Human papillomavirus as a target for cancer prevention

If we would know more about virus causing cancer, we would have the possibility to prevent the disease. Human Papillomavirus (HPV) causes cervical cancer and is one of the world’s most common sexually transmitted diseases (STD). Cervical cancer is a preventable disease, nevertheless, still each year around 550 women are diagnosed, and almost 200 women lose their life to this disease in Sweden.

This thesis aims to present: 1) an investigation on the cancer risk among immunosuppressed patients (I), 2) suggestions on how to, maintain a high-quality cervical cancer screening programme by annual clinical audits on HPV analysis (II), report quality indicators on cervical screening data (III), and use HPV genotype and viral load data to improve cervical cancer prediction in HPV primary screening (V), and 3) how to use registry linkages over the Nordic borders to miminize loss to follow-up (IV).

These population-based studies, and a follow-up study, utilized Nordic national and regional health-data and civil registries and a Belgium database to collect data on immunosuppressed patients, cancer outcomes, and cervical cancer screening and population data. We identified 43,912 immunosuppressed patients in Denmark and Sweden with 5,709 incident cancers (I). The overall standardized incidence ratio (SIR) varied between 1.6 in long-term dialysis patients in Denmark and 3.5 in the Swedish cohort of solid organ transplanted patients. The largest increase in SIR was observed in non-melanoma skin cancer in the Swedish cohort, 44.7 [n 994, 95% CI, 42–47.5].

Routine cytology has a method to estimate sensitivity to identify women diagnosed with cervical intraepithelial neoplasia grade 3 or worse. The HPV primary screening programme in Stockholm used similar method and estimated a sensitivity of 97 % (148/154 women) (II). Key quality indicators in the Swedish cervical screening programme in 2014-2016 presented a 69-70% population screening coverage and 96-97% of women who were followed-up with histology after abnormal cytology within 1 year (III).

In a Belgian case-control cohort, including 2,230 LBC samples with HPV genotypes and viral load analysis results, HPV 16 and 18 (>0 copies/μl) and HPV31/33/45/52 (3000 >copies/μl) could predict 87% of invasive cervical cancer within a year. By adding 8 HPV types only 9 additional cases were predicted during a 7 year-period. (V). A registry-based follow-up study an HPV-vaccination trial used registry searches over the Nordic borders, Denmark, Iceland, Norway, and Sweden to gain completeness.

In conclusion, we identified elevated cancer types in immunosuppressed patients that will need further investigations. We proposed strategies for quality assessment of HPV-analysis and cervical cancer screening, and how viral load and HPV-genotyping can improve prediction cervical cancer in a primary HPV screening.

List of scientific papers

I. HORTLUND M, Arroyo Mühr LS, Storm H, Engholm G, Dillner J, Bzhalava D. Cancer risks after solid organ transplantation and after long-term dialysis. Int J Cancer. 2017 Mar 1;140(5):1091-1101.
https://doi.org/10.1002/ijc.30531

II. HORTLUND M, Sundström K, Lamin H, Hjerpe A, Dillner J. Laboratory audit as part of the quality assessment of a primary HPV-screening program. J Clin Virol. 2016 Feb;75:33-6.
https://doi.org/10.1016/j.jcv.2015.12.007

III. HORTLUND M, Elfström KM, Sparén P, Almstedt P, Strander B, Dillner J. Cervical cancer screening in Sweden 2014-2016. PLoS One. 2018 Dec 17;13(12):e0209003.
https://doi.org/10.1371/journal.pone.0209003

IV. HORTLUND M, Nygard M, Sundström K, Trygvadottir L, Nordqvist Kleppe S, Berger S, Sigurdardottir L, Munk C, Enerly E, Saah A, Kjaer S. Dillner J. Multi-country registry-based follow-up of migrating subjects in a Human Papillomavirus vaccination trial. [Manuscript]

V. HORTLUND M, van Mol T, Van de Pol F, Bogers J, Dillner J. Human papillomavirus load and genotype analysis improves the prediction of invasive cervical cancer. Int J Cancer. 2021 Feb 14.
https://doi.org/10.1002/ijc.33519