Human Papillomavirus and Other Relevant Issues in Cervical Cancer Pathogenesis
Abstract
:1. Introduction
2. Risk Factors
3. Screening Methods and Some Related Issues
4. HPV-Negative Cervical Cancer
5. Low-Risk HPV in Cervical Lesions
6. Influence of HIV and HSV-2
7. Cervical Screening and Associated Complexities
8. Smoking and Cervical Cancer Risk
9. Hormonal Influences in Cervical Cancer
10. The Role of Vaginal Bacterial Population
10.1. Lactobacillus Species in Vaginal Bacterial Flora
10.2. Diminished Vaginal Lactobacillus Dominance and Cervical Lesions
11. Conclusions
Funding
Conflicts of Interest
References
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Tumor Type | Authors, Place of Study, and Year of Publication | Study Designs | Findings in Brief |
---|---|---|---|
Cervical cancer (neuroendocrine tumors) | Shen et al., 2025 (China) [48] | Neuroendocrine cervical carcinoma samples from eight patients were analyzed | One patient had cancer of mixed types, which was excluded but HPV-16 positive. Out of seven cases, six were HPV-18 positive, and one was positive for HPV-16. |
Park et al., 2025 (Korea) [49] | Case report: Primary malignant melanoma of the vagina from a 53-year-old female patient | The initial diagnosis was atypical squamous cells of undetermined significance, positive for HPV-39, -68, and -74; after 1 year, LSIL, positive for HPV-52 and -58; afterwards, ASC-H, positive for HPV-50 and -51. | |
Wei et al., 2024 (China) [50] | Two cases of cervical mixed cancer of large-cell neuroendocrine carcinoma and adenocarcinoma | One case was HPV-18 positive. | |
Liu et al., 2024 (China) [51] | Seven cases (out of eleven) with small-cell carcinoma of the cervix were tested for HPV before treatment—between 2017 and 2023 | All seven were positive for HPV; five cases were positive for HPV-18 and two cases were HPV-16. | |
Gordhandas et al., 2022 (United States) [52] | A total of 63 patients with small-cell neuroendocrine carcinoma of the cervix (41 had limited-stage and 22 had extensive-stage); from January 1990 to June 2021 | Overall, HPV positive cases were 17 (34%, limited-stage: 13 or 38%). Missing cases: 13. | |
Schultheis et al., 2022 (Germany and United States) [53] | Nine cases of uterine cervix small-cell carcinomas were detected over a 20-year period | Eight cases were HPV-18 and one case was HPV-16 positive. | |
Lu et al., 2022 (China) [54] | Evaluation of HPV for 9 cases with small-cell carcinoma (out of 19); from 2012 to 2021 | HPV infection rate was 77.77% (7/9); HPV-18: 5, HPV-16: 1, and HPV-52: 1. | |
Ordulu et al., 2022 (Multinational study) [55] | 14 cases (small-cell carcinoma: 6, large-cell carcinoma: 6, other neuroendocrine tumors: 2) | Except for three cases of small-cell carcinoma, all cases were positive for HPV. | |
Pei et al., 2021 (China) [56] | 51 patients with small-cell carcinoma, between 2007 and 2020 | In all cases, HPV infections were detected (HPV-18 in 47 cases). | |
Van Ta et al., 2019 (Vietnam) [57] | 30 neuroendocrine tumors | HPV was identified in 26 (86.7%) cases; HPV-18 in 15 cases. | |
Feng et al., 2018 (China) [58] | 82 patients with neuroendocrine carcinoma; from 2008 to 2016 (small-cell carcinoma: 74, large-cell carcinoma: 7, atypical carcinoid: 1) | HPV was detected in 72 cases; high-risk types in 70 cases, and HPV-18 in 49 cases. | |
Siriaunkgul et al., 2011 (Thailand) [59] | 97 cases with neuroendocrine carcinoma; between 1992 and 2009 | HPV was detected in 93 samples (95.87%), of which 76 were single HPV type infection; HPV-18: 70 cases. | |
Wang et al., 2006 (Taiwan) [60] | 26 specimens were analyzed (out of 31 cases, between 1991 and 2003) | In 18 cases, HPV infection was present; HPV-negative cases: 8, HPV-18: 17, and HPV-16: 1. | |
Ishida et al., 2004 (Japan) [61] | 10 cases of small-cell carcinoma, 3 were pure small-cell cancer | HPV was detected in 7/10; HPV-18 was detected in all pure tumors and four mixed tumors; no other HPV types were isolated. | |
Small-cell lung cancer and other neuroendocrine tumors of the lung | Han et al., 2024 (China) [62] | 36 SNPs from 4 genome-wide association studies’ data were examined with HPV-16 E7 and HPV-18 E7 | No significant association was found between small-cell lung carcinoma and HPV-16 E7 or HPV-18 E7. |
Sirera et al., 2022 (Spain) [63] | Specimens were collected from 41 patients with lung cancer, including 3 small-cell carcinoma cases (7%) | Two cases were positive for HPV: one case of HPV-16 infection, and in another case, HPV was not classified (low- or high-risk). | |
Zou et al., 2021 (China) [64] * | E6 and E7 mRNA levels of HPV-16 were detected in the bronchial brushing and TBNA of 184 patients with lung cancer (44 cases of small-cell lung cancer) and 126 benign lung diseases | Both E6 and E7 mRNA expression levels in small-cell carcinoma and squamous cell carcinoma (n = 80) were significantly higher compared to benign cells. Among small-cell cancer, the expression levels in 38 central type cases were significantly higher than in six cases of peripheral type. | |
