Clinicopathological features and prognosis of non-HPV-associated adenocarcinoma

Clinicopathological features and prognosis of non-HPV-associated adenocarcinoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinicopathological features and prognosis of non-HPV-associated adenocarcinoma Shuang Ju, Junhua Zhang, Xiaoli Liu, Sai Han, Qiuhong Qian, Youzhong Zhang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6900353/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background: Owing to the rarity of non-HPV-associated adenocarcinoma, clinicopathological features and prognosis remain poorly understood. The aim of our study is to analyze clinicopathological features and prognosis of non-HPV-associated adenocarcinoma (NHPVA) in comparison with HPV-associated adenocarcinoma (HPVA) and to investigate the expression of HENMT1 in NHPVAs. Methods: 336 patients with endocervical adenocarcinomas treated in Qilu Hospital of Shandong University from January 2010 to December 2020 was retrospectively reviewed. The cases were categorized into HPV-associated adenocarcinoma (HPVA) and NHPVA according to the International Endocervical Adenocarcinoma Criteria and Classification. Data on clinicopathological characteristics, treatment, and prognosis were retrospectively analyzed and compared between NHPVA and HPVA. Results: Among all patients, 64 cases (19.05%) were NHPVAs. The mean age of patients in the NHPVA group was (47.97±11.27) years, which was marginally older than that of the HPVA group, although the difference was not statistically significant ( p =0.136). Abnormal vaginal bleeding or contact bleeding was presented in 71.88% of patients. Compared to the HPVA group, the NHPVA group exhibited higher neutrophil-to-lymphocyte ratio and elevated positive rates of CA125 and CA199 ( p <0.05). NHPVAs demonstrated a significant correlation with advanced FIGO stage (≥stage Ⅱ), larger tumor diameter (≥4 cm), poor differentiation, deep stromal invasion (≥1/2), lymph node metastasis (LNM), and ovarian or oviduct metastasis ( p <0.05). Poor differentiation is identified as an independent risk factor for LNM. NHPVAs exhibited significantly higher positive rate of P53(55.9%) and lower positive rate of P16(66.7%) and Ki-67≥50% (44.1%) compared to HPVAs. Furthermore, the 5-year overall survival(OS) and disease-free survival(DFS) rates for NHPVAs were worse (74.5% and 73.3%, respectively) compared to HPVAs (88.1% and 84.1%, respectively). lymph node metastasis (LNM) and age were significantly associated with OS and DFS in NHPVAs. Poor differentiation ( p =0.042) was an independent predictor of LNM. Additionally, NHPVAs showed increased low expression rate of HENMT1( p =0.042) and NHPVA patients with low expression of HENMT1 had poorer OS ( p = 0.021) and DFS ( p = 0.020). Conclusions: NHPVAs differ from HPVAs in clinicopathological features and are associated with a poorer prognosis. HENMT1 might be a novel therapeutic target for NHPVAs. Endocervical adenocarcinoma Non-HPV-associated clinicopathological features Prognosis HENMT1 Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Cervical cancer is among the most common female cancer in the world with 60,4127 new cases and 34,1831 mortalities in 2020 worldwide [ 1 ]. Cervical squamous cell carcinoma is the most common subtype of cervical cancer, and is almost always human papillomavirus (HPV) related. In contrast, endocervical adenocarcinomas(EA) is less common, accounting for approximately 25% of cervical cancers, and they are much more heterogeneous with various etiologies, molecular drivers, morphologies, response to treatment and prognosis[ 2 ]. Unlike squamous cell carcinoma, 10%-15% EA are non-HPV related[ 3 , 4 ]. There is a reduction in cervical squamous lesions and glandular lesions appear to increase[ 5 ]. In North America, cervical adenocarcinomas increased from 5% to 8–27% over the past 20 years[ 6 ]. Non-HPV-associated cervical adenocarcinomas exhibit distinct clinicopathological features, worse clinical outcomes and unique molecular profiles[ 7 – 9 ]. Diagnosis of NHPVA remains challenging due to nonspecific symptoms, deep cervical stromal invasion patterns, and lack of clear etiological link to HPV. Appropriate classification is critical for patient management, especially in the era of the HPV vaccine and HPV screening. In recent years, the diagnosis of endocervical adenocarcinoma has shifted from morphologic criteria classification in 2014 World Health Organization (WHO) to etiology- based classification of International endocervical adenocarcinoma criteria and classification (IECC) [ 4 ]. IECC classified EA into HPV-associated adenocarcinoma (HPVA) and non-HPV-associated adenocarcinoma (NHPVA). NHPVAs are only a minority and can be divided into pathological subtypes such as gastric type, endometrioid type, clear cell type, serous type and mesonephric type[ 4 ]. IECC classification has good reproducibility and excellent prediction of HPV status[ 10 , 11 ]. HPVAs and NHPVAs by IECC differ significantly in tumor size[ 4 ], but the correlation between other clinicopathological features and survival prognosis are limited reported. Current management relies on radical surgery and adjuvant therapies, though evidence remains limited by the rarity and biological heterogeneity of these tumors. To improve cancer treatment outcomes, there is rapidly growing interest for the development of molecularly targeted therapeutics. With the development of bioinformatics technology and gene sequencing technology, many gene and molecular databases have been improved continuously, so that the exploration of human cancer treatment has been shared. In recent years, some studies of the competing endogenous RNA (ceRNA) hypothesis[ 12 ] and RNA modification-related proteins (RMPs)[ 13 ] have provided new insights into the treatment of cancers. HEN1 RNA methyltransferase (HENMT1) as an RNA methyltransferase, is closely related to the metabolism of small RNA and is involved in the modification of piRNA [ 14 ] and miRNA [ 15 ], which plays an important role in genome stability. The piRNA and miRNA have been shown to be associated with the development and progression of a variety of cancers in some studies[ 16 , 17 ]. Begik et al.[ 18 ] conducted a comprehensive analysis of the expression patterns of human RMPS in 32 tissues, 10 species, and 13,358 paired tumor normal human samples, HENMT1 was found to be one of the most frequently upregulated RMPS in a variety of cancers, including cervical cancer. In the present study, we report a cohort of 336 patients with endocervical adenocarcinomas, including 64 cases of NHPVAs. The aim of our study is to analyze the clinicopathological features and prognosis of NHPVA in comparison with HPVA and to investigate the expression of HENMT1 in NHPVAs. Methods Sdudy population Patients treated for endocervical adenocarcinomas (EA) from January 2010 to December 2020 at Qilu Hospital of Shandong University were retrospectively collected and reviewed by searching the cervical cancer database. Patients underwent radical hysterectomy with pelvic lymphadenectomy ± para-aortic lymphadenectomy followed by adjuvant radiotherapy or concurrent chemoradiation therapy according to pathological findings. In our study, the eligibility criteria included as following: (1) The pathological diagnosis were made and reviewed by two independent pathologists in our hospital. (2) EAs was staged by FIGO staging system[ 19 ] and categorized into HPVAs and NHPVAs according to the IECC[ 4 ] .(3) Comprehensive medical and histopathology records are available. Patients were excluded from the study if they: (1) did not take surgical treatment in our hospital; (2) took neoadjuvant chemotherapy or radiotherapy before surgery; (3) did not have complete medical and histopathology records. Using these criteria,336 patients were eligible and identified. Medical and histopathology records of the 336 patients were collected and reviewed retrospectively by searching the medical records and clinical database. The following information was taken from medical records or database: age at diagnosis, parity, telephone number, HPV and cytology result, clinical symptoms, tumor markers, treatment modalities, FIGO stage. Histopathological diagnosis was reviewed by two independent pathologists regarding histologic subtypes, differentiation, tumor diameter, deep stromal invasion (DSI), lymph node metastasis (LNM), ovarian or oviduct metastasis (OOM) and immunohistochemistry. Follow up After treatment, the patients were followed up regularly with cytology, HPV test, tumor markers, pelvic examination and imaging tests. Follow- up duration was defined from the day of initial surgery to the last follow-up visit or telephone or death. Disease recurrence was defined if clinical and/or imaging examinations demonstrated visible disease or histopathology-confirmed diagnosis of EAs after a documented disease-free interval following initial therapy or after a documented complete response to therapy. Disease-free survival (DFS) was defined as the time from the date of initial surgery to the date of disease progression or recurrence. Overall survival (OS) was defined as the time from the date of initial surgery to the date of death or last visit. For all patients the follow-up data were available until December 2024. Statistical methods The measurement data was expressed as ‾X ± S and the t-test was used for inter-group comparison. Enumeration data was evaluated using the chi-square test and Fisher’s exact test. For survival analysis, the event is defined as death of any cause. The survival curves were determined by Kaplan–Meier survival analysis and were compared by the Log–Rank test. The multivariate Cox regression model and Logistic regression analysis were used to explore risk factors affecting prognosis and LNM, respectively. Two sided p -values < 0.05 were considered statistically significant. Statistical analysis was conducted with SPSS 25.0 software (IBM Corp, Armonk, NY, USA). Immunohistochemistry Immunohistochemical studies determining the existence of HENMT1 were performed by using sections (4 µm). After being baked at a constant temperature of 65° for 1 hour, the paraffin-embedded sections were deparaffinized with xylene and hydrated in ethanol. Antigen was repaired by incubating the sample in sodium citrate. The hydrogen peroxide was used to block endogenous catalase, and non-specific antigens was closed by goat serum. Then, incubation of sections with primary antibody (HENMT1, 1:50, PA5-55866, Invitrogen, USA) at 4°C overnight. And we treated the sections by biotin-labeled goat anti-rabbit IgG polymer, followed by horseradish peroxidase-conjugated streptavidin. In the end, samples stained by 3,3′-diaminobenzidine, counterstained with hematoxylin, dehydrated and fixed. The sections were scored by two pathologists according to staining intensity and percentage of stained cells in mutually uninformed way. The staining intensity (SI): brown = 3, yellow- brown = 2, light-yellow = 1, no staining = 0. The percentage of positive cell (PP) : >75% of positive tumor cells = 4, 51%ཞ75% of positive tumor cells = 3, 26%ཞ50% of positive tumor cells = 2, 6%ཞ25% of positive tumor cells = 1, 0ཞ5% of positive tumor cells = 0. The immunoreactive score (IRS) was defined as the product of PP and SI. The high expression was defined as an IRS ≥ 5. Results Clinical and pathological features Among 336 endocervical adenocarcinoma (EA) patients, 64 (19.05%) cases were classified as NHPVAs and 272 as HPVA based on IECC criteria (Table 1 ). Among NHPVA, clear cell type accounted for 21 cases, followed by endometrioid type (19 cases), gastric type (15 cases), serous type (8 cases) and mesonephric type (1 case) (Table 3 ). Patient characteristics were compared and shown in Table 1 . The mean age of NHPVAs patients (47.97 ± 11.27 years) was slightly older than HPVAs patients (45.78 ± 10.36 years), though this difference lacked statistical significance (p = 0.136; Table 1 ). NHPVAs presented predominantly with abnormal genital bleeding or contact bleeding (71.88%), followed by watery discharge (14.06%), no complaints (10.94%), abdominal pain or distension (4.69%) and abnormal vaginal secretion (1.56%), which show similar symptomatology with HPVAs ( p = 0.82, Table 1 ). TCT sensitivity of NHPVAs (60.6%) was slightly lower than HPVAs (65.5%), but there is no statistical significance ( p = 0.595, Table 1 ). NHPVAs exhibited significantly elevated neutrophil-to-lymphocyte ratio (NLR) and the elevated rates of CA125 (37.2%) and CA199 (47.4%) compared to HPVAs ( p 0.05, Table 1 ). Table 1 Summary and comparison of the features of patients with NHPVAs and HPVAs. NHPVA (N = 64) HPVA (N = 272) χ 2 / t P -value Age 47.97 ± 11.267 45.78 ± 10.357 1.496 0.136 Pregnancy times 2.86 ± 1.390 3.06 ± 1.611 0.914 0.362 Parturition time 1.64 ± 1.029 1.65 ± 0.892 0.079 0.937 Chief complaints Abnormal genital bleeding, Contact bleeding 46 (71.88%) 186 (68.38%) 0.397 0.82 Watery discharge 9 (14.06%) 38 (13.97%) Abnormal vaginal secretion 1 (1.56%) 13 (4.78%) Abdominal pain or distension 3 (4.69%) 5 (1.84%) No complaints 7 (10.94%) 40 (14.71%) Cytology a ≥ASCUS 20(60.6%) 108(65.5%) 0.283 0.595 <ASCUS 13 57 Tumor marker a SCC ≥ 1.5(ng/mL) 4(10%) 30(15%) 0.685 0.408 < 1.5(ng/mL) 36 170 CA-125 ≥ 30(U/mL) 16(37.2%) 35(21.7%) 3.955 0.037 < 30(U/mL) 27 126 CA-199 ≥ 39(U/mL) 9(47.4) 29(22.8%) 0.046 < 39(U/mL) 10 98 NLR(M = 2.0998) 2.946 ± 2.522 2.334 ± 1.220 2.84 0.005 PLR(M = 164.86) 192.147 ± 87.529 177.879 ± 96.694 1.081 0.281 FIGO stage stage I 45 223 4.373 0.037 ≥ stage II-IV 19 49 Differentiation poorly 14 42 5.5 0.019 moderately and well 27 190 Tumor diameter ≥ 4cm 26 68 6.277 0.012 <4cm 38 204 Deep stromal invasion ≥ 1/2 45(70.3%) 144(52.9%) 6.353 0.012 <1/2 19 128 Lymph node metastasis Present 17(26.6%) 43(15.8%) 4.085 0.043 Absent 47 229 Ovarian and oviduct metastasis Present 5(7.8%) 8(2.6%) 4.129 0.042 Absent 59 264 P16 a Positive 22(66.7%) 124(88.6%) 9.729 0.002 Negative 11 16 P53 a Positive 19(55.9%) 28(31.1%) 6.434 0.011 Negative 15 62 Ki-67 a ≥ 50% 15(44.1%) 70(70.7%) 7.758 0.005 < 50% 19 29 Outcome Recurrence 20(31.3%) 45(16.5%) 7.181 0.007 Mortality 17(26.6%) 36(13.2%) 6.926 0.008 NHPVA : Non-HPV-associated adenocarcinoma; HPVA : HPV-associated adenocarcinoma; FIGO : International Federation of Gynecology and Obstetrics; SCC : Squamous cell carcinoma antigen; CA 125 : Cancer antigen 125; CA19-9 : Carbohydrate antigen 19 − 9; NLR : Neutrophil-to-lymphocyte ratio; PLR : Platelet-to-lymphocyte ratio. ≥ASC-US : Atypical squamous cells of undetermined significance (ASC-US), Low grade squamous intraepithelial lesion (LSIL), High grade squamous intraepithelial lesion (HSIL), Atypical squamous cells-cannot exclude HSIL(ASC-H), Atypical glandular cells (AGC), Adenocarcinoma in situ (AIS), Adenocarcinoma. <ASC-US : Negative for intraepithelial lesion or malignancy (NILM), Chronic inflammation of the cervix. a including missing data. NHPVAs demonstrated more significantly aggressive pathological features with FIGO stage (≥ stage Ⅱ), tumor diameter (≥ 4cm), poor differentiation, deep stromal invasion (DSI) (≥ 1/2), Lymph node metastasis (LNM) and Ovarian and oviduct metastasis (OOM) (all p < 0.05, Table 1 ). Multivariate Logistic regression analysis confirmed poor differentiation as an independent predictor of LNM ( p = 0.042, OR = 3.24, 95% CI 1.045–10.07; Table 2 ). However, NHPVAs is not an independent risk factor of LNM ( p = 0.799, Table 2 ). Table 2 Univariate (A) and multivariate (B) Logistic regressions for lymph node metastasis. Factor P -value OR 95%CI A NHPVAs 0.046 1.926 (1.012–3.665) Age 0.31 1.014 (0.987–1.041) CA125 (≥ 30 U/mL) P < 0.0001 4.32 (2.041–9.142) CA199 (≥ 39 U/mL) 0.024 2.623 (1.133–6.077) FIGO stage P < 0.0001 771.4 (164.627-3614.57) Differentiation 0.048 2.018 (1.005–4.053) Tumor diameter(≥4cm) 0.001 2.784 (1.562–4.961) Deep stromal invasion(≥1/2) P < 0.0001 4.327 (2.159–8.672) Ovarian and oviduct metastasis 0.012 4.27 (1.381–13.204) B NHPVAs 0.799 1.174 (0.34–4.055) CA125 (≥ 30 U/mL) 0.346 1.719 (0.557–5.301) CA199 (≥ 39 U/mL) 0.283 1.787 (0.619–5.165) Differentiation 0.042 3.244 (1.045–10.07) Tumor diameter(≥4cm) 0.336 1.723 (0.569–5.216) Deep stromal invasion(≥1/2) 0.254 1.95 (0.62–6.138) Ovarian and oviduct metastasis 0.519 0.528 (0.076–3.68) OR : Odd ratio; CI : Confidence interval Immunohistochemical profiling revealed distinct molecular signatures. NHPVAs exhibited significantly higher positive rate of P53(55.9%) and lower positive rate of P16(66.7%) and Ki-67 ≥ 50% (44.1%) than that of HPVAs (31.1%, 88.6% and 70.7%, respectively; all p < 0.05, Table 1 ). Table 3 showed more specifically the immunohistochemical characteristics of different type of NHPVAs. Clear cell type EA frequently expressed Napsin-A, P504S, PAX-8 and CK7, and the positive rates of P16 was 81.82%. Endometrioid type EA typically showed immunopositivity of ER and PR, and the positive rate of P16 was 76.92%. Gastric type EA are positive for PAX-8, CK7, MUC6, MUC-5AC, CA IX and PTEN, and the positive rates of P53 was 62.5%. Serous type EAs frequently expressed P16, P53, CA125 and PTEN. Besides, the expression of CEA and PAX-8 were different in all cases. Only one mesonephric type is positive for CEA and PAX-8. Table 3 The summary of immunohistochemical features of postoperative pathology of NHPVAs (64 cases). NHPVAs P16-positive(%) P53-positive(%) Other molecules Positive Mixed results Negative Clear cell type (N = 21) 9/11 (81.82%) 7/11 (63.64%) P504S、PAX-8、CK7、Napsin-A Vimentin WT-1、ER、PR、P63、CK5/6 Endometrioid type (N = 19) 10/13 (76.92%) 5/12 (41.67%) ER、PR P63、CEA、CK7、PAX-8、Vimentin WT-1、Napsin-A Gastric type (N = 15) 4/10 (40%) 5/8 (62.5%) PAX-8、CK7、MUC-5AC、MUC6、CA IX、 PTEN CEA、P63 WT-1、ER、PR、Vimentin Serous type (N = 8) 3/3 (100%) 5/5 (100%) CA125、PTEN CEA、PAX-8 Napsin-A、P63、CK5/6 Mesonephric type (N = 1) 0/1 (0%) — CEA、PAX-8 — WT-1、Napsin-A、ER、PR、 “—”: No relevant data Survival analysis Forty-five cases (70.31%) of NHPVAs and 192 cases (70.59%) of HPVAs received postoperative adjuvant chemotherapy or radiotherapy. In the NHPVAs group, the median follow-up time was 68 (2-158) months. Twenty cases (31.1%) of NHPVAs recurred and seventeen cases died (26.6%), which were significantly higher than HPVAs (16.5%, 13.2%) ( p = 0.007, p = 0.008, respectively; Table 1 ). NHPVAs showed significantly inferior survival outcomes. The 5-year OS was 74.5% and 88.1% in two groups, respectively( p = 0.006). The 5-year DFS was 73.3% in NHPVAs group and 84.1% in HPVAs group( p = 0.006). (Fig. 1 ). The risk factors on overall survival (OS) and disease-free survival (DFS) of NHPVAs in univariate analysis and and multivariate analysis are shown in Table 4 . Univariate analysis showed FIGO stage (stage I vs. ≥stage Ⅱ; p = 0.0001 and p = 0.001), differentiation (poorly differentiated vs. moderately and well differentiated; p = 0.028 and p = 0.030), LNM ( p = 0.001 and p = 0.001) and OOM ( p < 0.0001; p = 0.001) were significantly correlated with OS and DFS, while parameters including tumor diameter(≥ 4cm), DSI (≥ 1/2) and receiving postoperative adjuvant chemotherapy or radiotherapy were not significantly correlated with OS and DFS (all p > 0.05). Multivariate analysis showed LNM ( p = 0.038 and p = 0.027) and age ( p = 0.015 and p = 0.022) were the risk factor of OS and DFS. Survival curves showed that NHPVAs with LNM had worse OS and DFS. (Fig. 2 ). Table 4 The effect on overall survival (OS) and disease-free survival (DFS) of NHPVAs (64 cases) by univariate (A) and multivariate (B) analysis Factor P -value HR 95%CI OS DFS OS DFS OS DFS A Age 0.008 0.006 1.063 1.061 (1.016–1.111) (1.017–1.106) FIGO stage 0.001 0.001 4.977 4.622 (1.873–13.228) (1.873–11.404) Differentiation 0.028 0.030 3.643 3.095 (1.148–11.564) (1.118–8.565) Tumor diameter(≥4cm) 0.466 0.299 1.425 1.591 (0.550–3.694) (0.662–3.826) Deep stromal invasion(≥1/2) 0.205 0.112 2.241 2.705 (0.644–7.803) (0.792–9.239) Lymph node metastasis 0.001 0.001 5.024 4.983 (1.899–13.291) (1.997–12.431) Ovarian and oviduct metastasis P < 0.0001 0.001 21.509 16.329 (4.130-112.031) (3.253–81.967) Postoperative adjuvant therapy 0.1 0.269 0.449 0.604 (0.173–1.166) (0.246–1.478) B Age 0.015 0.022 1.074 1.061 (1.014–1.138) (1.009–1.116) Differentiation 0.081 0.104 2.941 2.408 (0.875–9.878) (0.835–6.947) Lymph node metastasis 0.038 0.027 3.880 4.012 (1.079–13.950) (1.171–13.751) Ovarian and oviduct metastasis 0.290 0.413 3.690 2.647 (0.329–41.403) (0.257–27.269) NHPVA : Non-HPV-associated adenocarcinoma; OS : Overall survival; DFS : Disease-free survival; HR : Hazard Ratio; CI : Confidence interval. Furthermore, OS and DFS in five subtypes of NHPVAs were analyzed and subtype-specific survival trends were observed:(endometrioid type > clear cell type > gastric type > serous type), though statistical power was limited by small subgroup sizes ( p = 0.024 and p = 0.020, Fig. 3 ) There was only one mesonephric type EA in our study, which account for too little to be represented. Immunohistochemical Analysis of HENMT1 Protein Expression Levels We evaluated the HENMT1 status in 80 cases (32 cases of NHPVA and 48 cases of HPVA) using immunohistochemistry. HENMT1 expression levels in different pathological subtypes of NHPVA and HPVA was showed by immunohistochemical staining (Table 5 ). A total of 32 (66.67%) HPVA patients showed high expression of HENMT1, whereas only 14 (43.75%) case in NHPVA patients. Table 5 Expression of HENMT1 in pathological subtypes of NHPVA and HPVA. N HENMT1 High-expression group Low-expression group HPVAs 48 32(66.67%) 16(33.33%) Usual type 35 24 11 Mucinous type 8 4 4 Villoglandular type 4 3 1 ISMC 1 1 0 NHPVAs 32 14(43.75%) 18(56.25%) Clear cell type 13 4 9 Endometrioid type 7 4 3 Gastric type 7 4 3 Serous type 4 2 2 Mesonephric type 1 0 1 ISMC Invasive stratified mucin-producing carcinoma. Comparison of the pathological features of patients with high and low expression of HENMT1 were shown in Table 6 . NHPVAs showed increased low expression rate of HENMT1( p = 0.042). However, age, FIGO stage (≥ stage Ⅱ), tumor diameter (≥ 4cm), poor differentiation, DSI (≥ 1/2) and LNM showed no significant discrepancy between high and low expression of HENMT1(all p > 0.05, Table 6 ). Kaplan-Meier analysis showed that NHPVA patients with low expression of HENMT1 had poorer OS ( p = 0.021) and DFS ( p = 0.020) (Fig. 4 ). Table 6 Comparison of the pathological features of patients with high and low expression of HENMT1 in EA. HENMT1 High-expression group (N = 46) Low-expression group (N = 34) χ 2 / t P- value Age 43.80 ± 10.08 48.15 ± 10.35 1.883 0.063 pathological subtype NHPVA 14(30.43%) 18(52.94%) 4.126 0.042 HPVA 32 16 FIGO stage stage I 38(82.6%) 23(66.68%) 2.417 0.120 ≥ stage II-IV 8 11 Differentiation a poorly 4(10.81%) 6(30.00%) 3.305 0.069 moderately and well 33 14 Tumor diameter ≥ 4cm 16(34.78%) 14(41.18%) 0.341 0.559 <4cm 30 20 Deep stromal invasion ≥ 1/2 19(41.30%) 20(58.82%) 2.402 0.121 <1/2 27 14 Lymph node metastasis Present 8(17.39%) 10(29.42%) 1.620 0.203 Absent 38 24 a including missing data. Discussion Our study comprehensively analyzed the clinicopathological characteristics and prognostic outcomes of non-HPV-associated endocervical adenocarcinomas (NHPVAs) compared to HPV-associated adenocarcinomas (HPVAs), with a focus on HER2 expression. The findings emphasize the distinct biological behavior and poorer prognosis of NHPVAs, in accordance with emerging evidence that highlights the clinical significance of IECC classification in guiding patient management [ 4 ] [ 10 ] [ 8 ]. NHPVAs accounted for 19.05% of all endocervical adenocarcinomas in our cohort, a proportion slightly higher than previous reports[ 4 ] [ 10 ] [ 3 ], potentially related to factors such as genetic factors and lifestyle of the population. Hodgson et al.[ 10 ] reported that NHPVA accounted for 18.4% in their 87 cases of EAs. A key diagnostic challenge lies in the limited utility of HPV testing for NHPVAs. While TCT demonstrated comparable sensitivity between NHPVAs (60.6%) and HPVAs (65.5%), which shows the significance of TCT for NHPVAs and advocates the necessity of other adjunct diagnostic measures to reduce rate of misdiagnosis. Combined with TCT, colposcopy screening, endocervical curettage (ECC) biopsy and immunohistochemical profiling may be used to assist in the diagnosis of NHPVAs. Compared with HPVAs, NHPVAs showed identified significantly elevated neutrophil-to-lymphocyte ratios (NLR) in our study, which aligns with its established role as a marker of systemic inflammation and immunosuppression in cancer progression. A high NLR is associated with adverse survival in many solid tumors, and NLR may serve as a readily available and inexpensive biomarker as well as a cost-effective prognostic biomarker[ 20 , 21 ]. Besides, in our study NHPVAs exhibited higher elevated rates of CA125 and CA199 compared to HPVAs, indicative of a gastrointestinal-like phenotype, particularly in gastric-type tumors[ 22 ]. Nakamura et al. found serum CA199 is a more useful marker than CEA in cervical gastric type adenocarcinoma[ 23 ]. Elevated CA125 may correlate with ovarian metastasis via mesothelin interactions [ 24 ]. The serum CA125 level at diagnosis and recurrence was related to the extent of disease and prognosis of cervical adenocarcinoma with adverse pathologic features[ 25 ]. These findings underscore the unique biological behavior of NHPVAs and highlight potential diagnostic and prognostic utilities of these biomarkers. SCC, however, showed limited diagnostic utility (10% vs. 15%, p = 0.408), reinforcing its specificity for squamous cell carcinomas. In our study, NHPVAs exhibited significantly more aggressive features, including advanced FIGO stages (≥ II), larger tumor diameters (≥ 4 cm), poor differentiation, deep stromal invasion (≥ 1/2), and higher rates of lymph node metastasis (LNM) and ovarian/oviduct metastasis (OOM). Aggressive features of NHPVAs were also reported in previous studies[ 9 , 10 , 26 ].Hodgson A[ 10 ] found NHPVA tumors were significantly associated with older age at diagnosis, larger horizontal extent, greater depth of invasion, presence of lymphovascular invasion, advanced stage (FIGO stage 2 or higher) and invasive pattern C. Similar findings were also reported in previous studies. Besides, aggressive clinical features and frequently metastasizes to lymph nodes, ovaries, the abdominal cavity, and the omentum were also reported in gastric-type mucinous carcinoma (GAS) [ 26 ], which is the most common type of NHPVA. Our multivariate analysis identified poor differentiation as an independent predictor of LNM (OR = 3.24, p = 0.042). Besides, we found that both age and LNM were significantly associated with OS and DFS. Similar findings were also reported in previous study. Nishio et al.[ 27 ] found that histopathological differentiation was significantly related to the OS and DFS of gastric type EAs ( p = 0.0015; p = 0.0003). However, the effect of histopathological differentiation on the prognosis of NHPVAs is still controversial. Another study reported that histopathological differentiation is not a prognostic factor for EAs[ 28 ]. Stolnicu et al.[ 8 ] also showed that there was unclear correlation between histopathological differentiation and clinical outcomes in NHPVAs. The role of differentiation on the prognosis of NHPVAs should be further confirmed in the future. There are no type-specific treatments in the management of NHPVAs. According to NCCN guidelines (NCCN Clinical Practice Guidelines in Oncology for Cervical Cancer, Version 1.2025), the primary treatment of early-stage cervical cancer is either surgery or radiotherapy. For stage IB3 to IVA disease chemoradiation is generally the primary treatment choice. However, fertility-sparing is not recommended for patients with small neuroendocrine tumors, gastric type adenocarcinoma or minimal deviation adenocarcinoma. Our study showed that receiving postoperative adjuvant radiotherapy and chemotherapy had not significant effect on OS and DFS. As Sartor et al.[ 29 ] reporteded that HPV-negative cervical cancers are insensitive to radiotherapy and chemotherapy. Kojima et al. [ 30 ]showed significant lower response rate of chemosensitivity and worse survival outcomes in GAS compared with usual-type endocervical adenocarcinoma. GAS was also reported significantly more resistant to radiotherapy[ 27 ].At present, some studies have shown that recurrence[ 27 ], LNM, ovarian metastases[ 31 ] and poor sensitivity to chemoradiotherapy are more likely to occur in NHPVAs. In our study, the recurrence rate of NHPVAs was 23.4%, which was significantly higher than that of the HPVAs group. The 5-year OS was significantly lower in the NHPVAs group. Karamurzin et al.[ 26 ] reported that NHPVAs are often associated with local and distant recurrence, including sites where recurrent HPVAs are rarely involved. The 5-year OS and DFS of NHPVAs was 74.5% and 73.3%, which have a worse prognosis. Similar finding was also found by Hodgson et al.