are based on immunohistochemical
studies in the literature. However, immunohistochemical
work-up is not easily accessible for all
pathologists. Endometrial curettage sampling is relatively
easy in terms of sampling compared to many other tumors,
and the curettage procedure is less material-dependent. For
this reason, it can be easily performed even in many centers
that do not have the opportunity to perform immunohistochemical
analysis. Therefore, we evaluated TILs with light
microscopy in patients with ECC, according to the recommendation
of the ITILWG, without additional cost and
time. Inter-observer agreement in our study was almost
excellent and these results suggest that similar results will
be obtained by different observers. Our study is the first
study of ECs using only a light microscope, without an
additional immunohistochemical study, as recommended
Lymph node dissection in ECs is not recommended in
patients with FIGO grade 1-2, endometrioid histology,
tumor size less than 2 cm, and myometrial invasion
below 50% 33. In our study, lymph node dissection
was performed in 80% of the patients, and lymph node
involvement was observed in 8%. Similarly, it has been
reported in the literature that lymph node dissection
is applied to a much larger number of patients than is
recommended in daily practice for surgical staging, as well
as prognosis estimation, and adjuvant treatment decision
34. However, lymph node dissection may cause various
complications such as bleeding, lymphedema, inflammatory
infiltration, vascular and nerve damage within the short and long term after surgery 35. In our study, lymph node
metastasis was not observed in the vast majority of patients
who met the dissection conditions of the guidelines.
These results show the necessity of additional parameters
to the existing parameters in the decision of lymph node
dissection. Therefore, TILs, which are associated with
prognostic parameters, can be evaluated in frozen sections
during surgery or in curettage materials before surgery. By
this way, TILs can be used as a parameter in the selection
of patients who need lymph node dissection. No significant
association was found between TIL and lymph node
metastasis in our study. This result could be explained by
the high number of low stage tumors in our cohort. Further
studies are needed on this aspect.
Based on the ITILWGs recommendation, TILs evaluation
using a light microscope has begun to take its place in the
pathology reports of many cancer types, especially in colon
and breast 10. Our study supports that reporting TILs
in ECCs without requiring any extra time and cost will
contribute to patient prognosis.
Our study consisted of patients whose molecular subtypes
were unknown, since molecular testing could not be
performed in our center. Therefore, an idea regarding the
association between TILs and molecular subtypes could
not be obtained. Based on the association between TILs and
molecular subtypes, which has been proven in many studies
in the literature, TILs can contribute to patient selection
for molecular testing by identifying tumors suspicious for
certain mutations. Similarly, it will be very useful in patient
management for centers that do not have the opportunity
to perform molecular analyses.
ECCs are observed at a very high rate in women all over the
world and the knowledge about their subtypes continues
to increase. It is not cost effective to refer all patients to
testing for molecular subtyping. For this reason, TILs,
which is evaluated practically on HE sections, is important
in patient selection for molecular tests and in determining
the prognosis of patients.
Conflict of Interest
Authors report no conflict of interest.
Concept: ÇÖ, GA, SDÖ, OO, Design: ÇÖ, GA, Data collection or
processing: ÇÖ, GA, SDÖ, OO, BŜ, Analysis or Interpretation: ÇÖ,
BŜ, RB, Literature search: ÇÖ, SDÖ, Writing: ÇÖ, GA, Approval:
ÇÖ, GA, OO, RB.
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