de Oliveira et al., 2018 (Brazil) [65] | 63 samples of lung cancer from different histological types | HPV was found in 33 samples; small-cell carcinoma: 18.18%, and large-cell carcinoma: 9.1%. | |
Shikova et al., 2017 (Bulgaria) [66] | 132 lung cancer specimens of different histological types including 24 small-cell carcinoma cases were analyzed for HPV | In the small-cell carcinoma group, HPV was present in seven cases (29.2%); HPV-16: two, HPV-18: three, HPV-16 + HPV-18 coinfection: two. | |
Hartley et al., 2015 (United States) [67] | 19 patients’ specimens; from 2004 to 2013 | No HPV was found. | |
Castillo et al., 2006 (Mexico, Colombia, and Peru) [68] | 36 lung carcinomas of different histological types including 9 cases of small-cell carcinoma | Among small-cell carcinomas, HPV was detected in three cases, which were positive for HPV-16. | |
Brouchet et al., 2005 (France) [69] | 122 cases of lung cancer, including small-cell carcinoma (n = 9), large-cell neuroendocrine carcinoma (n = 13), typical carcinoid (n = 6), and atypical carcinoid (n = 3). In tissue sections, the presence of HPV, EBV, HHV-8, CMV, and SV40 was investigated. | None of the cases showed any positive results. | |
Thomas et al., 1996 (France) [70] | 31 biopsies of lung cancer (different histological types), including 6 small-cell carcinoma cases | HPV was positive in 1 small-cell carcinoma (1/6) and in 1 other neuroendocrine tumor (1/1). | |
Schmitt et al., 2011 (Germany) [71] | Neuroendocrine tumors from various sites, including lungs and skin, were analyzed (n = 43) for different viruses (e.g., HPV, EBV, HBV, MCV) | EBV was positive in 1 case (1/6) of pulmonary large cell carcinoma and in 1 case (1/5) of small-cell carcinoma; 2 cases (2/3) of Merkel cell carcinoma were positive for MCV. | |
Pheochromocytoma | Oraibi et al., 2018 (United States) [72] | Case report: pheochromocytoma with primary adrenal lymphoma | Lymphoma was associated with EBV. |
Badani et al., 2016 (United States) [73] | 63 specimens of adrenal gland tissue, including 21 cases of pheochromocytoma, were analyzed for VZV and HSV-1 | VZV was found in four normal adrenal gland tissue samples. No VZV or HSV-1 was detected in cases of pheochromocytoma. | |
Sathe et al., 2012 (India) [74] | Case report: a pediatric case with bilateral adrenal neoplasms (without immunodeficiency) | Adrenal leiomyoma that was associated with EBV (initially, pheochromocytoma was suspected). | |
Pancreatic neuroendocrine tumors | Vemuri et al., 2022 (Australia) [75] | Case report: a patient with HIV and HBV coinfection | VIPoma in the pancreatic tail was diagnosed. |
Fiorino et al., 2015 (Italy) [76] | Case report: a patient with cirrhosis and two synchronous malignancies—in the liver (hepatocellular carcinoma) and in the pancreatic tail (neuroendocrine tumor) | In neuroendocrine tumor cells, the HBV genome was detected. |
Classification | HPV Genotypes |
---|---|
High-risk | 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 |
Probable high-risk | 26, 30, 34 *, 53, 66, 67, 68, 69, 70, 71, 73, 82, 90 |
Undetermined | 2, 3, 7, 10, 27, 57, 62, 85, 91 |
Low-risk | 6, 11, 32, 40, 42, 43, 44 **, 54, 61, 72, 74, 81, 83, 84, 86, 87, 89 |
Authors and Brief Study Outline | Findings |
---|---|
Lovane et al., 2025 [108]|40 cases of endocervical adenocarcinoma; Mozambique, 2017–2018. | A total of 14 were HIV-positive. Every case was positive for at least one of the HPV-16/-18/-45 genotypes; HPV-18 was the most common type. Multiple infections were exclusively detected in HIV-negative cases. |
Debeaudrap et al., 2025 [109]|2253 WLHIV; Côte d’Ivoire, Burkina Faso and Cambodia, 2019–2021. | A total of 932 (41%) were HPV-positive. Of the 777 HPV-positive participants with histopathology results, 105 (13.5%) had CIN2+ lesions, and 75 (9.5%) had CIN3+ lesions. |
Pillay et al., 2025 [110]|235 young sexually active women; South Africa | HIV was detected in 49 (20.4%) subjects. HPV DNA was found in 147 (62.6%) urinary and 177 (75.3%) cervico-vaginal lavage samples. HIV positivity is statistically associated with the presence of HPV DNA in urine and cervico-vaginal lavage. |
Strickler et al., 2024 [111]|WIHS ongoing cohort (enrolled 2793, CIN2 and CIN3: 124, controls: 247); United States. | In women with HIV, cigarette smoking, parity, and CD4 cell count displayed a positive association with cervical precancer condition. However, there was a strong inverse (protective) relationship between beta-/gamma-HPV infection and the risk of cervical precancer. |
Naicker et al., 2024 [112]|260 WLHIV; South Africa. | Approximately 67% of women were positive for high-risk HPV, and about one-third had abnormal cervical cytology. |
Mbulawa et al., 2024 [113]|325 participants (HIV-positive: 208); South Africa. | HPV prevalence was 67.8% among HIV-positive women, and HPV infection was found to decrease with increasing age. HPV-58 was the most prevalent type. Among HPV-vaccinated women, 12.9–42.2% (depending on the vaccines) were infected with one or more HPV types. |
