The comparison of inflammatory markers in geriatric and nongeriatric endometrial cancers

1. Introduction

Endometrial cancer (EC) is the fourth most common malignancy in women and the most common gynecological cancer in developed countries [1]. More than half of the patients newly diagnosed with cancer are age ⩾ 65 years old [2, 3]. With the increasing geriatric population and obesity prevalence, the number of endometrial cancer cases is expected to increase further [4].

The association between inflammation and cancer is known, but the details of these complex interactions remain to be elucidated [5]. Inflammation provides a suitable microenvironment for tumor initiation and progress. The neutrophils support the invasion, but they also prevent tumor progression by creating a hypoxic environment in the tumor that triggers the coagulation cascade. After that, the activated platelets surround the tumor cells and enable them to progress by evading the immune response [6, 7, 8]. The most common hematological alterations in human cancers include leukocytosis, neutrophilia, thrombocytosis, and lymphocytopenia [9].

Although Virchow proposed the functional relationship between inflammation and cancer in 1863, this important issue has not been studied thoroughly [10, 11]. Studies on cancer, inflammation, and hematological markers have gained importance in the last decade. Hematological parameters are the inflammatory biomarkers that are readily available, routinely measured, and inexpensive. Some hematological parameters, such as NLR (neutrophil/lymphocyte ratio), PLR (platelet lymphocyte ratio), MPV (mean platelet volume) are associated with poor prognosis in some solid tumors (breast, ovarian, cervical, stomach, colorectal, and esophageal carcinomas) [5]. In recent years, studies have been conducted on the relationship between endometrial cancer and inflammatory markers [12].

Early diagnosis and treatment of endometrial cancers is an important issue. The preoperative diagnosis of high-risk patients allows us to select cancer patients who will benefit from surgery or other treatment modalities. Preoperative risk stratification is crucial for elderlies [13]. Although many studies have been performed on the relationship between hematological inflammatory markers and cancer, age is an important confounding factor. The aging hematopoietic system may affect the overall results. This study aimed to investigate the hematologic inflammatory response of geriatric and nongeriatric endometrial cancers.

2. Methods

This retrospective study was performed in Haydarpaşa Numune Training and Research Hospital, Istanbul, Turkey between January 2010 and June 2020. A total of 342 women were included in the study. The women were categorized into two groups as endometrial cancers (n: 171) and control group (n: 171). Each group was also categorized into the geriatric group ( ⩾ 65 years old) and the nongeriatric group. The control group (n: 171) was selected from age-matched women with normal endometrial pathology (1: 1 ratio). The patients with pathology or operation performed in other centers, complete blood count more than a week before the surgery, active infections, synchronous tumors, hematologic problems, incomplete data, prior chemotherapy, radiotherapy were excluded from the study. Ethical approval was obtained from the Haydarpaşa Numune Ethics Committee (HNEAH-KAEK 2021/KK/11).

Demographic variables, age, parity, menopausal status, histopathological diagnosis, FIGO grade, myometrial invasion, lymphovascular invasion, lymph node involvement, cytology, and cancer stage were recorded from hospital files and computer data. All pathological information was extracted from the original pathology reports. The patients were staged according to the FIGO 2009 criteria [14]. Hysterectomy and bilateral salpingo-oophorectomy were performed for low-risk patients (endometrioid histology, grade 1–2, myometrial invasion ⩽ 50%, the greatest tumor diameter ⩽ 2 cm, and no metastasis at the time of surgery). The pelvic-paraaortic lymph node dissection was added if intermediate-high risk factors were positive (nonendometrioid histology, grade 3, myometrial invasion $>$ 50%, and the greatest tumor diameter $>$ 2 cm) [15]. Overall survival (OS) was defined as the time from diagnosis to death of all causes. The patients were followed up with clinical, cytological, and radio-imaging studies every three months for the first two years, then every six months. The follow-up time ranged from 6 to 120 months (mean 40 months). Twenty-nine women were lost to follow-up among endometrial cancers.

Patients’ complete blood count results were evaluated as leukocyte, neutrophil, lymphocyte, platelet, NLR, PLR, RDW (red blood cell distribution width), MPV, PDW (platelet distribution width).

The primary outcome measure was the difference between inflammatory markers (WBC, NLR, PLR, platelet, MPV, RDW, and PDW) of geriatric and nongeriatric EC. The secondary outcome measure was the association of inflammatory markers with risk factors as myometrial invasion, lymphovascular invasion, lymph node metastasis, stage, and overall survival.

3. Results

This study included a total of 171 endometrial cancer patients. The geriatric EC group had 63 women with a mean age of 72.4 ± 5.4 (65–86 years). The nongeriatric group EC had 108 women with a mean age of 55.2 ± 6.3 (36–64 years). The endometrial cancer risk factors as obesity, diabetes mellitus, hypertension, menopause, and infertility were similar ( $p>$ 0.05). Table 1 shows the details of patient characteristics in endometrial cancers.

