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International Journal of Clinical Oncology
Published in: International Journal of Clinical Oncology 8/2023

Open Access 09-06-2023 | Human Papillomavirus | Invited Review Article

Carcinogenesis and management of human papillomavirus-associated cervical cancer

Authors: Misako Kusakabe, Ayumi Taguchi, Kenbun Sone, Mayuyo Mori, Yutaka Osuga

Published in: International Journal of Clinical Oncology | Issue 8/2023

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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.
Literature
1.
Sung H, Ferlay J, Siegel RL et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249CrossRefPubMed
2.
3.
Nagase S, Ohta T, Takahashi F et al (2022) Annual report of the committee on gynecologic oncology, the Japan society of obstetrics and gynecology: annual patient report for 2018 and annual treatment report for 2013. J Obstet Gynaecol Res 48:541–552PubMed
4.
Stolnicu S, Hoang L, Soslow RA (2019) Recent advances in invasive adenocarcinoma of the cervix. Virchows Arch 475:537–549PubMedPubMedCentral
5.
Cancer Genome Atlas Research Network, Albert Einstein College of Medicine Analytical Biological Services et al. (2017) Integrated genomic and molecular characterization of cervical cancer. Nature 543:378–384
6.
Wang Q, Hu Y, He Y et al (2020) Glassy cell carcinoma of cervix: an analysis for 20 cases and literatures review. Transl Cancer Res 9:2357–2362PubMedPubMedCentral
7.
Schultheis AM, de Bruijn I, Selenica P et al (2022) Genomic characterization of small cell carcinomas of the uterine cervix. Mol Oncol 16:833–845PubMed
8.
Lei J, Ploner A, Elfström KM et al (2020) HPV vaccination and the risk of invasive cervical cancer. N Engl J Med 383:1340–1348PubMed
9.
Hall MT, Simms KT, Lew JB et al (2019) The projected timeframe until cervical cancer elimination in Australia: a modelling study. Lancet Public Health 4:e19–e27PubMed
10.
Ueda Y, Yagi A, Ikeda S et al (2018) Beyond resumption of the Japanese government’s recommendation of the HPV vaccine. Lancet Oncol 19:1563–1564PubMed
11.
Suzuki S, Hosono A (2018) No association between HPV vaccine and reported post-vaccination symptoms in Japanese young women: results of the Nagoya study. Papillomavirus Res 5:96–103PubMedPubMedCentral
12.
13.
14.
Clavel C, Masure M, Bory JP et al (2001) Human papillomavirus testing in primary screening for the detection of high-grade cervical lesions: a study of 7932 women. Br J Cancer 84:1616–1623PubMedPubMedCentral
15.
Mayrand MH, Duarte-Franco E, Rodrigues I et al (2007) Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med 357:1579–1588PubMed
16.
Saslow D, Solomon D, Lawson HW et al (2012) American cancer society, American society for colposcopy and cervical pathology, and American society for clinical pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin 62:147–172PubMedPubMedCentral
17.
Fontham ETH, Wolf AMD, Church TR et al (2020) Cervical cancer screening for individuals at average risk: 2020 guideline update from the American Cancer Society. CA Cancer J Clin 70:321–34621PubMed
18.
19.
20.
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (2012) Biological agents. IARC Monogr Eval Carcinog Risks Hum 100b:1–441
21.
Azuma Y, Kusumoto-Matsuo R, Takeuchi F et al (2014) Human papillomavirus genotype distribution in cervical intraepithelial neoplasia grade 2/3 and invasive cervical cancer in Japanese women. Jpn J Clin Oncol 44:910–917PubMed
22.
Narisawa-Saito M, Kiyono T (2007) Basic mechanisms of high-risk human papillomavirus-induced carcinogenesis: roles of E6 and E7 proteins. Cancer Sci 98:1505–1511PubMed
23.
Hu Z, Zhu D, Wang W et al (2015) Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism. Nat Genet 47:158–163PubMed
24.
Ojesina AI, Lichtenstein L, Freeman SS et al (2014) Landscape of genomic alterations in cervical carcinomas. Nature 506:371–375PubMed
25.
Delvenne P, Herman L, Kholod N et al (2007) Role of hormone cofactors in the human papillomavirus-induced carcinogenesis of the uterine cervix. Mol Cell Endocrinol 264:1–5PubMed
26.
López J, Ruíz G, Organista-Nava J et al (2012) Human papillomavirus infections and cancer stem cells of tumors from the uterine cervix. Open Virol J 6:232–240PubMedPubMedCentral
27.
Manga SM, Kincaid KD, Boitano TKL et al (2022) Misoprostol and estradiol to enhance visualization of the transformation zone during cervical cancer screening: an integrative review. Eur J Obstet Gynecol Reprod Biol 269:16–23PubMed
