European Journal of Gynaecological Oncology,2025,46(9):64-70 DOI:10.22514/ejgo.2025.121
Original Research
Effects of neutrophil-to-lymphocyte ratio, tumor-infiltrating lymphocyte and neutrophil scores on prognosis in low-risk endometrial cancer
Alparslan Pulur1, Şener Gezer1,*,, Seda Duman Öztürk2, Müzeyyen Dilşad Eser1

1Department of Obstetrics and Gynecology, Kocaeli University School of Medicine, 41001 İzmit, Turkey

2Department of Pathology, Kocaeli University School of Medicine, 41001 İzmit, Turkey

*Corresponding Author(s):sener.gezer@kocaeli.edu.tr (Şener Gezer)

History Submitted: 12 April 2025 | Accepted: 14 May 2025 | Published: 15 September 2025
Copyright:  ©2025 The Author(s). Published by MRE Press.
This is an open access article under the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).

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Abstract

Background: This study aimed to determine the association of neutrophil-to-lymphocyte ratio (NLR), tumor-infiltrating lymphocyte (TIL) and tumor-infiltrating neutrophil (TIN) scores with recurrence-free survival (RFS) in patients with low-risk endometrial cancer. Methods: A total of 233 low-risk endometrial cancer patients were retrospectively screened. The NLR values calculated from the peripheral blood and TIL and TIN scores from tumor tissues were compared for survival analyses. Results: There was no statistically significant difference in RFS according to the NLR with an optimal prognostic cut-off value of 2.4. The expected RFS time was 77.9 months (±0.7, 95% Confidence Interval (CI): 76.5–79.3) for patients with an NLR <2.4 and 76.5 months (±1.3, 95% CI: 73.7–79.2) for patients with an NLR ≥2.4 (p = 0.303). The expected RFS times were 69.9 months (±2.7, 95% CI: 64.6–75.3) for patients with a TIL score of 1, 65.5 months (±1.9, 95% CI: 61.3–69.4) for patients with a TIL score of 2, and 74.5 months for patients with a TIL score of 3 (±1.9, 95% CI: 70.8–78.2), respectively. (score 1 vs. score 2, p = 0.031) (score 1 vs. score 3, p = 0.302) (score 2 vs. score 3, p = 0.018). Patients with a TIN score of 1 had a worse RFS than those with a TIN score of 0; 55.9 months (±5.3, 95% CI: 45.4–66.4), versus 78.6 months (±0.3, 95% CI: 77.9–79.3) (p < 0.001). Conclusions: A TIN score of 1 and a TIL score of 2 were associated with worse RFS in patients with low-risk endometrial cancer. No significant association was found with the NLR.

Keywords:Neutrophil-to-lymphocyte ratio;Tumor-infiltrating lymphocyte;Tumor-infiltrating neutrophil;Low-risk endometrial cancer;Recurrence-free survival (RFS)
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Cite this article

Alparslan Pulur, Şener Gezer, Seda Duman Öztürk, Müzeyyen Dilşad Eser. Effects of neutrophil-to-lymphocyte ratio, tumor-infiltrating lymphocyte and neutrophil scores on prognosis in low-risk endometrial cancer.European Journal of Gynaecological Oncology,2025,46(9):64-70 DOI:10.22514/ejgo.2025.121

1. Introduction

Endometrial cancer, especially endometrioid-type adenocarcinoma, is the most common gynecological cancer in developed countries [1]. Fortunately, a significant proportion of patients are diagnosed in the early stages, leading to favorable survival outcomes [2]. The low-risk category in endometrial cancer encompasses individuals with grade 1 and 2 tumors of the endometrioid type, tumors confined to the uterus, myometrial invasion that is less than half of the myometrium, and either no lymphovascular invasion or only focal involvement. Such patients typically enjoy a robust life expectancy and a high rate of RFS, rendering adjuvant therapy unnecessary [3]. Despite these encouraging statistics, there remains a slight risk of recurrence, with success rates of treatment hovering at approximately 40%, potentially negatively impacting the overall survival (OS) [4, 5].