Table 2 shows the clinicopathological findings of endometrial cancers. Endometrioid tumors were the most common type in all ages. However, the Nonendometrioid type was more common in the elderlies (28.5% vs 11.1%). Lymphovascular invasion (34.9% vs 20.3%) and myometrial invasion (76.1% vs 53.7%), lymph node metastasis and advanced stage (30.1% vs. 16.6%) were more frequently diagnosed in elderly patients ( 0.05). FIGO grading was similar ( $p>$ 0.05). The OS rate was 97% in the nongeriatric EC, but 83% in the geriatric EC (p: 0.017).

Table 3 shows a comparison of inflammatory markers in geriatric and nongeriatric EC. The geriatric EC comparing to nongeriatric EC had significantly decreased lymphocyte count, PDW, and significantly increased PLR and NLR ( 0.05). The comparison of neutrophil, platelet, MPV, and RDW were similar ( $p>$ 0.05).

Table 4 shows the comparison of inflammatory markers between endometrial cancers and age-matched controls. Nongeriatric EC had significantly low MPV values and high NLR, PDW comparing to the control group ( 0.05). Geriatric EC had low MPV, lymphocyte and high neutrophil count, NLR, and PLR comparing to the control group ( 0.05).

Table 5 shows the comparison of inflammatory markers in endometrial cancers concerning the cancer stage. Early-stage geriatric cancers had higher PLR, NLR, and lower PDW, lymphocyte counts than non-geriatric cancers ( 0.05). However, in an advanced stage, decreased lymphocyte count was prominent in geriatric cancers (p: 0.029).

In nongeriatric group, the cancer stage was related to platelet count (r: 0.341, p: 0.0019), and PLR (r: 0.252, p: 0.01). OS was negatively related to PLR (r: - 0.267, p: 0.007) and NLR (r: - 0.353, p: 0.000) in nongeriatric group. ROC analysis of platelet count for stage had AUC: 0.667, CI: 0.5–0.8, p: 0.02. cut off: 300,000 platelets/mm 3 , sensitivity 50% and specificity 80%. If the cut off value of 400,000 platelets/mm 3 for platelet count was considered, there was a 16% sensitivity and 98.8% specificity. ROC analysis of PLR for stage had AUC: 0.571, CI: 0.4–0.7 (p: 0.006), cut off: 150 sensitivity 28% and specificity 86.4%. ROC analysis of NLR for stage had AUC: 0.562, CI: 0.3–0.7 (p: 0.007), cut off: 2.5 sensitivity 50% and specificity 80.2%.

In geriatric EC, the myometrial invasion was negatively correlated with lymphocyte count (r: - 0.268, p: 0.035). The stage was negatively related to MPV(r: - 0.335, p: 0.01). OS was negatively related to MPV (r: - 0.337, p: 0.02) and positively related to neutrophil count (p: 0.352, p: 0.01).

The diagnostic and prognostic value of inflammatory markers in endometrial cancers have been investigated, but the results are controversial. The inflammation studies have not been specifically conducted in the geriatric population [16]. This study investigated the inflammatory response of geriatric and nongeriatric endometrial cancers. Briefly, the geriatric endometrial cancers in the early and advanced stages had different inflammatory responses compared to the nongeriatric group.

Neutrophils, lymphocytes, and platelets are the main components of inflammation. Inflammation is related to the initiation, progression, metastasis, and clinical features of cancer. Tumor cell behavior depends on the host immune response [17, 18, 19]. Age-related change in the immune system is low-grade inflammation that is also called immunosenescence or inflammoaging. The decreased immune responses of older people increase the susceptibility to various diseases, such as autoimmune diseases, malignancies, and infection [20]. In this study, nongeriatric EC had significantly low MPV values and high neutrophil count, NLR, and PDW comparing to the age-matched control. Geriatric EC had low lymphocyte count, MPV, and high NLR, PLR compared to the age-matched control group. In our cohort, the elderly population endometrial cancer was more aggressive, notably in terms of immunohistological type and the stage at the diagnosis. Therefore, we also analyzed the inflammation concerning the cancer stage. Geriatric EC had significantly low PDW and high NLR, PLR compared to nongeriatric EC in early stages, not in advanced stages. The lymphocyte count in the geriatric population was lower than nongeriatric EC both in the early and advanced stages. These results suggested that decreased lymphocyte count in early and advanced stage geriatric cancers may be related to the more aggressive nature of cancers in elderlies.

High PLR may be secondary to a relative decrease of lymphocytes or increased coagulation cascade in elderlies. The activated platelets can attach endothelium, and secrete potent inflammatory and chemotactic factors to promote monocyte migration. When inflammation is prolonged, lymphocyte count decreases secondary to the apoptotic cascade in the lymphocytes [21, 22]. The relative decrease of lymphocytes by aging and tumor probably makes the inflammatory changes more prominent in elderlies. This may explain why geriatric endometrial cancers showed higher NLR and PLR results than nongeriatric cancers and the geriatric control group in our study.

