Clinicopathological and prognostic significance of pretreatment thrombocytosis in patients with endometrial cancer: a meta-analysis

Introduction

Endometrial cancer (EnCa) is the most common gynecological malignancy with a rising incidence in developed countries.¹ Most patients (80%) are commonly diagnosed at the early stage and can be surgically cured. However, patients with metastatic or recurrent disease portend a poor prognosis, with a 5-year survival rate of 5.3–20.1%, as there are limited treatment options.^2,3 Prognostic assessment is essential for treatment decision-making. Clinically, the prognosis of EnCa is heterogeneous due to variations in tumor biology.⁴ Some patients with the same stage or pathologic prognostic factors have various clinical courses and survival outcomes.⁵ Therefore, additional prognostic markers are needed to guide therapeutic options and surveillance strategies.

Recently, studies have shown that tumor–platelet interactions is associated with tumorigenesis. Specifically, elevated platelet count or thrombocytosis has been identified as a marker of cancer prognosis and may reflect tumor burden. Todenhöfer T et al reported thrombocytosis could be used as a prognostic parameter and constructed a more accurate prognostic model according to pretreatment platelet count and established pathological factors.⁶ Several studies have suggested that preoperative thrombocytosis associated with poor survival in gynecological malignancies, such as ovarian and cervicalcancer.^7,8 So the relationship between thrombocytosis and prognosis of EnCa is worth further study Pretreatment thrombocytosis has been reported by most researches to be correlated with poor prognosis of EnCa. However, conflicting results exist and a consensus cannot be achieved. Takahashi et al⁹ suggested that pretreatment thrombocytosis significantly predicted unfavorable survival. Heng and Benjapibal¹⁰ reported that thrombocytosis was not a prognostic factor of EnCa in the multivariate analysis. Against this background, we performed a comprehensive and quantitative evaluation of the literature about the relationships between pretreatment thrombocytosis and survival and clinicopathological features in EnCa.

Methods

The study was performed according to the PRISMA statement.¹¹

Search strategy

Our search was restricted to the English and Chinese using databases from PubMed, Embase, SpringerLink, ScienceDirect and China National Knowledge Infrastructure up to July 15, 2018. Both medical subject heading (Mesh) terms and free-text terms included EnCa, thrombocytosis and prognosis. The full search strategy is available in the Supplementary materials. The bibliographies of the retrieved articles were also manually scrutinized for potential related articles.

Selection criteria

The criteria for inclusion were as follows: 1) prospective or retrospective studies analyzed the relationship between thrombocytosis and clinicopathological factors or prognosis of EnCa; 2) the cutoff values of thrombocytosis were reported; and 3) the most complete study was included if multiple studies described the same cohorts studies were excluded based on the following criteria: (1) studies for the lack of information for further analysis; (2) laboratory articles; and (3) non-research articles (abstracts, letters, comments or reviews).

Definitions and data extraction

Overall survival (OS) was defined as the interval between the initial surgical procedure and the death or the last follow-up. Cancer/disease-specific survival (DSS) was defined as the time from initial diagnosis to date of death attributed to EnCa. Disease-free survival (DFS) was measured from the day of surgery to the time of local/distant disease progression or the date of last follow-up. The following data were collected: (1) publication details: first author’s surname, publication year, country of study, age and sample size; (2) study design: study type (prospective/retrospective study), cutoff points; (3) patients characteristics (patients number and age); and (4) follow-up data (median/mean follow-up duration, survival analysis).

Quality assessment

The Newcastle-Ottawa Scale (NOS) criterion¹² was used to evaluate the quality of the included studies (Table S1). The scores were judged based on the three aspects of NOS, namely, selection, comparability and outcomes. Studies achieving scores ≥6 were defined as high quality (Table S2).

Statistical analyses

For the quantitative aggregation of results, pooled OR with 95% CI were used to evaluate the association of thrombocytosis with clinicopathological features of patients. The HR with 95% CI were used to analyze postoperative OS, cancer/DSS, or DFS, which was directly retrieved from each of included article. Pooled OR and HR were calculated using random-effect model. Heterogeneity was performed by using chi-square-based Q-test. The I² value indicated the degree of heterogeneity. A P-value <0.10 or I²>50% indicated significant heterogeneity. All statistical analyses were carried out by Review Manager 5.3 (Cochrane Collaboration, London, UK).