The current risk stratification systems that depend on histomorphology have been criticized for being irreproducible; however, molecular classification provides a new opportunity to address this issue [2, 6]. Nevertheless, molecular classification and its alternative, ProMisE classification, which uses immunohistochemical (IHC) staining and less molecular sequencing to reduce the cost, have technical difficulties and are still expensive [7]. Therefore, there is a clear need for less expensive and reproducible surrogate markers that can predict the prognosis of low-risk patients with endometrial cancer.

The systemic inflammatory response plays a pivotal role in cancer progression, stemming from the intricate biointeraction between tumor cells and inflammatory cells [8]. This association is evidenced by the presence of neutrophilia, thrombocytosis and lymphocytopenia in the peripheral blood [9]. Neutrophils exert an inhibitory influence by dampening the activity of lymphocytes and T-cell responses [10]. Furthermore, neutrophils can actively foster the establishment of an inflammatory microenvironment conducive to tumor proliferation and metastasis by secreting of growth factors, chemokines and cytokines [11]. Conversely, the presence of tumor-infiltrating lymphocytes (TIL) is correlated with a favorable prognosis across diverse cancer types [11]. The serum neutrophil-to-lymphocyte ratio (NLR) can function as a readily available surrogate measure of the tumor microenvironment. Elevated NLR levels have consistently been linked to adverse outcomes in patients with endometrial cancer, as documented in the literature [12, 13, 14, 15, 16, 17, 18, 19].

Although the prognostic relevance of the NLR for endometrial cancer has been confirmed, the interplay among the NLR, TIL and tumor-infiltrating neutrophils (TIN) remains uncertain. Studies conducted on low-risk endometrial cancer patients who are not usually receiving adjuvant therapy have greater value in revealing patient prognosis [20]. We designed the present study to evaluate the prognostic value of the NLR, TIL and TIN scores in women with low-risk endometrial cancer, where the influence of possible confounding factors is minimal.

2. Methods

2.1 Study population

This study was conducted on low-risk endometrial cancer patients who underwent surgery between January 2017 and December 2022 at Kocaeli University Hospital. Patients were retrospectively screened following approval from the ethics committee of Kocaeli University (Approval number: GOKAEK-2022/247). All procedures were carried out in accordance with the principles outlined in the Declaration of Helsinki. Kocaeli University ethics committee waived informed consent.

Patients with endometrioid-type endometrial cancers, invasion less than half of the myometrium, grades 1 and 2, and no lymphovascular invasion were included in the study population. The exclusion criteria included non-endometrioid tumor types (e.g., serous, clear cell), grade 3 tumors, myometrial invasion greater than half of the myometrium, patients who had received adjuvant or neo-adjuvant chemotherapy or radiation therapy, individuals with concomitant malignancies, and subjects who were not available during the follow-up period.

During routine oncologic follow-up, physical examinations were performed four times in the first 2 years, twice for the next 3 years, and once a year thereafter. In the event of a suspected relapse, further assessments were performed, which included monitoring serum Cancer Antigen (CA)-125 levels and using advanced imaging techniques. The main study endpoint was RFS. The duration from surgery to recurrence or disease progression was denoted RFS.

2.2 Neutrophil-lymphocyte ratio

We measured the pretreatment complete blood count (CBC), and the NLR was calculated (neutrophil divided by lymphocyte count). The optimal cutoff value for the NLR was determined using the optimal decision threshold obtained from the receiver operating characteristic (ROC) curve analysis.

2.3 Pathological analysis

Four-micrometer sections were prepared from paraffin-embedded, formalin-fixed tissue blocks from each patient. Hematoxylin-eosin (H&E) stained tissues were used for histological examination by an experienced pathologist who was unaware of the clinical characteristics of the patients. The TIL evaluation was performed from the intratumoral area based on the recommendation of the International Immuno-Oncology Biomarkers Working Group because this evaluation was easier, more reliable and repeatable than the tumor stroma [21]. TILs (Cluster of Differentiation (CD)4+/CD8+ T cells) were assessed using the 200× objective (9E12224, Olympus, BX-51, Olympus Corporation, Tokyo, Japan, ocular 22 mm, field size 0.950 mm2). Their presence was categorized as follows: 0–10% deemed low (score 1), 20–40% classified as moderate (score 2), and 50–90% characterized as intense (score 3).