[ 10 ]. An international multicenter study[ 8 ] also showed that OS, DFS, and PFS of NHPVAs were significantly lower than HPVAs, and the risk of pelvic recurrence was higher than HPVAs[ 10 ]. The management of non-HPV-associated cervical adenocarcinoma presents unique challenges due to its rarity, aggressive behavior, and limited responsiveness to conventional therapies. Various multidisciplinary treatment strategies remain to be explored and definitive treatment guidelines for such cancers need to be established. NHPVAs are associated with unique molecular profiles and immunohistochemistry is of great value for the differential diagnosis of NHPVAs. In our study, the clear cell type accounted for the largest number of cases. Up to 1/3 of cases were p16 positive[ 32 , 33 ]. Some studies showed that Napsin-A is also positive[ 32 ], and most expressed wild-type p53[ 34 ], but CEA, ER, and PR are negative. Our study showed that Napsin-A, P504S, PAX-8, CK7 were positive, and the positive rates of P16 and P53 were over 50%, in addition to ER and PR, P63, WT-1, CK5/6 were also negative. The endometrioid type classified as NHPVAs may be developed from cervical endometriosis[ 35 ]. In our study, endometrioid type EA typically showed immunopositivity of ER and PR, which is consistent with previous related studies[ 36 ]. Gastric type EA are positive for p53, HIK1083, MUC6 and CA IX, and p16, ER and PR are negative[ 22 ]. In our NHPVAs group, gastric type EA frequently expresses MUC6, MUC-5AC, CA IX, PTEN, PAX-8 and CK7, and the positive rate of p53 was 62.5%. In addition, it does not express WT-1, ER, PR and Vimentin. However, four cases of gastric type EA were positive for P16, which was inconsistent with previous studies. Serous type EA shows immunopositivity for P16, P53, CA125 and PTEN, and it is negative for P63, CK5/6 and Napsin-A. But, the expression results of CEA and PAX-8 were mixed. Related studies have also shown that the positive rates of p53 and CEA are significantly higher than those of other common histological subtypes[ 32 ]. In addition, Togami et al.[ 37 ] found that both WT1 and HER2 expression were negative in serous type EA, and the majority of cases were strongly positive for CA125 expression. Only one mesonephric type EA showed that CEA and PAX-8 were positively stained, but it is negative for P16, WT-1, ER, PR and Napsin-A. Mesonephric type EA are positive for cytokeratin, vimentin, CD10, calretinin, TTF1 and HNF-1β. However, p16, MUC6, HIK1083, ER and PR are often negative[ 4 , 38 ]. Furthermore, Kenny et al.[ 38 ] reported that PAX8, HMGA2 and CA125 were expressed and WT1 was not unexpressed. In our study, we found that NHPVAs showed increased low expression rate of HENMT1compared to HPVAs. In addition, NHPVA patients expressing low levels of HENMT1 had poorer DFS and OS, which indicated that low expression of HENMT1 was associated with poor prognosis of NHPVA. Huang et al.[ 39 ] reported that HENMT1 plays an important role in the prognosis of cervical cancer. Li et al.[ 40 ] constructed a CESC-associated ceRNA network and developed a prognostic model for cervical cancer based on the ceRNA network, which suggested that HENMT1 is protective in patients with cervical cancer. The underlying mechanisms needed to be further investigated. There are some limits in this study. To begin with, this study is a retrospective study in nature. Besides, our study was based on patients in a single institution, so it is limited by its relatively small and single cohort size, and the number of some pathological subtypes was underrepresented in our study. In addition, due to the small sample size of NHPVAs, the discrepancies and correlation of clinical features and survival prognosis are not yet representative. These deficiencies could be solved with a larger scale of clinical study in future. Conclusions In summary, NHPVAs is different from HPVAs in clinicopathological features. NHPVAs demonstrate more significantly aggressive pathological features and have poorer prognosis. LNM and age are the risk factors for prognosis of NHPVAs. Additionally, our study found that NHPVAs showed increased low expression rate of HENMT1 and NHPVA patients with low expression of HENMT1 had poorer prognosis, which indicated HENMT1 might be a novel therapeutic target for NHPVAs. Abbreviations DSI deep stromal invasion DFS disease-free survival EA endocervical adenocarcinoma GAS gastric-type mucinous carcinoma HPVA HPV-associated adenocarcinoma HPV human papillomavirus HENMT1 HEN1 RNA methyltransferase IECC International endocervical adenocarcinoma criteria and classification IRS immunoreactive score LNM lymph node metastasis NHPVA non-HPV-associated adenocarcinoma NLR Neutrophil-to-lymphocyte ratio OOM ovarian or oviduct metastasis OS overall survival PLR Platelet-to-lymphocyte ratio RMP RNA modification-related protein WHO World Health Organization Declarations Ethics approval and consent to participate 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 retrospective study was performed according to the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethical Committee of Qilu Hospital in Jinan, Shandong Province, China (No. KYLL-2021(KS)-109) and individual consent for this retrospective analysis was waived. Consent for publication Not applicable. Availability of data and materials The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare no competing interests. Funding This work was supported by the Natural Science Fund youth project in Shandong Province (ZR2021QH044) and Jinan City “20 New Universities” independent innovation group (2021GXRC027). Authors' contributions QHQ and YZZ designed the study. Data collection and analysis were carried out by SJ, JHZ, XLL and SH. SJ and QHQ drafted the manuscript. The final manuscript was critically revised by YZZ and approved by all authors. Acknowledgements The authors thank the patients and the clinical teams involved in this study. 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Koh WJ, Abu-Rustum NR, Bean S, Bradley K, Campos SM, Cho KR, Chon HS, Chu C, Cohn D, Crispens MA, et al. Uterine Neoplasms, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Cancer Network: JNCCN. 2018;16(2):170–99. Sartor MA, Dolinoy DC, Jones TR, Colacino JA, Prince ME, Carey TE, Rozek LS. Genome-wide methylation and expression differences in HPV(+) and HPV(-) squamous cell carcinoma cell lines are consistent with divergent mechanisms of carcinogenesis. Epigenetics. 2011;6(6):777–87. Kojima A, Shimada M, Mikami Y, Nagao S, Takeshima N, Sugiyama T, Teramoto N, Kiyokawa T, Kigawa J, Nishimura R. Chemoresistance of Gastric-Type Mucinous Carcinoma of the Uterine Cervix: A Study of the Sankai Gynecology Study Group. Int J Gynecol Cancer. 2018;28(1):99–106. Mathew Thomas V, Alexander SA, Hadfield MJ, Vredenburgh J. A Rare Case of Clear Cell Adenocarcinoma of the Cervix with No Intrauterine Diethylstilbestrol Exposure. Cureus. 2020;12(4):e7796. Park KJ, Kiyokawa T, Soslow RA, Lamb CA, Oliva E, Zivanovic O, Juretzka MM, Pirog EC. Unusual endocervical adenocarcinomas: an immunohistochemical analysis with molecular detection of human papillomavirus. Am J Surg Pathol. 2011;35(5):633–46. Stolnicu S, Barsan I, Hoang L, Patel P, Chiriboga L, Terinte C, Pesci A, Aviel-Ronen S, Kiyokawa T, Alvarado-Cabrero I, et al. Diagnostic Algorithmic Proposal Based on Comprehensive Immunohistochemical Evaluation of 297 Invasive Endocervical Adenocarcinomas. Am J Surg Pathol. 2018;42(8):989–1000. Ueno S, Sudo T, Oka N, Wakahashi S, Yamaguchi S, Fujiwara K, Mikami Y, Nishimura R. Absence of human papillomavirus infection and activation of PI3K-AKT pathway in cervical clear cell carcinoma. Int J Gynecol cancer: official J Int Gynecol Cancer Soc. 2013;23(6):1084–91. Lu Z, Chen J. [Introduction of WHO classification of tumours of female reproductive organs, fourth edition]. Zhonghua bing li xue za zhi = Chin J Pathol. 2014;43(10):649–50. Ansari-Lari MA, Staebler A, Zaino RJ, Shah KV, Ronnett BM. Distinction of endocervical and endometrial adenocarcinomas: immunohistochemical p16 expression correlated with human papillomavirus (HPV) DNA detection. Am J Surg Pathol. 2004;28(2):160–7. Togami S, Sasajima Y, Kasamatsu T, Oda-Otomo R, Okada S, Ishikawa M, Ikeda S, Kato T, Tsuda H. Immunophenotype and human papillomavirus status of serous adenocarcinoma of the uterine cervix. Pathol Oncol research: POR. 2015;21(2):487–94. Kenny SL, McBride HA, Jamison J, McCluggage WG. Mesonephric adenocarcinomas of the uterine cervix and corpus: HPV-negative neoplasms that are commonly PAX8, CA125, and HMGA2 positive and that may be immunoreactive with TTF1 and hepatocyte nuclear factor 1-β. Am J Surg Pathol. 2012;36(6):799–807. Huang Z, Li F, Li Q. Expression profile of RNA binding protein in cervical cancer using bioinformatics approach. Cancer Cell Int. 2021;21(1):647. Li L, Guo Q, Lan G, Liu F, Wang W, Lv X. Construction of a four-mRNA prognostic signature with its ceRNA network in CESC. Sci Rep. 2022;12(1):10691. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 19 Jul, 2025 Reviewers agreed at journal 14 Jul, 2025 Reviewers invited by journal 14 Jul, 2025 Editor invited by journal 18 Jun, 2025 Editor assigned by journal 17 Jun, 2025 Submission checks completed at journal 17 Jun, 2025 First submitted to journal 15 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6900353","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":485254282,"identity":"49cb8c76-6073-482c-9e17-430b6c5715ac","order_by":0,"name":"Shuang Ju","email":"","orcid":"","institution":"Weifang People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shuang","middleName":"","lastName":"Ju","suffix":""},{"id":485254287,"identity":"ac538f2d-adad-41f1-84d4-e8484a09ea44","order_by":1,"name":"Junhua Zhang","email":"","orcid":"","institution":"Qilu Hospital of Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Junhua","middleName":"","lastName":"Zhang","suffix":""},{"id":485254289,"identity":"475f7234-dc3c-4686-8ee4-186a5950014b","order_by":2,"name":"Xiaoli Liu","email":"","orcid":"","institution":"Qilu Hospital of Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoli","middleName":"","lastName":"Liu","suffix":""},{"id":485254290,"identity":"83762c54-7246-4ad1-b52d-444a5cbfb506","order_by":3,"name":"Sai Han","email":"","orcid":"","institution":"Qilu Hospital of Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Sai","middleName":"","lastName":"Han","suffix":""},{"id":485254292,"identity":"97e25ac1-388a-4cc9-80a4-653c8516f753","order_by":4,"name":"Qiuhong Qian","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA80lEQVRIiWNgGAWjYDACZhBhwJAAJBkffKhg4CFJC7PhjDPEaIECkBY2ad42IpTyHWd+9uBNweE8fun2a9K88+pkzNkPMH74mINbi+RhNnPDOQaHiyXnnCm2nLvtMI9lTwKz5MxtuLUYHGYwk+YxOJy44UZO4o232w7wGBxIYGPmxauF/RtMS4IE75w6HoPzDwhp4YHZkn5IkreBmcfgBgFbJA/zlEnOMUhPnDkjBxjIxw4DtTxsxusXvvPHt0m8+WOd2C+R/vDBh5o6e4PzyQc/fMSjheEAEEOij8cAKsTYgEc9ihb2B/hVjoJRMApGwYgFAD1DVNnsqcf5AAAAAElFTkSuQmCC","orcid":"","institution":"Qilu Hospital of Shandong University","correspondingAuthor":true,"prefix":"","firstName":"Qiuhong","middleName":"","lastName":"Qian","suffix":""},{"id":485254294,"identity":"4b6769bd-d816-4650-8791-7dd9907522aa","order_by":5,"name":"Youzhong Zhang","email":"","orcid":"","institution":"Qilu Hospital of Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Youzhong","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2025-06-15 23:08:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6900353/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6900353/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87036666,"identity":"f5ca754a-641a-45fd-af84-1db3b003284e","added_by":"auto","created_at":"2025-07-18 13:21:46","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":66325,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival curve in NHPVA versus HPVA. Kaplan-Meier rates of overall survival (OS) and disease-free survival (DFS) in endocervical adenocarcinoma (NHPVA vs. HPVA).\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6900353/v1/c35c699399ae19d9f94b8f0c.png"},{"id":87036668,"identity":"7a0bb959-7c83-4fec-8579-3686b5cf049d","added_by":"auto","created_at":"2025-07-18 13:21:46","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":32352,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival curves in lymph node metastasis of NHPVAs. Kaplan-Meier rates of overall survival (OS) and disease-free survival (DFS) in lymph node metastasis of NHPVAs (Present vs. Absent).\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6900353/v1/53b15ae5a6498dc3f06e7d57.jpeg"},{"id":87038538,"identity":"a99a441c-e3fd-4618-bc5b-a90c158efa00","added_by":"auto","created_at":"2025-07-18 13:29:46","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":49492,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival curves in pathological subtypes of NHPVAs. Kaplan-Meier rates of overall survival (OS) and disease-free survival (DFS) in five subtypes of NHPVAs.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6900353/v1/aea25be532b82d06930eb320.jpeg"},{"id":87036665,"identity":"c17e4c04-a8fb-44d1-8f32-29d7e1004d16","added_by":"auto","created_at":"2025-07-18 13:21:46","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":33117,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier survival curves based on HENMT1 expression in the patients of NHPVA\u003c/p\u003e\n\u003cp\u003e(High expression vs. Low expression)\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6900353/v1/c40c93aa4b7975eb0b14876f.jpeg"},{"id":87039204,"identity":"5a240ed0-6f2c-4e81-8ad7-745a72d730e6","added_by":"auto","created_at":"2025-07-18 13:37:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1292902,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6900353/v1/c4ffb343-e632-455e-ad64-f7bb3097737b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinicopathological features and prognosis of non-HPV-associated adenocarcinoma","fulltext":[{"header":"Background","content":"\u003cp\u003eCervical cancer is among the most common female cancer in the world with 60,4127 new cases and 34,1831 mortalities in 2020 worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Cervical squamous cell carcinoma is the most common subtype of cervical cancer, and is almost always human papillomavirus (HPV) related. In contrast, endocervical adenocarcinomas(EA) is less common, accounting for approximately 25% of cervical cancers, and they are much more heterogeneous with various etiologies, molecular drivers, morphologies, response to treatment and prognosis[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Unlike squamous cell carcinoma, 10%-15% EA are non-HPV related[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. There is a reduction in cervical squamous lesions and glandular lesions appear to increase[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In North America, cervical adenocarcinomas increased from 5% to 8\u0026ndash;27% over the past 20 years[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eNon-HPV-associated cervical adenocarcinomas exhibit distinct clinicopathological features, worse clinical outcomes and unique molecular profiles[\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Diagnosis of NHPVA remains challenging due to nonspecific symptoms, deep cervical stromal invasion patterns, and lack of clear etiological link to HPV. Appropriate classification is critical for patient management, especially in the era of the HPV vaccine and HPV screening. In recent years, the diagnosis of endocervical adenocarcinoma has shifted from morphologic criteria classification in 2014 World Health Organization (WHO) to etiology- based classification of International endocervical adenocarcinoma criteria and classification (IECC) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. IECC classified EA into HPV-associated adenocarcinoma (HPVA) and non-HPV-associated adenocarcinoma (NHPVA). NHPVAs are only a minority and can be divided into pathological subtypes such as gastric type, endometrioid type, clear cell type, serous type and mesonephric type[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. IECC classification has good reproducibility and excellent prediction of HPV status[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. HPVAs and NHPVAs by IECC differ significantly in tumor size[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], but the correlation between other clinicopathological features and survival prognosis are limited reported.