Clinicopathological features and prognosis of non-HPV-associated adenocarcinoma

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.