To detect TINs, a pathologist blinded to the tumor subtype scanned all tumor areas for neutrophils. A 10× objective was used initially, and then the most intense field was evaluated with a magnification of 40× (9E12224, Olympus, BX-51, Olympus Corporation, Tokyo, Japan). As per the criteria, instances with ≤10 neutrophils per 100 epithelial cells were categorized as negative (score 0), whereas areas with >10 neutrophils per 100 epithelial cells were designated as positive (score 1) [22]. Microphotos of the TIL and TIN scores are shown in Fig. 1.

Microscopic view of TIL and TIN scores. (a) TIL score 1 (H&amp;E ×7.52), (b) TIL score 2 (H&amp;E ×8.30), (c) TIL score 3 (H&amp;E ×11.42), (d) TIN score 0 (H&amp;E ×4.40), (e) TIN score 1 (H&amp;E ×4.40). Arrows indicate neutrophil infiltration. H&amp;E: Hematoxylin and Eosin; TIL: Tumor-infiltrating Lymphocyte; TIN: Tumor-infiltrating Neutrophil.

Fig. 1.Microscopic view of TIL and TIN scores. (a) TIL score 1 (H&E ×7.52), (b) TIL score 2 (H&E ×8.30), (c) TIL score 3 (H&E ×11.42), (d) TIN score 0 (H&E ×4.40), (e) TIN score 1 (H&E ×4.40). Arrows indicate neutrophil infiltration. H&E: Hematoxylin and Eosin; TIL: Tumor-infiltrating Lymphocyte; TIN: Tumor-infiltrating Neutrophil.

2.4 Statistical analysis

All statistical analyses were performed using SPSS 20.0 (SPSS, Chicago, IL, USA). Continuous variables are expressed as the mean ± standard deviation or median (interquartile range), whereas categorical variables are presented as counts (percentages). Survival analysis was performed using the Kaplan-Meier with Log-rank test. A p-value < 0.05 was deemed statistically significant.

3. Results

The study enrolled 233 patients with low-risk endometrial cancer for whom both survival data and pathology specimens were accessible. The clinical and pathological characteristics of the patients are shown in Table 1. In the pathological examination, 146 of the endometrioid-type cancer cases were classified as grade 1, while 87 of them were classified as grade 2. The optimal prognostic cut-off for the NLR was 2.4 (specificity 60%, sensitivity 60%, Area under curve 0.67). There were 142 patients below the NLR cut-off value, while 91 patients’ NLR values were equal to or above 2.4. In terms of the TIL scores, 70 patients had a TIL score of 1, 76 patients had a TIL score of 2 and 87 patients had a TIL score of 3. Interestingly, the number of patients with a TIN score of 0 was 211, while the number of patients with a TIN score of 1 was 22.

Table 1.Demographic, clinical and pathologic characteristics of patients.
CharacteristicNumber/Median
Age (yr)58 (53–64)
Gravida3 (2–5)
Parity3 (2–4)
BMI (kg/m2)33 (30–37)
Menopausal status
Premenopause58 (24.9%)
Postmenopause175 (75.1%)
Co-morbidities
Hypertension134 (5.5%)
Diabetes84 (36.1%)
Grade
1146 (62.7%)
287 (37.3%)
Tumor size3 (2–4)
Lymphadenectomy status
None95 (40.8%)
Pelvic138 (59.2%)
Lymph node count19 (13–26)
NLR2.15 (1.67–2.69)
<2.4142 (60.9)
≥2.491 (39.1)
TIN score
0211 (90.6%)
122 (9.4%)
TIL score
170 (30%)
276 (32.6%)
387 (37.3%)
NLR: Neutrophil to lymphocyte ratio; TIN: Tumor-infiltrating Neutrophil; TIL: Tumor-infiltrating Lymphocyte; BMI: Body mass index. Numerical variables that do not correspond to the normal distribution are shown as Median (25–75 percentile), and the categorical variables are shown as n (%).

There were five recurrences in the study cohort. The median RFS for all patients in the study was 77.4 months (±0.6, 95% CI: 76.1–78.7). The survival analyses for RFS are shown in Fig. 2.