Rantshabeng et al., 2024 [114]|171 non-HPV-vaccinated indigenous women; Botswana. | A total of 53/171 (31%) and 56/171 (32.7%) were positive for HIV and high-risk HPV, respectively, and 23/171 (13.5%) had cervical dysplasia. In women with cervical dysplasia, commonly detected HPV types were HPV-39, HPV-51, HPV-52, and HPV-56, while HPV-16 and -18 were not found. |
Murenzi et al., 2024 [115]|Paraffin-embedded tissue sections from 227 cases (out of 440 cervical carcinomas) with valid HPV results; Tanzania, 2020. | A total of 65 (28.6%) were WLHIV. 19.8% (n = 45) were HIV negative, and 55.1% (n = 117) were of unknown HIV status. Interestingly, HPV-68 was associated with HIV positivity. |
Muchaili et al., 2024 [116]|4612 female subjects screened for HPV infection; Zambia, 2021–2022. | Among the 2734 WLHIV, 1960 were referred to the cancer clinic by the ART facility. Of the participants, 1640 (35.56%) were HPV-positive, of which 986 (36.06%) were also positive for HIV. |
Worku et al., 2024 [117]|915 HIV-positive patients at the ART clinic who were not screened for cervical cancer previously; Ethiopia, 2021. | The VIA test showed a positive result in 224 (24.48%) women. Among VIA-positive cases, the diagnostic assessment revealed that 72.4% had abnormal cervical pathology. |
Manga et al., 2024 [118]|599 female sex workers aged 30 years and older; Cameroon, 2020. | Overall, 372 (62.1%) were positive for HPV, and 218 were positive for both HPV and HIV. HPV-51 and -53 were the most common types, whereas HPV-18 and -16 were the least prevalent. HIV-positive cases were 1.65 times more likely to be infected with HPV compared to the HIV-negative group. |
Akakpo et al., 2023 [119]|330 WLHIV; Ghana, 2020–2021. | In total, 141 women had HIV/HPV co-infection. The most common high-risk HIV type was HPV-59 (50.3%, n = 71). |
Grover et al., 2023 [120]|1131 cervical cancer patients; Botswana, 2015–2020. | More than 68% (n = 770) of these patients were HIV-positive. |
Kangethe et al., 2023 [121]|647 WLHIV; Kenya, 2021–2022. | Out of 224 WLHIV with high-risk HPV infections, 21.4% had abnormal cervical cytology; HPV-52 was the most common genotype. |
Megersa et al., 2023 [122]|406 WLHIV; Ethiopia, 2022. | More than one-third of WLHIV had high-risk HPV (35.2%, n = 173). The commonest type was HPV-16 (15.3%, n = 62), |
Sørbye et al., 2023 [123]|Subjects n = 710: HIV-negative (373/52.5%), WLHIV (337/47.5%); South Africa, 2016–2020. | The HPV positivity rate and CIN3+ prevalence were significantly higher among WLHIV compared to HIV-negative women. |
Gupta et al., 2022 [124]|Cross-sectional study: 135 WLHIV and 160 HIV-negative women; India, 2019–2021. | WLHIV had significantly higher cervical cytological abnormalities (14.1%, n = 19) and high-risk HPV infection (28.9%, n = 39) than HIV-negative women (cytological abnormalities: 3.1%, n = 5; HPV: 9.3%, n = 15). |
Lewis et al., 2022 [125]|1405 women after first-time VIA screening (1305 WLHIV); Malawi, 2017–2019. | Among WLHIV, 65 cases had pre-cancerous lesions (5%), and suspected cancer cases were 13 (1%). In only three HIV-negative women (3%), pre-cancerous lesion was detected. There was no association between the screening outcome and the status of HIV. |
Nakisige et al., 2022 [126]|188 WLHIV and 116 HIV-negative women; Uganda, 2017–2020. | High-risk HPV was detected in 67% of WLHIV and 52% of HIV-negative women. CIN3 was present in 41 WLHIV (22%) and 7 HIV-negative women (6%); however cervical cancer was diagnosed in 13 WLHIV (4%) and 24 HIV-negative women (21%). HPV-16 was the most common high-risk type. |
Mcharo et al., 2021 [127]|Out of 2134 women, 804 were included (418 WLHIV and 386 HIV-negative); Tanzania, 2013–2020. | CIN1–61 WLHIV and 13 HIV-negative, HSIL (CIN 2 and 3)–52 WLHIV and 16 HIV-negative, cervical cancer–107 WLHIV and 129 HIV-negative. Roughly 80% of CIN1 and HSIL cases were WLHIV. |
Jary et al., 2021 [128]|144 women screened for cervical cancer (WLHIV: n = 44, high-risk HPV: n = 90); Mali, 2018. | High-risk HPV infection was significantly higher in WLHIV compared with HIV-negative women. Moreover, the prevalence of HSV-2 was significantly higher in WLHIV than in HIV-negative women, and in women with high-risk HPV infection compared with those not infected with high-risk HPV. |
Taku et al., 2021 [129]|Cross-sectional study: 205 cervical tissue specimens; South Africa, 2017–2018. | High-risk HPV, HIV, and HSV-2 were detected in 66 cases (32.2%), 79 cases (38.5%), and 12 cases (5.9%), respectively. Both high-risk HPV and HSV-2 infections were present in 8 subjects, and 34 subjects had both high-risk HPV and HIV infections. HIV and HSV-2 infections were significantly and positively associated with high-risk HPV infection. |
Positive Correlation | No Correlation |