Results

Characteristics of included studies

The detail search process is shown in Figure 1. The initial search retrieved a total of 339 published studies. Out of which, 146 studies were excluded due to duplicate records. After screening titles and abstracts, we removed 162 publications including 148 irrelevant studies and 14 reports without clinical specimens. Further evaluating, finally, we included 10 studies in the final meta-analysis.^9,10,13–20 Sample sizes ranged from 68 to 1166 patients. All included studies including 2995 patients were counted for the incidence of thrombocytosis ranged from 2.3% to 18.2%. The study by Njølstad et al¹⁵ was a prospective study. The remaining studies were retrospective. All the included studies did not report the methods to measure pretreatment thrombocytosis in detail. Three studies^10,16,19 stated that platelet count in each case was obtained within 14 days before surgery. The detailed characteristics of eligible studies are described in Table 1.

Figure 1 Flow diagram of the search strategy.

Table 1 Baseline characteristics of studies included in the meta-analysis

Correlation of preoperative thrombocytosis and clinicopathological feature

Four studies^9,10,13,17 involving 1133 patients reported the association of FIGO stage with preoperative thrombocytosis. The pooled OR revealed that patients with preoperative thrombocytosis were more likely to have high FIGO stage categories (OR 3.45, 95% CI 1.68–7.08, P=0.001; Figure 2A). Five studies^{9,10,13,15,17} including 1261 patients provided information regarding histological grade. The pooled analysis showed that thrombocytosis was linked to high histological grading (pooled OR 2.00, 95% CI 1.22–3.29, P=0.006; Figure 2B). Four studies^9,10,15,17 described preoperative thrombocytosis according to histologic subtype and lymph-vascular space invasion (LVSI). The pooled data showed thrombocytosis correlated with LVSI (pooled OR 2.04, 95% CI 1.35–3.07, P=0.001; Figure 2C), but there were no significant associations of histologic subtype (pooled OR 0.79, 95% CI 0.39–1.60, P=0.52; Figure 3A). The combined results showed that thrombocytosis was significantly associated with cervical involvement (pooled OR 2.54, 95% CI 1.56–4.15, P=0.000; Figure 3B) and myometrial invasion (pooled OR 2.14, 95% CI 1.39–3.32, P=0.001; Figure 3C) and in three studies.^9,10,15 The pooled OR revealed that preoperative thrombocytosis was associated with lymph node metastasis (OR 3.15, 95% CI 1.71–5.80, P=0.001 Figure 3D) by analyzing two studies.^9,10

Figure 2 Association of pretreatment thrombocytosis with clinicopathological parameters. (A) FIGO stage; (B) tumor differentiation; and (C) lymph-vascular space invasion.

Figure 3 Association of pretreatment thrombocytosis with clinicopathological factors. (A) histologic subtype; (B) cervical involvement; (C) myometrial invasion; and (D)lymph node metastasis.

Impact of preoperative thrombocytosis on survival

As seen in Figure 4, six^{9,10,13,16,19,20} of the included studies showed was preoperative thrombocytosis was not associated with OS in EnCa patients (pooled HR =1.65, 95% CI: 0.88–3.11, P=0.012, I²=82%, Figure 4A). The synthesized data from four studies^10,13,17,20 suggested that thrombocytosis did not correlate with poor DFS (pooled HR =1.66, 95% CI: 0.96–2.89, P=0.07, I²=59%, Figure 4B). There was no association between preoperative thrombocytosis and DSS (pooled HR =1.37, 95% CI: 0.80–2.36, P=0.25, I²=40%, Figure 4C). Particularly, Andersen et al¹⁴ divided the preoperative platelet count into two categories of thrombocytosis (mild, platelet count=400–550×10⁹/L; severe, platelet count >550×109/L). The study reported that mild and severe preoperative thrombocytosis was all not associated with cancer-specific mortality.

Figure 4 The association between thrombocytosis and survival outcomes (all multivariate analysis). (A) overall survival; (B) disease-free survival; and (C) cancer/disease-specific survival.

Subgroup and sensitivity analysis

Stratified analysis was conducted to assess the prognostic value of thrombocytosis on OS and DFS according to geographic region, sample size, and NOS score. As shown in Table 2, stratified analysis did not alter the prognostic role of preoperative thrombocytosis on OS, except for the subgroup small sample size (pooled HR =1.88, 95% CI: 1.26–2.80, P=0.002, I²=0%). However, the EnCa patients with preoperative thrombocytosis showed a significant worse DFS in subgroups of Asian patients (pooled HR =2.21, 95% CI: 1.17–4.21, P=0.02, I²=0%), NOS scores >7 (pooled HR=2.16, 95% CI: 1.34–3.56, P=0.002, I²=0%). We further performed a sensitivity analysis to gauge the stability of the results. The pooled effects of OS was significantly altered when the study by Heng and Benjapibal¹⁰ was omitted (pooled HR=2.04, 95% CI=1.11–3.73, P=0.02, Table 3). When the study by Moeini et al²⁰ was removed, the pooled results for DFS were significantly altered (pooled HR=2.23, 95% CI=1.45–3.42, P=0.000, Table 3). We did not evaluate publication bias since the number of included studies was limited.