\u003c/p\u003e\u003cp\u003eCurrent management relies on radical surgery and adjuvant therapies, though evidence remains limited by the rarity and biological heterogeneity of these tumors. To improve cancer treatment outcomes, there is rapidly growing interest for the development of molecularly targeted therapeutics. With the development of bioinformatics technology and gene sequencing technology, many gene and molecular databases have been improved continuously, so that the exploration of human cancer treatment has been shared. In recent years, some studies of the competing endogenous RNA (ceRNA) hypothesis[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] and RNA modification-related proteins (RMPs)[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] have provided new insights into the treatment of cancers. HEN1 RNA methyltransferase (HENMT1) as an RNA methyltransferase, is closely related to the metabolism of small RNA and is involved in the modification of piRNA [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] and miRNA [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], which plays an important role in genome stability. The piRNA and miRNA have been shown to be associated with the development and progression of a variety of cancers in some studies[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Begik et al.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] conducted a comprehensive analysis of the expression patterns of human RMPS in 32 tissues, 10 species, and 13,358 paired tumor normal human samples, HENMT1 was found to be one of the most frequently upregulated RMPS in a variety of cancers, including cervical cancer.\u003c/p\u003e\u003cp\u003eIn the present study, we report a cohort of 336 patients with endocervical adenocarcinomas, including 64 cases of NHPVAs. The aim of our study is to analyze the clinicopathological features and prognosis of NHPVA in comparison with HPVA and to investigate the expression of HENMT1 in NHPVAs.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eSdudy population\u003c/h2\u003e\u003cp\u003e Patients treated for endocervical adenocarcinomas (EA) from January 2010 to December 2020 at Qilu Hospital of Shandong University were retrospectively collected and reviewed by searching the cervical cancer database. Patients underwent radical hysterectomy with pelvic lymphadenectomy\u0026thinsp;\u0026plusmn;\u0026thinsp;para-aortic lymphadenectomy followed by adjuvant radiotherapy or concurrent chemoradiation therapy according to pathological findings. In our study, the eligibility criteria included as following: (1) The pathological diagnosis were made and reviewed by two independent pathologists in our hospital. (2) EAs was staged by FIGO staging system[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] and categorized into HPVAs and NHPVAs according to the IECC[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] .(3) Comprehensive medical and histopathology records are available. Patients were excluded from the study if they: (1) did not take surgical treatment in our hospital; (2) took neoadjuvant chemotherapy or radiotherapy before surgery; (3) did not have complete medical and histopathology records. Using these criteria,336 patients were eligible and identified.\u003c/p\u003e\u003cp\u003eMedical and histopathology records of the 336 patients were collected and reviewed retrospectively by searching the medical records and clinical database. The following information was taken from medical records or database: age at diagnosis, parity, telephone number, HPV and cytology result, clinical symptoms, tumor markers, treatment modalities, FIGO stage. Histopathological diagnosis was reviewed by two independent pathologists regarding histologic subtypes, differentiation, tumor diameter, deep stromal invasion (DSI), lymph node metastasis (LNM), ovarian or oviduct metastasis (OOM) and immunohistochemistry.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eFollow up\u003c/h3\u003e\n\u003cp\u003eAfter treatment, the patients were followed up regularly with cytology, HPV test, tumor markers, pelvic examination and imaging tests. Follow- up duration was defined from the day of initial surgery to the last follow-up visit or telephone or death. Disease recurrence was defined if clinical and/or imaging examinations demonstrated visible disease or histopathology-confirmed diagnosis of EAs after a documented disease-free interval following initial therapy or after a documented complete response to therapy. Disease-free survival (DFS) was defined as the time from the date of initial surgery to the date of disease progression or recurrence. Overall survival (OS) was defined as the time from the date of initial surgery to the date of death or last visit. For all patients the follow-up data were available until December 2024.\u003c/p\u003e\n\u003ch3\u003eStatistical methods\u003c/h3\u003e\n\u003cp\u003eThe measurement data was expressed as \u0026oline;X\u0026thinsp;\u0026plusmn;\u0026thinsp;S and the t-test was used for inter-group comparison. Enumeration data was evaluated using the chi-square test and Fisher\u0026rsquo;s exact test. For survival analysis, the event is defined as death of any cause. The survival curves were determined by Kaplan\u0026ndash;Meier survival analysis and were compared by the Log\u0026ndash;Rank test. The multivariate Cox regression model and Logistic regression analysis were used to explore risk factors affecting prognosis and LNM, respectively. Two sided \u003cem\u003ep\u003c/em\u003e-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant. Statistical analysis was conducted with SPSS 25.0 software (IBM Corp, Armonk, NY, USA).\u003c/p\u003e\n\u003ch3\u003eImmunohistochemistry\u003c/h3\u003e\n\u003cp\u003eImmunohistochemical studies determining the existence of HENMT1 were performed by using sections (4 \u0026micro;m). After being baked at a constant temperature of 65\u0026deg; for 1 hour, the paraffin-embedded sections were deparaffinized with xylene and hydrated in ethanol. Antigen was repaired by incubating the sample in sodium citrate. The hydrogen peroxide was used to block endogenous catalase, and non-specific antigens was closed by goat serum. Then, incubation of sections with primary antibody (HENMT1, 1:50, PA5-55866, Invitrogen, USA) at 4\u0026deg;C overnight. And we treated the sections by biotin-labeled goat anti-rabbit IgG polymer, followed by horseradish peroxidase-conjugated streptavidin. In the end, samples stained by 3,3\u0026prime;-diaminobenzidine, counterstained with hematoxylin, dehydrated and fixed. The sections were scored by two pathologists according to staining intensity and percentage of stained cells in mutually uninformed way. The staining intensity (SI): brown\u0026thinsp;=\u0026thinsp;3, yellow-\u003c/p\u003e\u003cp\u003ebrown\u0026thinsp;=\u0026thinsp;2, light-yellow\u0026thinsp;=\u0026thinsp;1, no staining\u0026thinsp;=\u0026thinsp;0. The percentage of positive cell (PP) : \u0026gt;75% of positive tumor cells\u0026thinsp;=\u0026thinsp;4, 51%ཞ75% of positive tumor cells\u0026thinsp;=\u0026thinsp;3, 26%ཞ50% of positive tumor cells\u0026thinsp;=\u0026thinsp;2, 6%ཞ25% of positive tumor cells\u0026thinsp;=\u0026thinsp;1, 0ཞ5% of positive tumor cells\u0026thinsp;=\u0026thinsp;0. The immunoreactive score (IRS) was defined as the product of PP and SI. The high expression was defined as an IRS\u0026thinsp;\u0026ge;\u0026thinsp;5.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eClinical and pathological features\u003c/h2\u003e\u003cp\u003eAmong 336 endocervical adenocarcinoma (EA) patients, 64 (19.05%) cases were classified as NHPVAs and 272 as HPVA based on IECC criteria (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Among NHPVA, clear cell type accounted for 21 cases, followed by endometrioid type (19 cases), gastric type (15 cases), serous type (8 cases) and mesonephric type (1 case) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Patient characteristics were compared and shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The mean age of NHPVAs patients (47.97\u0026thinsp;\u0026plusmn;\u0026thinsp;11.27 years) was slightly older than HPVAs patients (45.78\u0026thinsp;\u0026plusmn;\u0026thinsp;10.36 years), though this difference lacked statistical significance (p\u0026thinsp;=\u0026thinsp;0.136; Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). NHPVAs presented predominantly with abnormal genital bleeding or contact bleeding (71.88%), followed by watery discharge (14.06%), no complaints (10.94%), abdominal pain or distension (4.69%) and abnormal vaginal secretion (1.56%), which show similar symptomatology with HPVAs (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.82, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). TCT sensitivity of NHPVAs (60.6%) was slightly lower than HPVAs (65.5%), but there is no statistical significance (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.595, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). NHPVAs exhibited significantly elevated neutrophil-to-lymphocyte ratio (NLR) and the elevated rates of CA125 (37.2%) and CA199 (47.4%) compared to HPVAs (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The platelet-to-lymphocyte ratio (PLR) and the positive rates of SCC between two groups showed no significant discrepancy (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSummary and comparison of the features of patients with NHPVAs and HPVAs.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNHPVA (N\u0026thinsp;=\u0026thinsp;64)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHPVA (N\u0026thinsp;=\u0026thinsp;272)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eχ\u003csup\u003e2\u003c/sup\u003e/ t\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e47.97\u0026thinsp;\u0026plusmn;\u0026thinsp;11.267\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e45.78\u0026thinsp;\u0026plusmn;\u0026thinsp;10.357\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.496\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.136\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePregnancy times\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.86\u0026thinsp;\u0026plusmn;\u0026thinsp;1.390\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.06\u0026thinsp;\u0026plusmn;\u0026thinsp;1.611\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.914\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.362\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eParturition time\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.64\u0026thinsp;\u0026plusmn;\u0026thinsp;1.029\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.65\u0026thinsp;\u0026plusmn;\u0026thinsp;0.892\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.079\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.937\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChief complaints\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbnormal genital bleeding,\u003c/p\u003e\u003cp\u003eContact bleeding\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e46 (71.88%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e186 (68.38%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.397\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.82\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWatery discharge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9 (14.06%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e38 (13.97%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbnormal vaginal secretion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (1.56%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 (4.78%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbdominal pain or distension\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (4.69%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (1.84%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo complaints\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (10.94%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e40 (14.71%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCytology \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;ASCUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20(60.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e108(65.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.283\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.595\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;ASCUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTumor marker \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSCC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;1.5(ng/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4(10%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30(15%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.685\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.408\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;1.5(ng/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e170\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCA-125\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;30(U/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16(37.