Issues
Diagnostic capabilities of molecular genetic parameters of HPV-infection in treatment choice of radical radiotherapy programs for early-stage cervical cancer
«Radiation and Risk», 2025, vol. 34, No. 2, pp.94-108
DOI: 10.21870/0131-3878-2025-34-2-94-108
Authors
Boyko B.V. – Post-Graduate StudentMkrtchian L.S. – Lead. Researcher, MD. Contacts: 4 Korolev str., Obninsk, Kaluga region, Russia, 249035. Tel.: +7909-251-28-49; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it. .
Kiseleva V.I. – Lead. Researcher, D. Sc., Biol.
Ivanov S.A. – Director, Corr. Member of RAS, MD, Prof. of RUDN University Dep.
Zamulaeva I.A. – Head of Dep., D. Sc., Biol., Prof. A. Tsyb MRRC.
1 A. Tsyb MRRC, Obninsk
2 Peoples' Friendship University of Russia named after Patrice Lumumba, Moscow
3 Joint Institute for Nuclear Research, Dubna
Abstract
Cervical cancer (CC) remains one of the leading causes of female mortality. The relevance of the search for prognostic factors that allow preoperative assessment of unfavorable prognosis and avoid the need for a combined approach is beyond doubt. The prognostic significance of HPV parameters of high carcinogenic risk (HR) in relation to the course and results of СС treatment is widely discussed in the literature. At the same time, there are few studies, that highlighted relationship between traditional clinical and morphological factors with molecular genetic parameters of HPV infection and diagnostic ability of these parameters to detect unfavorable forms of the disease at the preoperative stage, and their prognostic role in the clinical outcome of early-stage CC. The results of studies are often contradicted each other, and the samples on which the studies are conducted, are heterogeneous. That justifies the relevance of the current study. The aim of the study was to investigate the relationship between clinical and morphological characteristics of CC and molecular genetic parameters of HPV infection with the assessment of diagnostic capabilities of these parameters in determining unfavorable forms of the disease and their prognostic significance with regard to the results of radical treatment of stage I CC patients. The study included 75 patients with histologically verified HPV-positive and HPV-negative stage I CC (Ia – 30/75 (40%); Ib – in 45/75 (60%)) who underwent radical specialized treatment in the form of surgery, combined treatment or combined radiation/chemoradiation therapy. The mean age of patients in the group was 43.64+-11.3 years. By morphologic form, squamous cell cancer prevailed in 73/75 (97.3%) cases. HPV molecular genetic parameters were determined by realtime PCR. The quantitative load of HPV DNA was expressed in logarithms of E7 genomic equivalents normalized per 100 thousand cells. In a single factor analysis, HPV mono-infection was more common in older patients (p=0.024). Viral load (VL) was lower in more advanced forms of disease (stage Ib2 compared to Ia1.2) (p=0.004), with tumor size greater than 2 cm (p=0.014) and depth of stromal tumor invasion greater than 1/3 (p=0.059). The correlation of VL before treatment with unfavorable factors, which were re-vealed in some patients during pathomorphological study of surgical material and were the basis for changing the stage of the disease, was analyzed. The prognostic value of VL in relation to stage change was shown: at a relatively low level of VL (lgE7/105<6.1) the probability of disease stage increase was 2.8 times higher than at a higher level of VL (lgE7/105>=6.1) (p=0.049). In multivariate analysis, no statistically significant prognostic factors for the clinical outcome of stage I CC were found (p>0.05). Molecular-genetic parameters of HPV HR can be used to assess the risk of detecting unfavorable clinical and morphological forms of stage I primary CC and to choose treatment tactics with preference of radical radiotherapy programs (combined radiotherapy/chemoradiotherapy) at low VL, in which there is a high probability of postoperative refined diagnosis with more advanced forms of disease and, accordingly, followed by adjuvant radiotherapy.
Key words
cervical cancer, radiology, human papillomavirus, high risk, HPV status, HPV genotype, multiple infection, viral load, integrated form.