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Smith et al., 2002 [138]. Samples were collected from seven countries. Cervical exfoliated cells were collected from all subjects, and biopsy specimens from cancer patients (1158 squamous cell carcinoma and 105 adenocarcinoma or adenosquamous carcinoma). HSV-2 seroprevalence was significantly higher (p < 0.001) among cancer patients than control subjects. Similar significance was observed among the HPV DNA-positive women. Among patients (total- 1263), 560 were HSV-2 seropositive, and among control subjects (n = 1117), 286 were HSV-2 positive. Cervical samples from 1098 (94.8%) squamous cell carcinoma, 95 (90.5%) adenocarcinoma or adenosquamous carcinoma, and 164 (14.7%) controls were positive for HPV DNA. | El-All et al., 2007 [141]. The study was conducted in the Egyptian population and included complete data from 5453 women. Abnormal changes in the cervical epithelium were found in 424 women. Among them, invasive carcinoma was diagnosed in four cases. Other abnormalities are: low-grade lesions (41.0%), high-grade lesions (5.2%), atypical glandular cell of undetermined significance (15.3%), and atypical squamous cells of undetermined significance (ASCUS) (34.4%). Only one case from the latter category was positive for HSV-2. HPV was evaluated in 217 cases; 66% were positive, 29% were negative, and 5% had no definite diagnosis. |
Paba et al., 2008 [142]. In this Italian study, 149 cervical cancer and CIN biopsies were examined. HPV DNA-positive cases were 136, Chlamydia trachomatis DNA was identified in 32 cases, and 29 were positive for HSV-2. C. trachomatis was significantly associated with multiple-type HPV infections (p = 0.0001). Whereas, there was a borderline significance (p = 0.053) for HSV-2 infection. Survivin, a member of the family of inhibitor-of-apoptosis proteins, was overexpressed in lesions that were positive for both HSV-2 and HPV (p = 0.027). | Wohlmeister et al., 2016 [143]. In this cross-sectional study in Brazil, cervical cytological samples were collected from 169 women during routine gynecologic examination. No cellular abnormalities were found in 75 women (HPV-positive: 9), reactive or inflammatory benign features were seen in 76 women (HPV-positive: 8), and atypia or cervical lesions were diagnosed in 18 cases (all were HPV-positive), which included 10 low-grade lesions, 3 high-grade lesions, and 4 cases of ASCUS. Only one subject was positive for HSV-2. |
Kwaśniewska et al., 2009 [144]. This study was conducted in Poland, and the study groups consisted of 520 patients with squamous cell carcinoma of the cervix (HPV-positive: 468, 90%), 50 adenocarcinomas, and 50 controls. In patients with squamous cell carcinoma, HSV-2 was detected in 145 cases (28%) and C. trachomatis in 135 cases (26%), and in adenocarcinoma, HSV-2 was detected in 15 cases (30%) and C. trachomatis in 12 cases (24%); 4 controls were positive for HSV-2 as well as for C. trachomatis. Compared to the control group, a significantly higher occurrence of HSV-2 and C. trachomatis was noticed in specimens from patients with cervical cancer (p < 0.05). No correlation was seen between HPV and HSV-2. | Moharreri et al., 2021 [145]. The study was performed on 195 liquid-based cytology specimens collected from Iranian women; 50 samples were from CIN cases. Finally, 148 HPV-positive samples were analyzed for different sexually transmitted pathogens such as Mycoplasma genitalium, C. trachomatis, and HSV-2. C. trachomatis infection was present in 24 cases, M. genitalium infection in 3 cases, and only 1 case was positive for HSV-2. No statistically significant differences were found between these pathogens and CIN. |
de Abreu et al., 2016 [146]. A total of 838 women were enrolled from basic health units of the Brazilian public health system for cervical screening. Among them, 614 women had no epithelial lesions (HPV: 101, high-risk HPV: 66), and 224 women had the following cervical abnormalities (HPV: 183, high-risk HPV: 164): 56 low-grade lesions, 71 high-grade lesions, 65 ASCUS, 27 atypical squamous cells- cannot exclude high-grade squamous intraepithelial lesion, and 5 atypical glandular cells. HSV-2 infection was present in 20 subjects who had no epithelial abnormalities, and in 13 cases who had cervical abnormalities. The coexistence of HPV-DNA and high-risk HPV infection with HSV-2 showed an elevated risk of ≥ ASCUS cytology, but no enhanced risk of high-grade lesions was noticed. | Jary et al., 2021 [128]. In this study in Mali, women infected with HIV (n = 44) and HIV-negative women (n = 96) who attended cervical cancer screening were included. The prevalence of high-risk HPV was higher in HIV-positive women (p = 0.014): high-risk HPV infection in HIV-positive cases was 34 (77%), and in HIV-negative women was 53 (55%). Overall, the prevalence rates of HPV and high-risk HPV were 74% (n = 104) and 63% (n = 90), respectively. VIA/VILI screening was positive for 20 subjects: 1 had normal histology, 6 had CIN1, 5 had CIN2 or higher, 5 had cervicitis, and no definite diagnosis for 3 women. Among patients with cervical lesions (n = 11), 7 were positive for high-risk HPV, and only 1 was HIV-positive. The prevalence of HSV-2 was higher in HIV-positive cases (n = 37, 84%) compared to HIV-negative women (n = 29, 32%) (p < 0.0001). Similarly, HSV-2 was higher in subjects who had high-risk HPV (n = 47, 56%) than in women without high-risk HPV infection (n = 19, 37%) (p = 0.035). |
