Abstract
Background
Endometrial carcinoma is a common gynecological malignancy, LNM is a crucial factor affecting the prognosis of endometrial cancer patients, with a significant impact on survival rates and treatment effectiveness. Serum lipocalin-2, PDK1, and NGALR have been found to be abnormally expressed in various tumors and are potentially associated with tumor metastasis. Therefore, this study aims to investigate these relationships and evaluate the predictive efficacy of these biomarkers, which may provide new insights and methods for the early diagnosis and treatment of postmenopausal endometrial cancer with LNM.
Methods
Totally 133 postmenopausal endometrial cancer patients treated in Harbin Medical University Cancer Hospital and 100 healthy subjects were included in this study. According to the postoperative pathological diagnosis, 133 patients were divided into LNM group (n=47) and non LNM group (n=86).
Results
The serum lipocalin-2, PDK1, and NGALR levels in patients with endometrial cancer were significantly higher than those in the healthy group (P<0.05). The results of logistic regression analysis showed that the lipocalin-2, PDK1, and NGALR were all factors affecting LNM (P<0.05). Area under the curve (AUC) of lipocalin-2, PDK1 and NGALR were 0.755, 0.778 and 0.856 respectively by establishing receiver operating characteristic (ROC) curve analysis, with the specificity of 67.50%, 67.50% and 82.50%, respectively. The sensitivities were 80.00%, 82.22% and 75.56%, respectively. The AUC (0.925), sensitivity (98.89%) and specificity (70.00%) of the joint tests were higher than those of the other three tests. The joint tests had higher diagnostic value for LNM of postmenopausal endometrial carcinoma.
Conclusions
The serum levels of lipocalin-2, PDK1, and NGALR in postmenopausal endometrial carcinoma patients and patients with LNM were significantly increased, and the combined detection had higher diagnostic value for postmenopausal endometrial carcinoma LNM, which would be beneficial to guide the diagnosis and treatment of postmenopausal endometrial carcinoma LNM in clinic.
Keywords: Lipocalin-2, phosphoinositide-dependent protein kinase-1 (PDK1), neutrophil gelatinase-associated lipocalin receptor (NGALR), postmenopausal endometrial carcinoma, lymph node metastasis (LNM)
Highlight box.
Key findings
• Serum levels of lipocalin-2, phosphoinositide-dependent protein kinase-1 (PDK1), and neutrophil gelatinase-associated lipocalin receptor (NGALR) are significantly elevated in postmenopausal endometrial cancer patients, especially those with lymph node metastasis (LNM). Combined detection of these biomarkers shows high diagnostic value for predicting LNM.
What is known and what is new?
• Endometrial cancer predominantly affects postmenopausal women, and LNM is a critical prognostic factor. Additionally, abnormal expressions of serum lipocalin-2, PDK1, and NGALR have been observed in endometrial cancer, though their combined role in predicting LNM remains unelucidated.
• This study shows how combining the detection of lipocalin-2, PDK1 and NGALR can help to diagnose LNM in postmenopausal endometrial cancer. When the test is done together, it gets an area under the curve of 0.925, a sensitivity of 98.89%, and a specificity of 70.00%. This is better than single marker detection. It also identifies myometrial invasion ≥1/2 and poor differentiation as independent risk factors for LNM.
What is the implication, and what should change now?
• The findings of this study imply that combined detection of serum lipocalin-2, PDK1, and NGALR can serve as an effective tool for early prediction of LNM in postmenopausal endometrial cancer, which is crucial for optimizing treatment strategies and improving patient prognosis.
• Clinically, there should be a shift towards incorporating this combined biomarker detection into routine practice for postmenopausal endometrial cancer patients. This can help avoid unnecessary blind lymph node dissection (reducing complications such as vascular/nerve injury and lymphedema) and guide personalized treatment decisions, thereby promoting more precise and patient-centered management of the disease.
