This retrospective study received approval from the Institutional Review Board of the Seoul National University Bundang Hospital (SNUBH; No. B-1602/336-103) and was performed in accordance with the principles of the Declaration of Helsinki. The requirement for informed consent was waived due to the retrospective nature of the study.
We retrospectively reviewed the medical records of 67 cervical cancer patients who were treated at Seoul National University Bundang Hospital, a tertiary hospital in Korea, from September 2014 to May 2018. All patients were restaged based on the revised 2018 International Federation of Gynecology and Obstetrics (FIGO) staging system for cervical cancer (24). We included patients who met the following inclusion criteria: (1) patients who had histologically confirmed cervical cancer of any stage; (2) those who underwent initial treatment, such as radical hysterectomy with lymphadectomy, concurrent chemoradiation therapy, radiation therapy or chemotherapy only; and (3) those who had HE4 levels assessed at diagnosis, before initiation of first treatment. Patients with the following conditions were excluded: (1) patients who had an incomplete treatment for any reason; (2) those who had insufficient clinical and pathological data; and (3) those with other malignancies that had the potential to influence survival outcomes.
For the patients who met the criteria mentioned above, we reviewed the medical records, surgical records, pathological findings, and clinical characteristics. Histology was pathologically evaluated in all patients. Tumor size, lymphovascular space invasion (LVSI), lymph node (LN) metastasis, and involvement of the parametrium were evaluated pathologically only in patients who initially received surgery, while magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography computed tomography were evaluated in patients who received initial treatment other than surgery.
The serum HE4 concentration was measured before initiation of patient treatment using the Architect Analyzer (Abbott Laboratories, USA). This is a two-step immunoassay that quantitatively measures HE4 levels in human serum using chemiluminescent microparticle technology. The inter-assay precision for measurement of HE4 was 3.5% (49.7 pmol/L), 3.6% (168.1 pmol/L) and 3.8% (648.2 pmol/L).
The 67 cervical patients had a mean serum HE4 level of 72.6 pmol/L (standard deviation = 95.0) prior to the initiation of treatment. As no definitive diagnostic thresholds for HE4 have been reported to date, we evaluated the differences in clinicopathological characteristics between patients who had lower HE4 levels (<72.6 pmol/L) and those who had higher HE4 levels (≥72.6 pmol/L) at initial diagnosis.
For comparison of continuous variables, the Student’s t-test and Mann-Whitney U test were used. Ordinal and categorical variables were analyzed using the Pearson’s chi-squared test or Fisher’s exact test, as applicable. The association between HE4 levels and the survival outcomes of patients with cervical cancer was assessed by comparing patients with lower HE4 levels (<72.6 pmol/L) and those with higher HE4 levels (≥72.6 pmol/L) before treatment started. Progression-free survival (PFS) and overall survival (OS) rates were calculated by the Kaplan-Meier method and the differences between curves were assessed using the log-rank test. Univariate analysis was performed using the Cox proportional hazards model to evaluate the impact of patient characteristics and clinical factors on survival. For multivariate survival analysis, Cox proportional hazards analysis was used to estimate the prognostic effects of several variables. All analyses were performed using SPSS software for Windows (version 25.0; SPSS Inc., Chicago, IL, USA). P < 0.05 indicated statistical significance.