Among 198 cases of ECA, HPV-negative ECA accounted for 62 cases (31.31%), and HPV-positive ECA accounted for 136 cases (68.69%). The average age of the HPV-negative group was 48.06 ± 9.73 years, which was significantly higher than that of the HPV-positive group (43.26 ± 9.23 years). The difference was statistically significant (p = 0.001; Table 1). However, there were no significant differences in the pregnancy and parturition times between the two groups (p = 0.671 and p = 0.311, respectively; Table 1).
Forty out of 62 patients with HPV-negative ECA (64.5%) and 93 out of 136 patients with HPV-positive ECA (68.4%) complained of abnormal genital bleeding or contact bleeding, although the difference was statistically insignificant (p = 0.591; Table 1). However, watery discharge was more frequent in the HPV-negative group (22.6%) than in the HPV-positive group (11.8%) (p = 0.049; Table 1). Those with abnormal vaginal secretions and no complaints were in the minority and were statistically insignificant (p = 1.00 and p = 0.36, respectively; Table 1).
Cervical cytology revealed that 26 out of 54 patients with HPV-negative ECA (48.1%) were diagnosed as having abnormalities. In the HPV-positive group, 84 out of 113 cases (74.3%) showed abnormal findings by cervical cytology. In other words, the sensitivity of cervical cytology in the HPV-negative group was 48.1% and that in the HPV-positive group was 74.3%; the difference was statistically significant (p = 0.001; Table 1). The results indicated that cervical cytology is less sensitive for HPV-negative ECA.
There was a statistically significant difference in the status of CA125 expression between HPV-negative cases and HPV-positive cases (p = 0.015). However, there were no statistically significant difference in the status of CA19-9 and CEA expression between the two groups (p = 0.84 and p = 1.00, respectively; Table 1). Of course, due to the small sample size of tumor markers, there may be some errors in the analysis of the results.
Compared with the HPV-positive group, the HPV-negative group had significant differences in FIGO stage, histologic subtypes, tumor diameter (< 3 cm), DSI, LVSI, ovarian metastasis and intermediate risk factors (all p < 0.05), but there were no significant differences in lymph node metastasis between the two groups (p = 0.077; Table 1). Lymph node metastasis was significantly more frequent in the HPV-negative group than in the HPV-positive group (24.2% vs. 14%; Table 1). Due to the small sample size, the difference was statistically insignificant.
Figure 1 shows the proportion of histologic subtypes of HPV-negative ECA in our study. Sixty-two patients had the following histologic types: usual-type endocervical adenocarcinoma (UEA) in 32 cases, gastric-type mucinous adenocarcinoma (GAS) in 4 cases, minimal deviation adenocarcinoma (MDA) in 5 cases, endometrioid adenocarcinoma in 3 cases, clear-cell carcinoma in 4 cases, serous carcinoma in 2 cases, mesonephric carcinoma in 1 case, intestinal-type adenocarcinoma in 1 case, mucinous adenocarcinoma-not otherwise specified (NOS) in 8 cases, and mixed neuroendocrine adenocarcinoma in 2 cases. These statistical results are not completely consistent with the classification and proportion of non-HPV-associated adenocarcinoma (NHPVA), and there may be HPV false negatives.
According to the analysis of FIGO stage, intermediate-risk and high-risk factors, 52 patients (83.87%) needed postoperative adjuvant therapy in the HPV-negative group. However, 50 patients (96.15%) received postoperative adjuvant therapy (2 patients [3.85%] did not). In the HPV-positive group, 77 patients (56.62%) needed postoperative adjuvant therapy, and only 65 patients (84.42%) received postoperative adjuvant therapy (12 patients [15.58%] did not). However, recurrence occurred in 16 out of 62 patients (25.81%) in the HPV-negative group and 4 out of 136 patients (2.94%) in the HPV-positive group. Recurrence was clearly more common among patients with HPV-negative group (p < 0.05). The mean OS of the HPV-negative group was 49.97 months and that of the HPV-positive group was 58.53 months. The difference in prognosis between the two groups was statistically significant (p < 0.05; Table 1). OS was poorer in patients with HPV-negative ECA than in patients with HPV-positive ECA. The results of the Kaplan–Meier analysis are shown in Fig. 2.
Tables 2 and 3 show the results from the univariate and multivariate Cox regression models, respectively. Variables significantly associated in the univariate analysis with OS included, HPV testing (negative vs. positive; HR 7.874, 95% CI 2.609–23.764; p = 0.000), FIGO stage (IIB-IV vs. IA-IIA; HR 11.02, 95% CI 4.306–28.203; p = 0.000), histologic subtype (special vs. usual; HR 2.802, 95% CI 1.137–6.909; p = 0.025 ), DSI (≥ 2/3 vs. <2/3; HR 8.943, 95% CI 2.967–26.96; p = 0.000), LVSI (present vs. absent; HR 5.752, 95% CI 2.277–14.529; p = 0.000), lymph node metastasis (present vs. absent; HR 8.681, 95% CI 3.467–21.726; p = 0.000), and ovarian metastasis (present vs. absent; HR 10.746, 95% CI 3.111–37.113; p = 0.000). In contrast, age and tumor diameter (< 3 cm) had no effect on OS. The multivariable analysis also confirmed that HPV testing (negative vs. positive; HR 4.646, 95% CI 1.14-18.936; p = 0.032), DSI (≥ 2/3 vs. <2/3; HR 4.47, 95% CI 1.271–15.726; p = 0.02) and lymph node metastasis (present vs. absent; HR 5.694, 95% CI 1.492–21.724; p = 0.011) had a significant impact on OS.
Additionally, multivariable logistic regressions were performed for the incidence rate of lymph node metastasis. Variables significantly associated with lymph node metastasis included LVSI (present vs. absent; HR 49.517, 95% CI 12.56-195.208; p = 0.000), DSI (≥ 2/3 vs. <2/3; HR 5.883, 95% CI 1.459–23.715; p = 0.013) and ovarian metastasis (present vs. absent; HR 124.002, 95% CI 4.474-3438.212; p = 0.004), as shown in Table 4.