Introduction
Endometrial carcinoma is a malignant tumor occurring in the endometrium, with a high incidence in the 50–60 years age group, more common in postmenopausal women, and a trend of younger in recent years (1). According to the latest global cancer data report, the number of new cases of female endometrial cancer in the world reached 420,000 in 2020, ranking sixth in the world in the incidence of female malignant tumors (2). According to statistics, the incidence of endometrial cancer increases year by year in our country, especially in women over the age of 50 years old, and its incidence has been among the forefront of female malignant tumors (3). The occurrence of postmenopausal endometrial carcinoma is associated with multiple factors, including long-term estrogen stimulation without progesterone antagonism, obesity, diabetes, and others. With the aging of the population, the prevention and early diagnosis of postmenopausal endometrial cancer are particularly important.
For local areas lymph node metastasis (LNM), radical endometrial cancer surgery and local lymph node dissection can be performed, and adjuvant radiotherapy and chemotherapy can be selected based on pathological staging to reduce the risk of local recurrence. However, if endometrial cancer is accompanied by distant LNM, such as inguinal, retroperitoneal, mediastinal, subclavian, and cervical LNM, surgical resection is generally not an option for radical treatment. Instead, comprehensive treatment methods such as systemic chemotherapy and immunotherapy can be used to control the condition (4,5). LNM is an important prognostic factor for endometrial cancer (6). Research has shown that the overall 5-year survival rate of endometrial cancer patients without LNM is higher than 90%, while patients with LNM have an overall 5-year survival rate of only 60%. In addition, the presence of LNM significantly reduces the tumor free survival rate and specific survival rate of patients (7,8). LNM is an important negative factor in the prognosis of endometrial cancer, directly affecting the survival rate and treatment effectiveness of patients. Therefore, in clinical practice, early detection and treatment of LNM are crucial for improving the prognosis of endometrial cancer patients. In recent years, the classification and management of endometrial cancer have evolved significantly, with a focus on personalized therapeutic approaches based on molecular profiling (9,10). These advances underscore the importance of identifying reliable biomarkers for early detection and treatment stratification. In recent years, studies have found that serum lipocalin-2 (11), phosphoinositide-dependent protein kinase-1 (PDK1) (12), and neutrophil gelatinase-associated lipocalin receptor (NGALR) (13) are abnormally expressed in a variety of tumors, which are closely related to the occurrence, development, invasion and metastasis of tumors. The purpose of this study was to investigate the relationship between serum lipocalin-2, PDK1, NGALR and LNM of postmenopausal endometrial carcinoma and evaluate its predictive efficacy, in order to provide a new method for early diagnosis and prediction of LNM of endometrial carcinoma. We present this article in accordance with the STARD reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2239/rc).
Methods
Study design and population
A total of 133 postmenopausal endometrial cancer patients were treated in Harbin Medical University Cancer Hospital from March 2022 to January 2024. Inclusion criteria: (I) confirmed by pathological examination, all patients met the diagnostic criteria of endometrial carcinoma (14); (II) no other treatments such as chemoradiotherapy and hormone treatment before operation; (III) age of patients was in 46–79 years old, with detailed medical records. Exclusion criteria: (I) concomitant endocrine system diseases and infectious diseases; (II) patients with heart function or liver and kidney dysfunction; (III) patients with other malignant tumors. Moreover, 100 healthy subjects were recruited from the health examination center of Harbin Medical University Cancer Hospital as the health group. Exclusion criteria: (I) concomitant endocrine system diseases and infectious diseases; (II) patients with heart function or liver and kidney dysfunction; (III) patients with other malignant tumors. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Harbin Medical University Cancer Hospital (No. KY2024-90). Informed consent was waived for this retrospective study due to the exclusive use of de-identified patient data, which posed no potential harm or impact on patient care.
Data collection
According to the pathological diagnosis, 133 postmenopausal endometrial cancer patients were divided into metastatic group (LNM) 47 cases and non LNM group (non-LNM) 86 cases. The clinical characteristics including age, course of disease, menopausal age, diabetes mellitus, tumor classification, ascites cytology, lesion diameter, hypertension, intravascular cancer thrombi, and differentiated degree of myometrial invasion were retrospectively collected.