Survival analysis for recurrence-free survival (RFS) with respect to NLR, TIL and TIN scores. NLR: Neutrophil to lymphocyte ratio; TIN: Tumor-infiltrating neutrophil; TIL: Tumor-infiltrating Lymphocyte; RFS: recurrence-free survival.

Fig. 2.Survival analysis for recurrence-free survival (RFS) with respect to NLR, TIL and TIN scores. NLR: Neutrophil to lymphocyte ratio; TIN: Tumor-infiltrating neutrophil; TIL: Tumor-infiltrating Lymphocyte; RFS: recurrence-free survival.

For patients with an NLR <2.4, the expected RFS time was 77.9 months (±0.7, 95% CI: 76.5–79.3), whereas for patients with an NLR ≥2.4, it was 76.5 months (±1.3, 95% CI: 73.7–79.2) (p = 0.303).

For TIL scores, the expected RFS times were 69.9 months (±2.7, 95% CI: 64.6–75.3), 65.5 months (±1.9, 95% CI: 61.3–69.4) and 74.5 months (±1.9, 95% CI: 70.8–78.2) for patients with scores of 1, 2 and 3, respectively. (score 1 vs. score 2, p = 0.031) (score 1 vs. score 3, p = 0.302) (score 2 vs. score 3, p = 0.018).

Furthermore, patients with a TIN score of 1 had a worse RFS than those with a TIN score of 0; 55.9 months (±5.3, 95% CI: 45.4–66.4), versus 78.6 months (±0.3, 95% CI: 77.9–79.3) (p < 0.001).

4. Discussion

This study evaluated inflammatory changes in the serum and tumor microenvironment of patients with low-risk endometrial cancer. There was no statistically significant difference in RFS for the NLR with a cut-off value of 2.4. A higher TIN score was associated with a statistically significantly worse RFS. Meanwhile, a TIL score of 2 was associated solely with poorer RFS compared with scores 1 and 3.

Systemic inflammation plays an important role in the progression of malignancy. Changes caused by the inflammatory response in the peripheral blood and tumor microenvironment can be used to predict a patient’s prognosis [8]. Serum NLR may project the prognosis and likelihood of benefit from therapy [13, 15, 17]. Two retrospective studies, each consisting of more than 500 endometrial cancer patients, revealed that the NLR is an independent prognostic factor [15, 23]. In addition, the NLR can predict myometrial invasion, lymphovascular invasion, lymph node positivity and distant organ metastasis [14, 18, 19]. Moreover, in patients with recurrent endometrial cancer who received immunotherapy, an NLR <6 could predict low OS but could not detect a difference in terms of RFS [24]. It should be mentioned that the NLR can also predict the response to immunotherapy.

In a meta-analysis, an NLR greater than the cut-off value of 2.95 was associated with a worse OS. A higher histological grade was the only clinicopathological factor found to be a modifier of the NLR on OS. Interestingly, a meta-regression analysis could not be performed because few studies provided hazard ratios for the effect of the NLR on RFS [25]. In a systematic review of 3390 endometrial cancer patients, it was concluded that an elevated NLR could be a prognostic marker [17].

In a prospective study, an NLR ≥2.38 had higher cancer-specific and total mortality rates; however, after adjusting for confounding factors, the effect of the NLR on survival could not be demonstrated [26]. Most patients in this study had low-grade, early-stage endometrioid tumors. These results are consistent with our results, and the predictive effect of the NLR on survival is probably invalidated in low-risk patients. In a study by Li et al. [27], it was concluded that the NLR predicts poor survival but is not an independent prognosticator in the Cox regression model. In another study that evaluated the relationships of NLR, platelet-lymphocyte ratio, lymphocyte-monocyte ratio, and their various formulations with prognosis, none of the inflammatory markers were associated with RFS [28].

The effects of TILs on the prognosis in endometrial cancer have been previously investigated, and the results showed an improved prognosis with increased TILs. High numbers of CD8+ T lymphocytes in the tumor microenvironment were an independent prognostic factor for better OS in a multivariate analysis [29, 30]. In addition, increased TIL scores have been associated with a lower histological grade, less myometrial invasion, and fewer metastatic lymph nodes [31]. A recent meta-analysis has shown that more TILs lead to improved survival in endometrial cancer [32]. In the current study, a TIL score of 2 was associated with a worse RFS than TIL scores of 1 and 3. This result contradicts the literature; however, it may be associated with the scarcity of studies focusing solely on low-risk patients.

