Clinicopathological Characteristics and Prognostic Factors for Cervical Adenocarcinoma: A Population-Based Study

Objective: We aimed to assess the clinicopathological features and determine prognostic factors of cervical adenocarcinoma (AC). Methods: Relevant data were extracted from Surveillance, Epidemiology and End Results (SEER) database from 2004 to 2015. The log-rank test and Cox proportional hazard analysis were utilized to identify independent prognostic factors Results: A total of 3102 patients were identied. The higher proportion of patients with early FIGO stage (stage I: 69.4%; stage II: 14.1%), low pathological grade (grade I/II: 49.1%) and tumor size ≤ 4cm (46.8%). The 5- and 10-year CSS rates were 74.47% and 70.00%. Meanwhile, the 5- and 10-year OS rates were 71.52% and 65.17%. Multivariate analysis found that married, surgery as well as chemotherapy were independent favorable prognostic indicators. Additionally, aged (cid:0) 45, grade III/IV, tumor size (cid:0) 4cm, advanced FIGO stage, pelvic lymph node metastasis (LNM) were unfavorable prognostic factors (all P<0.001). Stratied analysis found that patients without surgery could benet signicantly from chemotherapy and radiotherapy. In addition, chemotherapy could signicantly improved survival in stage II-IV patients and radiothrapy only improved stage III patients (all P < 0.01). Conclusion: Marital status, age, grade, tumor size, FIGO stage, pelvic LNM, surgery and chemotherapy were signicantly associated with prognosis of cervical AC.


Introduction
Uterine cervix carcinoma is a threatening cause of cancer-related death in females, which is reported to have approximately 311,000 death cases and 570,000 new cases in 2018 1 . Approximately 10-25% of cervical cancer is adenocarcinoma (AC), and squamous cell carcinoma (SCC) is the most prevalent histological classi cation 2,3 .
Additionally, the prevalence of cervical AC has been reported to increase in multiple regions 4 , the proportion of which has been demonstrated to double in the last ten years 5 . However, knowledge of cervical AC is currently limited to small case series, with unclear clinicopathological features and standard treatment 6,7 .
The standard therapeutic regimen of cervical AC is currently the same standard as SCC, which includes radical hysterectomy along with adjuvant radiotherapy (RT), radical hysterectomy or primary RT for early-stage cancer. In addition, concurrent chemoradiotherapy (CCRT) is prevalently recommended and promoted for locally advanced cancer as well as early-stage FIGO lesions 8 , which gives rise to equivalent outcomes. Nevertheless, cervical cancer in both cervical SCC and AC patients even with the same FIGO stage still have disparate prognostic outcomes 4,9,10 .
At present, whether the standard therapeutic regimen is equally suitable for SCC and AC patients has been questioned due to poorer prognostic outcomes of AC patients than SCC 4,10 . Therefore, it is signi cant to examine the prognostic indicators forAC, aiming at establishing a framework for new therapeutic strategies.
The NCI-supported Surveillance, Epidemiology and End Results (SEER) database, the most authoritative and largest cancer dataset in North America 11 , reports tumor data on approximately 30% of the US population by selecting relevant registries to represent population diversity 12 . As such, SEER is a valuable database to study such rare tumors 13,14 . Therefore, a retrospective study was conducted by collecting eligible patients from SEER database, aiming at summarizing clinical features, survival and treatment for patients with cervical AC to delineate prognostic factors.

Ethics statement
To acquire relevant data from the database, we signed the SEER Research Data Agreement (No.19817-Nov2018) and further searched for data based on the approved guidelines. All extracted data were publicly accessible and deidenti ed, and data analysis was considered to be non-human subjects by O ce for Human Research Protection.
Thus, no approval was requested by institutional review board.
Study population SEER*State v8.3.6 (released on August 8, 2019) was utilized for selecting and identifying quali ed subjects, which includes 18 SEER regions from 1998 to 2015 (2018 submission). The inclusion criteria were as follows: (1) primary cervical AC patients; (2) the diagnosis of cervical AC was based on ICD-O-3; coded as 8140-8490 15,16 .Patients were eliminated if they had: (1) more than one malignancies; (2)reported diagnosis source from autopsy or death certi cate or without pathological diagnosis; (3)without certain necessary clinicopathological data, including surgical style as well as FIGO stage; (4) without prognostic information. The rest of subjects were enrolled as the initial cohort of SEER.
The endpoint of our research included overall survival (OS) and cancer-speci c survival (CSS).The former was de ned as the duration from diagnosis to all-cause death, and the latter was referred to the duration from diagnosis to cervical AC-caused death.

Statistical analyses
Kaplan-Meier (K-M) method was employed to estimate the univariate analysis, followed by log-rank test for assessing the differences of CSS and OS in different FIGO stages. If variables had P values ≤ 0.1 in univariate analysis, they were incorporated into multivariate Cox proportional hazard analysis. In addition, strati ed analysis was performed by using Cox regression analysis. SPSS software (SPSS Inc., Chicago, USA, version 19.0) was utilized for statistical analysis, and GraphPad Prism 5 was utilized for plotting survival curves. A two-sided P < 0.05 was considered as statistically signi cant.