Detection of serum lipocalin-2, PDK1, and NGALR levels
The fasting samples (at least 8 h) were collected and centrifuged in a SIGMA 1-14K high-speed centrifuge (Beijing Pumai Jingyi Technology Co., Ltd., Beijing, China) at 4,000 r/min. The supernatant was stored in a 50086V-80 C ultra-low temperature refrigerator (Shanghai Fuze Trading Co., Ltd., Shanghai, China) for the detection of laboratory indicators. The enzyme linked immunosorbent assay (ELISA) was used to detect the levels of serum C-reactive protein (CRP), estrogen (E), lipocalin-2, PDK1 and NGALR in each group. Determination: the optical density (OD) value of the sample and the corresponding CRP concentration were automatically measured by an enzyme-labeled analyzer. Measure the OD of each well sequentially at the blank air conditioning zero, 470 nm wavelength. The assay should be performed within 15 minutes of the addition of the stop liquid. ELISA kits were purchased from Wuhan Aidi Anti-Biological Technology Co., Ltd. (Wuhan, China).
Statistical analysis
SPSS 24.0 was used for statistical analysis. The count data (tumor type, lesion diameter, and ascites cytology) were shown as examples (percentage), and assessed using χ2 test. Measurement data (age, course of disease, lipocalin-2, PDK1, NGALR, etc.) were in accordance with the normal distribution and in the form of mean ± standard deviation, the data between the research group and the control group, as well as the quantitative data between the metastatic and non metastatic groups, were analyzed using independent sample t-tests and multivariate logistic regression to identify independent risk factors for LNM in postmenopausal endometrial cancer. The receiver operating characteristic (ROC) curve predicts the value of lipocalin-2, PDK1, and NGALR in predicting LNM in patients. P<0.05 was considered statistical significance.
Results
Analysis of serum lipocalin-2, PDK1, and NGALR levels in the study group and the health group
Among the study group, the ages were 46–79 years, the average age was 63.85±6.84 years old, and the mean body mass index (BMI) was 21.62±1.75 kg/m2. The health group was in 52–75 years old, with the average age of 64.43±7.70 and the BMI level of 22.08±2.81 kg/m2. There is no difference between the two groups (P=0.55, 0.13). The serum lipocalin-2, PDK1, and NGALR levels in patients with endometrial cancer were significantly higher than those in the healthy group (P<0.001). From this, it can be seen that serum lipocalin-2, PDK1 and NGALR are involved in the occurrence and development of postmenopausal endometrial cancer (Table 1).
Table 1. Analysis of lipocalin-2, PDK1, and NGALR in serum of study group and health group.
| Group | Number of cases | Lipocalin-2 (ng/mL) | PDK1 (μg/L) | NGALR (ng/mL) | Age (years) | BMI (kg/m2) |
|---|---|---|---|---|---|---|
| Study group | 133 | 210.15±72.26 | 142.57±20.46 | 92.73±19.96 | 63.85±6.84 | 21.62±1.75 |
| Health group | 100 | 72.02±21.47 | 16.83±4.20 | 35.70±7.19 | 64.43±7.70 | 22.08±2.81 |
| t | 18.503 | 60.475 | 27.261 | 0.607 | 1.534 | |
| P | <0.001 | <0.001 | <0.001 | 0. 55 | 0.13 |
Data are presented as mean ± standard deviation. BMI, body mass index; NGALR, neutrophil-gelatinase associated lipocalin receptor; PDK1, phosphoinositide-dependent protein kinase-1.