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e35(21.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3.955\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.037\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;30(U/mL)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e126\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCA-199\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;39(U/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9(47.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e29(22.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.046\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;39(U/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNLR(M\u0026thinsp;=\u0026thinsp;2.0998)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.946\u0026thinsp;\u0026plusmn;\u0026thinsp;2.522\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.334\u0026thinsp;\u0026plusmn;\u0026thinsp;1.220\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePLR(M\u0026thinsp;=\u0026thinsp;164.86)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e192.147\u0026thinsp;\u0026plusmn;\u0026thinsp;87.529\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e177.879\u0026thinsp;\u0026plusmn;\u0026thinsp;96.694\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.081\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.281\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFIGO stage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003estage I\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e223\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4.373\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.037\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge; stage II-IV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDifferentiation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003epoorly\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.019\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003emoderately and well\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e190\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTumor diameter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;4cm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6.277\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.012\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;4cm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e204\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDeep stromal invasion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;1/2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45(70.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e144(52.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6.353\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.012\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;1/2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e128\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLymph node metastasis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17(26.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e43(15.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4.085\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.043\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbsent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e229\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOvarian and oviduct metastasis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5(7.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8(2.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4.129\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.042\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbsent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e264\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eP16 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePositive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22(66.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e124(88.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e9.729\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eP53 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePositive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19(55.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28(31.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6.434\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.011\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKi-67 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;50%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15(44.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e70(70.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e7.758\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;50%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOutcome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRecurrence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20(31.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e45(16.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e7.181\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.007\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMortality\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17(26.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e36(13.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6.926\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.008\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eNHPVA\u003c/b\u003e: Non-HPV-associated adenocarcinoma; \u003cb\u003eHPVA\u003c/b\u003e: HPV-associated adenocarcinoma; \u003cb\u003eFIGO\u003c/b\u003e: International Federation of Gynecology and Obstetrics; \u003cb\u003eSCC\u003c/b\u003e: Squamous cell carcinoma antigen; \u003cb\u003eCA 125\u003c/b\u003e: Cancer antigen 125; \u003cb\u003eCA19-9\u003c/b\u003e: Carbohydrate antigen 19\u0026thinsp;\u0026minus;\u0026thinsp;9; \u003cb\u003eNLR\u003c/b\u003e: Neutrophil-to-lymphocyte ratio; \u003cb\u003ePLR\u003c/b\u003e: Platelet-to-lymphocyte ratio.\u003c/p\u003e\u003cp\u003e\u003cb\u003e\u0026ge;ASC-US\u003c/b\u003e: Atypical squamous cells of undetermined significance (ASC-US), Low grade squamous intraepithelial lesion (LSIL), High grade squamous intraepithelial lesion (HSIL), Atypical squamous cells-cannot exclude HSIL(ASC-H), Atypical glandular cells (AGC), Adenocarcinoma in situ (AIS), Adenocarcinoma. \u003cb\u003e\u0026lt;ASC-US\u003c/b\u003e: Negative for intraepithelial lesion or malignancy (NILM), Chronic inflammation of the cervix.\u003c/p\u003e\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e including missing data.\u003c/p\u003e\u003cp\u003eNHPVAs demonstrated more significantly aggressive pathological features with FIGO stage (\u0026ge;\u0026thinsp;stage Ⅱ), tumor diameter (\u0026ge;\u0026thinsp;4cm), poor differentiation, deep stromal invasion (DSI) (\u0026ge;\u0026thinsp;1/2), Lymph node metastasis (LNM) and Ovarian and oviduct metastasis (OOM) (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Multivariate Logistic regression analysis confirmed poor differentiation as an independent predictor of LNM (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.042, OR\u0026thinsp;=\u0026thinsp;3.24, 95% CI 1.045\u0026ndash;10.07; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). However, NHPVAs is not an independent risk factor of LNM (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.799, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eUnivariate (A) and multivariate (B) Logistic regressions for lymph node metastasis.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFactor\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e95%CI\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNHPVAs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.046\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.926\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e(1.012\u0026ndash;3.665)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.014\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e(0.987\u0026ndash;1.041)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCA125 (\u0026ge;\u0026thinsp;30 U/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e(2.041\u0026ndash;9.142)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCA199 (\u0026ge;\u0026thinsp;39 U/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.623\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e(1.133\u0026ndash;6.077)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFIGO stage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e771.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e(164.627-3614.57)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDifferentiation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.048\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e(1.005\u0026ndash;4.053)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTumor diameter(\u0026ge;4cm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.784\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e(1.562\u0026ndash;4.961)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDeep stromal invasion(\u0026ge;1/2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.327\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e(2.159\u0026ndash;8.672)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOvarian and oviduct metastasis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.012\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e(1.381\u0026ndash;13.204)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNHPVAs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.799\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.174\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e(0.34\u0026ndash;4.055)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCA125 (\u0026ge;\u0026thinsp;30 U/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.346\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.719\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e(0.557\u0026ndash;5.301)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCA199 (\u0026ge;\u0026thinsp;39 U/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.283\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.787\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e(0.619\u0026ndash;5.165)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDifferentiation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.042\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.244\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e(1.045\u0026ndash;10.07)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTumor diameter(\u0026ge;4cm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.336\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.723\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e(0.569\u0026ndash;5.216)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDeep stromal invasion(\u0026ge;1/2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.254\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e(0.62\u0026ndash;6.138)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOvarian and oviduct metastasis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.519\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.528\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e(0.076\u0026ndash;3.68)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cb\u003eOR\u003c/b\u003e: Odd ratio; \u003cb\u003eCI\u003c/b\u003e: Confidence interval\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eImmunohistochemical profiling revealed distinct molecular signatures. NHPVAs exhibited significantly higher positive rate of P53(55.9%) and lower positive rate of P16(66.7%) and Ki-67\u0026thinsp;\u0026ge;\u0026thinsp;50% (44.1%) than that of HPVAs (31.1%, 88.6% and 70.7%, respectively; all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e showed more specifically the immunohistochemical characteristics of different type of NHPVAs. Clear cell type EA frequently expressed Napsin-A, P504S, PAX-8 and CK7, and the positive rates of P16 was 81.82%. Endometrioid type EA typically showed immunopositivity of ER and PR, and the positive rate of P16 was 76.92%. Gastric type EA are positive for PAX-8, CK7, MUC6, MUC-5AC, CA IX and PTEN, and the positive rates of P53 was 62.5%. Serous type EAs frequently expressed P16, P53, CA125 and PTEN. Besides, the expression of CEA and PAX-8 were different in all cases. Only one mesonephric type is positive for CEA and PAX-8.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eThe summary of immunohistochemical features of postoperative pathology of NHPVAs (64 cases).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNHPVAs\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eP16-positive(%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eP53-positive(%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eOther molecules\u003c/span\u003e\u003c/p\u003e\u003cp\u003ePositive Mixed results\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClear cell type\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9/11\u003c/p\u003e\u003cp\u003e(81.82%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7/11\u003c/p\u003e\u003cp\u003e(63.64%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP504S、PAX-8、CK7、Napsin-A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eVimentin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eWT-1、ER、PR、P63、CK5/6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEndometrioid type\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10/13\u003c/p\u003e\u003cp\u003e(76.92%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5/12\u003c/p\u003e\u003cp\u003e(41.67%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eER、PR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eP63、CEA、CK7、PAX-8、Vimentin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eWT-1、Napsin-A\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastric type\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4/10\u003c/p\u003e\u003cp\u003e(40%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5/8\u003c/p\u003e\u003cp\u003e(62.