Study Details | Key Results |
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George Onyango et al., 2025 [272]. A cross-sectional study in Kenya, which screened coinfections with HIV, HSV-2, and C. trachomatis in women with cervical abnormalities (n = 517). | The prevalence of CIN was 18.4%. Coinfections with HIV or HSV-2 were two times more likely to test positive for CIN in comparison with uninfected subjects. Similarly, C. trachomatis infected women were three times more likely to test positive for CIN. |
Klein et al., 2024 [273]. A cross-sectional study from seven centers in Ethiopia was conducted to examine asymptomatic pregnant women (n = 779). | C. trachomatis and HSV-2 were significantly more common among women who were positive for HPV (any, n = 257) and high-risk HPV (n = 172). |
Loonen et al., 2024 [274]. This study from the Netherlands analyzed the prevalence of pathogenic organisms from 500 high-risk HPV-negative and 492 high-risk HPV-positive cervical smears. | C. trachomatis, M. genitalium, and bacterial vaginosis * had a significantly higher prevalence in high-risk HPV-positive smears in comparison to high-risk HPV-negative samples. |
Wang et al., 2024 [275]. A multicenter cross-sectional study in China, which analyzed HPV-negative (n = 261) and HPV-positive (n = 270) women with normal or abnormal cervical histology. | As opposed to HPV-negative women, in the HPV-positive group, there were significantly higher incidence rates of lower genital tract infections with C. trachomatis, gonococcus, trichomonas, as well as mycotic infection. |
Disi et al., 2023 [276]. The study examined cervical specimens from 719 women who were referred for colposcopy in China. Among them, 615 were high-risk HPV-positive, and 104 were high-risk HPV-negative. | U. parvum and HSV-2 had significantly higher prevalence in high-risk HPV-positive women. Among HPV-16 positive (n = 165) and HPV-18 positive (n = 54) women, the prevalence of N. gonorrhoeae infection was significantly higher compared to other patients. The infection rate of C. trachomatis was significantly higher in LSIL or milder cases. |
Kaliterna et al., 2023 [277]. This study was conducted in Croatia on 1050 asymptomatic women and found 107 (10.2%) women were positive for high-risk HPV. | A total of 40 women had an abnormal PAP result; 16 of them were positive for high-risk HPV. Statistically significant associations were found between high-risk HPV positivity and infections with U. urealyticum, C. trachomatis, and G. vaginalis. |
Ortiz Segarra et al., 2023 [278]. This cross-sectional study collected materials by endocervical brushes from 396 sexually active women from the indigenous communities of Ecuador. | An infection rate of 28.28% was recorded for any type of HPV, 23.48% for high-risk HPV, and 10.35% for low-risk HPV. A statistically significant association was detected between high-risk HPV and C. trachomatis infections. |
Wang et al., 2023 [279]. This study from China managed genital tract infections of women with high-risk HPV (n = 246) and without high-risk HPV (control group, n = 354), and analyzed their cervical samples (secretion and exfoliated cells). | Multivariate logistic regression analysis showed that U. urealyticum and C. trachomatis were independent risk factors for high-risk HPV infection. |
Adhikari et al., 2022 [280]. This was a community-randomized trial on HPV-vaccinated women at ages 18.5 and 22 years in Finland. The total number of participants at 18.5 years of age was 11,701, and at 22 years of age were 6618. | At the first visit, 940 had squamous intraepithelial lesions (HPV-16/18 negative: 886). Without lesions, 480 were positive for HPV-16/18. Out of 11,701 participants, the cytological results were missing for 781. On the second visit, 129 had lesions (HPV-16/18 negative: 106, missing: 21). Without lesions, 49 were positive for HPV-16/18, and the cytological results were missing for 1133 (out of 6489 participants). The risk of intraepithelial lesions among HPV vaccinated women was increased significantly with C. trachomatis infection and prolonged use of oral contraceptives. |
Yu et al., 2022 [281]. This retrospective study included 132 patients from a hospital in China and found 104 were positive for HPV (high-risk type: n = 88). | The multivariable analysis showed that infections with HPV-16, C. trachomatis, and M. hominis were independent risk factors for cervical precancerous lesions. |
