Lower incidence of vaginal cancer after cervical human papillomavirus screening - long-term follow-up of Finnish randomized screening trial.

OBJECTIVE: Around 70% of vaginal cancers and 40-50% of vulvar cancers are attributable to human papillomavirus (HPV). Globally the burden of these diseases is estimated to grow due to the increasing HPV prevalence and rapidly aging global population. We aimed to examine if HPV screening for cervical cancer has an additional beneficial effect in preventing vaginal and vulvar cancers. To assess this, we used long-term follow-up data from the Finnish randomized HPV screening trial. METHODS: Between 2003 and 2008, over 236,000 women were individually randomized (1:1) to primary HPV or cytology screening in Southern Finland. We followed this cohort up to the year 2020. To compare the study arms, we calculated site-specific and pooled incidence rate ratios (IRRs) and mortality rate ratios (MRRs) for vaginal and vulvar cancers using Poisson regression. RESULTS: During 3,5 million person-years of follow-up, the IRR for vaginal cancer in the HPV arm compared to the cytology arm was 0.40 (95% CI 0.17-0.88) and the corresponding MRR was 0.74 (95% 0.21-2.24). The corresponding IRR for vulvar cancer was 0.73 (95% 0.50-1.08) and the MRR was 0.64 (95% 0.23-1.62). The pooled IRR was 0.67 (95% 0.47 ̶ 0.95) and MRR 0.67 (95% 0.31 ̶ 1.37). CONCLUSION: We found lower incidence of vaginal cancers with HPV screening compared to cytology screening. To validate our results, we recommend analyzing data on vaginal and vulvar cancers also from other HPV screening studies.

Similar effectiveness with primary HPV and cytology screening - Long-term follow-up of randomized cervical cancer screening trial.

BACKGROUND: Long-term effects of primary human papillomavirus (HPV) screening on cervical cancer incidence and mortality are still missing. We conducted a long-term follow-up of the Finnish randomized HPV screening trial, the first HPV screening trial run within the routine screening program, to assess these measures. METHODS: During 2003-2008, over 236,000 individuals were randomized (1:1) to HPV and cytology screening arms in Southern Finland. To compare the study arms, we calculated the cervical cancer incidence and mortality rate ratios using Poisson regression. RESULTS: During a total of 3.5 million person-years of follow-up, we observed 129 cervical cancers and 32 cervical cancer deaths in the cytology arm, 139 cervical cancers and 32 cervical cancer deaths in the HPV arm. Compared to the cytology arm, in the HPV arm, the incidence rate ratio was 1.08 (95% CI 0.85-1.37), and the mortality rate ratio was 1.01 (95% CI 0.61-1.64). CONCLUSIONS: We studied the effects of HPV screening on both cervical cancer incidence and mortality for the first time in a setting with an already well-established, high-quality cytology screening program. In this kind of setting with a low incidence of cervical cancer, HPV and cytology screening showed similar effectiveness. HPV screening provides, however, an objective, validated test system and enables self-sampling which can improve screening coverage. More attention is needed yet to ensure the balance between the harms and benefits of HPV screening.

Alternative cytology triage strategies for primary HPV screening.

OBJECTIVE: Primary HPV screening programmes for cervical cancer have been implemented in many European countries using a cytology triage. Nonetheless, the optimal cytology triage strategy for minimizing the harms and maximizing the benefits is yet unclear. We identified key characteristics of different algorithms for HPV screening with cytology triage. METHODS: Using the Finnish randomized HPV screening trial data, we formulated five post-hoc algorithms for HPV screening with a cytology triage, one for HPV screening without a triage and one for cytology screening. Sensitivity, specificity, positive predictive value, colposcopy referral rate and cumulative sensitivity for CIN II + s detected during the first and second screening rounds of the trial were calculated for all algorithms. RESULTS: In the first screening round, direct referral of HPV positives to colposcopy led to the highest sensitivity (94%) accompanied by the lowest specificity (93%). Following HPV positives up with one repeat screen showed 86% sensitivity and 97% specificity. The corresponding figures with two repeat screens were 84% and 98%. In HPV algorithms, where cytology negative HPV positive individuals had no follow-up, the sensitivities were 65-82% and the specificities 98-99%. The Cytology algorithm had a low sensitivity (69%) with a high specificity (99%). Compared to the first round, the second-round sensitivities were lower and specificities similar or higher. CONCLUSIONS: The best balance between sensitivity and specificity was achieved by an HPV algorithm with two repeated follow-up tests. However, all HPV algorithms with cytology triage increased colposcopy volume more than the cytology algorithm and thus provoked overdiagnosis.

Loss of ATRX/DAXX expression and alternative lengthening of telomeres in uterine leiomyomas.

BACKGROUND: Uterine leiomyomas (ULs) are the most common gynecologic tumors and affect 3 of every 4 women by the age of 50 years. The majority of ULs are classified as conventional tumors, whereas 10% represent various histopathological subtypes with features that mimic malignancy. These subtypes include cellular and mitotically active ULs and ULs with bizarre nuclei. Uterine leiomyosarcoma (ULMS), the malignant counterpart of UL, is an aggressive cancer with poor overall survival. The early diagnosis and preoperative differentiation of ULMS from UL are often challenging because their symptoms and morphology resemble one another. Recent studies have shown frequent loss of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated protein (DAXX) expression in ULMS, and this is often associated with an alternative lengthening of telomeres (ALT) phenotype. METHODS: To investigate ATRX and DAXX expression and the presence of ALT in UL subtypes, immunohistochemical and telomere-specific fluorescence in situ hybridization analyses were performed. The study material consisted of 142 formalin-fixed, paraffin-embedded tissue samples representing various UL subtypes and 64 conventional ULs. RESULTS: A loss of ATRX or DAXX and/or ALT was detected in 6.3% of the histopathological UL subtype samples (9 of 142). Two patients whose ULs showed either ATRX loss or ALT were later diagnosed with a pulmonary smooth muscle tumor. Pulmonary tumors displayed molecular alterations found in the corresponding uterine tumors, which indicated metastasis to the lungs. All conventional ULs displayed normal ATRX, DAXX, and telomeres. CONCLUSIONS: These results highlight the differences between conventional and histopathologically atypical ULs and indicate that some UL subtype tumors may harbor long-term malignant potential.