Relationship between LNM and clinical features of postmenopausal endometrial carcinoma
Between the metastatic group and the non-LNM group, there were no significant differences in age, disease course, menopausal age, CRP and E levels, as well as the proportions of diabetes, tumor type, ascites cytology, lesion diameter, hypertension, intravascular tumor thrombus (P>0.05). Compared with the non LNM group, the proportion of myometrial invasion ≥1/2 and degree of differentiation in the metastatic group was significantly increased, and the serum lipocalin-2, PDK1, and NGALR levels were significantly increased (P<0.05) (Table 2).
Table 2. Relationship between LNM and clinical features of postmenopausal endometrial carcinoma.
| Group | Transfer group (n=47) | Non-transfer group (n=86) | χ2/t | P |
|---|---|---|---|---|
| Age (years) | 63.23±8.15 | 62.85±8.64 | 0.247 | 0.81 |
| Course of disease (years) | 2.91±0.69 | 2.77±0.66 | 1.151 | 0.25 |
| Menopausal age (years) | 51.79±7.46 | 52.33±8.15 | 0.376 | 0.71 |
| Diabetes | 15 (31.91) | 25 (29.07) | 0.117 | 0.73 |
| Tumor type | 0.952 | 0.33 | ||
| Estrogen dependent type | 21 (44.68) | 31 (36.05) | ||
| Non-estrogen dependent | 26 (55.32) | 55 (63.95) | ||
| Lesion diameter (cm) | 3.040 | 0.08 | ||
| <2 | 34 (72.34) | 73 (84.88) | ||
| ≥2 | 13 (27.66) | 13 (15.12) | ||
| Ascites cytology | 1.919 | 0.17 | ||
| Negative | 26 (55.32) | 58 (67.44) | ||
| Positive | 21 (44.68) | 28 (32.56) | ||
| Hypertension | 11 (23.40) | 22 (25.58) | 0.077 | 0.78 |
| Intravascular tumor thrombus | 17 (36.17) | 18 (20.93) | 3.640 | 0.06 |
| Differentiation | 8.295 | 0.004 | ||
| Low | 28 (59.57) | 29 (33.72) | ||
| Medium + high | 19 (40.43) | 57 (66.28) | ||
| Myometrial invasion | 12.444 | <0.001 | ||
| <1/2 | 32 (68.09) | 79 (91.86) | ||
| ≥1/2 | 15 (31.91) | 7 (8.14) | ||
| CRP (mg/L) | 54.26±7.18 | 52.15±7.93 | 1.516 | 0.13 |
| E (ng/L) | 22.86±4.84 | 21.79±4.39 | 1.296 | 0.20 |
| Lipocalin-2 (ng/mL) | 235.71±67.41 | 86.87±25.79 | 18.224 | <0.001 |
| PDK1 (μg/L) | 174.62±36.79 | 105.58±18.13 | 14.505 | <0.001 |
| NGALR (ng/mL) | 117.93±26.28 | 48.26±17.95 | 18.074 | <0.001 |
Data are presented as mean ± standard deviation or n (%). CRP, C-reactive protein; E, estrogen; LNM, lymph node metastasis; NGALR, neutrophil gelatinase-associated lipocalin receptor; PDK1, phosphoinositide-dependent protein kinase-1.
Multi-factor analysis
Using the statistically significant indicators in Tables 1,2 as independent variables, and whether postmenopausal endometrial cancer patients experience LNM as the dependent variable, logistic multivariate analysis showed that the lipocalin-2, PDK1, and NGALR levels were all influencing factors for LNM (P<0.05). It can be seen that the occurrence of LNM in postmenopausal endometrial cancer patients is related to lipocalin-2, PDK1, and NGALR levels (Table 3).
Table 3. Factors influencing LNM by multivariate analysis.
| Index | B value | SE value | Wald value | P value | OR value | 95% CI |
|---|---|---|---|---|---|---|
| Lipocalin-2 | 1.284 | 0.447 | 8.251 | 0.001 | 3.611 | 1.504–8.671 |
| PDK1 | 1.417 | 0.419 | 11.437 | <0.001 | 4.125 | 1.815–9.375 |
| NGALR | 1.146 | 0.388 | 8.724 | <0.001 | 3.146 | 1.471–6.726 |
CI, confidence interval; LNM, lymph node metastasis; NGALR, neutrophil gelatinase-associated lipocalin receptor; OR, odds ratio; PDK1, phosphoinositide-dependent protein kinase-1; SE, standard error.