Mosmann et al., 2021 [282]. This cross-sectional study from Argentina included 50 women with normal cervical cytology and 50 women with abnormal cervical cytology (from a maternity hospital) to assess the status of oral and genital HPV and C. trachomatis infection. In the abnormal group, 9 had HSIL, and 41 had LSIL. | HPV DNA was detected in 27% of women (27/100), 18 from genital samples and 14 from oral samples; both mucosal samples were positive in 5 women—3 from the normal group. The most common type was HPV-16 in both normal and abnormal cytology; it was the only type in oral mucosa. HPV was detected more frequently in the normal group (n = 18) than in the abnormal group (n = 9). Conversely, C. trachomatis DNA was detected more frequently in the abnormal group (n = 30) than the normal group (n = 19). From genital samples, C. trachomatis was detected in 35 women, and in 31 from oral samples; both mucosal sites were infected in 17 women—8 from the normal group. Both HPV and C. trachomatis significantly correlated with cytological status. However, HPV and C. trachomatis coinfection was seen in 14 women—7 had normal cytology. |
Xie et al., 2021 [283]. A retrospective study in China, which included 668 patients from a gynecology department—of which 415 women were positive for HPV. | Logistic regression analysis showed that HPV-positive cases were significantly associated with C. trachomatis, U. parvum (serotypes 3 and 6), and M. hominis. Whereas M. genitalium and U. parvum (aforesaid serotypes) significantly correlated with CIN. |
Chen et al., 2020 [284]. This study in China collected cervical swab samples from three groups of women: apparently healthy women who came for a routine checkup (n = 1006), women who came for assistance at the reproductive support center (n = 666), and women who visited gynecology outpatient clinics (n = 3334). The total number of participants was 5006. | Overall, the prevalence of infection with HPV was 15.5% (778/5006), C. trachomatis was 4.7% (236/5006), and coinfection was 1.2% (59/5006). For the apparently healthy women (asymptomatic), infection with HPV was 10.8% (109/1006), C. trachomatis was 3.8% (38/1006), and coinfection was 0.6% (6/1006). A higher prevalence of infection with C. trachomatis was found in HPV-positive women compared to HPV-negative women; a similar phenomenon was also noticed in the opposite way. |
Escarcega-Tame et al., 2020 [285]. This cross-sectional study in Mexico was performed on endocervical samples obtained from 189 women with suspected infection. In fact, 184 had an infection with HPV, C. trachomatis, or both. | Fifty-six women were positive for HPV (one or more genotypes), 77 were positive for C. trachomatis, 51 had both infections, and 5 were not infected. There was an association between HPV and CIN1 (n = 22). HPV–C. trachomatis coinfection showed a correlation with the development of CIN1 (n = 31) and CIN3 (n = 7). However, only C. trachomatis infection was associated with cervicitis (n = 25). In this study, 60 women had CIN1, 11 had CIN3, and 40 women were suffering from cervicitis. |
Prokaryotic system | Analysis of the 16S ribosomal RNA (rRNA) gene is an excellent method for the detection and proper identification of any bacteria, apart from the usefulness of this method in the determination of phylogenetic connections among bacteria. In infections, the isolate might be really responsible for the disease or could be present without causing any harm or as a contaminant. Therefore, precise pathogen identification is important for an appropriate treatment strategy. It may be worth mentioning that 16S rRNA gene analysis is a powerful method for the identification of new pathogenic bacteria, non-cultured bacteria, phenotypically aberrant or rarely isolated strains, slow-growing organisms, fastidious pathogens, and bacteria that are poorly described or poorly distinguished by conventional approaches [289,290]. Fortunately, 16S rRNA analysis methods are currently available in many clinical microbiology laboratories due to the growing accessibility of molecular biology techniques such as PCR and sequencing facilities. The bacterial rRNA genes precisely consist of 5S, 16S, and 23S (as well as intergenic regions). With regard to the 16S rRNA gene, which is a part of the ribosome’s small subunit, this gene is usually around 1.5 kb long (i.e., roughly 1500 nucleotides) and has a number of important functions such as protein synthesis, positioning of ribosomal proteins, and supporting the binding of the 50S and 30S subunits [291]. In addition, all bacteria contain at least one copy of the 16S gene, which encompasses different sequences that include highly conserved, variable, and hypervariable regions. For each bacterial species, the hypervariable regions are unique and thus used for bacterial classification. On the other hand, the conserved regions are utilized to develop universal primers, which can bind to known sequences (common in other bacteria) [292]. By and large, in our routine laboratory practice, these universal primers are designed to target the first ~500 base pairs of the 16S rRNA gene, since the analysis of this portion (V1–V3 regions) is usually thought satisfactory for precise detection of most bacterial species [291]. Nevertheless, the 16S rRNA gene can be a target for a number of antibacterial drugs, and mutations in this gene may influence bacterial susceptibility to these drugs; thus, phenotypic resistance to these drugs can be distinguished by the 16S rRNA gene sequencing [293,294,295]. Therefore, analysis of the 16S rRNA gene perhaps has a direct impact on therapeutic management. |