28.
Herfs M, Yamamoto Y, Laury A et al (2012) A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer. Proc Natl Acad Sci U S A 109:10516–10521PubMedPubMedCentral
29.
Ren H, Jia M, Zhao S et al (2022) Factors correlated with the accuracy of colposcopy-directed biopsy: a systematic review and meta-analysis. J Invest Surg 35:284–292PubMed
30.
WHO Classification of Tumours Editorial Board (2020) Female genital tumours, 4, 5th ed.. World Health Organization classification of tumours
31.
32.
Ho GY, Bierman R, Beardsley L et al (1998) Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 338:423–428PubMed
33.
Matsumoto K, Oki A, Furuta R et al (2011) Predicting the progression of cervical precursor lesions by human papillomavirus genotyping: a prospective cohort study. Int J Cancer 128:2898–2910PubMed
34.
Loopik DL, Bentley HA, Eijgenraam MN et al (2021) The natural history of cervical intraepithelial neoplasia Grades 1, 2, and 3: A systematic review and meta-analysis. J Low Genit Tract Dis 25:221–231PubMed
35.
Taguchi A, Hara K, Tomio J et al (2020) Multistate markov model to predict the prognosis of high-risk human papillomavirus-related cervical lesions. Cancers (Basel) 12(2):270PubMed
36.
Ikesu R, Taguchi A, Hara K et al (2022) Prognosis of high-risk human papillomavirus-related cervical lesions: A hidden Markov model analysis of a single-center cohort in Japan. Cancer Med 11:664–675PubMed
37.
Bulk S, Berkhof J, Rozendaal L et al (2007) The contribution of HPV18 to cervical cancer is underestimated using high-grade CIN as a measure of screening efficiency. Br J Cancer 96:1234–1236PubMedPubMedCentral
38.
Woodman CB, Collins SI, Young LS (2007) The natural history of cervical HPV infection: unresolved issues. Nat Rev Cancer 7:11–22PubMed
39.
Stoler MH, Mills SE, Gersell DJ et al (1991) Small-cell neuroendocrine carcinoma of the cervix. A human papillomavirus type 18-associated cancer. Am J Surg Pathol 15:28–32PubMed
40.
Kusakabe M, Taguchi A, Tanikawa M et al (2023) Cells with stem-like properties are associated with the development of HPV18-positive cervical cancer. Cancer Sci 114:885–895PubMed
41.
Hasan UA, Zannetti C, Parroche P et al (2013) The human papillomavirus type 16 E7 oncoprotein induces a transcriptional repressor complex on the toll-like receptor 9 promoter. J Exp Med 210:1369–1387PubMedPubMedCentral
42.
Richards KH, Wasson CW, Watherston O et al (2015) The human papillomavirus (HPV) E7 protein antagonises an imiquimod-induced inflammatory pathway in primary human keratinocytes. Sci Rep 5:12922PubMedPubMedCentral
43.
Morgan EL, Macdonald A (2020) Manipulation of JAK/STAT signalling by high-risk HPVs: potential therapeutic targets for HPV-associated malignancies. Viruses 12(9):977PubMedPubMedCentral
44.
Park JS, Kim EJ, Kwon HJ et al (2000) Inactivation of interferon regulatory factor-1 tumor suppressor protein by HPV E7 oncoprotein. Implication for the E7-mediated immune evasion mechanism in cervical carcinogenesis. J Biol Chem 275:6764–6769PubMed
45.
Ronco LV, Karpova AY, Vidal M et al (1998) Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity. Genes Dev 12:2061–2072PubMedPubMedCentral
46.
Campo MS, Graham SV, Cortese MS et al (2010) HPV-16 E5 down-regulates expression of surface HLA class I and reduces recognition by CD8 T cells. Virology 407:137–142PubMed
47.
Cortese MS, Ashrafi GH, Campo MS (2010) All 4 di-leucine motifs in the first hydrophobic domain of the E5 oncoprotein of human papillomavirus type 16 are essential for surface MHC class I downregulation activity and E5 endomembrane localization. Int J Cancer 126:1675–1682PubMed
48.
Li W, Deng XM, Wang CX et al (2010) Down-regulation of HLA class I antigen in human papillomavirus type 16 E7 expressing HaCaT cells: correlate with TAP-1 expression. Int J Gynecol Cancer 20:227–232PubMed
49.
Guess JC, McCance DJ (2005) Decreased migration of Langerhans precursor-like cells in response to human keratinocytes expressing human papillomavirus type 16 E6/E7 is related to reduced macrophage inflammatory protein-3alpha production. J Virol 79:14852–14862PubMedPubMedCentral
50.
Iijima N, Goodwin EC, Dimaio D et al (2013) High-risk human papillomavirus E6 inhibits monocyte differentiation to Langerhans cells. Virology 444:257–262PubMed
51.
Jimenez-Flores R, Mendez-Cruz R, Ojeda-Ortiz J et al (2006) High-risk human papilloma virus infection decreases the frequency of dendritic Langerhans’ cells in the human female genital tract. Immunology 117:220–228PubMedPubMedCentral