ROC curve analysis
The area under the curve (AUC) of lipocalin-2, PDK1 and NGALR were 0.755, 0.778 and 0.856 respectively by establishing ROC curve analysis, with the specificity of 67.50%, 67.50% and 82.50%, respectively. The sensitivities were 80.00%, 82.22% and 75.56%, respectively. The AUC (0.925), sensitivity (98.89%) and specificity (70.00%) of the joint tests were higher than those of the other three tests. The joint tests had higher diagnostic value for LNM of postmenopausal endometrial carcinoma, by jointly testing these three indicators, it can provide strong reference basis for clinical doctors to better formulate treatment plans and evaluate patient prognosis (Table 4, Figure 1).
Table 4. Efficacy of lipocalin-2, PDK1, and NGALR in predicting LNM in patients.
| Index | AUC | 95% CI | Specificity (%) | Sensitivity (%) | Cut-off value | Youden index |
|---|---|---|---|---|---|---|
| Lipocalin-2 | 0.755 | 0.669–0.841 | 67.50 | 80.00 | 168.77 ng/mL | 0.475 |
| PDK1 | 0.778 | 0.686–0.871 | 67.50 | 82.22 | 142.53 μg/L | 0.497 |
| NGALR (ng/mL) | 0.856 | 0.792–0.920 | 82.50 | 75.56 | 178.37 pg/mL | 0.581 |
| Joint testing | 0.925 | 0.876–0.974 | 70.00 | 98.89 | – | 0.689 |
AUC, area under the curve; CI, confidence interval; LNM, lymph node metastasis; NGALR, neutrophil gelatinase-associated lipocalin receptor; PDK1, phosphoinositide-dependent protein kinase-1.
Figure 1.
ROC curve analysis of efficacy of lipocalin-2, PDK1, and NGALR in predicting LNM in patients. AUC, area under the curve; FPR, false positive rate; LNM, lymph node metastasis; NGALR, neutrophil gelatinase-associated lipocalin receptor; PDK1, phosphoinositide-dependent protein kinase-1; ROC, receiver operating characteristic; TPR, true positive rate.
Discussion
Surgery is the main treatment for endometrial cancer, but patients with endometrial cancer patients who have metastasized to the surrounding lymph nodes have a poor prognosis, and about 80% of high-risk patients need lymph node dissection (15). The vast majority of postmenopausal endometrial cancer patients are in the early stage, and blind lymph node dissection may cause a series of complications such as vascular and nerve injury and lymphedema (16). Therefore, early diagnosis of LNM and timely intervention are particularly important for improving the prognosis of patients with endometrial carcinoma. In this study, we analyzed the influencing factors of LNM of postmenopausal endometrial carcinoma and found that the degree of differentiation (low differentiation) and myometrial invasion (≥1/2) may affect the occurrence of LNM in the patient. The lower the cell differentiation, the higher the malignancy, and the higher the risk for the peripheral blood and lymphatic vessel proliferation. The myometrium is rich in blood and lymphatic vessels. Previous studies have found that about 30% of patients have deep muscular layer invasion (17,18). Similar to the results of this study. To understand the differentiation degree and uterine grassroots infiltration in postmenopausal patients with endometrial cancer is conducive to better targeted treatment for patients with higher risk of LNM.