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePAX-8、CK7、MUC-5AC、MUC6、CA IX、 PTEN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCEA、P63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eWT-1、ER、PR、Vimentin\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSerous type\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3/3\u003c/p\u003e\u003cp\u003e(100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5/5\u003c/p\u003e\u003cp\u003e(100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCA125、PTEN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCEA、PAX-8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNapsin-A、P63、CK5/6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMesonephric type\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0/1\u003c/p\u003e\u003cp\u003e(0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCEA、PAX-8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eWT-1、Napsin-A、ER、PR、\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u0026ldquo;\u0026mdash;\u0026rdquo;: No relevant data\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eSurvival analysis\u003c/h3\u003e\n\u003cp\u003eForty-five cases (70.31%) of NHPVAs and 192 cases (70.59%) of HPVAs received postoperative adjuvant chemotherapy or radiotherapy. In the NHPVAs group, the median follow-up time was 68 (2-158) months. Twenty cases (31.1%) of NHPVAs recurred and seventeen cases died (26.6%), which were significantly higher than HPVAs (16.5%, 13.2%) (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008, respectively; Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). NHPVAs showed significantly inferior survival outcomes. The 5-year OS was 74.5% and 88.1% in two groups, respectively(\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006). The 5-year DFS was 73.3% in NHPVAs group and 84.1% in HPVAs group(\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006). (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe risk factors on overall survival (OS) and disease-free survival (DFS) of NHPVAs in univariate analysis and and multivariate analysis are shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. Univariate analysis showed FIGO stage (stage I vs. \u0026ge;stage Ⅱ; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0001 and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), differentiation (poorly differentiated vs. moderately and well differentiated; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.028 and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.030), LNM (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001 and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) and OOM (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) were significantly correlated with OS and DFS, while parameters including tumor diameter(\u0026ge;\u0026thinsp;4cm), DSI (\u0026ge;\u0026thinsp;1/2) and receiving postoperative adjuvant chemotherapy or radiotherapy were not significantly correlated with OS and DFS (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Multivariate analysis showed LNM (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.038 and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.027) and age (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015 and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.022) were the risk factor of OS and DFS. Survival curves showed that NHPVAs with LNM had worse OS and DFS. (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eThe effect on overall survival (OS) and disease-free survival (DFS) of NHPVAs (64 cases) by univariate (A) and multivariate (B) analysis\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFactor\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eP\u003c/span\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e-value\u003c/span\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eHR\u003c/span\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e95%CI\u003c/span\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDFS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDFS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eOS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eDFS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.008\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.006\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.063\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.061\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(1.016\u0026ndash;1.111)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(1.017\u0026ndash;1.106)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFIGO stage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.977\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.622\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(1.873\u0026ndash;13.228)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(1.873\u0026ndash;11.404)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDifferentiation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.028\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.030\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.643\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.095\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(1.148\u0026ndash;11.564)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(1.118\u0026ndash;8.565)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTumor diameter(\u0026ge;4cm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.466\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.299\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.425\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.591\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(0.550\u0026ndash;3.694)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(0.662\u0026ndash;3.826)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDeep stromal invasion(\u0026ge;1/2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.205\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.112\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.241\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.705\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(0.644\u0026ndash;7.803)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(0.792\u0026ndash;9.239)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLymph node metastasis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.983\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(1.899\u0026ndash;13.291)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(1.997\u0026ndash;12.431)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOvarian and oviduct metastasis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e21.509\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e16.329\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(4.130-112.031)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(3.253\u0026ndash;81.967)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePostoperative adjuvant therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.269\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.449\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.604\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(0.173\u0026ndash;1.166)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(0.246\u0026ndash;1.478)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.015\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.074\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.061\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(1.014\u0026ndash;1.138)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(1.009\u0026ndash;1.116)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDifferentiation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.081\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.104\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.941\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.408\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(0.875\u0026ndash;9.878)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(0.835\u0026ndash;6.947)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLymph node metastasis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.038\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.027\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.880\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.012\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(1.079\u0026ndash;13.950)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(1.171\u0026ndash;13.751)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOvarian and oviduct metastasis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.290\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.413\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.690\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.647\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(0.329\u0026ndash;41.403)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(0.257\u0026ndash;27.269)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eNHPVA\u003c/b\u003e: Non-HPV-associated adenocarcinoma; \u003cb\u003eOS\u003c/b\u003e: Overall survival; \u003cb\u003eDFS\u003c/b\u003e: Disease-free survival; \u003cb\u003eHR\u003c/b\u003e: Hazard Ratio; \u003cb\u003eCI\u003c/b\u003e: Confidence interval.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFurthermore, OS and DFS in five subtypes of NHPVAs were analyzed and subtype-specific survival trends were observed:(endometrioid type\u0026thinsp;\u0026gt;\u0026thinsp;clear cell type\u0026thinsp;\u0026gt;\u0026thinsp;gastric type\u0026thinsp;\u0026gt;\u0026thinsp;serous type), though statistical power was limited by small subgroup sizes (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024 and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.020, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) There was only one mesonephric type EA in our study, which account for too little to be represented.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eImmunohistochemical Analysis of HENMT1 Protein Expression Levels\u003c/h3\u003e\n\u003cp\u003eWe evaluated the HENMT1 status in 80 cases (32 cases of NHPVA and 48 cases of HPVA) using immunohistochemistry. HENMT1 expression levels in different pathological subtypes of NHPVA and HPVA was showed by immunohistochemical staining (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). A total of 32 (66.67%) HPVA patients showed high expression of HENMT1, whereas only 14 (43.75%) case in NHPVA patients.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eExpression of HENMT1 in pathological subtypes of NHPVA and HPVA.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eHENMT1\u003c/span\u003e\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHigh-expression group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLow-expression group\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHPVAs\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e48\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e32(66.67%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e16(33.33%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUsual type\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMucinous type\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVilloglandular type\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eISMC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNHPVAs\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e32\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e14(43.75%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e18(56.25%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClear cell type\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEndometrioid type\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastric type\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSerous type\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMesonephric type\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eISMC\u003c/strong\u003e\u003cp\u003eInvasive stratified mucin-producing carcinoma.\u003c/p\u003e\u003c/p\u003e\u003cp\u003eComparison of the pathological features of patients with high and low expression of HENMT1 were shown in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e. NHPVAs showed increased low expression rate of HENMT1(\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.042). However, age, FIGO stage (\u0026ge;\u0026thinsp;stage Ⅱ), tumor diameter (\u0026ge;\u0026thinsp;4cm), poor differentiation, DSI (\u0026ge;\u0026thinsp;1/2) and LNM showed no significant discrepancy between high and low expression of HENMT1(all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05, Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). Kaplan-Meier analysis showed that NHPVA patients with low expression of HENMT1 had poorer OS (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021) and DFS (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.020) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComparison of the pathological features of patients with high and low expression of HENMT1 in EA.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eHENMT1\u003c/span\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHigh-expression group (N\u0026thinsp;=\u0026thinsp;46)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow-expression group (N\u0026thinsp;=\u0026thinsp;34)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eχ\u003csup\u003e2\u003c/sup\u003e/ t\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP-\u003c/em\u003evalue\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e43.80\u0026thinsp;\u0026plusmn;\u0026thinsp;10.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e48.15\u0026thinsp;\u0026plusmn;\u0026thinsp;10.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.883\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.063\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003epathological subtype\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNHPVA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14(30.43%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18(52.94%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.126\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.042\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHPVA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFIGO stage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003estage I\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38(82.