References
1. Malignant neoplasms in Russia in 2023 (morbidity and mortality). Eds.: A.D. Kaprin, V.V. Starinsky, A.O. Shakhzadova. Moscow, P.A. Herzen MNIOI, 2024. 276 p. (In Russian).
2. Sponholtz S.E., Mogensen O., Hildebrandt M.G., Schledermann D., Parner E., Markauskas A., Froding L.P., Fuglsang K., Vilstrup M.H., Bjornholt S.M., Jensen P.T. Sentinel lymph node mapping in early-stage cer-vical cancer – a national prospective multicenter study (SENTIREC trial). Gynecol. Oncol., 2021, vol. 162, no. 3, pp. 546-554.
3. Tantari M., Bogliolo S., Morotti M., Balaya V., Bouttitie F., Buenerd A., Magaud L., Lecuru F., Guani B., Mathevet P. Lymph node involvement in early-stage cervical cancer: is lymphangiogenesis a risk factor? Results from the MICROCOL study. Cancers, 2022, vol. 14, no. 1, pp. 212. DOI: 10.3390/cancers14010212.
4. Gemer O., Lavie O., Gdalevich M., Eitan R., Mamanov E., Piura B., Rabinovich A., Levavi H., Saar-Ryss B., Halperin R., Finci S., Beller U., Bruchim I., Levy T., Meirovitz A., Shachar I.B., Arie A.B. Evaluation of clinical and pathologic risk factors may reduce the rate of multimodality treatment of early cervical cancer. Am. J. Clin. Oncol., 2016, vol. 39, no. 1, pp. 37-42.
5. Ditto A., Leone Roberti Maggiore U., Evangelisti G. Bogani G., Chiappa V., Martinelli F., Raspagliesi F. Diagnostic accuracy of magnetic resonance imaging in the pre-operative staging of cervical cancer patients who underwent neoadjuvant treatment: a clinical-surgical-pathologic comparison. Cancers, 2023, vol. 15, no. 7, pp. 2061. DOI: 10.3390/cancers15072061.
6. Kaneyasu Y., Fujiwara H., Nishimura T., Sakurai H., Kazumoto T., Ikushima H., Uno T., Tokumaru S., Harima Y., Gomi H., Toita T., Kita M., Noda S.E., Takahashi T., Kato S., Ohkawa A., Tozawa-Ono A., Ushijima H., Hasumi Y., Hirashima Y., Niibe Y., Nakagawa T., Akita T., Tanaka J., Ohno T.; Working Group of the Gynecological Tumor Committee of the Japanese Radiation Oncology Study Group (JROSG). A multi-institutional survey of the quality of life after treatment for uterine cervical cancer: a comparison between radical radiotherapy and surgery in Japan. J. Radiat. Res., 2021, vol. 62, no. 2, pp. 269-284.
7. Cibula D., Borčinová M., Kocian R., Feltl D., Argalacsova S., Dvorak P., Fischerová D., Dundr P., Jarkovsky J., Höschlová E., Slama J., Scambia G. CERVANTES: an international randomized trial of radical surgery followed by adjuvant (chemo) radiation versus no further treatment in patients with early-stage, intermediate-risk cervical cancer (CEEGOG-CX-05; ENGOT-CX16). Int. J. Gynecol. Cancer, 2022, vol. 32, no. 10, pp. 1327-1331.
8. Volesky-Avellaneda K.D., Laurie C., Tsyruk-Romano O., El-Zein M., Franco E.L. Human papillomavirus detectability and cervical cancer prognosis: a systematic review and meta-analysis. Obstet. Gynecol., 2023, vol. 142, no. 5, pp. 1055-1067.
9. Chen X., Zhang P., Chen S., Zhu H., Wang K., Ye L., Wang J., Yu J., Mei S., Wang Z., Cheng X. Better or worse? The independent prognostic role of HPV-16 or HPV-18 positivity in patients with cervical cancer: a meta-analysis and systematic review. Front. Oncol., 2020, vol. 10. P. 1733. DOI: 10.3389/fonc.2020.01733.