Eukaryotic system | Like the utilization of 16S rRNA gene characteristics in the prokaryotic system, 18S rRNA in eukaryotic cells is a common molecular marker. Different studies reported that analysis of 18S rRNA is very useful in the detection of various protozoal infections/presence—for example, Trichomonas vaginalis and a range of vaginal fungal species such as Candida albicans, Candida glabrata, and Saccharomyces cerevisiae [296,297,298]. Like 16S rRNA of the small subunit, 18S rRNA (1.8 kb) is a part of the small 40S ribosomal subunit, while 5S, 5.8S, and 28S rRNAs constitute the large 60S subunit (complete ribosome with ribosomal proteins—80S in eukaryotes compared to 70S in prokaryotes). Both conserved and variable regions are present in the 18S rRNA gene. Sequencing of the 18S rRNA gene, particularly with the internal transcribed spacers (ITS: intervening noncoding regions), is advantageous in molecular diagnosis [299]. |
Investigators | Study Design | Salient Observations |
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Guo et al., 2025 [309]. China | Between June 2021 and June 2022, vaginal DNA samples were collected from 151 Uygur and Han women—Han controls (n = 22), HPV transient infection (n = 26), and persistent infection group (n = 28), as well as Uygur controls (n = 28), transient infection (n = 17), and persistent infection group (n = 30). | Ethnic-specific differences in vaginal microbes were observed. In Han women, Sneathia increased significantly in persistent HPV cases. In Uygur women, Gardnerella, Streptococcus, Prevotella, and Shuttleworthia increased significantly in the transient infection group, with lower Lactobacillus in comparison with other groups. |
Li and Wu 2025 [310] China | DNA was extracted from vaginal samples of normal controls (n = 16), HPV-positive women (n = 16), CIN1 (n = 14), CIN2 (n = 6), CIN3 (n = 15), and cervical cancer patients (n = 2) between December 2018 and September 2020. | Lactobacillus was the prevalent bacterium in all groups, and the prevalence rates are: 70.9% in normal controls, 60.2% in HPV-positive women, 63.9% in CIN1, 97.7% in CIN2, 52.0% in CIN3, and 36.9% in cervical cancer. An increased proportion of Gardnerella was detected with HPV infection, possibly associated with the progression of cervical lesions. |
Parvez et al., 2025 [311] India | Between December 2018 and April 2022, vaginal swabs were collected, and DNA extraction was performed in 58 subjects—62% were HPV-positive and 38% were HPV-negative. Among the HPV-positive group, symptomatic cases were 57%, and 39% were asymptomatic cases. | Lactobacillus showed a high abundance in HPV-negative samples (76.7%), although lower in HPV-positive samples (60.3%). Gardnerella was significantly higher in HPV-positive (22.4%) than HPV-negative (10.0%). Similarly, Coriobacteriaceae, Prevotella, Aerococcus, and Clostridium had elevated levels in HPV-positive samples. Interestingly, L. iners was more prevalent in HPV-positive, while L. helveticus was dominant in HPV-negative samples. |
Asensio-Puig et al., 2024 [312] Spain | Out of 22 pairs of cervicovaginal samples (liquid-based cytology samples and self-collected specimens), 14 samples met the sequencing quality criteria, and 8 were HPV-positive. | Compared to HPV-negative samples, HPV-positive samples documented a lower abundance of Lactobacillus, but a higher abundance of L. iners, and a high bacterial diversity that specifically included Atopobium, Parvimonas, Mageeibacillus, Sneathia, Megasphaera, Peptoniphilus, and Dialister. In the HPV-negative cases, a higher abundance of L. crispatus and L. gasseri were detected. |
Fan et al., 2024 [313] China | From June to December 2020, enrolment of 125 subjects who underwent HPV test, cytology test, and colposcopy. There were 27 normal women, 40 with high-risk HPV infection, 40 with CIN and 18 cervical cancer patients. | The diversity of vaginal bacterial species in cervical cancer patients was primarily associated with a decrease in Lactobacillus and Cyanobacteria and was also correlated with an enhanced number of Dialister and Peptoniphilus. Compared to normal controls and the high-risk HPV group, the relative abundance of Cyanobacteria in the CIN group was significantly decreased. |