The detection of tumor serological markers can serve as an auxiliary tool for clinical diagnosis, improving the accuracy of diagnosis. The detection of tumor serological markers can dynamically observe the changes in the condition of tumor patients, providing a basis for clinical treatment. During chemotherapy or targeted therapy, changes in tumor markers can reflect treatment outcomes and help doctors adjust treatment plans in a timely manner (19). In this study, the serum levels of lipocalin-2, PDK1, and NGALR were detected. The results showed that the serum levels of lipocalin-2, PDK1, and NGALR in patients with endometrial carcinoma and endometrial carcinoma with LNM were significantly increased. The levels of lipocalin-2, PDK1, and NGALR can be used as important indicators for diagnosing the occurrence of LNM of endometrial carcinoma. Lipocalin-2 is an exocrine glycoprotein. Previous studies have indicated that lipocalin-2 is associated with the risk of metabolic syndrome and diabetes (20,21). In recent years, studies have shown that the expression level of lipocalin-2 in breast cancer, ovarian cancer and other diseases is significantly increased, and it may participate in the occurrence of cancer (22,23). NGAL is a cell membrane surface receptor for NGALR homologue 24p3. A study of colon cancer found that NGAL can bind to NGALR and inhibit the expression of E-cadherin (EC), resulting in increased mobility and invasiveness of tumor cells (24). PKD1 is mainly present in smooth muscle cells, vascular endothelial cells, or interstitial cells. An elevated level of PKD1 can promote the transcriptional activity of genes in cancer cell nuclei, alter the biological characteristics of cancer cells, and enhance the infiltration and self-proliferation abilities of cancer cells (25). It has been reported that the expression of PKD1 in ovarian cancer is closely related to the condition of extraovarian metastasis and tumor size (26). A study suggests that an increase in PKD1 concentration can enhance the ability of endometrial glandular cells to break through the basement membrane, leading to increased cancer cell metastasis (27).
According to the literature, lipocalin-2, as an inflammatory mediator, is highly expressed in many tumors and is closely related to tumor invasion, metastasis and patient prognosis (28). As a key enzyme in the phosphoinositide metabolic pathway, PDK1 participates in such processes as cell proliferation, differentiation, and survival, which is closely related to the occurrence and development of tumors (29). NGALR is a receptor of NGAL and its expression is up-regulated in many tumors, which is related to tumor invasion and metastasis (30). Based on the results of this study, we speculate that these three biomarkers may be related to LNM of postmenopausal endometrial carcinoma through the following mechanisms (31): on the one hand, they may increase the risk of LNM by promoting the invasion and migration ability of tumor cells; on the other hand, they may participate in the regulation of the tumor microenvironment and promote the interaction of tumor and immune cells, thus affecting the occurrence of LNM. In addition, it has been found in the present study that the combined detection of lipocalin-2, PDK1, and NGALR has a high diagnostic value for LNM in postmenopausal patients with endometrial cancer. The monitoring of serum lipocalin-2, PDK1, and NGALR levels is conducive to the early diagnosis of LNM in patients with endometrial cancer. The combined detection of these three indicators can provide a powerful reference for clinicians to better develop treatment options and evaluate the prognosis of patients. In addition, it can facilitate early detection and intervention of the risk of LNM, thereby improving the patient’s quality of life and survival rate.
Conclusions
In summary, serum lipocalin-2, PDK1, and NGALR levels of postmenopausal endometrial cancer patients and patients with LNM were significantly increased. The degree of differentiation (low differentiation), myometrial invasion (≥1/2), lipocalin-2, PDK1, and NGALR levels were all factors affecting LNM. Lipocalin-2, PDK1, and NGALR have high diagnostic value for LNM of postmenopausal endometrial cancer, and are conducive to clinical guidance for the diagnosis and treatment of LNM of postmenopausal endometrial cancer. However, this study is a retrospective analysis, and the research sample size is small. The specific mechanisms of action of lipocalin-2, PDK1, and NGALR in endometrial carcinoma and their impact on the long-term prognosis deserve further study.
Supplementary
The article’s supplementary files as
Acknowledgments
None.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Harbin Medical University Cancer Hospital (No. KY2024-90). Informed consent was waived for this retrospective study due to the exclusive use of de-identified patient data, which posed no potential harm or impact on patient care.
Footnotes
Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2239/rc
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2239/coif). The authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2239/dss
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