Both DNA polymerase epsilon (POLE) and missmatch-repair deficient (MMRd) subtypes are characterized by more TIL infiltrates and a higher mutation rate; their sensitivity to immunotherapy depends on this [33]. A high amount of antigenic peptides on the surfaces of cancer cells causes a significant immune response and a higher mutational burden, which explains the more favorable prognosis for these molecular groups [34]. In a study by Shia et al. [35], TIL counts (40 TILs/10 high-power fields) and lymphocytes in the peritumoral area were determined as independent predictors of MMRd status.

Neutrophils usually suppress lymphocyte activity, and inversely TILs, TINs may be associated with progression and metastasis [10, 36]. Many studies have reported a close relationship between TINs and clinical outcomes in various types of cancer [37]. TINs were found to be associated with a worse prognosis in renal, gastric and pancreatic carcinomas [38, 39, 40]. The number of studies examining the effects of TINs on survival in genital tract cancers is minimal. In a study evaluating the effects of TINs in cervical cancer, TIN density was significantly associated with a shorter PFS, and the authors concluded that TIN is an independent prognostic factor in multivariate analysis [41]. High phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) expression regulates neutrophils in the tumor microenvironment by acting through the T cell receptor signaling pathway and is associated with a poor prognosis in endometrial cancer [42]. Neutrophils can adapt to the tumor microenvironment and exhibit changing phenotypes. The changing tumor microenvironment due to tumor progression mediates the reprogramming of neutrophils and the emergence of immunosuppressive phenotypes [43].

We did not explore the molecular subgroups of the patients in the study cohort. Low-grade, early-stage endometrial carcinomas are more associated with mismatch repair protein deficiency and a low number of somatic copy-number alterations; the association of these molecular subtypes with a prognosis is weak [7]. Endometrial cancer has shown a heterogeneous immune response, varying between tumor grades and molecular subtypes, and these responses could be dysregulated in low-grade, early-stage tumors [44]. In a study evaluating the tumor immune microenvironment and clinical outcome in low-grade, early-stage endometrial cancers, the immune phenotypes showed a weak correlation with the molecular subtypes. In addition, the correlation between the immune phenotypes and POLE or Catenin beta-1 (CTNNB1) mutation status was non-significant [45].

The strengths of this study are that it included only low-risk patients, adjuvant therapy that may affect prognosis was not used, and the prognostic markers NLR, TIL score and TIN score were evaluated simultaneously. As expected in low-risk endometrial cancer patients, survival analysis could not be performed because there were not enough events for OS. The study’s retrospective design and relatively small patient cohort, attributed to its single-center nature, may be regarded as limitations.

While more data is needed before effectively utilizing the TIN score to tailor endometrial cancer therapy recommendations, the TIN score is an easily accessible, low-cost, reproducible test representing the tumor microenvironment. If our results are validated in a large independent cohort, the TIN score could point to a simple prognostic test that could refine risk assessment, especially in low-risk endometrial cancer. On the other hand, TIN assessment combined with p53 immunohistochemistry might be used as a screening test to select patients at risk of recurrence.

5. Conclusions

A high TIN score was able to predict recurrence, in contrast to the NLR and TIL score. To our knowledge, this is the first study to prove that a high TIN score is associated with a worse prognosis in low-risk endometrial cancer. On the other hand, the TIN score is a cheap and reproducible surrogate marker for prognosis prediction compared to IHC studies and molecular classification.

Availability of data and materials

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Author contributions

ŞG, AP—conception, design, and acquisition of data. ŞG, SDÖ, MDE—analysis and interpretation of data. All authors contributed to the manuscript writing; administrative support; study supervision or coordination. And all authors approved the final manuscript.

Ethics approval and consent to participate

This study protocol was reviewed and approved by ethics committee of Kocaeli University (Approval number: GOKAEK-2022/247). Kocaeli University ethics committee waived informed consent.

Acknowledgment

Not applicable.

Funding

This research received no external funding.

Conflict of interest

The authors declare no conflict of interest.

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