Table 2 Subgroup analyses for OS and DFS

Table 3 Sensitivity analysis for OS and DFS

Discussion

Thrombocytosis in cancer patients is a common finding and preoperative thrombocytosis has a strong connection to cancer outcomes.^21,22 However, conflicting studies exist regarding the prognostic effects of thrombocytosis on EnCa patients.^9,10 So we performed the meta-analysis to reassess the association of preoperative thrombocytosis with clinicopathological factors and prognosis of EnCa. In the current study, the pooled effects indicated that preoperative thrombocytosis was positively correlated with high FIGO stage, high histological grading, LVSI, myometrial invasion, cervical involvement and lymph node metastasis in EnCa patients. Nonetheless, preoperative thrombocytosis was not associated with poor OS, DFS, and DSS (all included studies were used multivariate analysis). According to NOS quality assessment, all included studies were high quality and the scores of ranged from 6 to 9 (median 7). So we defined the cutoff value of NOS quality as 7 when performing stratification analysis. EnCa patients with preoperative thrombocytosis showed a reduced DFS in subgroups of Asian patients and studies with NOS scores larger than 7.

The prognosis remains dismal for patients with recurrent or metastatic EnCa. In order to improve survival, it is imperative that we identify the tumors with aggressive behaviors and treat them appropriately. Recently, studies have been reported that circulating biomarkers can predict the course of EnCa. Indices of systemic inflammation such as elevated platelet/lymphocyte ratio, platelet count and platelet volume have shown potential for prognostic surveillance.^23,24 In addition, such circulating markers are readily monitored by relatively noninvasive means. Therefore, it is of great clinical significance to identify new circulating markers, combining with the established clinicopathologic prognostic factors, to improve the outcomes of patients with EnCa.

The mechanisms by which preoperative thrombocytosis correlates clinicopathological features of EnCa patients remains to be not fully elucidated. Several studies which put forward to plausible hypotheses may explain the correlations. Platelets can infiltrate into tumor tissue and contribute to tumor growth by secreting pro-angiogenic and pro-tumorigenic factors including vascular endothelial growth factor, insulin-like growth factor 1 and 2 .²⁵ Platelet-tumor cell adhesion established a pro-metastatic microenvironment that protects cancer cells from immune surveillance.²⁶ Orellana et al²⁷ found that platelets acted as chemo-attractants to facilitate cancer cells migration through co-cultivating cancer cells with human platelets. The authors concluded that platelet–cancer interactions contributed to the cancer metastasis. On the one hand, a variety of tumor-related cytokines stimulates thrombopoiesis in cancer. Among them are IL-1, IL-6, and thrombopoietin (TPO).²⁸ Stone et al²⁹ established mouse models of ovarian cancer and demonstrated that tumor-derived IL-6 stimulates hepatic production of TPO, which stimulates megakaryocyte growth and thrombopoiesis. In addition, Inhibition of IL-6 by neutralizing antibody reduced tumor growth and enhanced the therapeutic efficacy of paclitaxel. Recently, Guillem-Llobat et al³⁰ reported that low-dose aspirin which inhibits platelet activation prevented colorectal cancer metastasis in mice. Other antiplatelet agents such as heparinoids may be beneficial for cancer patients.

Limitations

Certain limitations exist in the current study. First, the cutoff point of preoperative thrombocytosis is still not established. Most of the included studies set cutoff point as platelet count >400×10⁹/L, but Njølstad et al¹⁸ report thrombocytosis as platelet count >390×10⁹ platelets/L, which may lead to inter-study heterogeneity. Besides, the majority of included studies were retrospective, so the possibility of selection bias cannot be ruled out. Second, several disease conditions such as inflammatory hematological diseases may affect platelet count, but some included studies did not control these confounding factors. Third, the sample size of the included studies ranged from 68 to 714, which may result in between-study heterogeneity. The limited number of included studies might impact the validity of our analysis, so further studies are warranted. These limitations may also contribute to the conflicting results of the prognostic significance of thrombocytosis in EnCa. Besides, a study by Oge T et al²⁴ reported that platelet volume can be used as a parameter for platelet activation and prediction of advanced-stage EnCa. All included studies highlighted on platelet count, rather than function. Thus, the association of platelet volume with the survival of EnCa deserves further investigation.

Conclusion

In summary, the current meta-analysis shows that preoperative thrombocytosis is correlated with high FIGO stage, poor tumor differentiation, LVSI, myometrial invasion, cervical involvement, and lymph node metastasis. No significance was found between thrombocytosis and OS, DFS, and DSS. However, further studies are needed to update our results.