Prior studies investigated the relationship between NLR, PLR, and EC in the general population [23, 24, 25, 26, 27, 28]. Two studies showed the predictive value of NLR and PLR for lymph node involvement [24, 25]. In our manuscript, both NLR and PLR were related to an advanced stage in nongeriatric women. PLR $>$ 150 and NLR $>$ 2,5 had low sensitivity, but high specificity for the advanced stage. Some studies found NLR linked to OS [23, 24, 25]. Other studies found that both NLR and PLR related to OS [26, 27, 28]. The analysis of 3 studies by Jiang et al. reported that PLR was not associated with OS [29]. Another search by Comert et al. noted that PLR, but not NLR, was a prognostic marker of OS [30]. The recent meta-analysis with 3390 endometrial cancers showed that high NLR and PLR were poor prognostic markers [31]. Similarly, in this study, OS was related to both PLR and NLR in nongeriatric women.

Our manuscript noted the relationship between thrombocytosis and advanced stage in nongeriatric women. Platelet count may increase secondary to the release of cytokines by tumor cells. Platelets are involved in protecting tumor cells from cytolysis, thereby contributing to hematogenous metastasis. Previous studies have reported that 7–41% of patients with endometrial cancer have thrombocytosis with different cut-offs (platelet count as $>$ 350 × 10 3 or 400 × 10 3 platelets/mm 3 ) [32, 33, 34, 35]. The meta-analysis of 11 studies stated that pre-treatment thrombocytosis ( $>$ 400 × 10 3 platelets/mm 3 ) was an independent predictor of OS regardless of the clinical stage [32]. In our study, platelet count above 300 × 10 3 platelets/mm 3 had a sensitivity of 50% and specificity of 80% for the advanced stage. The platelet count above 400 × 10 3 platelets/mm 3 had low sensitivity, but high specificity (98.8%) for the advanced stage. Thus, high preoperative platelet counts even in normal ranges may reflect advanced stage EC in the younger group.

There is limited and inconclusive literature on MPV and endometrial cancer prognosis. Increased MPV is a predictor of early platelet activation. Some conditions such as cardiovascular diseases, cerebral stroke, respiratory diseases, chronic renal failure, intestinal diseases, rheumatological diseases, diabetes, and various cancers increase MPV. On the other hand, tuberculosis, ulcerative colitis, SLE, renal cell cancer, and lung cancer decrease MPV [36, 37]. Prior studies showed that endometrial cancers had high MPV values comparing to benign cases [38, 39]. Unlike previous studies, both geriatric and nongeriatric EC had low MPV compared to age-matched controls in this study. We also found similar MPV values in geriatric and nongeriatric EC in both the early and advanced stages. Oge et al. reported that high MPV is related to advanced-stage EC [40]. However, there was no relation between MPV and prognostic factors of endometrial cancer in the study by Temur et al. [25]. In our study, MPV was negatively related to overall survival in the elderlies. There is a negative correlation between thrombocyte count and MPV in the literature [36, 37]. So, this may explain why some cancers have high MPV while others do not.

PDW is a marker of platelet function and is related to the heterogeneity of platelet volume. It is not affected by single platelet distention resulting from platelet swelling, as in the case of MPV values [37]. Some studies reported that a high PDW level was associated with an unfavorable prognosis for various types of tumors, including breast cancer, colorectal cancer, and laryngeal cancer. However, studies in bladder and lung cancer were associated with unfavorable prognosis with reduced PDW [36, 37]. There are limited studies about PDW and endometrial cancer. Song et al. found no difference in early and late-stage EC patients for PDW, but they found decreased PDW in endometrial cancers compared to benign cases [41]. Kurtoğlu et al. [39] found low PDW in advanced EC. In our study, the nongeriatric EC had increased PDW compared to the nongeriatric control group. However, PDW was similar in the geriatric EC and geriatric control. Nongeriatric EC had significantly high PDW compared to the elderly EC in the early cancer stages.

There are some concerns when interpreting results regarding inflammation. The fact that inflammation is affected by many comorbid conditions such as age, obesity, and chronic diseases makes it difficult to establish a cause-effect relationship in the study results. The major limitation of our study was its retrospective design and small sample size. On the other hand, our study has several strengths. We evaluated the elderly group separately. We also considered comorbid conditions. To the best of our knowledge, this article is the first study investigating the inflammatory response in geriatric and nongeriatric endometrial cancers.

5. Conclusions

Endometrial cancers both in geriatric and nongeriatric ages had increased inflammatory markers compared to healthy controls. Furthermore, the inflammatory response of geriatric and nongeriatric cancers was different in both the early and advanced stages. Geriatric cancers in the early stages had high PLR, NLR, and low PDW comparing to nongeriatric ones. The lymphocyte count was decreased both in early and advanced stage geriatric cancers. These results suggested that decreased lymphocyte count may reflect the aggressive nature of endometrial cancers in the elderly. Further studies are needed about inflammoaging, lymphocyte therapy in geriatric endometrial cancers.