Patients' Characteristics
A total of 3102 cervical AC patients were identi ed, including 2153(69.4%)patients with stage I, 437 (14.1%) patients with stage II, 401 (12.9%) patients with stage III as well as 111 (3.6%) patients with stage IV. The detailed screening process was shown in Fig. 1. Patient features and therapy regimens were listed in Table 1. To be speci c, the median age was 45 years (range: 6-98 years). Among them, 11 cases (0.4%) were ≤ 18 years old, 1618 (52.20%) were ≤ 45 years old, and 422 cases (13.6%) were ≥ 65 years old.Most of cervical AC cases were low pathological grade (grade I/II: 49.1%), tumor size ≤ 4 cm (46.8%) and treated by surgery (69.4%).More patients received ≥ 4 pelvic LN dissection(47.6%) and 12.6% of them had positive pelvic LN.  Strati ed analysis of the effect of chemotherapy and radiotherapy on survival In order to explore the bene ts of chemotherapy and radiotherapy, we conducted strati ed analysis of patients with different FIGO stage and surgical style. As a result, patients with stage III/IV could signi cant bene t from chemotherapy (both CSS and OS), and stage II patients could bene t in terms of OS. Meanwhile, patients without surgery could also bene t signi cantly from chemotherapy and radiotherapy. In addition, only patients with stage III could bene t signi cantly from radiotherapy (Table 3 and Table 4).

Discussion
This population-based research revealed the clinicopathological features as well as survival of patients with cervical AC.Cervical AC constitutes only approximately 20%-25% of all cervical carcinomas 2,3 . AC is the second most common primary cervical cancer, secondly only to SCC 22 .Previous studies predominantly enrolling patients with SCC have provided most of our knowledge about the treatment of cervical cancer 23,24 . However, the different outcomes for AC have been rarely reported. Furthermore, prospective studies have not focused on the treatment of AC as the only histology. Consequently, our understanding of the natural history, prognosis factors and optimal management of cervical AC is limited 25 . For this purpose, by including a total of 3102 cervical AC patients, we aimed atdescribing the clinicopathological features and treatment, as well as examining prognostic indicators for cervical AC.
Depth of cervical invasion, tumor size, FIGO stage, nodal status 26,27 , tumor grade and patient age 28,29 were the most widely studied clinicopathological parameters for cervical AC. Although these studies are most based on small sample, single center retrospective studies, the results are basically consistent with ours. In addition, we also found that marital status is an independent prognostic factor for cervical AC.  30 . Our study also found that surgery is an independent favorable prognostic factor.
Radiotherapy is an alternative option for patients not t for surgery or who refuse surgery. For patients with stage IB2-IVA cervical cancer, concurrent cisplatin based-chemoradiotherapy plus brachytherapy is the standard therapeutic regimen 7 . Our study found that for patients without surgery, radiotherapy and chemotherapy can bring signi cant survival bene ts. However, in terms of tumor stage, only patients with stage III can gain signi cant survival bene ts from radiotherapy.The worse e cacy of cervical AC is possibly caused by insensitivity of radiotherapy. Cervical AC patients have been reported to have poorer complete response (CR) as well as local control rates, therefore requiring longer time to obtain CR than SCC populations following CCRT or de nitive radiotherapy 23,31,32 . Similarly, local failure is also more common in cervical AC patients. In addition, Hu revealed higher probability of distant failure in AC patients 10 . In consideration of poor outcomes of patients with cervical AC, more effective protocols are required for these patients.Adjuvant chemotherapy or neoadjuvant is a possible strategy. According to a Chinese clinical trial, 880 patients with FIGO stage IIB-IVA cervical AC were randomly assigned to receive only CCRT or CCRT with one cycle of neoadjuvant chemotherapy and two cycles of consolidation chemotherapy. Subsequently, patients treated by CCRT along with chemotherapy had better OS, DFS and local control after a median follow-up of 60 months. The above outcomes implicate that combined CCRT and chemotherapy is promising to enhance the survival of patients with cervical AC 33 .
The NCI-supported SEER database is the most authoritative and largest source for tumor incidence and survival. The large-scale, publicly available SEER dataset can be reliably used to guide anti-cervical AC therapy.As far as we know, our research includes the largest subjects to investigate prognostic parameters for cervical AC in the past ten years. Inevitably, there are also several limitations in our study. Firstly, selection bias and the effects of inaccessible variables from the SEER dataset are unavoidable due to the nonrandomized nature of our research 13,34 ; Secondly, information on human papilloma virus 18 subtype 7,35 were inaccessible from SEER database, which are considered as valuable indicators for survival of cervical cancer. Thirdly, SEER fails to provide all data to completely address our hypothesis, such as detailed information on chemotherapy and radiotherapy. Nevertheless, the currently accessible information from SEER database could t our objectives. While the above-mentioned issues should be further investigated.

Conclusions
Marital status, age, grade, tumor size, FIGO stage, pelvic LNM, surgery and chemotherapy were signi cantly associated with prognosis of cervical AC. Patients without surgery could signi cantly bene t from chemotherapy and radiotherapy.Stage II-IV patients could signi cant bene t from chemotherapy. In addition, only stage III patients could get signi cant survival bene t from radiotherapy. This is the largest series to discuss clinicopathological characteristics and outcomes for patients with cervical AC, and these results are vital to disease management and future prospective studies for this rare cancer.

Funding
No funding.  Figure 1 Flow chart of patient screening process.