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23(66.68%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.417\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.120\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge; stage II-IV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDifferentiation \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003epoorly\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4(10.81%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6(30.00%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.305\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.069\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003emoderately and well\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTumor diameter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;4cm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16(34.78%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14(41.18%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.341\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.559\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;4cm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDeep stromal invasion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;1/2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19(41.30%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20(58.82%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.402\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.121\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;1/2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLymph node metastasis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8(17.39%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10(29.42%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.620\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.203\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbsent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e including missing data.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study comprehensively analyzed the clinicopathological characteristics and prognostic outcomes of non-HPV-associated endocervical adenocarcinomas (NHPVAs) compared to HPV-associated adenocarcinomas (HPVAs), with a focus on HER2 expression. The findings emphasize the distinct biological behavior and poorer prognosis of NHPVAs, in accordance with emerging evidence that highlights the clinical significance of IECC classification in guiding patient management [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. NHPVAs accounted for 19.05% of all endocervical adenocarcinomas in our cohort, a proportion slightly higher than previous reports[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], potentially related to factors such as genetic factors and lifestyle of the population. Hodgson et al.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] reported that NHPVA accounted for 18.4% in their 87 cases of EAs. A key diagnostic challenge lies in the limited utility of HPV testing for NHPVAs. While TCT demonstrated comparable sensitivity between NHPVAs (60.6%) and HPVAs (65.5%), which shows the significance of TCT for NHPVAs and advocates the necessity of other adjunct diagnostic measures to reduce rate of misdiagnosis. Combined with TCT, colposcopy screening, endocervical curettage (ECC) biopsy and immunohistochemical profiling may be used to assist in the diagnosis of NHPVAs.\u003c/p\u003e\u003cp\u003eCompared with HPVAs, NHPVAs showed identified significantly elevated neutrophil-to-lymphocyte ratios (NLR) in our study, which aligns with its established role as a marker of systemic inflammation and immunosuppression in cancer progression. A high NLR is associated with adverse survival in many solid tumors, and NLR may serve as a readily available and inexpensive biomarker as well as a cost-effective prognostic biomarker[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Besides, in our study NHPVAs exhibited higher elevated rates of CA125 and CA199 compared to HPVAs, indicative of a gastrointestinal-like phenotype, particularly in gastric-type tumors[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Nakamura et al. found serum CA199 is a more useful marker than CEA in cervical gastric type adenocarcinoma[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Elevated CA125 may correlate with ovarian metastasis via mesothelin interactions [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The serum CA125 level at diagnosis and recurrence was related to the extent of disease and prognosis of cervical adenocarcinoma with adverse pathologic features[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. These findings underscore the unique biological behavior of NHPVAs and highlight potential diagnostic and prognostic utilities of these biomarkers. SCC, however, showed limited diagnostic utility (10% vs. 15%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.408), reinforcing its specificity for squamous cell carcinomas.\u003c/p\u003e\u003cp\u003eIn our study, NHPVAs exhibited significantly more aggressive features, including advanced FIGO stages (\u0026ge;\u0026thinsp;II), larger tumor diameters (\u0026ge;\u0026thinsp;4 cm), poor differentiation, deep stromal invasion (\u0026ge;\u0026thinsp;1/2), and higher rates of lymph node metastasis (LNM) and ovarian/oviduct metastasis (OOM). Aggressive features of NHPVAs were also reported in previous studies[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].Hodgson A[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] found NHPVA tumors were significantly associated with older age at diagnosis, larger horizontal extent, greater depth of invasion, presence of lymphovascular invasion, advanced stage (FIGO stage 2 or higher) and invasive pattern C. Similar findings were also reported in previous studies. Besides, aggressive clinical features and frequently metastasizes to lymph nodes, ovaries, the abdominal cavity, and the omentum were also reported in gastric-type mucinous carcinoma (GAS) [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], which is the most common type of NHPVA. Our multivariate analysis identified poor differentiation as an independent predictor of LNM (OR\u0026thinsp;=\u0026thinsp;3.24, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.042). Besides, we found that both age and LNM were significantly associated with OS and DFS. Similar findings were also reported in previous study. Nishio et al.[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] found that histopathological differentiation was significantly related to the OS and DFS of gastric type EAs (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0015; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0003). However, the effect of histopathological differentiation on the prognosis of NHPVAs is still controversial. Another study reported that histopathological differentiation is not a prognostic factor for EAs[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Stolnicu et al.[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] also showed that there was unclear correlation between histopathological differentiation and clinical outcomes in NHPVAs. The role of differentiation on the prognosis of NHPVAs should be further confirmed in the future.\u003c/p\u003e\u003cp\u003eThere are no type-specific treatments in the management of NHPVAs. According to NCCN guidelines (NCCN Clinical Practice Guidelines in Oncology for Cervical Cancer, Version 1.2025), the primary treatment of early-stage cervical cancer is either surgery or radiotherapy. For stage IB3 to IVA disease chemoradiation is generally the primary treatment choice. However, fertility-sparing is not recommended for patients with small neuroendocrine tumors, gastric type adenocarcinoma or minimal deviation adenocarcinoma. Our study showed that receiving postoperative adjuvant radiotherapy and chemotherapy had not significant effect on OS and DFS. As Sartor et al.[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] reporteded that HPV-negative cervical cancers are insensitive to radiotherapy and chemotherapy. Kojima et al. [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]showed significant lower response rate of chemosensitivity and worse survival outcomes in GAS compared with usual-type endocervical adenocarcinoma. GAS was also reported significantly more resistant to radiotherapy[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].At present, some studies have shown that recurrence[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], LNM, ovarian metastases[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] and poor sensitivity to chemoradiotherapy are more likely to occur in NHPVAs. In our study, the recurrence rate of NHPVAs was 23.4%, which was significantly higher than that of the HPVAs group. The 5-year OS was significantly lower in the NHPVAs group. Karamurzin et al.[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] reported that NHPVAs are often associated with local and distant recurrence, including sites where recurrent HPVAs are rarely involved. The 5-year OS and DFS of NHPVAs was 74.5% and 73.3%, which have a worse prognosis. Similar finding was also found by Hodgson et al.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. An international multicenter study[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] also showed that OS, DFS, and PFS of NHPVAs were significantly lower than HPVAs, and the risk of pelvic recurrence was higher than HPVAs[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The management of non-HPV-associated cervical adenocarcinoma presents unique challenges due to its rarity, aggressive behavior, and limited responsiveness to conventional therapies. Various multidisciplinary treatment strategies remain to be explored and definitive treatment guidelines for such cancers need to be established.\u003c/p\u003e\u003cp\u003eNHPVAs are associated with unique molecular profiles and immunohistochemistry is of great value for the differential diagnosis of NHPVAs. In our study, the clear cell type accounted for the largest number of cases. Up to 1/3 of cases were p16 positive[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Some studies showed that Napsin-A is also positive[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], and most expressed wild-type p53[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], but CEA, ER, and PR are negative. Our study showed that Napsin-A, P504S, PAX-8, CK7 were positive, and the positive rates of P16 and P53 were over 50%, in addition to ER and PR, P63, WT-1, CK5/6 were also negative. The endometrioid type classified as NHPVAs may be developed from cervical endometriosis[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. In our study, endometrioid type EA typically showed immunopositivity of ER and PR, which is consistent with previous related studies[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Gastric type EA are positive for p53, HIK1083, MUC6 and CA IX, and p16, ER and PR are negative[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In our NHPVAs group, gastric type EA frequently expresses MUC6, MUC-5AC, CA IX, PTEN, PAX-8 and CK7, and the positive rate of p53 was 62.5%. In addition, it does not express WT-1, ER, PR and Vimentin. However, four cases of gastric type EA were positive for P16, which was inconsistent with previous studies. Serous type EA shows immunopositivity for P16, P53, CA125 and PTEN, and it is negative for P63, CK5/6 and Napsin-A. But, the expression results of CEA and PAX-8 were mixed. Related studies have also shown that the positive rates of p53 and CEA are significantly higher than those of other common histological subtypes[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. In addition, Togami et al.[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] found that both WT1 and HER2 expression were negative in serous type EA, and the majority of cases were strongly positive for CA125 expression. Only one mesonephric type EA showed that CEA and PAX-8 were positively stained, but it is negative for P16, WT-1, ER, PR and Napsin-A. Mesonephric type EA are positive for cytokeratin, vimentin, CD10, calretinin, TTF1 and HNF-1β. However, p16, MUC6, HIK1083, ER and PR are often negative[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Furthermore, Kenny et al.[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] reported that PAX8, HMGA2 and CA125 were expressed and WT1 was not unexpressed.\u003c/p\u003e\u003cp\u003eIn our study, we found that NHPVAs showed increased low expression rate of HENMT1compared to HPVAs. In addition, NHPVA patients expressing low levels of HENMT1 had poorer DFS and OS, which indicated that low expression of HENMT1 was associated with poor prognosis of NHPVA. Huang et al.[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] reported that HENMT1 plays an important role in the prognosis of cervical cancer. Li et al.[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e] constructed a CESC-associated ceRNA network and developed a prognostic model for cervical cancer based on the ceRNA network, which suggested that HENMT1 is protective in patients with cervical cancer. The underlying mechanisms needed to be further investigated.\u003c/p\u003e\u003cp\u003eThere are some limits in this study. To begin with, this study is a retrospective study in nature. Besides, our study was based on patients in a single institution, so it is limited by its relatively small and single cohort size, and the number of some pathological subtypes was underrepresented in our study. In addition, due to the small sample size of NHPVAs, the discrepancies and correlation of clinical features and survival prognosis are not yet representative. These deficiencies could be solved with a larger scale of clinical study in future.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn summary, NHPVAs is different from HPVAs in clinicopathological features. NHPVAs demonstrate more significantly aggressive pathological features and have poorer prognosis. LNM and age are the risk factors for prognosis of NHPVAs. Additionally, our study found that NHPVAs showed increased low expression rate of HENMT1 and NHPVA patients with low expression of HENMT1 had poorer prognosis, which indicated HENMT1 might be a novel therapeutic target for NHPVAs.