Jimenez et al., 2024 [314] United States | The study included 100 primarily Hispanic and non-Hispanic White premenopausal women. There were 20 HPV-negative and 31 HPV-positive women without dysplasia, 12 with low-grade lesions (LSIL), 27 with high-grade lesions (HSIL), and 10 with invasive cervical cancer (samples were not available from one participant). | Atopobiacaeae colonization was associated with increased vaginal pH, vaginal dysbiosis, and decreased Lactobacillus dominance. A higher prevalence of Atopobiaceae was detected among Hispanic subjects as well as women with higher gravidity and parity. In cervical cancer, Atopobiaceae and particularly Fannyhessea vaginae had a higher prevalence. Atopobiacaeae were positively correlated with vaginal microbiome, such as Anaerococcus, Dialister, Prevotella, Sneathia, and Bifidobacterium/Gardnerella *, as well as with pro-inflammatory cytokines such as IL-1α, IL-1β, and TNFα. (* Gardnerella vaginalis belongs to the Bifidobacteriaceae family) |
Łaniewski et al., 2024 [315] United States | This pilot study recruited 31 women (16 Native American and 15 non-Native women) between December 2020 and April 2022. | Women with vaginal dysbiosis had higher vaginal pH and were more frequently infected with high-risk HPV. There was also an association between high-risk HPV and Gardnerella vaginalis infections. Women with higher levels of Lactobacillus had normal vaginal pH and tended to have HPV-negative status. L. crispatus (not L. iners) was negatively associated with bacterial vaginosis-associated bacteria, e.g., Gardnerella, Fannyhessea, Prevotella, Sneathia, and Megasphaera. Interestingly, vaginal dysbiosis was linked with larger household size, lower education level, and high parity. |
Liu et al., 2024 [316] China | Cases were collected from the Gynecology and Obstetrics department between Mar 2022 and Mar 2023. HPV-positive cases were 241, and HPV-negative cases were 1759. | A significant deficiency in Lactobacilli was noticed in HPV-positive cases compared to the HPV-negative group. Moreover, in comparison to HPV-negative subjects, the results showed that bacterial vaginitis and aerobic vaginitis were closely associated with HPV-positive cases. |
Ou et al., 2024 [317] China | Based on the histological assessment (from January to October 2021), the subjects were categorized as follows: normal controls (without neoplasia, n = 10), CIN1 (n = 15), CIN2 (n = 25), CIN3 (n = 25), and invasive cancer (n = 25). | Among controls, L. crispatus was dominant. Compared to controls, the proportion of Lactobacillus was reduced with the progression of cervical dysplasia. In cancer patients, the abundance of L. johnsonii and L. iners was higher, and taxa such as Atopobiaceae, Prevotellaceae, and Streptococcaceae were dominant. |
Yang et al., 2024 [318] China | The study subjects were married women who visited the gynecology outpatient clinic between September 2019 and February 2020. Participants were categorized into five groups: persistent high-risk HPV without cervical pathology (n = 20), with low-grade lesions (LSIL, n = 20), high-grade lesions (HSIL, n = 20), squamous cancer (n = 20), and HPV-negative controls (n = 19). | In the non-infected controls, the predominant bacteria were Lactobacillus, Gardnerella, Prevotella, and Streptococcus. On the other hand, the vaginal bacterial composition in subjects of all groups with HPV showed alterations that were predominantly associated with a reduction in Lactobacillus and an increase in Gardnerella when compared with the normal HPV-negative control group. The findings revealed a decrease in Lactobacillus and an increase in Gardenerella subsequent to persistent HPV infection. |
Yu et al., 2024 [319] China | Subjects diagnosed with cervical lesions for the first time were included. There were 30 healthy controls, 29 with low-grade squamous intraepithelial lesions, 33 with high-grade lesions (HSIL), and 29 cervical cancer patients. | Compared to the other groups, decreased Lactobacillus abundance was documented in cancer patients. The abundance of Acinetobacter, Bacillus, Corynebacterium, Escherichia, Fenollaria, Peptoniphilus, Staphylococcus, and Streptococcus showed a rising trend with the degrees of cervical lesions and cancer. |
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Ray, A. Human Papillomavirus and Other Relevant Issues in Cervical Cancer Pathogenesis. Int. J. Mol. Sci. 2025, 26, 5549. https://doi.org/10.3390/ijms26125549
Ray A. Human Papillomavirus and Other Relevant Issues in Cervical Cancer Pathogenesis. International Journal of Molecular Sciences. 2025; 26(12):5549. https://doi.org/10.3390/ijms26125549
Chicago/Turabian StyleRay, Amitabha. 2025. "Human Papillomavirus and Other Relevant Issues in Cervical Cancer Pathogenesis" International Journal of Molecular Sciences 26, no. 12: 5549. https://doi.org/10.3390/ijms26125549
APA StyleRay, A. (2025). Human Papillomavirus and Other Relevant Issues in Cervical Cancer Pathogenesis. International Journal of Molecular Sciences, 26(12), 5549. https://doi.org/10.3390/ijms26125549