52.
Jiang B, Xue M (2015) Correlation of E6 and E7 levels in high-risk HPV16 type cervical lesions with CCL20 and Langerhans cells. Genet Mol Res 14:10473–10481PubMed
53.
Miura S, Kawana K, Schust DJ et al (2010) CD1d, a sentinel molecule bridging innate and adaptive immunity, is downregulated by the human papillomavirus (HPV) E5 protein: a possible mechanism for immune evasion by HPV. J Virol 84:11614–11623PubMedPubMedCentral
54.
Matsumoto K, Maeda H, Oki A et al (2012) HLA class II DRB1*1302 allele protects against progression to cervical intraepithelial neoplasia grade 3: a multicenter prospective cohort study. Int J Gynecol Cancer 22:471–478PubMed
55.
Paaso A, Jaakola A, Syrjänen S et al (2019) From HPV infection to lesion progression: the role of HLA alleles and host immunity. Acta Cytol 63:148–158PubMed
56.
Chan PK, Cheung JL, Cheung TH et al (2006) HLA-B alleles, high-risk HPV infection and risk for cervical neoplasia in southern Chinese women. Int J Cancer 118:1430–1435PubMed
57.
58.
Kojima S, Kawana K, Tomio K et al (2013) The prevalence of cervical regulatory T cells in HPV-related cervical intraepithelial neoplasia (CIN) correlates inversely with spontaneous regression of CIN. Am J Reprod Immunol 69:134–141PubMed
59.
Molling JW, de Gruijl TD, Glim J et al (2007) CD4(+)CD25hi regulatory T-cell frequency correlates with persistence of human papillomavirus type 16 and T helper cell responses in patients with cervical intraepithelial neoplasia. Int J Cancer 121:1749–1755PubMed
60.
Kawachi A, Yoshida H, Kitano S et al (2018) Tumor-associated CD204+ M2 macrophages are unfavorable prognostic indicators in uterine cervical adenocarcinoma. Cancer Sci 109:863–870PubMedPubMedCentral
61.
Chen XJ, Han LF, Wu XG et al (2017) Clinical significance of CD163+ and CD68+ tumor-associated macrophages in high-risk HPV-related cervical cancer. J Cancer 8:3868–3875PubMedPubMedCentral
62.
Tewari KS, Sill MW, Penson RT et al (2017) Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (gynecologic oncology group 240). Lancet 390:1654–1663PubMedPubMedCentral
63.
Colombo N, Dubot C, Lorusso D et al (2021) Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med 385:1856–1867PubMed
64.
Sunami K, Ichikawa H, Kubo T et al (2019) Feasibility and utility of a panel testing for 114 cancer-associated genes in a clinical setting: a hospital-based study. Cancer Sci 110:1480–1490PubMedPubMedCentral
65.
Zehir A, Benayed R, Shah RH et al (2017) Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med 23:703–713PubMedPubMedCentral
66.
Trimble CL, Morrow MP, Kraynyak KA et al (2015) Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial. Lancet 386:2078–2088PubMedPubMedCentral
67.
Hillemanns P, Denecke A, Woelber L et al (2022) A therapeutic antigen-presenting cell-targeting DNA vaccine VB10.16 in HPV16-positive high-grade cervical intraepithelial neoplasia: Results from a phase I/IIa trial. Clin Cancer Res 28:4885–4892PubMed
68.
Ikeda Y, Adachi K, Tomio K et al (2021) A placebo-controlled, double-blind randomized (phase IIB) trial of oral administration with HPV16 E7-expressing Lactobacillus, GLBL101c, for the treatment of cervical intraepithelial neoplasia Grade 2 (CIN2). Vaccines (Basel) 9:329PubMed
69.
Domingos-Pereira S, Galliverti G, Hanahan D et al (2019) Carboplatin/paclitaxel, E7-vaccination and intravaginal CpG as tri-therapy towards efficient regression of genital HPV16 tumors. J Immunother Cancer 7:122PubMedPubMedCentral
70.
Nagarsheth NB, Norberg SM, Sinkoe AL et al (2021) TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers. Nat Med 27:419–425PubMedPubMedCentral
71.
Stevanović S, Draper LM, Langhan MM et al (2015) Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J Clin Oncol 33:1543–1550PubMedPubMedCentral
72.
Coleman RL, Lorusso D, Gennigens C et al (2021) Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol 22:609–619PubMed
Metadata
Title
Carcinogenesis and management of human papillomavirus-associated cervical cancer
Authors
Misako Kusakabe
Ayumi Taguchi
Kenbun Sone
Mayuyo Mori
Yutaka Osuga
Publication date
09-06-2023
Publisher
Springer Nature Singapore
Published in
International Journal of Clinical Oncology / Issue 8/2023
Print ISSN: 1341-9625
Electronic ISSN: 1437-7772
DOI
https://doi.org/10.1007/s10147-023-02337-7

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