Long-Term Survival Outcomes of HPV DNA–Negative Cervical Cancer Compared with HPV DNA–Positive Disease in a Thai Tertiary Cohort

Thidarat Phisalmonhkhon,1 Nuttavut Kantathavorn,1,2 Thanita Wetcho,1 Jidapa Samrarn,1 Ruai Kittikhun,1 Hathaipat Sukjariangporn,1 Man Thongaram1 1Department of Obstetrics and Gynecology, Chulabhorn Hospital, Chulabhorn Royal Academy, Bangkok, Thailand; 2Princess Srisavangavadhana Faculty of Medicine, Chulabhorn Royal Academy, Bangkok, ThailandCorrespondence: Nuttavut Kantathavorn, Princess Srisavangavadhana Faculty of Medicine, Chulabhorn Royal Academy, Bangkok, Thailand, Tel +66-2-576-6000, Email [email protected]: To evaluate 5-year progression-free survival (PFS) among patients with human papillomavirus (HPV) DNA–negative cervical cancer treated at a tertiary referral center in Thailand, and to compare survival outcomes with HPV DNA–positive patients.Methods: This retrospective cohort study included Thai women diagnosed with cervical cancer between 2012 and 2014 at Chulabhorn Hospital, Bangkok. HPV genotyping was performed using an HPV DNA genotyping test (Linear Array, Roche Molecular Systems). HPV status was determined solely by HPV DNA testing without p16 immunohistochemical confirmation. After excluding 14 patients with incomplete data, 150 women were analyzed. Patients were classified as HPV DNA–positive or HPV DNA–negative based on genotyping results. The primary outcome was 5-year PFS. Secondary outcomes included overall survival (OS) and prevalence of HPV DNA–negative disease. Survival outcomes were evaluated using Kaplan–Meier analysis and Cox proportional hazards regression.Results: Among 150 patients (mean age 54.2 years), 139 (92.7%) were HPV DNA–positive and 11 (7.3%) HPV DNA–negative. HPV DNA–negative tumors were more frequently associated with adenosquamous histology and earlier-stage disease, while HPV DNA–positive cases were more often diagnosed at stages II–III. Groups also differed significantly in primary treatment modality, with higher rates of surgery in HPV DNA–negative patients and chemoradiotherapy in HPV DNA–positive patients. During a median follow-up of 9.8 years, 54 patients experienced recurrence, metastasis, or death within 5 years. The overall 5-year PFS rate was 62.2%. Five-year PFS was 62.0% in HPV DNA–positive patients and 70.0% in HPV DNA–negative patients (HR 1.06; 95% CI 0.38– 2.93; p=0.916). Corresponding 5-year OS rates were 66.7% and 63.6%, respectively (HR 0.93; 95% CI 0.33– 2.58; p=0.885). These results should be interpreted cautiously given the small HPV DNA–negative subgroup and resulting wide confidence intervals.Conclusion: In this exploratory analysis, HPV DNA–negative cervical cancer patients did not demonstrate significantly different survival outcomes compared with HPV DNA–positive patients; however, these findings should be interpreted with caution given the small HPV DNA–negative sample size (n=11) and resulting limited statistical power. The absence of p16 immunohistochemistry precludes definitive WHO-based classification. Larger prospective multicenter studies incorporating both HPV DNA testing and p16 immunohistochemistry are required to clarify prognostic implications.Plain Language Summary: In this Thai cervical cancer cohort, 7.3% of tumors were HPV DNA–negative. These cases were more frequently associated with adenosquamous histology and earlier-stage disease at diagnosis. Five-year progression-free and overall survival did not differ significantly between HPV DNA–negative and HPV DNA–positive groups. However, these findings should be interpreted with caution given the small number of HPV DNA–negative cases (n=11), which substantially limits statistical power. Furthermore, HPV status was determined solely by HPV DNA testing without p16 immunohistochemical confirmation; therefore, true WHO-defined HPV-independent classification cannot be confirmed. Larger prospective studies with standardized molecular classification are needed.Keywords: cervical cancer, HPV DNA–negative, HPV DNA–positive, progression-free survival, overall survival, Thailand