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDSI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003edeep stromal invasion\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDFS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003edisease-free survival\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eEA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eendocervical adenocarcinoma\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eGAS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003egastric-type mucinous carcinoma\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHPVA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHPV-associated adenocarcinoma\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHPV\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ehuman papillomavirus\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHENMT1\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHEN1 RNA methyltransferase\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIECC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eInternational endocervical adenocarcinoma criteria and classification\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIRS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eimmunoreactive score\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLNM\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003elymph node metastasis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNHPVA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003enon-HPV-associated adenocarcinoma\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNLR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNeutrophil-to-lymphocyte ratio\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eOOM\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eovarian or oviduct metastasis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eOS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eoverall survival\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePLR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePlatelet-to-lymphocyte ratio\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRMP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRNA modification-related protein\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eWHO\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eWorld Health Organization\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe 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 retrospective study was performed according to the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethical Committee of Qilu Hospital in Jinan, Shandong Province, China (No. KYLL-2021(KS)-109) and individual consent for this retrospective analysis was waived.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Natural Science Fund youth project in Shandong Province (ZR2021QH044) and Jinan City “20 New Universities” independent innovation group (2021GXRC027).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQHQ and YZZ designed the study. Data collection and analysis were carried out by SJ, JHZ, XLL and SH. SJ and QHQ drafted the manuscript. The final manuscript was critically revised by YZZ and approved by all authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the patients and the clinical teams involved in this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePark KJ. Cervical adenocarcinoma: integration of HPV status, pattern of invasion, morphology and molecular markers into classification. 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Am J Surg Pathol. 2019;43(1):75\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eQi X, Zhang DH, Wu N, Xiao JH, Wang X, Ma W. ceRNA in cancer: possible functions and clinical implications. J Med Genet. 2015;52(10):710\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJonkhout N, Tran J, Smith MA, Schonrock N, Mattick JS, Novoa EM. The RNA modification landscape in human disease. RNA (New York NY). 2017;23(12):1754\u0026ndash;69.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAyadi L, Galvanin A, Pichot F, Marchand V, Motorin Y. RNA ribose methylation (2'-O-methylation): Occurrence, biosynthesis and biological functions. Biochim et Biophys acta Gene Regul Mech. 2019;1862(3):253\u0026ndash;69.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiang H, Jiao Z, Rong W, Qu S, Liao Z, Sun X, Wei Y, Zhao Q, Wang J, Liu Y, et al. 3'-Terminal 2'-O-methylation of lung cancer miR-21-5p enhances its stability and association with Argonaute 2. Nucleic Acids Res. 2020;48(13):7027\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLee E, Lokman NA, Oehler MK, Ricciardelli C, Grutzner F. A Comprehensive Molecular and Clinical Analysis of the piRNA Pathway Genes in Ovarian Cancer. Cancers 2020, 13(1).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMori MA, Ludwig RG, Garcia-Martin R, Brand\u0026atilde;o BB, Kahn CR. Extracellular miRNAs: From Biomarkers to Mediators of Physiology and Disease. Cell Metabol. 2019;30(4):656\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBegik O, Lucas MC, Liu H, Ramirez JM, Mattick JS, Novoa EM. Integrative analyses of the RNA modification machinery reveal tissue- and cancer-specific signatures. Genome Biol. 2020;21(1):97.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBhatla N, Aoki D, Sharma DN, Sankaranarayanan R. Cancer of the cervix uteri. Int J Gynaecol Obstet. 2018;143(Suppl 2):22\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTempleton AJ, McNamara MG, Šeruga B, Vera-Badillo FE, Aneja P, Oca\u0026ntilde;a A, Leibowitz-Amit R, Sonpavde G, Knox JJ, Tran B, et al. Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst. 2014;106(6):dju124.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWu J, Chen M, Liang C, Su W. Prognostic value of the pretreatment neutrophil-to-lymphocyte ratio in cervical cancer: a meta-analysis and systematic review. Oncotarget. 2017;8(8):13400\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCarleton C, Hoang L, Sah S, Kiyokawa T, Karamurzin YS, Talia KL, Park KJ, McCluggage WG. A Detailed Immunohistochemical Analysis of a Large Series of Cervical and Vaginal Gastric-type Adenocarcinomas. Am J Surg Pathol. 2016;40(5):636\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNakamura A, Yamaguchi K, Minamiguchi S, Murakami R, Abiko K, Hamanishi J, Kondoh E, Baba T, Mandai M, Matsumura N. Mucinous adenocarcinoma, gastric type of the uterine cervix: clinical features and HER2 amplification. Med Mol Morphol. 2019;52(1):52\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRump A, Morikawa Y, Tanaka M, Minami S, Umesaki N, Takeuchi M, Miyajima A. Binding of ovarian cancer antigen CA125/MUC16 to mesothelin mediates cell adhesion. J Biol Chem. 2004;279(10):9190\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKim N, Park W, Cho WK, Bae DS, Kim BG, Lee JW, Choi CH, Kim TJ, Lee YY. Significance of serum CA125 level in surgically resected cervical adenocarcinoma with adverse features. J Gynecol Oncol. 2021;32(5):e72.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKaramurzin YS, Kiyokawa T, Parkash V, Jotwani AR, Patel P, Pike MC, Soslow RA, Park KJ. Gastric-type Endocervical Adenocarcinoma: An Aggressive Tumor With Unusual Metastatic Patterns and Poor Prognosis. Am J Surg Pathol. 2015;39(11):1449\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNishio S, Mikami Y, Tokunaga H, Yaegashi N, Satoh T, Saito M, Okamoto A, Kasamatsu T, Miyamoto T, Shiozawa T, et al. Analysis of gastric-type mucinous carcinoma of the uterine cervix - An aggressive tumor with a poor prognosis: A multi-institutional study. Gynecol Oncol. 2019;153(1):13\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKoh WJ, Abu-Rustum NR, Bean S, Bradley K, Campos SM, Cho KR, Chon HS, Chu C, Cohn D, Crispens MA, et al. Uterine Neoplasms, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Cancer Network: JNCCN. 2018;16(2):170\u0026ndash;99.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSartor MA, Dolinoy DC, Jones TR, Colacino JA, Prince ME, Carey TE, Rozek LS. Genome-wide methylation and expression differences in HPV(+) and HPV(-) squamous cell carcinoma cell lines are consistent with divergent mechanisms of carcinogenesis. Epigenetics. 2011;6(6):777\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKojima A, Shimada M, Mikami Y, Nagao S, Takeshima N, Sugiyama T, Teramoto N, Kiyokawa T, Kigawa J, Nishimura R. Chemoresistance of Gastric-Type Mucinous Carcinoma of the Uterine Cervix: A Study of the Sankai Gynecology Study Group. Int J Gynecol Cancer. 2018;28(1):99\u0026ndash;106.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMathew Thomas V, Alexander SA, Hadfield MJ, Vredenburgh J. A Rare Case of Clear Cell Adenocarcinoma of the Cervix with No Intrauterine Diethylstilbestrol Exposure. Cureus. 2020;12(4):e7796.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePark KJ, Kiyokawa T, Soslow RA, Lamb CA, Oliva E, Zivanovic O, Juretzka MM, Pirog EC. Unusual endocervical adenocarcinomas: an immunohistochemical analysis with molecular detection of human papillomavirus. Am J Surg Pathol. 2011;35(5):633\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eStolnicu S, Barsan I, Hoang L, Patel P, Chiriboga L, Terinte C, Pesci A, Aviel-Ronen S, Kiyokawa T, Alvarado-Cabrero I, et al. Diagnostic Algorithmic Proposal Based on Comprehensive Immunohistochemical Evaluation of 297 Invasive Endocervical Adenocarcinomas. Am J Surg Pathol. 2018;42(8):989\u0026ndash;1000.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUeno S, Sudo T, Oka N, Wakahashi S, Yamaguchi S, Fujiwara K, Mikami Y, Nishimura R. Absence of human papillomavirus infection and activation of PI3K-AKT pathway in cervical clear cell carcinoma. Int J Gynecol cancer: official J Int Gynecol Cancer Soc. 2013;23(6):1084\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLu Z, Chen J. [Introduction of WHO classification of tumours of female reproductive organs, fourth edition]. Zhonghua bing li xue za zhi = Chin J Pathol. 2014;43(10):649\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAnsari-Lari MA, Staebler A, Zaino RJ, Shah KV, Ronnett BM. Distinction of endocervical and endometrial adenocarcinomas: immunohistochemical p16 expression correlated with human papillomavirus (HPV) DNA detection. Am J Surg Pathol. 2004;28(2):160\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTogami S, Sasajima Y, Kasamatsu T, Oda-Otomo R, Okada S, Ishikawa M, Ikeda S, Kato T, Tsuda H. Immunophenotype and human papillomavirus status of serous adenocarcinoma of the uterine cervix. Pathol Oncol research: POR. 2015;21(2):487\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKenny SL, McBride HA, Jamison J, McCluggage WG. Mesonephric adenocarcinomas of the uterine cervix and corpus: HPV-negative neoplasms that are commonly PAX8, CA125, and HMGA2 positive and that may be immunoreactive with TTF1 and hepatocyte nuclear factor 1-β. Am J Surg Pathol. 2012;36(6):799\u0026ndash;807.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHuang Z, Li F, Li Q. Expression profile of RNA binding protein in cervical cancer using bioinformatics approach. Cancer Cell Int. 2021;21(1):647.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi L, Guo Q, Lan G, Liu F, Wang W, Lv X. Construction of a four-mRNA prognostic signature with its ceRNA network in CESC. Sci Rep. 2022;12(1):10691.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Endocervical adenocarcinoma, Non-HPV-associated, clinicopathological features, Prognosis, HENMT1","lastPublishedDoi":"10.21203/rs.3.rs-6900353/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6900353/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eOwing to the rarity of non-HPV-associated adenocarcinoma, clinicopathological features and prognosis remain poorly understood. The aim of our study is to analyze clinicopathological features and prognosis of non-HPV-associated adenocarcinoma (NHPVA) in comparison with HPV-associated adenocarcinoma (HPVA) and to investigate the expression of HENMT1 in NHPVAs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e 336 patients with endocervical adenocarcinomas treated in Qilu Hospital of Shandong University from January 2010 to December 2020 was retrospectively reviewed. The cases were categorized into HPV-associated adenocarcinoma (HPVA) and NHPVA according to the International Endocervical Adenocarcinoma Criteria and Classification. Data on clinicopathological characteristics, treatment, and prognosis were retrospectively analyzed and compared between NHPVA and HPVA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eAmong all patients, 64 cases (19.05%) were NHPVAs. The mean age of patients in the NHPVA group was (47.97±11.27) years, which was marginally older than that of the HPVA group, although the difference was not statistically significant (\u003cem\u003ep\u003c/em\u003e=0.136). Abnormal vaginal bleeding or contact bleeding was presented in 71.88% of patients. Compared to the HPVA group, the NHPVA group exhibited higher neutrophil-to-lymphocyte ratio and elevated positive rates of CA125 and CA199 (\u003cem\u003ep\u003c/em\u003e\u0026lt;0.05). NHPVAs demonstrated a significant correlation with advanced FIGO stage (≥stage Ⅱ), larger tumor diameter (≥4 cm), poor differentiation, deep stromal invasion (≥1/2), lymph node metastasis (LNM), and ovarian or oviduct metastasis (\u003cem\u003ep\u003c/em\u003e\u0026lt;0.05). Poor differentiation is identified as an independent risk factor for LNM. NHPVAs exhibited significantly higher positive rate of P53(55.9%) and lower positive rate of P16(66.7%) and Ki-67≥50% (44.1%) compared to HPVAs. Furthermore, the 5-year overall survival(OS) and disease-free survival(DFS) rates for NHPVAs were worse (74.5% and 73.3%, respectively) compared to HPVAs (88.1% and 84.1%, respectively). lymph node metastasis (LNM) and age were significantly associated with OS and DFS in NHPVAs. Poor differentiation (\u003cem\u003ep\u003c/em\u003e=0.042) was an independent predictor of LNM. Additionally, NHPVAs showed increased low expression rate of HENMT1(\u003cem\u003ep\u003c/em\u003e=0.042) and NHPVA patients with low expression of HENMT1 had poorer OS (\u003cem\u003ep\u003c/em\u003e = 0.021) and DFS (\u003cem\u003ep\u003c/em\u003e = 0.020).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e NHPVAs differ from HPVAs in clinicopathological features and are associated with a poorer prognosis. HENMT1 might be a novel therapeutic target for NHPVAs.\u003c/p\u003e","manuscriptTitle":"Clinicopathological features and prognosis of non-HPV-associated adenocarcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-18 13:21:41","doi":"10.21203/rs.3.rs-6900353/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2025-07-19T15:38:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"10640960905564108567486299946828907702","date":"2025-07-14T12:12:04+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-14T11:56:34+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-06-18T09:53:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-17T06:37:25+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-17T06:36:32+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2025-06-15T22:55:19+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9d974432-5004-4f53-b944-842d64907c8c","owner":[],"postedDate":"July 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-07-18T13:21:42+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-18 13:21:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6900353","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6900353","identity":"rs-6900353","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}