Carcinogenesis and management of human papillomavirus-associated cervical cancer

Abstract

Approximately 95% of cervical cancer are caused by human papillomavirus (HPV) infection. Although it is estimated that HPV-associated cervical cancer will decrease with the widespread use of HPV vaccine, it may take time for HPV-associated cervical cancer to be eliminated. For the appropriate management of HPV-associated cervical cancer, it is important to understand the detailed mechanisms of cervical cancer development. First, the cellular origin of most cervical cancers is thought to be cells in the squamocolumnar junction (SCJ) of the uterine cervix. Therefore, it is important to understand the characteristics of SCJ for cervical cancer screening and treatment. Second, cervical cancer is caused by high risk HPV (HR-HPV) infection, however, the manner of progression to cervical cancer differs depending on the type of HR-HPV: HPV16 is characterized by a stepwise carcinogenesis, HPV18 is difficult to detect in precancerous lesions, and HPV52, 58 tends to remain in the state of cervical intraepithelial neoplasia (CIN). Third, in addition to the type of HPV, the involvement of the human immune response is also important in the progression and regression of cervical cancer. In this review, we demonstrate the carcinogenesis mechanism of HPV-associated cervical cancer, management of CIN, and the current treatment of CIN and cervical cancer.

Keywords: Cervical cancer; Human papillomavirus; Squamocolumnar junction.

Fig. 1

Carcinogenesis mechanism of cervical cancer. A Carcinogenesis mechanism of uterine squamous cell carcinoma and adenocarcinoma. Human papillomavirus (HPV) infects cells in the basal layer of the cervix and causes carcinogenesis over the years. Squamous cell carcinoma develops through a stepwise progression of its precancer lesions (cervical intraepithelial neoplasia, CIN). The steps to carcinogenesis include expression of HPV-derived oncogenes, E6/E7, HPV integration, and accumulation of human oncogene mutations. The figure was created with BioRender.com. B Changes in HPV genomic status. During persistent HPV infection, the integration of the HPV genome into the human genome occurs. HPV integration contributes to the sustained expression of HPV-derived E6/E7 as well as induces various genetic changes such as amplification of oncogenes, chromosomal rearrangements, and chromosomal instability around the HPV integration site

Fig. 2

Structure of the uterine cervix. The uterine cervix consists of three distinct types of epithelia. The boundary between the squamous and columnar epithelium is referred to as the squamocolumnar junction (SCJ). Reserve cells are located in the basal layer of the cervical SCJ. SCJ squamocolumnar junction, TZ transformation zone. The figure was created with BioRender.com

Fig. 3

The natural history of HPV-associated cervical lesions. A Bidirectional transition of cervical intraepithelial neoplasia (CIN). The natural history of CIN shows a bidirectional transition between different states (normal, CIN1, CIN2, and CIN3). B HPV-genotype-specific characteristics of cervical cancer development. HPV16-related lesion is characterized by stepwise progression to CIN3 or higher, whereas HPV52 and HPV58-related lesions are characterized by their persistency between CIN1 and CIN2. HPV18 is frequently detected in rate in cervical cancer, but its detection rate in precancerous lesions is low. HPV human papillomavirus, CIN cervical intraepithelial neoplasia

Fig. 4

Immune escape mechanisms of HPV-infected cells. TLR toll-like receptors, DC Dendritic cell, TAM tumor-associated macrophage, CTL cytotoxic T lymphocyte, Treg regulatory T cell, IFN interferon, IRF interferon regulatory factor, NKT natural killer T cell, IL-10 interleukin-10, TGF tumor growth factor, NFκB nuclear factor-kappa B, MIP macrophage inflammatory protein, HLA human leukocyte antigen, STAT1 signal transducer and activator of transcription 1. The figure was created with BioRender.com