10. Bosch F.X., Lorincz A., Muñoz N., Meijer C.J., Shah K.V. The causal relation between human papilloma-virus and cervical cancer. J. Clin. Pathol., 2002, vol. 55, no. 4, pp. 244-265.
11. Zuo J., Huang Y., An J., Yang X., Li N., Huang M., Wu L. Nomograms based on HPV load for predicting survival in cervical squamous cell carcinoma: an observational study with a long-term follow-up. Chin. J. Cancer Res., 2019, vol. 31, no. 2, pp. 389-399.
12. Das P., Thomas A., Kannan S., Deodhar K., Shrivastava S.K., Mahantshetty U., Mulherkar R. Human papillomavirus (HPV) genome status & cervical cancer outcome – a retrospective study. Indian J. Med. Res., 2015, vol. 142, no. 5, pp. 525-532.
13. Mkrtchian L., Zamulaeva I., Krikunova L., Kiseleva V., Matchuk O., Liubina L., Kulieva G., Ivanov S., Kaprin A. HPV status and individual characteristics of human papillomavirus infection as predictors for clinical outcome of locally advanced cervical cancer. J. Pers. Med., 2021, vol. 11, no. 6, pp. 479. DOI: 10.3390/jpm11060479.
14. WHO classification of tumors of the female reproductive organs. 4th ed. Eds.: R.J. Kurman, M.L. Carcangiu, C.S. Harrington, R.H. Young. Lyon, IARC, 2014. 307 p.
15. FIGO Committee on Gynecologic Oncology. FIGO staging for carcinoma of the vulva, cervix, and corpus uteri. Int. J. Gynaecol. Obstet., 2014, vol. 125, no. 2, pp. 97-98.
16. Eisenhauera E.A., Therasse P., Bogaerts J., Schwartz L.H., Sargent D., Ford R., Dancey J., Arbuck S., Gwyther S., Mooney M., Rubinstein L., Shankar L., Dodd L., Kaplan R., Lacombe D., Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer, 2009, vol. 45, no. 2, pp. 228-247.
17. Mkrtchian L.S., Kaprin A.D., Ivanov S.A., Kiseleva V.I., Minakova J.V., Lyubina L.V., Bezyaeva G.P., Panarina L.V., Zamulaeva I.A., Krikunova L.I. Prevalence of high-risk carcinogenic human papillomavirus types in women with proved neoplastic lesions in the cervix. Radiatsiya i Risk – Radiation and Risk, 2018, vol. 27, no. 3, pp. 55-64. (In Russian).
18. Shukla S., Jadli M., Thakur K., Shishodia G., Mahata S., Basir S.F., Das B.C., Bharti A.C. Level of phos-pho-STAT3 (Tyr705) correlates with copy number and physical state of human papillomavirus 16 genome in cervical precancer and cancer lesions. PLoS One, 2019, vol. 14, no. 9, pp. e0222089. DOI: 10.1371/jour-nal.pone.0222089.
19. Del Río-Ospina L., Soto-De León S.C., Camargo M., Moreno-Pérez D.A., Sánchez R., Pérez-Prados A., Patarroyo M.E., Patarroyo M.A. The DNA load of six high-risk human papillomavirus types and its association with cervical lesions. BMC Cancer, 2015, vol. 15, pp. 100. DOI: 10.1186/s12885-015-1126-z.
20. Olthof N.C., Huebbers C.U., Kolligs J., Henfling M., Ramaekers F.C., Cornet I., van Lent-Albrechts J.A., Stegmann A.P., Silling S., Wieland U., Carey T.E., Walline H.M., Gollin S.M., Hoffmann T.K., de Winter J., Kremer B., Klussmann J.P., Speel E.J. Viral load, gene expression andmapping of viral integration sites in HPV16-associated HNSCC cell lines. Int. J. Cancer, 2015, vol. 136, no. 5, pp. е207-е218.
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